Transcranial Magnetic Stimulation and Cranial Electrical Stimulation
Number: 0469
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses transcranial magnetic stimulation and cranial electrical stimulation.
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Medical Necessity
Aetna considers transcranial magnetic stimulation (TMS) medically necessary when all of the following criteria are met:
- Administered by a Food and Drug Administration (FDA) cleared device (includes intermittent theta burst stimulation [iTBS]) and utilized in accordance with the FDA labeled indications; and
- Member is age 15 years or older; and
- Member has a confirmed diagnosis by a psychiatrist of severe major depressive disorder (single or recurrent episode) without psychosis documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.); severity of depression should be measured during the current depressive episode at baseline with a validated depression rating scale, and changes from baseline with TMS treatment should be assessed using the same depression rating scale though the entire treatment course; and
- Member has no contraindications to TMS (refer to contraindications below); and
- Medication trial requirements:
TMS may be considered when member has met the following criteria during the current depressive episode occurring within the past 5 years: Note: For purposes of this policy, the current depressive episode begins with the most recent onset of acute symptoms; see Appendix for information regarding antidepressant medications and augmentation therapy.
- Adults (18 years of age or older):
Member has experienced inadequate response to both of the following:
- Two antidepressants from at least 2 different classes, having different mechanisms of action, at the maximally tolerated labeled dose, each used for at least 8 weeks (to qualify as adequate drug trials, doses must have been at or above the minimal effective therapeutic dose); and
- Augmentation therapy used in combination with a primary antidepressant for at least 8 weeks. If the augmenting agent is an antidepressant, the augmenting agent must be from a different class than the primary antidepressant. The augmenting agent should have been at or above the minimal effective therapeutic dose (which is typically the minimal labeled dose); or
- Adolescents (15 to 17 years of age):
Member meets both of the following:
- TMS will be used as adjunctive therapy in conjunction with an antidepressant at a maximally tolerated labeled dose; and
- Member has experienced inadequate response to both of the following:
- Two antidepressant trials, each administered at a maximally tolerated labeled dose for at least 8 weeks (to qualify as adequate trials, doses must have been at or above the minimal effective therapeutic dose); and
- At least one of the following:
- A trial of evidence-based psychotherapy (e.g., cognitive behavioral therapy [CBT], interpersonal psychotherapy [IPT]); or
- Augmentation therapy used in combination with a primary antidepressant for at least 8 weeks. If the augmenting agent is an antidepressant, it must be from a different class than the primary antidepressant and must have been administered at or above the minimal effective therapeutic dose (typically the minimal labeled dose); and
- Adults (18 years of age or older):
- Treatment consists of a maximum of 30 sessions (5 days a week for 6 weeks) plus 6 tapering sessions (6 sessions over three weeks). Notes: Treatments beyond 36 sessions (e.g., 30 treatment sessions followed by 6 tapering sessions) may be reviewed for medical necessity. There is a lack of evidence of the effectiveness of additional sessions beyond 36 to treat "late responders", to solidify response, or to attain remission. There is a lack of evidence that persons who fail to respond or become refractory to one brand of TMS device will respond to another brand of TMS, theta burst stimulation (TBS), or deep TMS (dTMS) device; and
- TMS treatment is delivered by a device that is approved or cleared by the FDA for the treatment of major depressive disorder. Note: TMS treatment should generally follow the protocol and parameters specified in the manufacturer’s user manual, with modifications only as supported by the published scientific evidence base; and
- The order for treatment (or retreatment) will be written by a psychiatrist (MD or DO) or psychiatric-mental health nurse practitioner (PMHNP) who will examine the patient and review the record and determine that TMS is indicated for use in a particular patient. In addition to patient selection, the psychiatrist or PMHNP must oversee initial patient motor threshold determinations, mapping and treatment parameter definitions and overall TMS treatment course planning for each patient. The psychiatrist or PMHNP must certify that the treatment will be given under direct supervision of this physician or PMHNP (i.e., the physician or PMHNP will be in the area and will be immediately available for each treatment). If the psychiatrist or PMHNP is not performing the daily TMS treatment sessions, then the psychiatrist or PMHNP should assign properly trained personnel who may perform the daily treatment sessions. The psychiatrist or PMHNP is also responsible for the evaluation of the patient during the course of their TMS Therapy treatment; and
- The TMS operator will be a clinical professional who is conducting TMS Therapy under the supervision of a physician, nurse practitioner or physician assistant who is at the facility at the time of treatment. The TMS operator should possess sufficient clinical expertise to monitor the patient during the conduct of a TMS treatment session. The operator must be able to observe the patient’s physical status for the potential occurrence of adverse events, and make routine adjustments as required and consistent with product labeling, or determine circumstances under which treatment interruption or treatment termination should be considered. The TMS operator should be present in the treatment room with the patient at all times. The operator must be qualified to monitor the patient for seizure activity and to provide seizure management care.
Aetna considers TMS not medically necessary and experimental, investigational, or unproven in members with any of the following contraindications to TMS because the safety and effectiveness in persons with these contraindications has not been established:
- Abuse of substances with known abuse potential during the last 90 days; or
- Active suicidality; or
- Metal implant in or around the head (e.g., aneurysm coil or clip, metal plate, ocular implant, stent); or
- Metal or metal fragments in or around the head within 30 cm of the coil (e.g. bullets); or
- Neurological conditions (e.g., cerebrovascular disease, dementia, history of repetitive or severe head trauma, increased intracranial pressure or primary or secondary tumors in the central nervous system); or
- Presence of implanted devices (e.g., cardiac pacemaker or defibrillator, cochlear implant, deep brain stimulator, implantable infusion pump, spinal cord stimulator, vagus nerve stimulator, etc.); or
- Severe cardiovascular disease (unless member has been evaluated and cleared for TMS treatment by a cardiologist); or
- Tattoos in the head or neck made with ferromagnetic-containing ink; or
- Unstable general medical disorders.
Aetna considers TMS retreatment medically necessary for members with depression relapse who meet all of the following criteria:
- The member met initiation criteria above; and
- The member has relapsed following TMS despite other treatment approaches (e.g., psychotherapy, pharmacotherapy), as appropriate; and
- The member had previously had at least a 50% reduction in depressive symptoms with TMS, as documented by standardized rating scales that reliably measure depressive symptoms (e.g., Beck Depression Scale [BDI], Hamilton Depression Rating Scale [HDRS], Montgomery-Asberg Depression Rating Scale [MADRS], etc.), and this improvement was maintained for at least two months after the prior TMS treatment course; repeat TMS treatment within 60 days following the termination of the prior TMS course is considered not medically necessary.
Aetna considers one TMS re-mapping during a course of TMS for depression medically necessary. Additional courses of re-mapping are considered medically necessary if the member is not responding to ensure the most accurate treatment location, or if there is concern that motor threshold may have changed (for example, because of a change in medication). Note: Re-mapping does not increase the medically necessary number of TMS sessions, as treatment is provided during remapping.
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Experimental, Investigational, or Unproven
Aetna considers the following procedures experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- Accelerated TMS, as well as, MRI-guided TMS (repetitive and theta-burst stimulation), including but not limited to the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), for the treatment of depression and other psychiatric/neurologic disorders
- Adjunctive use of ketamine with TMS
- Combined TMS and electroencephalography (EEG) for evaluation of unconscious state (e.g., medication-induced unconscious state, minimally conscious state, and unresponsive wakefulness syndrome)
- Delivery of TMS using a non-standard protocol with increased hertz under sedation
- Navigated TMS for motor function mapping and/or treatment planning of neurological diseases/disorders (e.g., amyotrophic lateral sclerosis, epilepsy, and resection of brain tumors)
- Magnetic e-Resonance Therapy (MeRT) for the treatment of autism, concussion, depression, post-traumatic stress disorder, traumatic brain injury, and all other indications
- TMS maintenance therapy (i.e., treatment outside of the established 30 treatment sessions over 6 weeks plus six tapering sessions over 3 weeks)
- TMS for the following conditions because its value and effectiveness has not been established (not an all-inclusive list):
- Alzheimer's disease
- Amyotrophic lateral sclerosis
- Anxiety disorders
- Auditory verbal hallucinations
- Bipolar disorder
- Blepharospasm
- Bulimia nervosa
- Cerebellar ataxia (including spinocerebellar ataxia type 3)
- Cerebral palsy
- Chronic pain including neuropathic pain (e.g., orofacial pain, and central post-stroke pain)
- Communication and swallowing disorders (e.g., aphasia (including post-stroke aphasia), dysarthria, dysphagia (including post-stroke dysphagia), and linguistic deficits)
- Complex regional pain syndrome
- Concussion
- Differential diagnosis of Alzheimer disease from frontotemporal dementia
- Executive function deficits
- Epilepsy (including status epilepticus)
- Congenital hemiparesis
- Dyslexia
- Dystonia
- Fibromyalgia
- Functional neurological disorder
- Gambling disorder
- Insomnia
- Levodopa-induced dyskinesia
- Major depressive disorder with psychosis
- Migraine
- Mood disorders
- Multiple sclerosis
- Musical obsession (stuck song syndrome)
- Neurodevelopmental disorders (e.g., attention deficit/hyperactivity disorder, autism spectrum disorder, and tic disorders)
- Neuropathic pain associated with spinal cord injury
- Obsessive-compulsive disorder
- Panic disorder
- Parkinson disease
- Peri-partum depression
- Phantom limb pain
- Phantom pain associated with spinal cord injury
- Post-stroke fatigue
- Post-traumatic stress disorder
- Psychosis
- Restless legs syndrome
- Schizo-affective disorder
- Schizophrenia
- Smell and taste dysfunction (e.g., phantosmia and phantageusia)
- Smoking cessation
- Somatic symptom disorder (somatization disorder)
- Spasticity
- Stroke treatment (e.g., motor impairment, post-stroke hemiplegia, and post-stroke spasticity)
- Substance addiction (substance use disorders)
- Tourette syndrome (see CPB 0480 - Tourette's Syndrome)
- Tinnitus
- Traumatic brain injury
- Visual hallucinations after stroke.
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Cranial electrical stimulation (also known as cerebral electrotherapy, craniofacial electrostimulation, electric cerebral stimulation, electrosleep, electrotherapeutic sleep, transcerebral electrotherapy, transcranial electrotherapy, as well as the Fisher Wallace stimulator (formerly known as the Liss Body Stimulator) for any indication (not an all-inclusive list):
- Alcoholism
- Alzheimer's disease
- Anxiety
- Autism
- Chemical dependency
- Chronic pain
- Dementia
- Depression
- Disorders of consciousness
- Dyslexia
- Headaches
- Fibromyalgia
- Insomnia
- Mood and sleep disturbances
- Neuropathic pain
- Parkinson disease
- Phantom pain associated with spinal cord injury
- Progressive supranuclear palsy
- Restless legs syndrome
- Stroke treatment (e.g., motor impairment, post-stroke aphasia, and post-stroke hemiplegia)
- Traumatic brain injury
- Visual rehabilitation.
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Related Policies
Background
Transcranial magnetic stimulation (TMS) is a non-invasive method of induction of a focal current in the brain and transient modulation of the function of the targeted cerebral cortex. This procedure entails placement of an electromagnetic coil on the scalp; high-intensity electrical current is rapidly turned on and off in the coil through the discharge of capacitors. Depending on stimulation parameters (frequency, intensity, pulse duration, stimulation site), repetitive TMS (rTMS) to specific cortical regions can either increase or decrease the excitability of the affected brain structures.
TMS has been investigated in the treatment of various psychiatric disorders, especially depression. This procedure is usually carried out in an outpatient setting. In contrast to electroconvulsive therapy, TMS does not require anesthesia or analgesia. Furthermore, it does not affect memory and usually does not cause seizures. However, the available peer-reviewed medical literature has not established the effectiveness of rTMS in the treatment of psychiatric disorders other than major depression. In addition, more research is needed to ascertain the roles of various stimulation parameters of rTMS for its optimal outcome as well as its long-term effectiveness in the treatment of psychiatric disorders.
Addiction / Substance Use Disorders
Gorelick et al. (2014) noted that TMS is still in the early stages of study as an addiction treatment. These researchers identified 19 human studies using repetitive transcranial magnetic stimulation (rTMS) to manipulate drug craving or use, which exposed a total of 316 adults to active rTMS. Nine studies involved tobacco, six involved alcohol, three involved cocaine, and one involved methamphetamine. The majority of studies targeted high-frequency (5 to 20 Hz; expected to stimulate neuronal activity) rTMS pulses to the dorsolateral prefrontal cortex. Only five studies were controlled clinical trials: two of four nicotine trials found decreased cigarette smoking, and the cocaine trial found decreased cocaine use. Many aspects of optimal treatment remain unknown, including rTMS parameters, duration of treatment, relationship to cue-induced craving, and concomitant treatment. The mechanisms of rTMS's potential therapeutic action in treating addictions are poorly understood but may involve increased dopamine and glutamate function in cortico-mesolimbic brain circuits and modulation of neural activity in brain circuits that mediate cognitive processes relevant to addiction, such as response inhibition, selective attention, and reactivity to drug-associated cues. The authors concluded that rTMS treatment of addiction must be considered experimental at this time but appears to have a promising future.
Makani and associates (2017) stated that addiction and related disorders are devastating due to their tremendous social, psychological, and physical consequences, for which the development of optimally effective treatments is long overdue; rTMS is relatively safe and is becoming an emerging therapeutic tool for these conditions. These investigators carried out a systematic review using PubMed, PsycINFO, PsychiatryOnline, and Cochrane Library, covering the years 2001 to 2017. They retrieved 70 related articles, of which, based on the Strength of Recommendation Taxonomy (SORT) guidelines, 33 indicated Level-1 study quality and Class-B strength of recommendation for rTMS in nicotine addiction (effective in 218/289 subjects who received rTMS, as found in 11 studies). Level-2/Class-B evidence was found for alcohol and cocaine addictions (alcohol: effective in 126/193 subjects who received rTMS, as found in 8 studies; cocaine: effective in 86/128 subjects, as found in 5 studies). For food cravings, Level-3/Class-B evidence was noted (effective in 134/169, found in 7 studies). However, the evidence was limited to Level-3/Class-C for heroin (10/20 subjects received active rTMS, effective in 1 study), methamphetamine (33/48 subjects received active rTMS, effective in 2 studies), cannabis (18/18 subjects received active rTMS, effective in 1 study), and pathological gambling (31/31 subjects received active rTMS, effective in 2 studies). The authors concluded that rTMS may serve as an emerging therapeutic option for addiction and related disorders. The major voids in this field include important methodological limitations and a dearth of knowledge about the precise mechanism of action that need to be addressed in future studies.
Torres-Castano and colleagues (2021) noted that long-term cocaine use is associated with cognitive deficits and neuropsychiatric pathologies, and rTMS is an emerging therapeutic strategy related to changes in brain activity. It stimulates the prefrontal cortex and is involved in inhibitory cognitive control, decision-making, and care. In a systematic review, these investigators examined the evidence on the safety, effectiveness, and cost-effectiveness of rTMS for the treatment of cocaine addiction. They carried out a systematic review of the literature. The following electronic databases were consulted from inception to October 2020: Medline, Embase, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science; RCTs, non-RCTs, case series, and full economic evaluations were included. A total of 12 studies were included. No identified study reported data on cost-effectiveness. Significant results of the effectiveness of TMS have been observed in terms of the reduction of craving to consume and the number of doses consumed. No serious adverse effects have been observed. The authors concluded that despite the low quality of the studies, the first results were observed in terms of the reduction of cocaine use and craving. In any case, this effect was considered moderate. Since not all studies were RCTs, and given that the included studies had small sample sizes and a short follow-up, the evidence obtained did not allow for conclusive statements. Moreover, these researchers stated that in order to consider TMS as a procedure likely to be recommended for the treatment of cocaine addiction, controlled clinical trials need to be performed under rigorous standards with respect, for example, to the characterization of the participants, the randomization, and the blinding procedures. In this regard, there are a number of variables specific to the technique that make it difficult to obtain the “perfect” protocol for each subject and to achieve the best possible results. In the future, it will be necessary to conduct comparative studies to evaluate these key variables, among which it is necessary to mention the target region to be stimulated, the methods to locate the target, the type of coil to be used, the number and frequency of the pulses, and the number of sessions.
Kedzior and colleagues (2018) stated that deep TMS (DTMS) is a non-invasive method of stimulating widespread cortical areas and, presumably, deeper neural networks. In a systematic review, these researchers examined the effects of DTMS in the treatment of substance use disorders (SUD). An electronic literature search (PsycInfo, Medline until April 2017) identified k = 9 studies (k = 4 RCTs, with inactive sham, and k = 5 open-label studies). DTMS was most commonly applied using HF/intensity (10 to 20 Hz/100 to 120% of the resting motor threshold, MT) protocols for 10 to 20 daily sessions in cases with alcohol, nicotine, or cocaine use disorders. The outcome measures were craving and dependence (according to standardized scales) or consumption (frequency, abstinence, or results of biological assays) at the end of the daily treatment phases and at the last follow-up. Acute and longer-term (6 to 12 months) reductions in alcohol craving were observed after 20 sessions (20 Hz, 120% MT) relative to baseline in k = 4 open-label studies with co-morbid SUD and MDD. In k = 2 RCTs without MDD, alcohol consumption acutely decreased after 10 to 12 sessions (10 to 20 Hz, 100 to 120% MT) relative to baseline or to sham. Alcohol craving was reduced only after HF/intensity DTMS (20 Hz, 120% MT) relative to sham in k = 1 RCT. Nicotine consumption was reduced, and abstinence was increased after 13 sessions (10 Hz, 120% MT) and at the 6-month follow-up relative to sham in k = 1 RCT. Cocaine craving was reduced after 12 sessions (15 Hz, 100% MT) and at the 2-month follow-up relative to baseline in k = 1 open-label study, while consumption was reduced after 12 sessions (10 Hz, 100% MT) relative to baseline but not to sham in k = 1 RCT. The authors concluded that HF-DTMS may be effective at treating some SUD both acutely and in the longer term. These researchers stated that large RCTs with inactive sham are needed to determine the efficacy and the optimal stimulation parameters of DTMS for the treatment of SUD.
Bormann et al. (2024) stated that TMS and transcranial direct current stimulation (tDCS) have evidence for their potential in the treatment of SUD. Medication for addiction treatment (MAT) is underutilized and not always effective. These researchers identified RCTs and case studies that examined the effectiveness of TMS or tDCS used concurrently with MAT in the treatment of SUD. They carried out a systematic review of published literature following PRISMA guidelines on June 1, 2023, by a medical librarian. Craving-related scales were extracted for an effect size calculation. The Physiotherapy Evidence Database (PEDro) scale assessed study quality. A total of 8 studies (7 RCTs, 1 case study) including 253 individuals were published from 2015 to 2022, five of which had available data for meta-analysis. TMS or tDCS combined with MAT significantly reduced craving-related measures relative to sham stimulation (Hedges' g = -0.42, CI: -0.73 to -0.11, p < 0.01). Opioid use disorder, methadone, and the dorsolateral prefrontal cortex were the most commonly studied SUD, MAT, and target region. The authors concluded that this review showed a significant effect; however, it was limited by a small number of studies with heterogeneous methodology across intervention methods and SUDs. These researchers stated that additional studies are needed to examine the clinical impact and mechanisms of combined brain stimulation and pharmacotherapy.
Gambling Disorder
Concerto et al. (2023) stated that gambling disorder (GD) is a behavioral addiction listed within the diagnostic category of substance-related and addictive disorders. Recently, TMS, which non-invasively stimulates the brain and has neuro-modulatory properties, has emerged as an innovative treatment tool for GD, offering a new option for the management of this complex disorder. In a systematic review, these investigators examined the effectiveness of TMS as a possible non-pharmacological treatment for GD. They carried out an exhaustive search across the Medline, Web of Science, and Embase databases using a specific search string related to GD and TMS. A total of 20 studies were selected for full-text examination, out of which 8 met the inclusion criteria and were analyzed in the present review. This review included 8 studies: 3 RCTs, 3 non-controlled studies, 1 case-series study, and 1 case report. Two crossover RCTs described a decrease in craving after high-frequency (excitatory) rTMS over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (PFC), respectively; another study applying low-frequency (inhibitory) rTMS on the right DLPFC did not find any positive effect on craving. Among uncontrolled studies, one showed the beneficial effect of high-frequency rTMS over the left DLPFC, while another showed the effectiveness of a continuous theta burst stimulation protocol directed over the pre-supplementary motor area bilaterally. The authors concluded that the included studies demonstrated the promising effect of excitatory stimulation over the left PFC. Moreover, these researchers stated that further investigation is needed. They indicated that future research should place greater emphasis on characterizing study samples based on specific symptoms, and further longitudinal RCTs should be conducted to monitor the safety and long-term effects of non-invasive brain stimulation techniques in GD and other addiction disorders.
The authors stated that this systematic review had several drawbacks. The inclusion of diverse clinical populations, as well as the inclusion of case reports and case series, the high risk of bias in multiple domains of the included studies, and the concurrent use of other treatments introduce limitations and confounding factors regarding treatment effectiveness. In particular, the placebo effect may have influenced many of the results obtained, and randomized sham control trials are needed in the future.
Amyotrophic Lateral Sclerosis
In a review on the diagnosis of amyotrophic lateral sclerosis (ALS), Elman and McCluskey (2010) stated that rTMS remains a largely experimental technique and is not used routinely for clinical diagnosis. In a Cochrane review on rTMS for the treatment of ALS or motor neuron disease, Guo et al. (2011) concluded that there is currently insufficient evidence to draw conclusions about the safety and effectiveness of rTMS in the treatment of ALS. They noted that further studies may be helpful if their potential benefit is weighed against the impact of participation in a RCT on people with ALS.
Anxiety Disorders
Prasko et al. (2007) examined whether rTMS would facilitate the effect of serotonin reuptake inhibitors (SRIs) in patients with panic disorder (n = 15). Patients suffering from panic disorder resistant to SRI therapy were randomly assigned to either active or sham rTMS. The objective of the study was to compare the 2- and 4-week effectiveness of the 10 sessions of low-frequency rTMS with sham rTMS as an add-on to SRI therapy. These researchers used 1-Hz, 30-minute rTMS at 110% of the motor threshold administered over the right dorsolateral prefrontal cortex (DLPFC). The same time schedule was used for sham administration. Psychopathology was evaluated by means of the rating scales CGI, HAMA, PDSS, and BAI before the treatment, immediately after the experimental treatment, and 2 weeks after the experimental treatment by an independent reviewer. Both groups improved during the study period, but the treatment effect did not differ between groups in any of the instruments. The authors concluded that low-frequency rTMS administered over the right dorsolateral prefrontal cortex after 10 sessions did not differ from sham rTMS as an add-on to SRIs in patients with panic disorder.
Pigot and colleagues (2008) noted that rTMS has also been investigated for the treatment of some anxiety disorders (e.g., obsessive-compulsive disorder, post-traumatic stress disorder, and panic disorder). While anecdotal reports and open studies have suggested a therapeutic role for rTMS in anxiety disorders, controlled studies, which have varied greatly in terms of rTMS administration, have not shown it to be superior to placebo. Furthermore, reports in animal models of anxiety have not been consistent. Thus, there is currently no convincing evidence for the clinical role of rTMS in the treatment of anxiety disorders. The authors stated that more research is needed, drawing on advances in the understanding of pathological neurocircuitry in anxiety disorders and the mechanisms of action by which rTMS may alter that neurocircuitry. In a review on OCD, Abramowitz and colleagues (2009) stated that although rTMS has not been extensively assessed in this disorder, available data do not support its therapeutic efficacy for this condition.
Berlim et al. (2014) stated that rTMS applied to the dorsolateral prefrontal cortex (DLPFC) has yielded promising results as a treatment for post-traumatic stress disorder (PTSD). However, to date, no quantitative review of its clinical utility has been published. These investigators searched for randomized and sham-controlled trials from 1995 to March 2013 using MEDLINE, Embase, PsycINFO, CENTRAL, and SCOPUS. They then performed an exploratory random effects meta-analysis. Studies on rTMS applied to the right DLPFC included 64 adults with PTSD. The pooled Hedges g effect size for pre- and post-changes in clinician-rated and self-reported PTSD symptoms were, respectively, 1.65 (p < 0.001) and 1.91 (p < 0.001), indicating significant and large-sized differences in outcome favoring active rTMS. Additionally, there were significant pre- and post-decreases with active rTMS in overall anxiety (Hedges g = 1.24; p = 0.02) and depressive (Hedges g = 0.85; p < 0.001) symptoms. Drop-out rates at study end did not differ between active and sham rTMS groups. Regarding rTMS applied to the left DLPFC, there was only one study published to date (using a high-frequency protocol), and its results showed that active rTMS seems to be superior overall to sham rTMS. The authors concluded that this exploratory meta-analysis showed that active rTMS applied to the DLPFC seems to be effective and acceptable for treating PTSD. However, they stated that the small number of subjects included in the analyses limits the generalizability of these findings. They indicated that future studies should include larger samples and deliver optimized stimulation parameters.
An assessment by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2014) concluded that, for PTSD, there is early evidence that TMS may improve clinical outcomes. For generalized anxiety disorder, no evidence was found.
Parikh and colleagues (2022) carried out a systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) in adults with generalized anxiety disorder (GAD). These investigators conducted a systematic literature review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Pre- and post-treatment anxiety scores were extracted, and a random-effects meta-analysis was performed to determine the magnitude of improvement (SMD). Standard assessments of heterogeneity (e.g., Q-statistic, I², and τ²) and publication bias were performed. The initial search resulted in 3,194 citations, of which 6 studies were included in the meta-analysis. A total of 152 patients were studied, including 97 patients who received active treatment and 55 who received sham treatment, and heterogeneity was modest (I² = 13.32, Q = 5.77). In patients with GAD, rTMS produced a SMD of -1.857 (CI: -2.219 to -1.494; p < 0.001) with a prediction interval of -2.55 to -1.16. The authors concluded that the findings of this review suggested a robust effect of rTMS in GAD in the context of limited, heterogeneous studies. Moreover, these researchers stated that rigorously designed RCTs of rTMS for GAD and related anxiety disorders are urgently needed. These studies will provide opportunities for biomarker development and integration of concurrent evidence-based psychotherapy to maximize results.
Autism
In a review on autism, Levy et al. (2009) stated that biologically based treatments include anti-infectives, chelation medications, gastrointestinal medications, hyperbaric oxygen therapy, off-label drugs (e.g., secretin), and intravenous immunoglobulins. Non-biologically based treatments include auditory integration training, chiropractic therapy, craniosacral manipulation, facilitated communication, interactive metronome, and transcranial stimulation. However, few studies have addressed the safety and effectiveness of most of these treatments.
Masuda and colleagues (2019) noted that cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain; TMS motor-evoked potentials (MEPs) are a non-invasive tool for examining cortical inhibition in ASD. These investigators carried out a systematic review on TMS neurophysiology in the motor cortex (M1), such as MEPs and short-interval intracortical inhibition (SICI), between individuals with ASD and controls. Out of 538 initial records, these investigators identified 6 articles; 5 studies measured MEP, while 4 studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy (MRS) and post-mortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. The authors concluded that reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Thus, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.
The authors stated that the main drawback of this systematic review was the small sample size for each parameter. Additionally, each study included a limited number of individuals, which did not allow these investigators to control for the confounding effects of age, gender, accompanying medication, or comorbidity such as other neurodevelopmental disorders. Furthermore, in this study, because of the limited number of articles examining the non-motor areas in ASD, only M1 could be systematically reviewed. These researchers stated that further well-designed studies addressing current limitations and the knowledge gap are needed.
Cerebellar Neuromodulation for the Treatment of Autism Spectrum Disorders
Elandaloussi et al. (2025) noted that ASD is a complex neurodevelopmental condition characterized by social atypicalities and repetitive behaviors. Growing evidence suggests that alterations in brain networks may contribute to ASD symptoms. The cerebellum has emerged as a potential key player in ASD. Non-invasive neuromodulation techniques, such as tDCS or rTMS offer a promising approach for modulating brain activity and potentially alleviating ASD symptoms. Furthermore, pre-clinical studies in rodents further emphasized the therapeutic effect of cerebellar stimulation to target autism-related symptoms. These investigators reviewed both clinical and pre-clinical studies aiming to modulate cerebellar circuits to improve symptoms of ASD. They identified 10 pertinent studies examining the effect of cerebellar neuromodulation in human and pre-clinical models. Posterior cerebellar tDCS represented the most commonly employed neuromodulation method and suggested that cerebellar tDCS can result in improvements in symptoms of ASD and restore cerebellar connectivity in individuals with ASD. In neurotypical participants, there is evidence that cerebellar tDCS can enhance social cognitive abilities. These results were in line with pre-clinical studies, suggesting that chemo-genetic stimulation can modulate cerebellar circuits involved in ASD and improve related behaviors. The authors concluded that further investigations are needed to establish standardized protocols, evaluate long-term effects, and examine the underlying mechanisms of cerebellar stimulation; they examined research questions that need to be addressed before launching large-scale randomized clinical trials.
Bipolar Disorder
Yang and colleagues (2019) noted that patients with bipolar disorder (BD) present widespread and significant neurocognitive impairments during all stages of the disorder. rTMS has been tried to improve clinical outcomes in common psychiatric diseases, such as depression, anxiety disorders, schizophrenia, and BD. Whether rTMS can improve cognitive function in BD patients remains unclear. These researchers examined the effects of rTMS on cognitive function in patients with BD. A total of 52 eligible subjects with BD were randomly assigned to receive active or sham rTMS via a high-speed magnetic stimulator with a figure-of-eight coil for 10 consecutive days. In the active rTMS group, a total of 25,000 stimuli were applied over the left dorsolateral prefrontal cortex at 110% of the motor threshold. The sham group received corresponding sham stimulation. Clinical manifestations and cognitive functions were assessed using a modified 24-item HDRS, the Young Mania Rating Scale (YMRS), and the MATRICS Consensus Cognitive Battery (MCCB). These investigators found that 10 consecutive days of HF-rTMS improved scores on the Wechsler Memory Scale-III Spatial Span and the MCCB Category Fluency subtest, without intolerable adverse effects. No significant differences in HDRS or YMRS scores were found between groups. The authors concluded that short-term rTMS could improve cognitive function in BD patients. The main drawbacks of this study were its relatively small sample size (n = 52), the lack of follow-up after the intervention, and the effect of the drug on cognitive function in subjects was not excluded.
In a triple-blinded, randomized, placebo-controlled pilot study, McIntyre and colleagues (2021) examined whether rTMS would improve cognitive function in adults with BD. Subjects (aged 18 to 60 years) with a diagnosis of DSM-5-defined BD (I or II) were recruited and randomized (n = 36) to receive either a sham treatment (n = 20) or an active rTMS treatment (n = 16). Patients completed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) at baseline and 1 to 2 weeks after the rTMS intervention. A significant group-by-time interaction was observed in the Hopkins Verbal Learning Test-Revised (HVLT-R) (F(1, 34) = 17.0, p < 0.001, partial η² = 0.33). Post-hoc analysis revealed that although both groups did not significantly differ at baseline (p = 0.58), patients in the active rTMS group significantly improved following neurostimulation (p = 0.02) for HVLT-R. Moreover, within-subject analysis indicated that the active rTMS group significantly improved in score from pre-treatment to post-treatment (p < 0.001), while the sham group did not improve (p = 0.94) for HVLT-R. No significant differences were observed in the other cognitive measures. The authors concluded that this pilot study, which was intended to establish feasibility, suggested that rTMS may offer benefits in select domains of cognitive functioning in BD. None of the measures across sub-domains revealed a dyscognitive effect. Moreover, these investigators stated that this study had a small sample (n = 16 in the rTMS group); larger, rigorous studies are needed to replicate and extend the results of this pilot study.
Blepharospasm
- a conventional circular coil (C-coil),
- a sham coil (S-coil), and
- a Hesed coil (H-coil, which allows stimulation of deeper brain regions.
Primary outcome was the clinical effects on BEB (blink rate, number of spasms rated by a blinded physician and patient rating before, immediately after, and 1 hour after stimulation); secondary outcome was the blink reflex recovery curve. Subjective stimulation comfort was similar for each coil with no stimulation-associated adverse events. Stimulation with the H- and C-coils resulted in a significant improvement in all 3 outcome measures and was still detectable in physician rating and patient rating 1-hr after stimulation. S-coil stimulation had no effects. The active motor threshold was significantly lower for the H-coil compared to the other 2 coils. The authors concluded that rTMS could be used as a therapeutic tool in BEB. Moreover, they noted that compared to the well-established and long-lasting effects of botulinum toxin and in view of the time-consuming nature of rTMS and its short-lasting effects, it should not be used in routine clinical setting at this stage. Furthermore, they stated that further studies will be necessary to show whether repeated stimulation applications result in lasting clinical effects.
Bulimia Nervosa
In a single-center, randomized, double-blind, sham-controlled study, Walpoth et al. (2008) examined the effects of rTMS in bulimia nervosa (BN). A total of 14 women meeting DSM-IV criteria for BN were included in the study. In order to exclude patients highly responsive to placebo, all patients were first submitted to a 1-week sham treatment. Randomization was followed by 3 weeks of active treatment or sham stimulation. The main outcome was the change in binges and purges. Secondary outcome variables were the decrease of the HDRS, the BDI and the Yale-Brown Obsessive Compulsive Scale (YBOCS) over time. The average number of binges per day declined significantly between baseline and the end of treatment in the 2 groups. There was no significant difference between sham and active stimulation in terms of purge behavior, BDI, HDRS and YBOCS over time. The authors concluded that these preliminary results indicated that rTMS in the treatment of BN does not exert additional benefit over placebo.
Central Neuropathic Pain
In a randomized, double-blinded, sham-controlled, 3-arm parallel study, Galhardoni and colleagues (2019) compared the analgesic effects of stimulation of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep (d) rTMS in patients with central neuropathic pain (CNP) following stroke or SCI. Subjects were randomly allocated into the active PSI-rTMS, ACC-rTMS, sham-PSI-rTMS, or sham-ACC-rTMS arms. Stimulations were carried out for 12 weeks, and a comprehensive clinical and pain assessment, psychophysics, and cortical excitability measurements were performed at baseline and during treatment. The main outcome measure was pain intensity (numeric rating scale [NRS]) after the last stimulation session. A total of 98 patients (age of 55.02 ± 12.13 years) completed the study; NRS score was not significantly different between groups at the end of the study. Active rTMS treatments had no significant effects on pain interference with daily activities, pain dimensions, neuropathic pain symptoms, mood, medication use, cortical excitability measurements, or QoL. Heat pain threshold was significantly increased after treatment in the PSI-dTMS group from baseline (1.58, 95% CI: 0.09 to 3.06) compared to sham-dTMS (-1.02, 95% CI: -2.10 to 0.04, p = 0.014), and ACC-dTMS caused a significant decrease in anxiety scores (-2.96, 95% CI: -4.1 to -1.7) compared to sham-dTMS (-0.78, 95% CI: -1.9 to 0.3; p = 0.018). The authors concluded that ACC- and PSI-dTMS were not different from sham-dTMS for pain relief in CNP despite a significant anti-nociceptive effect following insular stimulation and anxiolytic effects of ACC-dTMS. These findings showed that the different dimensions of pain can be modulated in humans non-invasively by directly stimulating deeper SNC cortical structures without necessarily affecting clinical pain per se. The main drawbacks of this study were that it was a single-center trial and the subjects varied in their CNP etiologies.
Cerebellar Ataxia
In a systematic review and meta-analysis, Wang et al. (2023) examined the effectiveness of TMS in improving cerebellar ataxia. PubMed, Embase, the Cochrane Library, Springer, Science Direct, the China National Knowledge Infrastructure (CNKI), and the China Science and Technology Journal Database (VIP) were searched until 2022. Trials with TMS on the effects on cerebellar ataxia were included, and the effect size was evaluated using the SMD or MD and a 95% CI. A total of 8 studies comprising 272 participants, published between 2014 and 2022, were included. The results revealed that the effect of TMS on patients with cerebellar ataxia, as assessed by the International Cooperative Ataxia Rating Scale (ICARS), the Scale for the Assessment and Rating of Ataxia (SARA), the Berg Balance Scale (BBS), and the Timed Up and Go (TUG) test, was statistically significant (p < 0.01) with low heterogeneity among the studies (I² = 4, 27, 0, and 0%, respectively). The authors concluded that the effects of TMS in improving cerebellar ataxia in the affected patients were significant. TMS targeting the cerebellar structures could induce changes in the excitability of the cerebellar-thalamus-cortical pathways; therefore, it is necessary to perform large-scale research with good design and high quality in the future.
Qiu et al. (2024) noted that therapeutic alternatives for spinocerebellar ataxia type 3 (SCA3) are limited; rTMS as a potential intervention has drawn heightened interest because of its ease of implementation, cost-effectiveness, and safety profile. In a systematic review and meta-analysis, these investigators examined the effectiveness of rTMS in the treatment of SCA3. They systematically searched databases—PubMed, Embase, the Cochrane Library, and Springer—for RCTs examining the use of rTMS in the treatment of SCA3. Major effectiveness outcomes were assessed, including ICARS scores, SARA scores, and ICARS sub-scale scores. A total of 6 RCTs entailing 175 patients were included in the analysis. The meta-analysis results indicated statistically significant increases in ICARS (MD of -3.88, 95% CI: -7.46 to -0.30; p = 0.03) and SARA (MD of -1.59, 95% CI: -2.99 to -0.19; p = 0.03) scores. No significant heterogeneity was observed across all outcomes (I² = 0%). Dynamic function within the ICARS scale markedly improved with rTMS (MD of -2.19, 95% CI: -3.82 to -0.55; p = 0.009). The majority of the included studies exhibited a low risk of bias, and no severe AEs were noted. The authors concluded that the findings of this meta-analysis suggested that rTMS exhibited effectiveness in alleviating both ataxic symptoms and certain aspects of motor function in patients with SCA3.
Cerebral Palsy
In a systematic review and meta-analysis, Sun et al. (2023) examined the quality of the evidence of the effectiveness of rTMS in the treatment of motor and language ability of patients with cerebral palsy (CP). Medline, Cochrane Library, Web of Science, Embase, PubMed, and CNKI databases were searched up to July 2021 by two independent reviewers. RCTs that were published in English and Chinese and met the following criteria were included. The population comprised patients who met the diagnostic criteria for CP. The intervention included comparisons between rTMS and sham rTMS or comparisons of rTMS combined with other physical therapy (PT). Outcomes included motor function, as follows: gross motor function measure (GMFM), Gesell Development Diagnosis Scale, fine motor function measure (FMFM), Peabody developmental motor scale, and modified Ashworth scale. For language ability, the sign-significant relation (S-S) was included. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. A total of 29 studies were included in the meta-analysis. Results of evaluation using the Cochrane Collaborative Network Bias Risk Assessment Scale showed that 19 studies specifically explained randomization, among which 2 studies described allocation concealment, 4 studies blinded participants and had a low risk of bias, and 6 studies explained that the assessment of outcome measures was blinded. Significant improvements in motor function were observed. The GMFM total score was determined using the random-effect model (I² = 88%; MD = -1.03; 95% CI: -1.35 to -0.71; p < 0.0001), and FMFM was determined using the fixed-effect model (p = 0.40 and I² = 3%; SMDs = -0.48, 95% CI: -0.65 to -0.30; p < 0.01). For language ability, the language improvement rate was determined using a fixed-effect model (p = 0.88 and I² = 0%; MD = 0.37, 95% CI: 0.23 to 0.57; p < 0.01). According to the PEDro scale, 10 studies had low quality, 4 studies had excellent quality, and the remaining studies had good quality. Using the GRADEpro GDT online tool, these researchers included a total of 31 outcome indicators, as follows: 22 for low quality, 7 for moderate quality, and 2 for very low quality. The authors concluded that rTMS could improve the motor function and language ability of patients with CP; however, rTMS prescriptions varied, and the studies had low sample sizes. These researchers stated that studies using rigorous and standard research designs regarding prescriptions and large samples are needed to collect sufficient evidence regarding the effectiveness of using rTMS for the treatment of patients with CP.
In a comprehensive review, Chen (2025) examined the effectiveness of rTMS in the treatment of pediatric CP. Methodological details, including stimulation protocols, were examined. Statistical tests employed in the reviewed studies were outlined, providing insight into the scientific rigor applied in evaluating rTMS outcomes. The main findings from the literature review highlighted the positive impact of rTMS on motor function and spasticity reduction in children with CP. The synergistic effects observed when combining rTMS with conventional therapies such as physical therapy (PT), occupational therapy (OT), and constraint-induced movement therapy (CIMT) were emphasized. The author concluded that available evidence confirmed that rTMS yielded constructive outcomes, encompassing enhanced motor function and diminished spasticity, especially when combined with PT, OT, and CIMT. Nevertheless, optimizing rTMS necessitates further fine-tuning of stimulation parameters. Ethical considerations and adherence to safety guidelines are crucial in pediatric settings, despite rare and typically benign side effects. These investigators stated that future studies should focus on larger samples, more stringent research designs, and long-term follow-ups to rTMS as an effective therapy for managing motor impediments in children with CP.
Chronic Pain Syndromes
There is also a lack of scientific evidence in the use of TMS as a diagnostic tool for psychiatric disorders and treatment for chronic pain. Pridmore et al. (2005) stated that in studies of TMS for the treatment of chronic pain, there is some evidence that temporary relief can be achieved in a proportion of sufferers. Work to this point is encouraging, but systematic assessment of stimulation parameters is necessary if TMS is to attain a role in the treatment of chronic pain. Furthermore, Canavero and Bonicalzi (2005) noted that TMS has no role in the management of patients with central pain, a major chronic pain syndrome.
In a double-blind, randomized, crossover study, Andre-Obadia et al. (2008) evaluated, against placebo, the pain-relieving effects of high-rate rTMS on neuropathic pain (n = 28). The effect of a change in coil orientation (postero-anterior versus latero-medial) on different subtypes of neuropathic pain was further tested in a subset of 16 patients. Pain relief was evaluated daily during 1 week. High-frequency, postero-anterior rTMS decreased pain scores significantly more than placebo. Postero-anterior rTMS also outmatched placebo in a score combining subjective (pain relief, quality of life) and objective (rescue drug intake) criteria of treatment benefit. Changing the orientation of the coil from postero-anterior to latero-medial did not yield any significant pain relief. The analgesic effects of postero-anterior rTMS lasted for approximately 1 week. The pain-relieving effects were observed exclusively on global scores reflecting the most distressing type of pain in each patient. Conversely, rTMS did not specifically modify any of the pain subscores that were separately tested (ongoing, paroxysmal, stimulus-evoked, or dysesthetic pain). The authors concluded that postero-anterior rTMS was more effective than both placebo and latero-medial rTMS. When obtained, pain relief was not specific to any particular submodality but rather reduced the global pain sensation, whatever its type. Moreover, they stated that these findings were derived from a small number of subjects; thus, they need to be replicated.
Plow and associates (2012) stated that chronic neuropathic pain is one of the most prevalent and debilitating disorders. Conventional medical management, however, remains frustrating for both patients and clinicians due to poor specificity of pharmacotherapy, delayed onset of analgesia, and extensive side effects. Neuromodulation presents as a promising alternative, or at least an adjunct, as it is more specific in inducing analgesia without the associated risks of pharmacotherapy. These investigators discussed common clinical and investigational methods of neuromodulation. Compared to clinical spinal cord stimulation, investigational techniques of cerebral neuromodulation, both invasive (DBS and motor cortical stimulation [MCS]) and non-invasive (rTMS and tDCS), may be more advantageous. By adaptively targeting the multidimensional experience of pain, subtended by integrative pain circuitry in the brain, including somatosensory and thalamo-cortical, limbic, and cognitive pathways, cerebral methods may modulate the sensory-discriminative, affective-emotional, and evaluative-cognitive spheres of the pain neuromatrix. Despite promise, the current state of results alludes to the possibility that cerebral neuromodulation has thus far not been effective in producing analgesia as intended in patients with chronic pain disorders. These techniques, thus, remain investigational and off-label. These investigators discussed issues implicated in inadequate efficacy, variability of responsiveness, and poor retention of benefit, while recommending design and conceptual refinements for future trials of cerebral neuromodulation in the management of chronic neuropathic pain.
Leung et al. (2009) performed a meta-analysis on the analgesic effect of rTMS on various neuropathic pain states based on their neuroanatomical hierarchy. Available RCTs were screened. Pooled individual data (PID) were coded for age, gender, pain neuroanatomical origins, pain duration, and treatment parameters analyses. Coded pain neuroanatomical origins consist of peripheral nerve (PN), nerve root (NR), spinal cord (SC), trigeminal nerve or ganglion (TGN), and post-stroke supraspinal related pain (PSP). Raw data of 149 patients were extracted from 5 (1 parallel, 4 crossover) selected (from 235 articles) RCTs. A significant (p < 0.001) overall analgesic effect (mean percent difference in pain visual analog scale [VAS] score reduction with 95% CI) was detected, with greater reduction in VAS with rTMS in comparison to sham. Including the parallel study (Khedr et al.), the TGN subgroup was found to have the greatest analgesic effect (28.8%), followed by PSP (16.7%), SC (14.7%), NR (10.0%), and PN (1.5%). The results were similar when these researchers excluded the parallel study, with the greatest analgesic effect observed in TGN (33.0%), followed by SC (14.7%), PSP (10.5%), NR (10.0%), and PN (1.5%). In addition, multiple (versus single, p = 0.003) sessions and lower (greater than 1 and less than or equal to 10 Hz) treatment frequency range (versus greater than 10 Hz) appeared to generate better analgesic outcomes. In short, rTMS appears to be more effective in suppressing centrally than peripherally originated neuropathic pain states. The authors stated that this was the first PID-based meta-analysis to assess the differential analgesic effect of rTMS on neuropathic pain based on the neuroanatomical origins of the pain pathophysiology and treatment parameters. The derived information serves as a useful resource regarding treatment parameters and patient population selection for future rTMS-pain studies.
Lindholm and colleagues (2015) examined the effects of rTMS in neuropathic orofacial pain and compared two cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, these researchers assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. A total of 16 patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (p = 0.0071) or the sham (p = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than at pre-treatment baseline (p = 0.0127 for the intensity of pain and p = 0.0074 for the interference of pain) or after the S1/M1 (p = 0.001 and p = 0.0001) and sham (p = 0.0491 and p = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The authors concluded that the right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.
Jin and colleagues (2015) stated that the optimal parameters of rTMS (stimulation frequency and treatment sessions) for achieving long-term analgesic effects remain unknown. These investigators evaluated the optimal parameters of rTMS for neuropathic pain (NP), including the rTMS sessions needed for inducing acute as well as long-term analgesic effects. They performed a meta-analysis of the analgesic effect of high-frequency rTMS (HF-rTMS) for neuropathic patients. This meta-analysis examined all studies involving the analgesic effectiveness of HF-rTMS for NP. PubMed, Embase, and the Cochrane Library were searched for clinical studies of rTMS treatment on NP published before December 31, 2014. Crude standardized mean difference (SMD) with 95% CI was calculated for pain intensity after different treatment sessions (from 1 to 10) and follow-up of 1 or 2 months after rTMS treatment using random effect models. A total of 25 studies (including 32 trials and 589 patients) were selected for the meta-analysis according to the inclusion and exclusion criteria. All three HF-rTMS treatments (5, 10, and 20 Hz) produced pain reduction, while there were no differences between them, with the maximal pain reduction found after 1 and 5 sessions of rTMS treatment. Furthermore, this significant analgesic effect remained for 1 month after 5 sessions of rTMS treatment. The authors concluded that HF-rTMS stimulation on the primary motor cortex is effective in relieving pain in NP patients. Although 5 sessions of rTMS treatment produced a maximal analgesic effect and may be maintained for at least 1 month, further large-scale and well-controlled trials are needed to determine if this enhanced effect is specific to certain types of NP, such as post-stroke related central NP. The main drawbacks of this meta-analysis were that the long-term analgesic effects of different HF-rTMS and low-frequency (LF) rTMS sessions, including the single session of rTMS on different NP of varying origins, have yet to be evaluated, and the full degree of pain relief is still unclear for many rTMS studies.
Mulla et al. (2015) noted that central post-stroke pain is a chronic neuropathic disorder that follows a stroke. Current research on its management is limited, and no review has evaluated all therapies for central post-stroke pain. These investigators conducted a systematic review of RCTs to evaluate therapies for central post-stroke pain. They identified eligible trials, in any language, by systematic searches of AMED, CENTRAL, CINAHL, DARE, EMBASE, HealthSTAR, MEDLINE, and PsychINFO. Eligible trials enrolled greater than or equal to 10 patients with central post-stroke pain, randomly assigned them to an active therapy or a control arm, and collected outcome data greater than or equal to 14 days after treatment. Pairs of reviewers, independently and in duplicate, screened titles and abstracts of identified citations, reviewed full texts of potentially eligible trials, and extracted information from eligible studies. These researchers used a modified Cochrane tool to evaluate the risk of bias of eligible studies and collected patient-important outcomes according to recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. They conducted, when possible, random effects meta-analyses and evaluated the certainty in treatment effects using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) System. A total of 8 eligible English language RCTs (459 patients) tested anti-convulsants, an anti-depressant, an opioid antagonist, rTMS, and acupuncture. Results suggested that all therapies had little to no effect on pain and other patient-important outcomes. The certainty in the treatment estimates ranged from very low to low. The authors concluded that these findings were inconsistent with major clinical practice guidelines; the available evidence suggested no beneficial effects of any therapies that researchers have evaluated in RCTs.
Communication and Swallowing Disorders
Gadenz et al. (2015) systematically review RCTs that evaluated the effects of rTMS on rehabilitation aspects related to communication and swallowing functions. A search was conducted on PubMed, Clinical Trials, Cochrane Library, and ASHA electronic databases. Studies were judged according to the eligibility criteria and analyzed by 2 independent and blinded researchers. These researchers analyzed 9 studies: 4 about aphasia, 3 about dysphagia, 1 about dysarthria in Parkinson's disease and 1 about linguistic deficits in Alzheimer's disease. All aphasia studies used low-frequency rTMS to stimulate Broca's homologous area. High-frequency rTMS was applied over the pharyngo-esophageal cortex from the left and/or right hemisphere in the dysphagia studies and over the left dorso-lateral prefrontal cortex in the Parkinson's and Alzheimer's studies. Two aphasia and all dysphagia studies showed a significant improvement of the disorder, compared to the sham group. The other 2 studies related to aphasia found a benefit restricted to subgroups with a severe case or injury on the anterior portion of the language cortical area, respectively, whereas the Alzheimer's study demonstrated positive effects specific to auditory comprehension. There were no changes for vocal function in the Parkinson's study. The authors concluded that the benefits of the technique and its applicability in neurogenic disorders related to communication and deglutition are still uncertain; other RCTs are needed to clarify the optimal stimulation protocol for each disorder studied and its real effects.
Complex Regional Pain Syndrome Treatment
Nardone and colleagues (2018) noted that the sensory and motor cortical representation corresponding to the affected limb is altered in patients with complex regional pain syndrome (CRPS). In this review, these investigators performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and rTMS for the treatment of CRPS. Literature searches were conducted using PubMed and Embase. They identified 8 articles matching the inclusion criteria; 114 patients (76 females and 38 males) were included in these studies. Most of them have applied TMS in order to physiologically characterize CRPS type I. Changes in motor cortex excitability and brain mapping have been reported in CRPS-I patients. Sensory and motor hyper-excitability were in the most studies bilateral and likely involve corresponding regions within the central nervous system (CNS) rather than the entire hemisphere. Conversely, sensorimotor integration and plasticity were found to be normal in CRPS-I. TMS examinations also revealed that the nature of motor dysfunction in CRPS-I patients differed from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia. TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS-I patients; 2 studies have begun to therapeutically use rTMS. The authors concluded that this non-invasive brain stimulation approach could have therapeutic utility in CRPS, but further well-designed studies are needed to corroborate initial findings.
Concussion
Mollica and colleagues (2021) noted that post-concussive symptoms (PCSs) are common, disabling, and challenging to manage. Evolving models of concussion pathophysiology suggested evidence of brain network dysfunction that may be amenable to neuromodulation; and rTMS has emerged as a potential novel therapeutic option for PCSs. These researchers systematically examined rTMS trials for the treatment of symptoms following concussion/mild TBI (mTBI). They carried out a systematic review of PubMed/Medline, Embase, and PsychINFO databases up to May 19, 2020. Studies were included if they were prospective rTMS treatment studies of patients with mTBI/concussion. Variables including patient demographics, study design, rTMS protocol parameters, primary outcome measures, and efficacy data were extracted and qualitatively synthesized; rTMS methodology and study quality were also evaluated. Of the 342 studies identified, 11 met eligibility criteria and were included for synthesis. A total of 41 of patients were women, and age ranged from 18 to 65 (average age of 38.5 years). Post-concussive depression (7 studies) and headache (4 studies) were the most commonly investigated symptoms. The majority of trials were sham-controlled with RCT designs; however, all were small pilot samples (n less than 30). Methodological heterogeneity and a low number of identified trials precluded quantitative meta-analysis. Regarding rTMS for post-concussive depression, positive results were found in 2 out of 4 studies with depression as a primary outcome, and all 3 studies that evaluated depression as a secondary outcome. All 4 rTMS studies for post-concussive headache reported positive results. The authors concluded that rTMS for the treatment of concussion/mTBI showed promising preliminary results for post-concussive depression and headache, symptoms that otherwise have limited effective therapeutic options. Moreover, these researchers stated that more studies with larger sample sizes are needed to further establish potential efficacy.
Congenital Hemiparesis
- either real rTMS plus mCIMT (n = 10) or
- sham rTMS plus mCIMT (n = 9).
Main outcome measures included adverse events, physician assessment, ipsilateral hand function, stereognosis, cognitive function, subject report of symptoms assessment, and subject questionnaire. No major adverse events occurred. Minor adverse events were found in both groups. The most common events were headaches (real: 50%, sham: 89%; p = 0.14) and cast irritation (real: 30%, sham: 44%; p = 0.65). No differences between groups in secondary cognitive and unaffected hand motor measures were found. The authors concluded that primed rTMS can be used safely with mCIMT in congenital hemiparesis. They provided new information on the use of rTMS in combination with mCIMT in children. They stated that these findings could be useful in research and future clinical applications in advancing function in congenital hemiparesis.
Dementia
Freitas et al. (2011) performed a systematic search of all studies using non-invasive stimulation in Alzheimer's disease (AD) and reviewed all 29 identified articles; 24 focused on measures of motor cortical reactivity and (local) plasticity and functional connectivity, with 8 of these studies also assessing the effects of pharmacological agents, and 5 studies focused on the enhancement of cognitive function in AD. Short-latency afferent inhibition (SAI) and resting motor threshold are significantly reduced in AD patients compared to healthy elders. Results on other measures of cortical reactivity (e.g., intra-cortical inhibition [ICI]) are more divergent. Acetylcholine-esterase inhibitors and dopaminergic drugs may increase SAI and ICI in AD. Motor cortical plasticity and connectivity are impaired in AD. Transcranial magnetic stimulation/transcranial direct current stimulation (tDCS) can induce acute and short-duration beneficial effects on cognitive function, but the therapeutic clinical significance in AD is unclear. The safety of TMS/tDCS is supported by studies to date. The authors concluded that TMS/tDCS appears safe in AD, but longer-term risks have been insufficiently considered. They stated that TMS holds promise as a physiologic biomarker in AD to identify therapeutic targets and monitor pharmacologic effects. In addition, TMS/tDCS may have therapeutic utility in AD, though the evidence is still very preliminary, and cautious interpretation is warranted.
Transcutaneous electrical nerve stimulation (TENS) is the application of an electrical current through electrodes attached to the skin and is most commonly used for pain relief. It has also been employed for the treatment of a range of neurological and psychiatric conditions such as alcohol and drug dependence, depression, as well as headaches. Transcutaneous electrical nerve stimulation is rarely used for the treatment of dementia. The use of TENS for these indications entails peripherally applied TENS as well as TENS applied to the head, also known as cranial electrical stimulation (CES). Although several studies suggested that TENS may produce short-lived improvements in some neurological or psychiatric conditions, the limited data from these studies did not allow for definite conclusions on the possible benefits of this intervention.
Rose and colleagues (2008) noted that family caregivers of persons with dementia and their care recipients frequently experience sleep and mood disturbances throughout their caregiving and disease trajectories. Because conventional pharmacological treatments of sleep and mood disturbances pose numerous risks and adverse effects to elderly persons, the investigation of other interventions is warranted. As older adults use complementary and alternative medicine interventions for the relief of sleep and mood disturbances, CES may be a viable intervention. These investigators examined the effects of CES on sleep disturbances, depressive symptoms, and caregiving appraisal in spousal caregivers of persons with Alzheimer's disease (Rose et al., 2009). A total of 38 subjects were randomly assigned to receive active CES or sham CES for 4 weeks. Both intervention groups reported improvement in study measures from baseline scores. A trend toward statistically significant differences in daily sleep disturbances was found between the groups. No differences in depressive symptoms and caregiving appraisal were found between the groups. The authors concluded that these findings did not fully support the efficacy of the short-term use of active CES versus sham CES to improve sleep disturbances, depressive symptoms, or caregiving appraisal.
Guse et al. (2010) stated that TMS was introduced as a non-invasive tool for the investigation of the motor cortex. The repetitive application (rTMS), causing longer-lasting effects, was used to study the influence on a variety of cerebral functions. High-frequency (greater than 1 Hz) rTMS is known to depolarize neurons under the stimulating coil and to indirectly affect areas connected to emotion and behavior. Researchers found selective cognitive improvement after high-frequency (HF) stimulation specifically over the left dorsolateral prefrontal cortex (DLPFC). These researchers performed a systematic review of HF-rTMS studies (1999 to 2009) stimulating over the prefrontal cortex of patients suffering from psychiatric/neurological diseases or healthy volunteers, where the effects on cognitive functions were measured. The cognitive effect was analyzed with regard to the impact of clinical status (patients/healthy volunteers) and stimulation type (verum/sham). Repetitive TMS at 10, 15, or 20 Hz, applied over the left DLPFC, within a range of 10 to 15 successive sessions and an individual motor threshold of 80 to 110%, is most likely to cause significant cognitive improvement. In comparison, patients tend to reach a greater improvement than healthy participants. Limitations concern the absence of healthy groups in clinical studies and partly the absence of sham groups. Thus, future investigations are needed to assess cognitive rTMS effects in different psychiatric disorders versus healthy subjects using an extended standardized neuropsychological test battery. Since the pathophysiological and neurobiological basis of cognitive improvement with rTMS remains unclear, additional studies including genetics, experimental neurophysiology, and functional brain imaging are necessary to explore stimulation-related functional changes in the brain. The authors noted that "[a]ll in all, investigations have to prove the efficacy of rTMS in randomized sham-controlled trials with higher statistical power using larger sample sizes and improved methodology."
Koch et al. (2022) investigated whether repetitive transcranial magnetic stimulation (rTMS) applied to the precuneus could slow cognitive and functional decline in patients with mild-to-moderate Alzheimer’s disease. Fifty participants were randomized to receive either active precuneus rTMS or sham stimulation over a 24-week period, which included an initial two-week intensive phase of daily sessions followed by a 22-week maintenance phase with weekly sessions. The primary outcome was the change in Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score, with secondary outcomes including ADAS-Cog, MMSE, and ADCS-ADL. Neurophysiological assessments using TMS-EEG measured cortical excitability and oscillatory activity. Results showed that patients receiving active rTMS maintained stable CDR-SB scores, while those in the sham group experienced significant decline. Active treatment also led to better performance on secondary cognitive and functional measures. Neurophysiologically, precuneus excitability remained stable in the active group but decreased in the sham group, and gamma oscillations increased only in the active group. The procedure was safe and well tolerated, with only mild adverse events reported. Limitations included the lack of individualized targeting using functional imaging, the single-site design, faster-than-expected decline in the sham group, absence of biomarker data, and uncertainty about long-term effects beyond 24 weeks. Overall, the findings suggest that precuneus rTMS is a promising, non-pharmacological intervention for Alzheimer’s disease, warranting further research with personalized protocols and extended treatment durations.
Koch et al. (2025) investigated whether personalized repetitive transcranial magnetic stimulation (rTMS) applied to the precuneus for 52 weeks could slow cognitive and functional decline in patients with mild-to-moderate Alzheimer’s disease. Forty-eight participants were randomized into active rTMS or sham groups, with treatment consisting of an initial two-week intensive phase followed by weekly sessions for 50 weeks. Stimulation was personalized using neuronavigation and TMS-EEG. The primary outcome was the change in Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score from baseline to week 52, while secondary outcomes included ADAS-Cog11, MMSE, ADCS-ADL, and NPI scores. Results showed that patients receiving rTMS had a significantly smaller increase in CDR-SB scores compared to the sham group (1.36 vs. 2.45), indicating slower cognitive decline. Secondary measures also favored rTMS, with less deterioration in cognition, daily living activities, and behavioral symptoms. The treatment was well tolerated, with only mild adverse events reported. Exploratory analyses found no significant changes in neurophysiological measures, though stronger baseline Default Mode Network connectivity correlated with better response. Limitations included a modest sample size, single-center design, high dropout rates due to COVID-19, potential bias from participants continuing from a prior trial, and lack of biomarker data. Overall, the findings suggest that long-term precuneus-targeted rTMS is safe and may help preserve cognitive and functional abilities in Alzheimer’s disease, warranting confirmation in larger, multicenter studies.
Differential Diagnosis of Alzheimer Disease from Frontotemporal Dementia
Benussi and colleagues (2017) examined if a TMS multi-paradigm approach can be used to distinguish AD from frontotemporal dementia (FTD). Paired-pulse TMS was used to investigate short-interval intra-cortical inhibition (SICI) and facilitation (ICF), long-interval intra-cortical inhibition, and short-latency afferent inhibition (SAI) to measure the activity of different intra-cortical circuits in patients with AD, patients with FTD, and healthy controls (HC). The primary outcome measures were sensitivity and specificity of TMS measures, derived from receiver operating curve analysis. A total of 175 participants met the inclusion criteria. These researchers diagnosed 79 patients with AD, 64 patients with FTD, and 32 HC. They found that while patients with AD were characterized by a specific impairment of SAI, FTD showed a remarkable dysfunction of SICI-ICF intra-cortical circuits. With the use of the best indexes, TMS differentiated FTD from AD with a sensitivity of 91.8 % and specificity of 88.6%, AD from HC with a sensitivity of 84.8% and specificity of 90.6%, and FTD from HC with a sensitivity of 90.2% and specificity of 78.1%. These results were confirmed in patients with mild disease. The authors concluded that TMS is a non-invasive procedure that reliably distinguishes AD from FTD and HC and, if these findings are replicated in larger studies, could represent a useful additional diagnostic tool for clinical practice. This study provided Class III evidence that TMS measures can distinguish patients with AD from those with FTD. These researchers stated that further studies should examine if the AD/FTD-specific pattern of cortical dysfunction, classified according to the SICI-ICF/SAI ratio identified here, could also provide relevant prognostic information. The SICI-ICF/SAI measure has been shown to provide the footprints of the specific underlying neurotransmitter deficit, having the potential to be used as an additional diagnostic instrument in clinical practice and eventually in clinical trials.
Depression
Martin et al. (2003) conducted a systematic review of randomized controlled trials that compared rTMS with sham in patients with depression. The authors concluded that current trials are of low quality and provide insufficient evidence to support the use of rTMS in the treatment of depression. This is in accordance with the observations of Fitzgerald and colleagues (2002), who noted that TMS has a considerable role in neuropsychiatric research. It appears to have considerable potential as a therapeutic tool in depression and perhaps a role in several other disorders, although widespread application requires larger trials and establishment of sustained response, as well as Gershon et al. (2003), who stated that TMS shows promise as a novel anti-depressant treatment. Systematic and large-scale studies are needed to identify patient populations most likely to benefit and treatment parameters most likely to produce success.
A health technology assessment prepared for the Ontario Ministry of Health and Long-Term Care (2004) concluded: “Due to several serious methodological limitations in the studies (Level 2 to 4 evidence) that examined the effectiveness of rTMS in patients with MDD [major depressive disorder], to date, it is not possible to conclude that rTMS is effective or not effective for the treatment of MDD (treatment resistant or not treatment resistant MDD).”
Nemeroff (2007) stated that the role of non-pharmacological therapies such as electro-convulsive therapy (ECT), vagus nerve stimulation (VNS), deep brain stimulation (DBS), and TMS in the treatment of patients with severe depression remains an active avenue of investigation.
A randomized clinical trial (RCT) conducted for the National Coordinating Centre for Health Technology Assessment found that ECT is a more effective and potentially cost-effective antidepressant treatment than 3 weeks of rTMS (McLoughlin et al., 2007). A total of 46 patients with major depression were randomized to receive a 15-day course of rTMS (n = 24) or a course of ECT (n = 22). One patient was lost to follow-up at the end of treatment and another 8 at 6 months. The end-of-treatment Hamilton Rating Scale for Depression (HRSD) scores were lower for ECT (95% confidence interval [CI]: 3.40 to 14.05, p = 0.002), with 13 (59%) achieving remission compared with four (17%) in the rTMS group (p = 0.005). However, HRSD scores did not differ between groups at 6 months. Beck Depression Inventory-II (BDI-II), visual analogue mood scales (VAMS), and Brief Psychiatric Rating Scale (BPRS) scores were lower for ECT at the end of treatment and remained lower after 6 months. Improvement in subjective reports of side effects following ECT correlated with anti-depressant response. There was no difference between the two groups before or after treatment on global measures of cognition. The NCCHTA study also evaluated the comparative costs of ECT and rTMS. The investigators reported that, although individual treatment session costs were lower for rTMS than ECT, the cost for a course of rTMS was not significantly different from that for a course of ECT, as more rTMS sessions were given per course. Service costs were not different between the groups in the subsequent 6 months, but informal care costs were significantly higher for the rTMS group (p = 0.04) and contributed substantially to the total cost for this group during the 6-month follow-up period. The investigators reported that there was also no difference in gain in quality-adjusted life years (QALYs) for ECT and rTMS patients. The report noted that analysis of cost-effectiveness acceptability curves demonstrated that rTMS has a very low probability of being more cost-effective than ECT.
The Australian Medical Services Advisory Committee (MSAC, 2007) found insufficient evidence of rTMS to support funding. The Australian MSAC considered the safety and effectiveness of rTMS for moderate to severe refractory treatment-resistant depression compared to ECT and found evidence that rTMS is safe and less invasive than ECT. However, MSAC also found limited evidence that rTMS may be less effective than ECT. A more recent MSAC review reached similar conclusions (MSAC, 2014): "After considering the available evidence in relation to safety, clinical effectiveness, and cost-effectiveness, MSAC did not support public funding because of uncertain effectiveness and cost-effectiveness due to insufficient comparative data in treatment-resistant patients against current antidepressant treatments and uncertain costs."
On October 8, 2008, the U.S. Food and Drug Administration (FDA) cleared for marketing via the 510(k) process the NeuroStar TMS (transcranial magnetic stimulation) Therapy system, which is specifically indicated for the treatment of major depressive disorder in adult patients who have failed to achieve satisfactory improvement from one prior anti-depressant medication at or above the minimal effective dose and duration in the current episode. A treatment course usually consists of 6 weeks of 40-minute sessions (5 days a week). However, the evidence supporting NeuroStar's effectiveness is less clear than its safety profile. The FDA cleared the NeuroStar based on data that found patients did modestly better when treated with TMS than when they received a sham treatment. It was a study fraught with statistical questions that concerned the agency's own scientific advisers. For a clearer answer, the National Institutes of Health has an independent study underway that tracks 260 patients (Associated Press, 2008).
Randomized, controlled studies of rTMS compared to sham treatment have produced conflicting results (O'Reardon et al., 2007; Avery et al., 2008; Mogg et al., 2008).
In a double-blind, multi-site study, O'Reardon et al. (2007) examined if TMS over the left dorsolateral prefrontal cortex (DLPFC) is effective and safe in the acute treatment of major depression. A total of 301 medication-free patients with major depression who had not benefited from prior treatment were randomized to active (n = 155) or sham TMS (n = 146) conditions. Sessions were conducted 5 times per week with TMS at 10 pulses/sec, 120% of motor threshold, 3,000 pulses/session, for 4 to 6 weeks. The primary outcome was the symptom score change as assessed at week 4 with the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included changes on the 17- and 24-item Hamilton Depression Rating Scale (HAMD) and response and remission rates with the MADRS and HAMD. Active TMS was significantly superior to sham TMS on the MADRS at week 4 (with a post hoc correction for inequality in symptom severity between groups at baseline), as well as on the HAMD17 and HAMD24 scales at weeks 4 and 6. Response rates were significantly higher with active TMS on all three scales at weeks 4 and 6. Remission rates were approximately two-fold higher with active TMS at week 6 and significant on the MADRS and HAMD24 scales (but not the HAMD17 scale). Active TMS was well-tolerated with a low drop-out rate for adverse events (4.5%) that were generally mild and limited to transient scalp discomfort or pain. The authors concluded that TMS was effective in treating major depression with minimal side effects reported.
Avery and colleagues (2008) described the results of an open-label extension study of active TMS in medication-resistant patients with MDD who did not benefit from an initial course of therapy in a previously reported 6-week RCT of active versus sham TMS. Patients with DSM-IV-defined MDD were actively enrolled in the study from February 2004 through September 2005 and treated with left pre-frontal TMS administered 5 times per week at 10 pulses per second, at 120% of motor threshold, for a total of 3,000 pulses/session. The primary outcome was the baseline to endpoint change score on the MADRS. In those patients who received sham in the preceding RCT (n = 85), the mean reduction in MADRS scores after 6 weeks of open-label active TMS was -17.0 (95% CI: -14.0 to -19.9). Further, at 6 weeks, 36 (42.4%) of these patients achieved response on the MADRS, and 17 patients (20.0%) remitted (MADRS score less than 10). For those patients who received and did not respond to active TMS in the preceding randomized controlled trial (n = 73), the mean reduction in MADRS scores was -12.5 (95% CI: -9.7 to -15.4), and response and remission rates were 26.0% and 11.0%, respectively, after 6 weeks of additional open-label TMS treatment. The authors concluded that this open-label study provides further evidence that TMS is a safe and effective treatment of MDD. Furthermore, continued active TMS provided additional benefit to some patients who failed to respond to 4 weeks of treatment, suggesting that longer courses of treatment may confer additional therapeutic benefit.
On the other hand, Mogg and co-workers (2008) noted that the effectiveness of rTMS for major depression is unclear. These investigators performed a RCT comparing real and sham adjunctive rTMS with 4-month follow-up. A total of 59 patients with major depression were randomly assigned to a 10-day course of either real (n = 29) or sham (n = 30) rTMS of the left DLPFC. Primary outcome measures were the 17-item HAMD and proportions of patients meeting criteria for response (50% reduction in HAMD) and remission (HAMD < 8) after treatment. Secondary outcomes included mood self-ratings on Beck Depression Inventory-II and visual analog mood scales, Brief Psychiatric Rating Scale score, and both self-reported and observer-rated cognitive changes. Patients had 6-week and 4-month follow-ups. Overall, HAMD scores were modestly reduced in both groups but with no significant group x time interaction (p = 0.09) or group main effect (p = 0.85); the mean difference in HAMD change scores was -0.3 (95% CI: -3.4 to 2.8). At the end-of-treatment time-point, 32% of the real group were responders compared with 10% of the sham group (p = 0.06); 25% of the real group met the remission criterion compared with 10% of the sham group (p = 0.2); the mean difference in HAMD change scores was 2.9 (95% CI: -0.7 to 6.5). There were no significant differences between the two groups on any secondary outcome measures. Blinding was difficult to maintain for both patients and raters. The authors concluded that adjunctive rTMS of the left DLPFC could not be shown to be more effective than sham rTMS for treating depression.
Demirtas-Tatlidede et al. (2008) examined the impact of rTMS throughout the long course of MDD and the effectiveness of rTMS in the treatment of depressive relapses. A total of 16 medication-free patients with refractory MDD (diagnosed according to DSM-IV) who initially had clinically significant anti-depressant responses to a 10-day course of 10-Hz rTMS were consecutively admitted to the protocol from 1997 to 2001 and were followed for 4 years. The cohort was studied during a total of 64 episodes of depressive relapse. Severity of depression was evaluated with the HAMD and the BDI prior to and after completion of each rTMS treatment course. Clinically significant response was defined as a reduction in HAMD score of at least 50%. Safety was assessed by serial neurological examinations and neuropsychological evaluations. Approximately 50% of the patients individually sustained a clinically significant response to the repeated courses of rTMS; the mean ± SD decrease in HAMD scores was 64.8% ± 12.6% (p < 0.0001), and in BDI scores, 60.4% ± 20.6% (p < 0.0001). Despite the lack of adjuvant anti-depressant medication, the mean interval between treatment courses was approximately 5 months, and the medication-free period ranged from 26 to 43 months. Transcranial magnetic stimulation was well-tolerated, and evaluations regarding the safety of the repeated applications of rTMS revealed no findings of concern. The authors concluded that repeated rTMS applications have demonstrated a reproducible anti-depressant effect in patients with refractory depression who initially showed a clinically significant benefit. The duration of effect varied across patients, but benefits were sustained for a mean of nearly 5 months. They stated that further studies with larger cohorts will be useful in determining the long-term effectiveness of rTMS maintenance therapy.
In a systematic review and meta-analysis, Lam and colleagues (2008) examined the effectiveness of rTMS for treatment-resistant depression (TRD). The systematic review was conducted by identifying published RCTs of active rTMS compared with a sham control condition in patients with defined TRD (i.e., at least 1 failed trial). The primary outcome was clinical response as determined from global ratings or 50% or greater improvement on a rating scale. Other outcomes included remission and standardized mean differences in endpoint scores. Meta-analysis was conducted for absolute risk differences using random effects models. Sensitivity and subgroup analyses were also conducted to explore heterogeneity and robustness of results. A total of 24 studies (n = 1,092 patients) met criteria for quantitative synthesis. Active rTMS was significantly superior to sham conditions in producing clinical response, with a risk difference of 17% and a number-needed-to-treat of 6. The pooled response and remission rates were 25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively. Sensitivity and subgroup analyses did not significantly affect these results. Drop-outs and withdrawals owing to adverse events were very low. The authors concluded that for patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggested that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD. This is in agreement with the observations of Daskalakis and colleagues as well as Loo and associates. The former group of researchers (Daskalakis et al., 2008) stated that more studies are needed to address the current limitations of rTMS and to optimize the effectiveness of this promising therapeutic option in TRD. The latter group of investigators (Loo et al., 2008) noted that long-term effects of repeated rTMS sessions are yet unknown. When given within recommended guidelines, the overall safety profile of rTMS is good and supports its further development as a clinical treatment. It is also interesting to note that Knapp and co-workers (2008) stated that ECT is more cost-effective than rTMS in the treatment of severe depression.
Demitrack and Thase (2009) studied the clinical significance of the treatment effects seen with TMS in pharmaco-resistant major depression in their recently completed studies by comparing these outcomes with the results reported in several large, comprehensive published reference data sets of anti-depressant medications studied in both treatment-responsive and treatment-resistant patient populations. The efficacy of TMS reported in RCTs was comparable to that of anti-depressants studied in similarly designed registration trials and to the adjunctive use of atypical anti-psychotic medications in controlled trials of anti-depressant non-responders. The authors noted that these data may be helpful in treatment-planning decisions when using TMS in clinical practice.
In a prospective, multi-site, randomized, active sham-controlled (1:1 randomization) trial, George et al. (2010) examined if daily left pre-frontal rTMS safely and effectively treats major depressive disorder. About 860 outpatients were screened, yielding 199 anti-depressant drug-free patients with unipolar non-psychotic major depressive disorder. These researchers delivered rTMS to the left pre-frontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3,000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. In the intention-to-treat sample (n = 190), remission rates were compared for the two treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (p = 0.02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% CI: 1.32 to 13.24). The number needed to treat was 12. Most remitters had low anti-depressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). The authors concluded that the findings of this study suggested that daily left pre-frontal rTMS produced statistically significant and clinically meaningful anti-depressant therapeutic effects for unipolar depressed patients who are refractory to or intolerant of medications.
- as a consequence of the extensive work in designing a sham system, which delayed the start of the trial, the study failed to enroll the projected 240 subjects suggested by the initial power analysis. This power issue may be the reason why the treatment condition effect on remission rate in the fully adherent sample analysis was not statistically significant. Treaters were able to guess randomization assignment better than chance, without much confidence, which was not explained by covarying for clinical benefit,
- although the treatment effect was statistically significant on a clinically meaningful variable (remission), the overall number of remitters and responders was less than one would like with a treatment that requires daily intervention for 3 weeks or more, and
- it is unclear how long the clinical benefit lasts once achieved.
Slotema et al. (2010) examined if rTMS is effective for various psychiatric disorders. A literature search was performed from 1966 through October 2008 using PubMed, Ovid Medline, Embase Psychiatry, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and PsycINFO. The following search terms were used: transcranial magnetic stimulation, TMS, repetitive TMS, psychiatry, mental disorder, psychiatric disorder, anxiety disorder, attention-deficit hyperactivity disorder, bipolar disorder, catatonia, mania, depression, obsessive-compulsive disorder, psychosis, post-traumatic stress disorder, schizophrenia, Tourette's syndrome, bulimia nervosa, and addiction. Data were obtained from randomized, sham-controlled studies of rTMS treatment for depression (34 studies), auditory verbal hallucinations (AVH, 7 studies), negative symptoms in schizophrenia (7 studies), and obsessive-compulsive disorder (OCD, 3 studies). Studies of rTMS versus ECT (6 studies) for depression were meta-analyzed. Standardized mean effect sizes of rTMS versus sham were computed based on pre-treatment versus post-treatment comparisons. The mean weighted effect size of rTMS versus sham for depression was 0.55 (p < 0.001). Monotherapy with rTMS was more effective than rTMS as adjunctive to anti-depressant medication. Electro-convulsive therapy was superior to rTMS in the treatment of depression (mean weighted effect size -0.47, p = 0.004). In the treatment of AVH, rTMS was superior to sham treatment, with a mean weighted effect size of 0.54 (p < 0.001). The mean weighted effect size for rTMS versus sham in the treatment of negative symptoms in schizophrenia was 0.39 (p = 0.11) and for OCD, 0.15 (p = 0.52). Side effects were mild, yet more prevalent with high-frequency rTMS at frontal locations. While the authors concluded that it is time to provide rTMS as a clinical treatment method for depression, for auditory verbal hallucinations, and possibly for negative symptoms, they do not recommend rTMS for the treatment of OCD. Furthermore, the authors also stated that "[a]lthough the efficacy of rTMS in the treatment of depression and AVH may be considered proven, the duration of the effect is as yet unknown. Effect sizes were measured immediately after the cessation of rTMS treatment. There are indications that the effects of rTMS may last for several weeks to months. Future studies should assess symptom relief with longer follow-up periods to assess the cost-effectiveness of rTMS treatment and to indicate its economic advantages and disadvantages... Although rTMS cannot replace ECT in depressive patients, there may be subgroups in which rTMS can replace antidepressant medication."
The National Institute for Health and Clinical Excellence's interventional procedure overview of TMS for severe depression (2007) concluded that current evidence suggests there are no major safety concerns associated with TMS for severe depression, but there is no evidence that the procedure has clinically useful efficacy. Thus, TMS should be performed only in the context of research studies. Any future research should focus on factors including dose intensity, frequency, and duration. Furthermore, the Institute for Clinical Systems Improvement's guideline on major depression in adults in primary care (2008) stated that results of research studies to date on rTMS for the treatment of MDD have been inconsistent and inconclusive.
The BCBS Association's Medical Advisory Panel (BCBSA, 2009) concluded that the use of rTMS in the treatment of depression does not meet the TEC criteria. The TEC assessment stated that an important limitation of the evidence is the lack of information beyond the acute period of treatment. The TEC assessment noted that most of the clinical trials of rTMS evaluate the outcomes at the point of the last rTMS treatment, between 1 and 4 weeks, and that very few studies evaluated patients beyond this time period. Although meta-analyses are consistent with short-term antidepressant effects, the clinical significance of the effect is uncertain. The TEC assessment stated that the large clinical trial of rTMS by O'Reardon et al. (2007) that was reviewed in this assessment did not unequivocally demonstrate efficacy, as the principal endpoint was not statistically significant at 4 weeks, and some results were sensitive to the methods of analysis. The TEC assessment stated that patients in whom rTMS is indicated are usually treated with a second course of antidepressant therapy. The clinical trial by O'Reardon et al. (2007), which was sham-controlled without active treatment, cannot determine whether rTMS would be more or less successful than this standard treatment. Referring to the study by George et al. (2010), the TEC assessment also noted that a clinical trial sponsored by the National Institute of Mental Health has recruited subjects for another clinical trial of rTMS; however, this trial also appears to have only a short duration (3 weeks) in which the participants are randomized to rTMS or sham before crossovers or alternative treatments are offered.
An assessment by the California Technology Assessment Forum (CTAF, 2009) of rTMS for treatment-resistant depression concluded that rTMS does not meet CTAF technology assessment criteria. This report stated that there is insufficient evidence to conclude that rTMS improves net health outcomes for patients with treatment-resistant depression or that it is as effective as current alternatives (e.g., augmentation, ECT, or new drugs). The report noted that many of the individual studies of rTMS for treatment-resistant depression randomized less than 20 patients and were under-powered to detect changes in net health outcomes, particularly remission of depression. The CTAF assessment stated that the largest and most recent clinical trials of rTMS for depression failed to demonstrate significant improvements on their primary outcome measures. The CTAF assessment noted, in addition, that there is no consensus on how to perform rTMS and a dearth of evidence on the efficacy of rTMS after cessation of therapy. "Undoubtedly because of the evidence that treatment does have some clinical effect, there is active ongoing research into rTMS. However, it is too early to conclude that rTMS improves net health outcomes for patients with treatment-resistant depression, much less that it is as effective as current alternatives such as augmentation, new drugs, or ECT."
An assessment of rTMS by the Health Council of the Netherlands (2008) stated that efficacy studies should focus, in particular, on the use of rTMS to treat patients suffering from depression who are not responding well to medication. The assessment stated that it would also be useful to study the longer-term effects of rTMS therapy in depression.
An assessment of rTMS for depression by the Swedish Council on Technology Assessment in Health Care (SBU) (Brorrson et al., 2009) concluded that although the results of the studies are promising, they continue to regard the treatment as experimental. The assessment noted that one issue is that it is not known to what extent the treatment is effective in drug-resistant depression. The assessment also called for additional studies examining potential adverse effects of rTMS on memory.
An American Psychiatric Association practice guideline on major depression (2010, reaffirmed 2015) stated: "For patients whose symptoms have not responded adequately to medication, ECT remains the most effective form of therapy and should be considered [I]. In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective MAOI [II] after allowing sufficient time between medications to avoid deleterious interactions [I]. Transdermal selegiline, a relatively selective MAO B inhibitor with fewer dietary and medication restrictions, or transcranial magnetic stimulation could also be considered [II]... Based on the results of a multisite randomized sham-controlled clinical trial of high-frequency TMS over the left dorsolateral prefrontal cortex, TMS was cleared by the FDA in 2008 for use in individuals with major depressive disorder who have not had a satisfactory response to at least one antidepressant trial in the current episode of illness. However, another large, randomized sham-controlled trial of TMS added to antidepressant pharmacotherapy showed no significant benefit of left dorsolateral prefrontal cortex TMS. In comparisons of actual TMS versus sham TMS, most but not all recent meta-analyses have found relatively small to moderate benefits of TMS in terms of clinical response. Although the primary studies used in these meta-analyses are highly overlapping and the variability in TMS stimulus parameters and treatment paradigms complicates the interpretation of research findings, these meta-analyses also support the use of high-frequency TMS over the left dorsolateral prefrontal cortex. Lesser degrees of treatment resistance may be associated with a better acute response to TMS. In comparison with ECT, TMS has been found in randomized studies to be either less effective than ECT or comparable in efficacy to ECT, but in the latter studies, TMS was more effective and ECT was less effective than is typically seen in clinical trials. A fewer number of studies have compared cognitive effects of TMS and ECT. One randomized trial found no significant difference between TMS and non-dominant unilateral ECT on performance on neuropsychological tests at 2 and at 4 weeks of treatment, although a small open-label trial reported a greater degree of memory difficulties with ECT than with TMS shortly after the treatment course."
In a review on “Transcranial magnetic stimulation in the management of mood disorders,” Allan et al. (2011) presented an up-to-date meta-analysis of TMS in the treatment of depression. These investigators searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcomes measured using a version of the Hamilton Depression Rating Scale (or similar). They identified 1,789 studies; 31 were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. These researchers found a moderately sized effect in favor of TMS [Random Effects Model Hedges' g = 0.64, 95% CI: 0.50 to 0.79]. The corresponding pooled Peto odds ratio for treatment response (less than or equal to 50% reduction in depression scores) was 4.1 (95% CI: 2.9 to 5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. A total of 9 studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges' g = -0.02, 95% CI: -0.22 to +0.18) and no heterogeneity in outcome. The authors concluded that TMS appears to be an effective treatment; however, at 4 weeks' follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind RCTs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen.
The BlueCross BlueShield Technology Evaluation Center (TEC)'s assessment on TMS for depression (2011) concludes that "[t]he available evidence does not permit conclusions regarding the effect of TMS on health outcomes or compared with alternatives. Comparison to alternatives using other observational studies may not be valid due to unmeasured differences in severity of depression between studies and other differences in studies." It also states that "the current body of evidence cannot determine in a rigorous way whether TMS would be as effective as a second course of antidepressant therapy. Other important gaps in current knowledge include whether TMS is effective as an adjunctive treatment to second-line drug therapy, the durability of TMS treatment, and the effectiveness of retreatment."
- ECT,
- rTMS,
- VNS, and
- cognitive behavioral therapy (CBT) or inter-personal psychotherapy.
With respect to maintaining remission (or preventing relapse), there were no direct comparisons (evidence) involving ECT, rTMS, VNS, or CBT. Regarding indirect evidence, there were 3 fair trials compared rTMS with a sham procedure and found no significant differences, however, too few patients were followed during the relapse prevention phases in 2 of the 3 studies (20-week and 6-month follow-up) and patients in the 3rd study (3-month follow-up) received a co-intervention providing insufficient evidence for a conclusion. There were no eligible studies for ECT, VNS, or psychotherapy. The review concluded that that comparative clinical research on non-pharmacologic interventions in a TRD population is early in its infancy, and many clinical questions about efficacy and effectiveness remain unanswered. Interpretation of the data is substantially hindered by varying definitions of TRD and the paucity of relevant studies. The greatest volume of evidence is for ECT and rTMS. However, even for the few comparisons of treatments that are supported by some evidence, the strength of evidence is low for benefits, reflecting low confidence that the evidence reflects the true effect and indicating that further research is likely to change our confidence in these findings. This finding of low strength is most notable in 2 cases: ECT and rTMS did not produce different clinical outcomes in TRD, and ECT produced better outcomes than pharmacotherapy. No trials directly compared the likelihood of maintaining remission for non-pharmacologic interventions. The few trials addressing adverse events, subpopulations, subtypes, and health-related outcomes provided low or insufficient evidence of differences between non-pharmacologic interventions. The most urgent next steps for research are to apply a consistent definition of TRD, to conduct more head-to-head clinical trials comparing non-pharmacologic interventions with themselves and with pharmacologic treatments, and to delineate carefully the number of treatment failures following a treatment attempt of adequate dose and duration in the current episode.
Using data from the AHRQ report, the Institute for Clinical and Economic Review (ICER, 2011) conducted a cost-effectiveness modeling study, assuming that transcranial electrical stimulation and electroconvulsive therapy have equivalent efficacy. The model predicted a cost-utility ratio of $216,468 per quality-adjusted life year from a payer perspective and $321,880 per quality-adjusted life year from a societal perspective.
An assessment by the University of Calgary Health Technology Assessment Unit (Leggett et al., 2014) stated that, in adults with treatment-resistant depression (TRD), rTMS is more effective than no treatment, but the optimal protocol remains unclear. The assessment found that few studies have reported on the effectiveness of rTMS compared to ECT. The assessment stated that pooled estimates for response and remission provide conflicting results, indicating rTMS may be more effective at achieving response but less effective at achieving remission. The assessment concluded that the effectiveness of rTMS compared to ECT remains unclear. The assessment also concluded that the effectiveness in youth and young adult populations is uncertain.
An assessment by the Galician Health Technology Assessment Agency (AVALIA-T, 2014) reached similar conclusions: "Transcranial magnetic stimulation is not currently recommended as a treatment for depression, due to uncertainty about its clinical efficacy."
An assessment by the Alberta Health Technology Assessment Unit (2014) concluded that, in adults with treatment-resistant depression, repetitive transcranial magnetic stimulation is more effective than no treatment, but the optimal protocol remains unclear. No statistically significant differences were found between repetitive transcranial magnetic stimulation and electroconvulsive therapy; it is unclear which is most efficacious. The assessment also found that the effectiveness in youth and young adult populations is uncertain.
Hayes (2014) reported on a meta-analysis of controlled trials of TMS with sham stimulation. Most studies required patients to have one or more, and most typically two or more, previously failed trials of antidepressant medication. The post-treatment difference between transcranial magnetic stimulation and sham stimulation favored TMS; most differences were reported to be statistically significant, but the magnitude was generally small as measured by the MADRS scale and the various HAMD scales. No standard definition of clinically relevant improvement or a clinically relevant effect was identified in the literature. There is evidence of a strong placebo effect. A small quantity of data suggested that the durability of effect, i.e., the continued advantage of active transcranial magnetic stimulation over sham transcranial magnetic stimulation, may not last beyond 2 or 3 weeks after the end of treatment. Low-quality evidence suggested that transcranial magnetic stimulation may be at least as effective as electroconvulsive therapy under certain circumstances, but under other circumstances, electroconvulsive therapy may be superior; this evidence is of low quality because of unexplained inconsistency in study results. Low-quality evidence suggested that if transcranial magnetic stimulation has any effect on quality of life or function, it is very small. The review found insufficient evidence on the use of transcranial magnetic stimulation as maintenance therapy after acute response.
An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2014) concluded that transcranial magnetic stimulation for depression does not meet the TEC criteria. The assessment stated that “adequately powered trials do not provide convincing evidence of improved health outcomes.” The assessment noted that meta-analyses included a large number of trials, but their pooled results do not change the conclusions drawn from the large trials. The authors of the TEC assessment found that short-term randomized comparisons from three trials (two reporting adequate power to detect effects and the third trial similar in size) do not provide consistent evidence that TMS improves remission of major depressive disorder compared with a sham procedure in patients failing one or more antidepressant trials. The authors stated that comparisons reported beyond the initial treatment period (3 weeks of TMS) in two of the trials (O’Reardon et al., 2007; George et al., 2010) are problematic given the planned crossover and dropouts. Analyses that take into account potential confounding introduced by crossovers were not reported. The assessment found no evidence comparing TMS with changing antidepressant or augmentation similar to the strategy employed in the Sequenced Treatment Alternatives to Relieve Depression (STAR-D) study (Rush et al., 2006).
The TEC assessment included meta-analyses published from 2010 through the search date and trials enrolling more than 150 patients. The quality of meta-analyses was appraised using the 11-item Assessment of Multiple Systematic Reviews (AMSTAR) criteria. Randomized controlled trial quality was assessed using the U.S. Preventive Services Task Force criteria. Three randomized, controlled trials were identified that met inclusion criteria. Results from two trials were published at the time of the assessment—George et al. (2010) and O’Reardon et al. (2007)—and documents submitted to the FDA for the Brainsway device (subsequently published as Levkovitz et al., 2015). The two published trials employed a so-called “duration adaptive design” or “forced dropout strategy” after 3 weeks of active TMS or sham. The TEC assessment rated trial quality separately for results after 3 and 6 weeks of TMS: O’Reardon et al. (2007) was rated fair at 3 weeks and poor at 6 weeks. Response rates at three weeks for TMS versus sham were 20.6 percent and 11.6 percent at three weeks, which was statistically significant; however, the differences in remission rates at three weeks between TMS and sham were not statistically significant. There was also no statistically significant difference in remission rates at six weeks. George et al. (2010) was rated good at 3 weeks and poor at 6 weeks. There was no statistically significant difference in remission rates between TMS and sham at three weeks. Although statistically significant differences in response and remission rates were reported at six weeks, trial quality for the 6-week results was rated poor because of crossover and dropouts during the second 3 weeks of treatment. Limited data are available from the Brainsway device trial that assessed outcomes at 4 and 16 weeks. Although there were significant differences between TMS and sham in per protocol and "modified intention to treat" analyses, treatment differences between TMS and sham in the intention-to-treat (ITT) analysis were not significantly different.
The BlueCross BlueShield Assessment (2014) also looked at the results of the extension studies, finding that the response rates seen in the extension studies were difficult to interpret given the open-label nature of treatment and the lack of randomized comparator. Longer-term follow-up was examined in extension studies to the O’Reardon et al. (2007) and George et al. (2010) trials, as well as in the meta-analysis by Allan et al. (2011). Patients in the O’Reardon et al. trial who did not respond (both active TMS and sham) were allowed to participate in an additional 6 weeks of repetitive TMS. The response and remission rates improved for both groups, and these outcome improvements occurred more frequently in the extension phase than in the original randomization phase. Another extension of this trial followed responders from either the initial randomized trial or the extension study above. Participants were followed for 12 weeks for recurrence or additional TMS treatments, with a relapse rate of 12.9% with additional TMS treatment in 40.6%. The extension study to the George et al. (2010) trial enrolled 141 patients who failed to achieve remission in the original randomized phase of the trial. These participants were given additional TMS treatment for 6 weeks, but the TEC assessment noted that these results are difficult to interpret because the study lacked a control group. Any participant who remitted in the original trial or the extension study was eligible for inclusion into the third phase of the trial. Fifty patients underwent repetitive TMS tapering and were followed for 3 months. By the end of follow-up, 29 (58%) maintained remission, 2 (4%) were reclassified as partial responders, and 1 (2%) relapsed. The TEC assessment stated that the study’s unblinded, nonrandomized design and high loss to follow-up prevent any conclusions about the efficacy of repetitive TMS. The TEC assessment concluded that, because of the lack of demonstrable efficacy in the randomized comparisons, the results of the longer follow-ups reported in O’Reardon et al. (2007) and George et al. (2010) offer little toward establishing treatment benefit. The TEC assessment stated that the higher response rates seen in the extension studies are difficult to interpret given the open-label nature of treatment and lack of randomized comparator.
The TEC assessment identified concerns about publication bias affecting the conclusions of the meta-analyses. Seven meta-analyses published in 2010 or later were identified. The four largest meta-analyses included between 24 and 34 trials. Besides differing by year of publication and available studies, the meta-analyses applied different selection criteria and analytic approaches. All meta-analyses examined clinical endpoints at the conclusion of TMS treatment (i.e., 1 to 5 weeks). Limited evidence on the durability of outcomes was reported in one analysis. The meta-analyses concluded that repetitive TMS is superior to sham for treating medication-resistant depression over the short term, and possibly over a longer term. A single meta-analysis satisfied all AMSTAR criteria, and it was the only analysis to assess trial quality (risk of bias). One meta-analysis suggested a possibility of publication bias, others did not report examining potential publication bias, and some found no indication to suspect it. A large majority of trials were small, and there was considerable overlap among the trials included in the meta-analyses. The only meta-analysis to satisfy all AMSTAR criteria included the 6-week results from O’Reardon et al. (2007), and it was conducted prior to the availability of the Brainsway results. The TEC assessment was unable to identify published results for 11 completed trials registered on ClinicalTrials.gov; the published evidence is incomplete. Concerns by the authors of the TEC assessment about conclusions from the meta-analyses center on the potential for publication bias and inclusion of the problematic 6-week results from two trials. The TEC assessment stated that the three adequately powered trials do not provide convincing evidence of improved health outcomes. The meta-analyses included a large number of trials, but their pooled results do not change the conclusions drawn from the large adequately powered trials. The TEC assessment stated that, although durability of any effects is relevant, absent demonstrable benefit compared with a sham, the question is of lesser or even little importance.
An assessment by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2014) stated that some studies of transcranial magnetic stimulation may show a benefit, but four health technology assessments have been unable to make conclusions. The assessment concluded that “evidence is generally inconsistent and of low quality.”
- its observational, naturalistic design (no concurrent control group),
- conclusions regarding the influence of concomitant treatments, including the role of TMS re-introduction, cannot be fully explored, and
- analysis using an LOCF (last-observation-carried-forward) analysis method may exaggerate the consistency of the scores.
Silverstein et al. (2015) systematically synthesized the literature on the neurobiological predictors of rTMS in patients with depression. Medline (1996 to 2014), Embase (1980 to 2014), and PsycINFO (1806 to 2014) were searched under set terms. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 1,673 articles, 41 of which met both inclusion and exclusion criteria. Various biological factors at baseline appear to predict response to rTMS, including levels of certain molecular factors, blood flow in brain regions implicated in depression, electrophysiological findings, and specific genetic polymorphisms. The authors concluded that significant methodological variability in rTMS treatment protocols limited the ability to generalize conclusions. However, response to treatment may be predicted by baseline frontal lobe blood flow and the presence of polymorphisms of the 5-hydroxytryptamine (5-HT) -1a gene, the LL genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) gene, and Val/Val homozygotes of the brain-derived neurotrophic factor (BDNF) gene.
Noda et al. (2015) systematically synthesized the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996 to 2014), Embase (1980 to 2014), and PsycINFO (1806 to 2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1,647 articles identified, 66 studies met both inclusion and exclusion criteria; rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limited the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggested that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology, as well as blood flow and activity in the brain in a frequency-dependent manner. The authors concluded that more research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.
- being an original paper in a peer-reviewed journal, and
- having analyzed the effect of rTMS on neurocognitive functioning in TRD.
The combined search strategy yielded a total of 91 articles, of which, after a complete analysis, 22 fulfilled the inclusion criteria. Based on the main findings, most of the selected studies suggested the existence of a trend towards improvements in the neurocognitive profile using rTMS. Negative findings have also been reported. However, most studies were limited by their small sample size or included mixed samples, or the adopted single-blind designs potentially biased the blinding of the study design. The authors concluded that rTMS is a non-invasive brain stimulation that may be considered a valuable and promising technique for cognitive enhancement in TRD.
- short treatment duration that might be lengthened with corresponding improvements in effectiveness,
- limited duration of follow-up,
- small sample size, and
- an open-label design requiring randomized controlled replication.
It is not known if maintenance treatment with repetitive TMS for unipolar major depression is beneficial (Holtzheimer, 2019). Although several observational studies of patients who responded to acute TMS suggest that maintenance TMS may perhaps be beneficial. few randomized trials using standard protocols have been conducted. Rapinesi and colleagues (2015) examined the role of deep TMS (dTMS) maintenance sessions in protecting patients with bipolar disorder (BD) or recurrent MDD from developing depressive or manic relapses in a 12-month follow-up period. A total of 24 drug-resistant patients with a current depressive episode and a diagnosis of MDD or BD were enrolled in the study. All the participants underwent daily dTMS sessions for 4weeks. One group (maintenance -- M group) received additional maintenance dTMS sessions weekly or twice-weekly. After the 1st dTMS cycle, a significant reduction of Hamilton Depression Rating Scale (HDRS) scores was observed in all participants. Subsequently, the HDRS mean scores did not significantly change over time in the M group, while it significantly increased in the non-M-group after 6 and 12 months. The authors concluded that the findings of this study confirmed previous evidence of a positive therapeutic effect of dTMS on depressive symptoms and suggested that, after recovery from acute episodes, maintenance dTMS sessions may be helpful in maintaining euthymia in a 12-month follow-up period. The major drawbacks of this study were:
- its open design,
- small sample size (n =24),
- a possible confounding effect of add-on medication,
- the lack of a sham control, and
- the population heterogeneity.
Moreover, these researchers stated that their results should be considered as preliminary; future studies should use larger and more homogeneous samples with double-blind to better evaluate the potential effectiveness of dTMS in the treatment and the prevention of depressive episodes in mood disorders.
Pridmore et al. (2018) reported on a prospective 10-month study to determine whether 5 TMS sessions at about monthly intervals are effective in keeping depressed patients relatively well. Thirty-nine patients (72% female) received 168 series of 5 TMS sessions and remained in the program for an average of 21 weeks. Pre-post-treatment scores showed significant reductions on all measures. The post-series HAMD6 score of 3.30 (2.28) indicates that remission has been achieved. Pre-series scores of 6.24 (2.78) indicate a post-series decline in mood, in the direction of relapse. Before the TMS series, 70% were no longer in remission (being in partial remission or relapse), and after the TMS series, 79% were in remission. The authors concluded that, in severe relapsing depression, monthly series of TMS move mood from the relapse/partial remission range in the direction of remission and is appropriately termed early relapse ER-TMS. Limitations of this study include its open nature and lack of a placebo group.
Richieri et al. (2013) sought to determine whether maintenance is associated with a decrease in the relapse rate of depression following successful acute treatment. The investigators enrolled 59 consecutive patients with pharmacoresistant depression who had responded (greater than 50% decrease in symptom severity) to up to 6 weeks of acute TMS treatment. These patients received either 20 weeks of maintenance TMS (n = 37) or no additional TMS treatment (n = 22). The investigators performed propensity-adjusted analysis to examine the association between the relapse rate over this 20-week period and maintenance TMS. Propensity analysis eliminated differences in baseline characteristics between patients with and without maintenance TMS and approximated the conditions of random site-of-treatment assignment. At 20 weeks, the relapse rate was significantly different between the two groups (p = 0.004, propensity analysis): 14 patients in the maintenance TMS group (37.8%) vs. 18 in the non-maintenance TMS group (81.8%), with an adjusted Hazard Ratio (HR) = 0.288 (0.124 to 0.669). The investigators concluded that maintenance TMS was associated with a significantly lower relapse rate in patients with pharmacoresistant depression in routine practice among responders. The study had several limitations. First, this open-label trial suffered from the absence of standard features of clinical trials, such as placebo controls and blinding of response raters. The treatment was not based on random assignment; therefore, the results may be confounded by other factors. Although the propensity score can adjust for confounding by indication and selection bias, it cannot eliminate residual confounding due to unobserved factors. Second, the enrolled subjects were receiving pharmacologic treatment during the acute and maintenance phases, so TMS has to be considered as add-on therapy. However, changes in medication treatment were not allowed, which may not influence the study findings. Third, the investigators used two different protocols of stimulation in the maintenance treatment. Fourth, the investigators used a self-rating subjective scale (BDI) to measure the severity of depression, instead of more standardized objective tools such as the Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), or the Bech-Rafaelsen Melancholia Scale (BRMS). The investigators stated that well-designed randomized controlled trials are needed to confirm these findings and that future research should identify patients who will benefit the most from maintenance TMS.
Wang et al. (2017) reported on an assessor-blinded, randomized controlled study to evaluate the efficacy and safety of rTMS as mono- and combination therapy in the prevention of depressive relapse/recurrence. A total of 281 depressed patients who had achieved stable full or partial remission on a 6-month antidepressant (ADP) run-in treatment were randomly assigned to an rTMS (n = 91), ADP (n = 108), or combined (rTMS + ADP, n = 82) treatment group for 12 months. Monthly clustered rTMS was conducted in 5-10 sessions over a 3-5 day period. Maintenance outcomes were assessed using time to relapse/recurrence and relapse/recurrence rate. Overall, 71.2% (200/281) of the participants completed the treatment per the protocol. rTMS + ADP and rTMS significantly reduced the risk of relapse/recurrence compared with ADP (P = 0.000), with hazard ratios of 0.297 and 0.466, respectively. Both rTMS-containing regimens produced significantly lower relapse/recurrence rates than ADP (15.9% and 24.2% vs. 44.4%, P < 0.001). In the relapsed/recurrent subgroup, first-episode depressed, rTMS-treated patients had a markedly lower relapse/recurrence rate than ADP-treated patients. Five patients on the ADP-containing regimens, but none on rTMS alone, developed acute mania. The rTMS-containing regimens had considerably more certain side effects than did the ADP group. The authors concluded that TMS, whether as mono- or additional therapy, is superior to antidepressants in preventing depressive relapse/recurrence, particularly in first-episode depressed patients. The treatment does not increase the risk of manic switch but may increase the risk of certain side effects. The study had several limitations. First, sham rTMS was not included as an inactive control, and patients were aware of their assignment. Second, it is unclear if clustered rTMS could be superior to those “usual” rTMS regimens in achieving maintenance efficacy, safety, and tolerability. Third, participants who were required to gradually discontinue antidepressants when the maintenance treatment was initiated may have been placed at significant risk of relapse. Finally, participants in this study were those who had achieved partial or full remission during run-in treatment with antidepressants, rather than with rTMS. Whether rTMS as run-in and maintenance treatment could achieve similar outcomes in treatment-resistant depressed populations needs further evaluation.
Janicak et al. (2010) assessed the durability of the antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. Three hundred one patients were randomly assigned to active or sham TMS in a 6-week controlled trial. Nonresponders could enroll in a second, 6-week open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening, and 32/38 (84.2%) reached symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. The investigators concluded that these initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse. Limitations of the study include a lack of a controlled comparison. Further, all patients were continued on antidepressant medication monotherapy as a primary maintenance strategy during the 24-week follow-up.
Fitzgerald et al. (2013) reported on an open-label trial of clustered maintenance transcranial magnetic stimulation (rTMS) for treatment-resistant depression. Thirty-five patients with treatment-resistant depression were included. All patients had responded to two courses of rTMS treatment for depression. Following their second course of rTMS, they received clustered maintenance rTMS, which involved monthly maintenance sessions of five rTMS treatments over a two-day period. The time to relapse and clinical characteristics are described. Twenty-five patients experienced a relapse within the study period, with a mean treatment duration of 10.5 ± 10.3 months. This was substantially longer than their period of wellness following their initial acute treatment without maintenance (<3 months). Ten additional patients continued maintenance until withdrawal from the study without having experienced relapse (4 at a mean of 6.2 ± 4.3 months) or until study end (6 patients with a mean duration of 12.0 ± 9.7 months). The authors concluded that, although preliminary, this study suggests that clustered maintenance rTMS has the potential to substantially delay the occurrence of relapse following a successful course of rTMS treatment.
Connolly et al. (2012) reported on a retrospective cohort study examining the effectiveness and safety of TMS in the first 100 consecutive patients treated for depression (full DSM-IV criteria for major depressive episode in either major depressive disorder or bipolar disorder) at an academic medical center between July 21, 2008, and March 25, 2011. TMS was flexibly dosed in a course of up to 30 sessions, adjunctive to current medications, for 85 patients treated for acute depression. The primary outcomes were response and remission rates at the treatment endpoint as measured by the Clinical Global Impressions-Improvement scale (CGI-I) at 6 weeks. Secondary outcomes included change in the Hamilton Depression Rating Scale (HDRS); Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR); Beck Depression Inventory (BDI); Beck Anxiety Inventory (BAI); and the Sheehan Disability Scale (SDS). Enduring benefit was assessed over 6 months in patients receiving maintenance TMS treatment. Data from 12 patients who received TMS as maintenance or continuation treatment after prior electroconvulsive therapy (ECT) or TMS given in a clinical trial setting were also reviewed. The clinical cohort was treatment-resistant, with a mean of 3.4 failed adequate trials in the current episode. Thirty-one individuals had received prior lifetime ECT, and 60% had a history of psychiatric hospitalization. The CGI-I response rate was 50.6%, and the remission rate was 24.7% at 6 weeks. The mean change was -7.8 points in HDRS score, -5.4 in QIDS-SR, -11.4 in BDI, -5.8 in BAI, and -6.9 in SDS. The HDRS response and remission rates were 41.2% and 35.3%, respectively. Forty-two patients (49%) entered 6 months of maintenance TMS treatment. Sixty-two percent (26/42 patients) maintained their responder status at the last assessment during the maintenance treatment. TMS treatment was well tolerated, with a discontinuation rate of 3% in the acute treatment phase. No serious adverse events related to TMS were observed during acute or maintenance treatment.
Philip et al. (2016) reported on a randomized controlled trial that found that initially administering maintenance TMS only once per month provided no advantage over watchful waiting. These investigators reported on a pilot feasibility study investigating 12-month outcomes comparing two maintenance TMS approaches—a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS). Antidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial. Sixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥ 2 antidepressants (p = 0.035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI 0.38-3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study. The authors concluded that maintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. The authors also observed that those who initially respond to TMS have a strong chance of re-responding if relapse occurs.
Kaster et al. (2019) conducted a study to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. This was a secondary analysis of a randomized noninferiority trial (N = 388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥ 18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. Four trajectories were identified: nonresponse (N = 43, 11%); rapid response (N = 73, 19%); higher baseline symptoms, linear response (N = 118, 30%); and lower baseline symptoms, linear response (N = 154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. The authors concluded that major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. The authors stated that these response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols. The study had several limitations. First, the selection criteria prevent the generalization of results to individuals over age 65, individuals with bipolar depression, and individuals with significant psychiatric comorbidity. Second, two different treatments were used in this study (HFL rTMS and iTBS rTMS), which was a noninferiority trial, and although the investigators performed multiple sensitivity analyses, and despite the fact that the original study found nearly identical longitudinal response trajectories, residual trajectory differences between treatment techniques remain possible. Third, the analysis of the characteristics associated with response trajectories was exploratory and data-driven. Fourth, this analysis only considered clinical characteristics associated with response trajectories and did not use any biological markers such as baseline anatomical or functional MRI scans or neurophysiological markers.
- 14.6% of the intention-to-treat analysis set were not treated at the stimulation intensity defined by the protocol and had to be excluded from the PP analysis. This was presumably due to the flexibility of the operator in titrating stimulation intensity from 100% up to 120% of individual motor threshold in order to improve tolerability. Thus, patients were more likely to stay at an intensity below the optimal level compared to trials where rTMS was defined at a fixed intensity after a brief lead-in period. The importance of adequate intensity (120% of individual motor threshold) should be highly emphasized when training operators to use this system for anti-depressant treatment, as lower intensity does not allow stimulation of deep prefrontal cortex areas and is therefore less likely to produce the desired clinical response,
- patients with psychotic depression were excluded from the study. This decision was based on a previous trial that demonstrated the superiority of electro-convulsive therapy to rTMS in this patient group. However, it cannot be ruled out that psychotic patients may benefit from dTMS treatment, particularly if it is administered concomitantly with anti-psychotic medication, and
- in the present study patients were withdrawn from anti-depressant medications prior to dTMS as required by regulatory authorities.
However, in a real-life clinical setting, anti-depressant medication that leads to a partial response might be augmented with dTMS.
Philip et al. (2016a) stated that current treatment options for post-traumatic stress disorder (PTSD) offer modest benefits, underscoring the need for new treatments. Repetitive transcranial magnetic stimulation depolarizes neurons in a targeted brain region with magnetic fields typically pulsed at low (1 Hz) or high (10 Hz) frequency to relieve major depressive disorder (MDD). Prior work suggested that an intermediate pulse frequency, 5 Hz, is also effective for treating co-morbid depressive and anxiety symptoms. In this chart review study, these researchers systematically examined the clinical and safety outcomes in 10 patients with co-morbid MDD and PTSD syndromes who received 5-Hz rTMS therapy at the Providence VA Medical Center Neuromodulation Clinic. Self-report scales measured illness severity prior to treatment, after every 5 treatments, and upon completion of treatment. Results showed significant reductions in symptoms of PTSD (p = 0.003, effect size = 1.12, 8/10 with reliable change) and MDD (p = 0.005, effect size = 1.09, 6/10 with reliable change). The authors concluded that stimulation was well-tolerated and there were no serious adverse events. They stated that these data indicated 5-Hz rTMS may be a useful option to treat these co-morbid disorders; larger, controlled trials are needed to confirm the benefits of 5-Hz protocols observed in this pilot study.
Health Quality Ontario’s systematic review and meta-analysis on “Repetitive transcranial magnetic stimulation for treatment-resistant depression” (2016) examined the antidepressant effectiveness of rTMS in patients with treatment-resistant unipolar depression. A literature search was performed for randomized controlled trials (RCTs) published from January 1, 1994, to November 20, 2014. The search was updated on March 1, 2015. Two independent reviewers evaluated the abstracts for inclusion, reviewed full texts of eligible studies, and abstracted data. Meta-analyses were conducted to obtain summary estimates. The primary outcome was changes in depression scores measured by the Hamilton Rating Scale for Depression (HRSD), and these researchers considered, a priori, the mean difference of 3.5 points to be a clinically important treatment effect. Remission and response to the treatment were secondary outcomes, and these investigators calculated the number needed to treat based on these outcomes. They examined the possibility of publication bias by constructing funnel plots and by Begg's and Egger's tests. A meta-regression was undertaken to examine the effect of specific rTMS technical parameters on the treatment effects. A total of 23 RCTs compared rTMS with sham, and 6 RCTs compared rTMS with electroconvulsive therapy (ECT). Trials of rTMS versus sham showed a statistically significant improvement in depression scores with rTMS (weighted mean difference [WMD] 2.31, 95% CI: 1.19 to 3.43; p < 0.001). This improvement was smaller than the pre-specified clinically important treatment effect. There was a 10% absolute difference between rTMS and sham in the rates of remission or response. This translated to a number needed to treat of 10. Risk ratios for remission and response were 2.20 (95% CI: 1.44 to 3.38, p = 0.001) and 1.72 (95% CI: 1.13 to 2.62, p = 0.01), respectively, favoring rTMS. No publication bias was detected. Trials of rTMS versus ECT showed a statistically and clinically significant difference between rTMS and ECT in favor of ECT (WMD 5.97, 95% CI: 0.94 to 11.0, p = 0.02). Risk ratios for remission and response were 1.44 (95% CI: 0.64 to 3.23, p = 0.38) and 1.72 (95% CI: 0.95 to 3.11, p = 0.07), respectively, favoring ECT. The authors concluded that overall, the body of evidence favored ECT for the treatment of patients who are treatment-resistant; rTMS had a small short-term effect for improving depression in comparison with sham, but follow-up studies did not show that the small effect would continue for longer periods. The meta-analysis showed a positive, short-term effect. However, the issue is that the larger trials, which is the point that the BCBS TEC assessment made, failed to reach statistical significance on intention-to-treat analysis, and there was a suggestion of publication bias with the smaller trials.
An assessment by the National Institute for Health and Care Excellence (NICE, 2015) concluded that the evidence on repetitive transcranial magnetic stimulation for depression shows no major safety concerns, and that the evidence on its efficacy in the short term is adequate, although the clinical response is variable. The NICE assessment found little data on efficacy in the long term. The assessment stated that, during the consent process, clinicians should, in particular, inform patients about the other treatment options available and make sure that patients understand the possibility that the procedure may not provide them with benefit. The NICE assessment cited the need for the publication of further evidence on patient selection, details of the precise type and regimen of stimulation used, the use of maintenance treatment, and long-term outcomes.
The Treatment of Resistant Depression in Adolescents (TORDIA) trial was a multicenter, randomized controlled trial evaluating second-line treatment strategies for adolescents (aged 12–18 years) with major depressive disorder who did not respond to an adequate initial selective serotonin reuptake inhibitor (SSRI). A total of 334 adolescents were randomized to 4 treatment arms over 12 weeks: switch to another SSRI, switch to venlafaxine, switch to another SSRI plus cognitive behavioral therapy (CBT), or switch to venlafaxine plus CBT. The primary outcome was clinical response, defined as a Clinical Global Impressions-Improvement score of ≤2 and ≥50% reduction in Children’s Depression Rating Scale–Revised (CDRS-R) score. The trial demonstrated that combination therapy (medication switch plus CBT) resulted in significantly higher response rates compared with medication switch alone (approximately 54.8% vs 40.5%, p=0.009), while no significant difference was observed between switching to another SSRI versus venlafaxine. These findings support the addition of CBT to pharmacotherapy in adolescents with SSRI-resistant depression, with no evidence of superior efficacy for venlafaxine over a second SSRI but a higher rate of adverse effects with venlafaxine (Brent et al., 2008; Dubicka, 2008; Vitiello et al., 2011).
The American Academy of Child and Adolescent Psychiatry (Walter et al., 2023) developed and published a clinical practice guideline to enhance the quality of care and clinical outcomes for children and adolescents with major depressive disorder and persistent depressive disorder. The guideline addressed assessment and treatment of these disorders as defined by the DSM‑5‑TR and summarized empirically based guidance for psychosocial and psychopharmacologic treatments as well as expert-based guidance for assessment and clinical implementation. The population included children and adolescents with confirmed diagnoses of major depressive disorder or persistent depressive disorder, with treatment of very young children, subsyndromal depression, and prevention excluded from scope. Treatment statements were informed primarily by a critical systematic review conducted by the Agency for Healthcare Research and Quality–Research Triangle Institute–University of North Carolina Evidence‑based Practice Center that included 60 studies, of which 77% enrolled participants with major depressive disorder, 8% focused on children aged 5 to 12 years, 50% on adolescents aged 11 to 18 years, and 42% included mixed child and adolescent samples, and by additional meta‑analyses published after that review. Outcomes assessed across studies included depressive symptom reduction, response, remission, functional impairment, relapse or recurrence, suicidality, serious adverse events, and treatment withdrawal due to adverse events. The guideline reported that cognitive‑behavioral therapy and interpersonal therapy and selective serotonin reuptake inhibitor medications, except paroxetine and preferably fluoxetine, had some empirical support from randomized controlled trials and meta‑analyses, that combination treatment with cognitive‑behavioral therapy plus fluoxetine showed benefit in adolescents, and that continuation of fluoxetine alone or with cognitive‑behavioral therapy reduced relapse or recurrence among responders. The document also emphasized comprehensive, evidence‑based assessment as integral to treatment planning and implementation. Explicitly stated limitations included a small and heterogeneous evidence base, brief follow‑up durations, variable outcome and adverse event reporting, insufficient data to assess suicidal behavior risk, limited ability to disaggregate findings by age group or disorder type, sparse representation of young children and minority populations, and reliance on expert opinion for assessment and implementation guidance. TMS was noted as an area that needs additional treatment research.
In 2024, the U.S. FDA granted 510(k) marketing clearance for the use of NeuroStar Advanced Therapy System (Neuronetics, Inc.) as an adjunct for the treatment of major depressive disorder (MDD) in adolescent patients (age 15-21). Real-world clinical data provided by the manufacturer indicate that, when used as an adjunct to antidepressant therapy, the NeuroStar Advanced Therapy System demonstrates a comparable safety and efficacy profile in adolescents aged 15 to 21 years relative to adults, supporting its substantial equivalence to previously FDA-cleared predicate devices, with labeling updates limited to indications for use and clinical summaries and no changes to device specifications or performance characteristics.
Trapp et al. (2025) reviewed the use of TMS for depressive disorders and included a focused discussion of adolescents with depression. The publication described evidence from 16 unique adolescent datasets comprising approximately 400 individuals and reported wide variability in response and remission rates, with higher placebo response rates than in adults complicating efficacy estimates. It reported that the largest double-blind, randomized, sham-controlled trial in adolescents with treatment-resistant major depressive disorder (n=103) showed similar remission rates in active and sham groups after 30 sessions, with comparable safety and tolerability to adults and no differences in suicidality between groups. The review further reported that, based on unpublished real-world manufacturer data and available published literature, TMS was cleared by the US Food and Drug Administration (FDA) in March 2024 as a first-line add-on treatment for adolescent depression in individuals aged 15 years and older, and it noted that, unlike antidepressant medications in this age group, transcranial magnetic stimulation did not carry a black box warning for increased suicidal thoughts or behaviors. The authors stated that TMS in adolescents appeared to have a safety profile similar to adults, with adverse events such as headache and neck pain reported and serious adverse events occurring infrequently. They concluded that TMS could be considered as an adjunctive treatment option for adolescents aged 15 years and older within the limits of the available evidence and regulatory labeling.
Wang et al. (2026) conducted a systematic review and meta-analysis to assess the overall effect and safety of TMS therapy on treating children and adolescents with depression based on all available studies. They note that pharmacotherapy is typically the treatment of choice for moderate to severe depression. However, both clinical experience and previous research have indicated that youth with depressive disorder do not sufficiently benefit from selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants compared with adult patients. Additionally, medication use in children and adolescents is limited due to a lack of evidence and concerns regarding safety and acceptability. The authors searched PubMed, WanFang, CNKI, PsychINFO, EMBASE, the Cochrane Library, and Web of Science up to February 2025 for RCTs comparing active any type of TMS with sham/no stimulation in depressed children and youths. Data extraction, quality assessment, and synthesis via random-effects models were performed. The primary outcome was the depression scale score changes; secondary outcomes included safety and adverse events. The authors identified 34 RCTs (n = 2705) which indicated that TMS was significantly effective in reducing depression severity (SMD = -1.55, 95% CI: [-1.88, -1.23], p < 0.001, I2 = 93%). In pairwise comparisons, the high-frequency repetitive TMS (HF-rTMS) showed the largest effect (SMD = -1.90, 95% CI: [-2.42, -1.37], p < 0.001). Low-frequency rTMS and bilateral TMS showed smaller effects. Intermittent theta-burst stimulation (iTBS) effects were not significant. Subgroup analysis revealed that efficacy varied by diagnostic criteria and control group intervention. Safety assessments revealed that TMS was generally safe (OR = 1.713, 95% CI: [1.422, 2.064], p < 0.001). The authors concluded that their meta-analysis demonstrated that TMS is safe and effective for depressed children and youths, particularly HF-rTMS. However, further research is needed to confirm iTBS efficacy.
Dyslexia
Turker and Hartwigsen (2022) stated that non-invasive brain stimulation (NIBS) allows to actively and non-invasively modulate brain function. Aside from inhibiting specific processes, NIBS may also enhance cognitive functions, which might be employed for the prevention and intervention of learning disabilities such as dyslexia. However, despite the growing interest in modulating learning abilities, a comprehensive, up-to-date review synthesizing NIBS studies with dyslexics is missing. These investigators examined the potential of NIBS as a therapeutic option in dyslexia. Searches included the key words “dyslexia” in combination with “transcranial magnetic stimulation”, “transcranial direct current stimulation”, and “non‐invasive brain stimulation”. The findings of the 15 included studies suggested that repeated sessions of reading training combined with different NIBS protocols may induce long-lasting improvements of reading performance in child and adult dyslexics, opening promising avenues for future research. In particular, the "classical" reading areas appeared to be most successfully modulated through NIBS, and facilitatory protocols could improve various reading-related sub-processes. Moreover, these researchers emphasized the need to further examine the potential to modulate auditory cortex function as a pre-intervention and intervention approach for affected children (e.g., to avoid the development of auditory and phonological difficulties at the core of dyslexia). The authors outlined how future studies may increase the understanding of the neurobiological basis of NIBS-induced improvements in dyslexia. Transcranial direct current stimulation was one of the keywords of this systematic review.
Epilepsy
Zeiler et al. (2015) performed a systematic review on the use of rTMS in the treatment of status epilepticus (SE) and refractory status epilepticus (RSE). MEDLINE, BIOSIS, EMBASE, Global Health, Healthstar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform, clinicaltrials.gov (inception to August 2015), and gray literature were searched. The strength of evidence was adjudicated using Oxford and GRADE methodology. These investigators identified 11 original articles; 21 patients were described, with 13 adults and 8 pediatric cases. All studies were retrospective. Seizure reduction/control with rTMS occurred in 15 of the 21 patients (71.4%), with 5 (23.8%) and 10 (47.6%) displaying partial and complete responses, respectively. Seizures recurred after rTMS in 73.3% of the patients who had initially responded. All studies were rated as Oxford level 4, GRADE D level of evidence. The authors concluded that Oxford level 4, GRADE D evidence exists to suggest a potential impact on seizure control with the use of rTMS for FSE and FRSE, though the durability of the therapy is short-lived. They stated that routine use of rTMS in this context cannot be recommended at this time, and further prospective study of this intervention is needed.
Pereira et al. (2016) noted that about one-third of patients with epilepsy remain with pharmacologically intractable seizures. An emerging therapeutic modality for seizure suppression is rTMS. Despite being considered a safe technique, rTMS carries the risk of inducing seizures, among other milder adverse events, and thus its safety in the population with epilepsy should be continuously assessed. These researchers performed an updated systematic review on the safety and tolerability of rTMS in patients with epilepsy, similar to a previous report published in 2007, and estimated the risk of seizures and other adverse events during or shortly after rTMS application. They searched the literature for reports of rTMS being applied to patients with epilepsy, with no time or language restrictions, and obtained studies published from January 1990 to August 2015. A total of 46 publications were identified, of which 16 were new studies published after the previous safety review of 2007. The investigators noted the total number of subjects with epilepsy undergoing rTMS, medication usage, incidence of adverse events, and rTMS protocol parameters: frequency, intensity, total number of stimuli, train duration, inter-train intervals, coil type, and stimulation site. Their main data analysis included separate calculations for crude per subject risk of seizure and other adverse events, as well as risk per 1,000 stimuli. They also performed an exploratory, secondary analysis on the risk of seizure and other adverse events according to the type of coil used (figure-of-8 or circular), stimulation frequency (less than or equal to 1 Hz or greater than 1 Hz), pulse intensity in terms of motor threshold (less than 100% or greater than or equal to 100%), and number of stimuli per session (less than 500 or greater than or equal to 500). Presence or absence of adverse events was reported in 40 studies (n = 426 subjects). A total of 78 (18.3%) subjects reported adverse events, of which 85% were mild. Headache or dizziness was the most common, occurring in 8.9%. These researchers found a crude per subject seizure risk of 2.9% (95% CI: 1.3 to 4.5), given that 12 subjects reported seizures out of 410 subjects included in the analysis after data from patients with epilepsia partialis continua or status epilepticus were excluded from the estimate. Only 1 of the reported seizures was considered atypical in terms of the clinical characteristics of the patients' baseline seizures. The atypical seizure happened during high-frequency rTMS with maximum stimulator output for speech arrest, clinically arising from the region of stimulation. Although these investigators estimated a larger crude per subject seizure risk compared with the previous safety review, the corresponding confidence intervals contained both risks. Furthermore, the exclusive case of atypical seizure was the same as reported in the previous report. The authors concluded that the risk of seizure induction in patients with epilepsy undergoing rTMS was small and that the risk of other adverse events was similar to that of rTMS applied to other conditions and to healthy subjects. They stated that these findings should be interpreted with caution, given the need for adjusted analysis controlling for potential confounders, such as baseline seizure frequency. Moreover, they noted that the similarity between the safety profiles of rTMS applied to the population with epilepsy and to individuals without epilepsy supports further investigation of rTMS as a therapy for seizure suppression.
In a Cochrane review, Chen and colleagues (2016) evaluated the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side effects. The authors judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for the efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges.
Executive Function Deficits
Cristancho et al. (2023) noted that executive function deficits (EFD) in late life depression (LLD) are associated with poor outcomes. Dysfunction of the cognitive control network (CCN) has been posited in the pathophysiology of LLD with EFD. A total of 17 older adults with depression and EFD were randomized to intermittent theta burst stimulation (iTBS) or sham for 6 weeks. Intervention was delivered bilaterally using a recognized connectivity target. A total of 89% (17/19) participants completed all study procedures; no serious AEs occurred. Pre- to post-intervention change in mean MADRS scores was not different between iTBS or sham (p = 0.33). No significant group-by-time interaction for MADRS scores (F 3, 44 = 0.51; p = 0.67) was found. No significant differences were observed in the effects of time between the 2 groups on executive measures: Flanker scores (F 1, 14 = 0.02, p = 0.88), Dimensional-change-card-sort scores (F 1, 14 = 0.25, p = 0.63), and working memory scores (F 1, 14 = 0.98, p = 0.34). The Group-by-time interaction effect for functional connectivity (FC) within the Fronto-parietal-network was not significant (F 1, 14 = 0.36, p = 0.56). No significant difference in the effect-of-time between the 2 groups was found on FC within the Cingulo-opercular-network (F 1, 14 = 0, p = 0.98). The authors concluded that bilateral iTBS was feasible in LLD. Preliminary results were unsupportive of effectiveness on depression, EF, or target engagement of the CCN. Moreover, these researchers stated that a future randomized clinical trial requires a larger sample size with stratification of cognitive and executive variables and refinement in the target engagement.
Fibromyalgia
In a randomized, controlled pilot study, Short et al. (2011) examined the effects of adjunctive left pre-frontal rTMS on patients with fibromyalgia pain. A total of 20 patients with fibromyalgia, defined by American College of Rheumatology criteria, were randomized to receive 4,000 pulses at 10 Hz TMS (n = 10) or sham TMS (n = 10) treatment for 10 sessions over 2 weeks, along with their standard medications, which were fixed and stable for at least 4 weeks before starting sessions. Subjects recorded daily pain, mood, and activity. Blinded raters assessed pain, mood, functional status, and tender points weekly using the Brief Pain Inventory, Hamilton Depression Rating Scale, and Fibromyalgia Impact Questionnaire. No statistically significant differences between groups were observed. Patients who received active TMS had a mean 29% (statistically significant) reduction in pain symptoms in comparison to their baseline pain. Sham-TMS participants had a 4% non-significant change in daily pain from their baseline pain. At 2 weeks after treatment, there was a significant improvement in depression symptoms in the active group compared to baseline. Pain reduction preceded anti-depressant effects. TMS was well-tolerated, with few side effects. The authors concluded that further studies addressing study limitations (small sample size and short follow-up) are needed to determine whether daily prefrontal TMS may be an effective, durable, and clinically useful treatment for fibromyalgia symptoms.
Marlow et al. (2013) systematically reviewed the literature to date applying rTMS or tDCS for patients with fibromyalgia syndrome (FMS). Electronic bibliography databases screened included PubMed, Ovid MEDLINE, PsychINFO, CINAHL, and Cochrane Library. The keyword "fibromyalgia" was combined with ("transcranial" and "stimulation") or "TMS" or "tDCS" or "transcranial magnetic stimulation" or "transcranial direct current stimulation." Nine of 23 studies were included; brain stimulation sites comprised either the primary motor cortex (M1) or the dorso-lateral pre-frontal cortex (DLPFC). Five studies used rTMS (high-frequency M1: 2, low-frequency DLPFC: 2, high-frequency DLPFC: 1), while 4 applied tDCS (anodal M1: 1, anodal M1/DLPFC: 3); 8 were double-blinded RCTs. Most (80%) rTMS studies that measured pain reported significant decreases, while all (100%) tDCS studies with pain measures reported significant decreases. Greater longevity of significant pain reductions was observed for excitatory M1 rTMS/tDCS. The authors concluded that studies involving excitatory rTMS/tDCS at M1 showed analogous pain reductions as well as considerably fewer side effects compared to FDA-approved FMS pharmaceuticals. The most commonly reported side effects were mild, including transient headaches and scalp discomfort at the stimulation site. Yearly use of rTMS/tDCS regimens appears costly ($11,740 to $14,507/year); however, analyses to appropriately weigh these costs against clinical and quality of life benefits for patients with FMS are lacking. Consequently, rTMS/tDCS should be considered when treating patients with FMS, particularly those who are unable to find adequate symptom relief with other therapies. Moreover, they stated that further work into optimal stimulation parameters and standardized outcome measures is needed to clarify associated efficacy and effectiveness.
In a double-blind, randomized, placebo-controlled study, Boyer and colleagues (2014) examined the impact of rTMS on the quality of life (QOL) of patients with fibromyalgia and its possible brain metabolic substrate. A total of 38 patients were randomly assigned to receive high-frequency rTMS (n = 19) or sham stimulation (n = 19), applied to the left primary motor cortex in 14 sessions over 10 weeks. Primary clinical outcomes were QOL changes at the end of week 11, measured using the Fibromyalgia Impact Questionnaire (FIQ). Secondary clinical outcomes included mental and physical QOL components measured using the 36-Item Short Form Health Survey (SF-36), as well as pain, mood, and anxiety. Resting-state [(18)F]-fluorodeoxyglucose-PET metabolism was assessed at baseline, week 2, and week 11. Whole-brain voxel-based analysis was performed to study between-group metabolic changes over time. At week 11, patients in the active rTMS group had greater QOL improvement in the FIQ (p = 0.032) and in the mental component of the SF-36 (p = 0.019) than the sham stimulation group. No significant impact was found for other clinical outcomes. Compared with the sham stimulation group, patients in the active rTMS group presented an increase in right medial temporal metabolism between baseline and week 11 (p < 0.001), which was correlated with FIQ and mental component SF-36 concomitant changes (r = -0.38, p = 0.043; r = 0.51, p = 0.009, respectively). Improvement in QOL involved mainly affective, emotional, and social dimensions. The authors concluded that the findings of this study showed that rTMS improves the QOL of patients with fibromyalgia. This improvement is associated with a concomitant increase in right limbic metabolism, arguing for a neural substrate to the impact of rTMS on emotional dimensions involved in QOL. The major drawback of this study was its small sample size (n = 38). Furthermore, 9 patients did not complete the maintenance phase, reducing the sample size to 29. The authors stated that replication with a larger sample size is needed. They also noted that recent studies recommended that investigators test for the success of blinding, which was not done in this trial.
Winkelmann et al. (2012) stated that the scheduled update to the German S3 guidelines on fibromyalgia syndrome by the Association of the Scientific Medical Societies was planned starting in March 2011. The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy, 9 scientific medical societies, as well as 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest, and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus, and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Center for Evidence-Based Medicine. The formulation and grading of recommendations were accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. The authors concluded that low-to-moderate intensity aerobic exercise and strength training are strongly recommended; chiropractic, laser therapy, magnetic field therapy, massage, and transcranial current stimulation are not recommended.
Saltychev and Laimi (2017) examined whether there is evidence of rTMS being effective in decreasing the severity of pain among patients with fibromyalgia. CENTRAL, Medline, Embase, CINAHL, SCOPUS, Web of Science, and relevant references of the identified studies were searched. Randomized controlled studies on adults with fibromyalgia were included. The outcome studied was change in pain severity. Methodological quality was assessed using the scale introduced in the Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group. A random-effects meta-analysis was carried out with a test for heterogeneity using the I² statistic and pooled estimates as a non-standardized mean of difference in change in pain severity measures by a numeric rating scale. The search resulted in 791 records, 8 relevant, and meta-analyses on 7 trials. The risk of bias was considered low for 7 studies. Pain severity before and after the last stimulation decreased by -1.2 points on a 0 to 10 numeric rating scale (95% CI: -1.7 to -0.8). Pain severity before and 1 week to 1 month after the last stimulation decreased by -0.7 points (95% CI: -1.0 to -0.3). Both pooled results were below the minimal clinically important difference of 1.5 points. The authors concluded that there is moderate evidence that rTMS is not more effective than sham in reducing the severity of pain in fibromyalgia patients, questioning the routine recommendation of this method for fibromyalgia treatment.
Functional Neurological Disorder and Somatic Symptom Disorder (Somatization Disorder)
Oriuwa and colleagues (2022) noted that functional neurological disorder and somatic symptom disorder (somatization disorder) are complex neuropsychiatric conditions that have been linked to circuit-based dysfunction of brain networks. Neuromodulation is a novel therapeutic strategy capable of modulating relevant brain networks, making it a promising potential candidate for the treatment of these patient populations. These researchers carried out a systematic review of Medline, Embase and PsycINFO up to March 4, 2021. Trials examining neuromodulation devices for the treatment of functional neurological disorder or somatic symptom disorder were selected. Extracted variables included study design, demographic and clinical characteristics, psychiatric co-morbidity, neurostimulation protocols, clinical outcome measures and results. A total of 404 studies were identified with 12 meeting inclusion criteria. A total of 221 patients were treated in the included studies with mean study sample size of 18 (4 to 70); 5 studies were randomized clinical trials. Functional motor symptoms (6 weakness, 4 movement disorders) were the most studied subpopulations; TMS was the most frequently used device (10 studies), followed by ECT (1 study) and direct-current stimulation (1 study). Treatment protocols varied in intended therapeutic mechanism(s): 8 studies aimed to modulate underlying network dysfunction, 5 aimed to demonstrate movement (1 also leveraged the former) and 3 boosted their primary mechanism with enhanced suggestion/expectation. All but 1 study reported positive results; however, methodological/outcome heterogeneity, mixed study quality and small sample sizes precluded quantitative meta-analysis. The authors concluded that neuromodulation, especially TMS for the treatment of functional motor symptoms, shows preliminary promise in a growing line of research. These researchers stated that larger, sham-controlled studies are needed to further establish effectiveness and better understand therapeutic mechanisms.
Insomnia
Sun and colleagues (2021) noted that rTMS might be a promising approach in the treatment of insomnia. In a meta-analysis, these researchers examined the safety and efficacy of rTMS for the treatment of insomnia; either as monotherapy or as a complementary strategy. CENTRAL, PubMed, Embase, PsycINFO, CINAHL, PEDro, CBM, CNKI, WanFang, and VIP were searched from earliest record to August 2019; RCTs published in English and Chinese examining effects of rTMS on patients with insomnia were included. Two authors independently completed the article selection, data extraction and rating. Physiotherapy Evidence Database (PEDro) scale was used to examine the methodological quality of the included studies. The RevMan software was used for meta-analysis. The quality of the evidence was examined by the GRADE approach. A total of 36 trials from 28 eligible studies were included, involving a total of 2,357 adult participants (mean age of 48.80 years; 45.33% men). Compared with sham rTMS, rTMS was associated with improved Pittsburgh sleep quality index (PSQI) total score (SMD -2.31, 95% CI: -2.95 to -1.66; Z = 7.01, p < 0.00001) and scores of 7 subscales. Compared to other treatment, rTMS as an adjunct to other treatment was associated with improved PSQI total score (SMD -1.44, 95% CI -2.00 to -0.88; Z = 5.01, p < 0.00001), and may have effects on scores of 7 subscales. Compared with other treatment, rTMS was associated with improved PSQI total score (SMD -0.63, 95% CI: -1.22 to -0.04; Z = 2.08, p = 0.04), and may have a better score in sleep latency, sleep disturbance and hypnotic using of 7 subscales. In the 3 pair of comparisons, the results for polysomnography (PSG) outcomes were varied. In general, rTMS may improve sleep quality through increasing slow wave and rapid eye movement (REM) sleep. The rTMS group was more prone to headache than the sham or blank control group (relative risk [RR] 1.71, 95% CI: 1.03 to 2.85; Z = 2.07, p = 0.04). No severe AEs were reported. Reporting biases and low and very-low grade of some evidences should be considered when interpreting the results of this meta-analysis. The authors concluded that these findings indicated that rTMS may be a safe and effective option for insomnia. Moreover, these researchers stated that further international, multi-center, high-quality RCTs with more objective, QOL related and follow-up assessments are needed.
Migraine
Funak and colleagues (2006) noted that in healthy volunteers (HV), 1 session of 1-Hz rTMS over the visual cortex induces dishabituation of visual evoked potentials (VEPs) on average for 30 minutes, while in migraineurs, 1 session of 10-Hz rTMS replaces the abnormal VEP potentiation with a normal habituation for 9 minutes. These investigators examined whether repeated rTMS sessions (1-Hz in 8 HV; 10-Hz in 8 migraineurs) on 5 consecutive days can modify VEPs for longer periods. In all 8 HV, the 1-Hz rTMS-induced dishabituation increased in duration over consecutive sessions and persisted for several hours (n = 4) and several weeks (n = 4) after the 5th session. In 6 of the 8 migraineurs, the normalization of VEP habituation by 10-Hz rTMS lasted longer after each daily stimulation but did not exceed several hours after the last session, except in 2 patients, where it persisted for 2 days and 1 week. The authors concluded that daily rTMS can induce long-lasting changes in cortical excitability and VEP habituation patterns. However, whether this effect may be useful in preventing migraines remains to be determined.
Guidance from the National Institute for Health and Care Excellence (NICE, 2014) concluded that the evidence on the efficacy of TMS for the treatment of migraine is limited in quantity, and for the prevention of migraine, it is limited in both quality and quantity. Evidence on its safety in the short and medium term is adequate, but there is uncertainty about the safety of long-term or frequent use of TMS.
Moisset et al. (2020) noted that several neuromodulation methods exist for migraine treatment. These researchers carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) focusing on migraine treatment using neurostimulation methods. They searched Medline and Embase up to July 1, 2020, for RCTs reporting acute or preventive treatment of migraine with either non-invasive or invasive neurostimulation methods. Two researchers independently assessed the eligibility of the retrieved studies and extracted data. Outcomes for the quantitative synthesis were 2 hours pain-free for acute treatment and headache days per month for preventive treatment. These investigators also carried out subgroup analyses by treatment (stimulation method and site of application). Estimates were pooled using random-effects meta-analysis. A total of 38 articles were included in the qualitative analysis (7 acute, 31 preventive) and 34 in the quantitative evaluation (6 acute, 28 preventive). Remote electrical neuromodulation (REN) was effective for acute treatment. Data were insufficient to draw conclusions for any other techniques (single studies). Invasive occipital nerve stimulation (ONS) was effective for migraine prevention, with a large effect size but considerable heterogeneity, whereas supra-orbital TENS, percutaneous electrical nerve stimulation (PENS), and high-frequency rTMS over the primary motor cortex (M1) were effective, with small to medium effect sizes. Vagus nerve stimulation (VNS), left prefrontal cortex rTMS, and cathodal tDCS over the M1 had no significant effect, and heterogeneity was high. The authors concluded that several neuromodulation methods are of potential interest for migraine management, but the quality of the evidence is very poor. These researchers stated that future large and well-conducted studies are needed and could improve on the present results.
The authors stated that this review had several limitations. First, the meta-analysis was based on a very limited number of articles for each study subgroup, and the estimation of effect size may not be properly powered. Thus, the conclusions should be interpreted with caution. Further research is very likely to have a large impact on the confidence in the estimated effect. Even within the subgroups, in which the same technique and target were tested, the parameters could be quite different in terms of stimulation intensity and the number of sessions, again limiting the reliability of the estimates. Second, although the included studies only considered migraine patients, these researchers could not exclude the presence of confounding factors due to migraine frequency at baseline and potential associated medication overuse or the presence of overlapping headache disorders among the included subjects, which could affect the validity of these findings. Third, the methodological quality of the included studies was heterogeneous, with only 12 out of 38 studies being of high or very high quality in the present review, as shown in previous neuro-modulatory reviews for chronic pain in general. Moreover, it is often difficult to obtain proper blinding in studies involving neurostimulation devices that usually induce paresthesia. Finally, the follow-up period was generally relatively short; therefore, long-term benefits of neuromodulation techniques are yet to be proven.
Lloyd et al. (2021) stated that migraine is a common disabling primary headache condition. Although strides have been made in treatment, there remains an unmet need for safe, effective acute and preventative treatments. The promising concept of neuromodulation of relevant neuronal targets in a non-invasive fashion for the treatment of primary headache disorders has led to the trial of numerous devices over the years. These investigators reviewed the evidence on current neuromodulation treatments available for the management of primary headache disorders; RCTs, as well as open-label and real-world studies on central and peripheral cephalic and non-cephalic neuromodulation modalities in primary headaches, were critically reviewed. The current evidence suggests a role for single-pulse TMS, supra-orbital nerve (SON) stimulation, and remote non-cephalic electrical stimulation as migraine abortive treatments, with stronger evidence in episodic migraine (EM) rather than in chronic migraine (CM). Single-pulse TMS and SON stimulation also hold promising evidence in EM prevention and initial positive evidence in CM prevention. More evidence should clarify the therapeutic role of external VNS and tDCS in migraine. However, external VNS may be effective in the acute treatment of episodic but not chronic cluster headache, in the prevention of hemicrania continua and paroxysmal hemicrania, but not of short-lasting neuralgiform headache attacks. The difficulty in setting up sham-controlled studies has thus far prevented the publication of robust trials. This limitation, along with the cost of these therapies, has meant that their use is limited in most countries. The authors concluded that neuromodulation is a promising non-pharmacological treatment approach for primary headaches. These researchers stated that more studies with appropriate blinding strategies and reduction of device costs may allow more widespread approval of these treatments and, in turn, increase clinicians' experience in neuromodulation.
Movement Disorders
Schneider et al. (2010) stated that dystonia is associated with impaired somatosensory ability. The electrophysiological method of rTMS can be used for non-invasive stimulation of the human cortex and can alter cortical excitability and associated behavior. Among others, rTMS can alter/improve somatosensory discriminatory abilities, as shown in healthy controls. These researchers applied 5Hz-rTMS over the left primary somatosensory cortex (S1) in 5 patients with right-sided writer's dystonia and 5 controls. They studied rTMS effects on tactile discrimination accuracy and concomitant rTMS-induced changes in hemodynamic activity measured by functional magnetic resonance imaging (fMRI). Before rTMS, patients performed worse on the discrimination task than controls even though fMRI showed greater task-related activation bilaterally in the basal ganglia (BG). In controls, rTMS led to improved discrimination; fMRI revealed this was associated with increased activity of the stimulated S1, bilateral premotor cortex and BG. In dystonia patients, rTMS had no effect on discrimination; fMRI showed similar cortical effects to controls except for no effects in BG. Improved discrimination after rTMS in controls is linked to enhanced activation of S1 and BG. Failure of rTMS to increase BG activation in dystonia may be associated with the lack of effect on sensory discrimination in this group and may reflect impaired processing in BG-S1 connections. Alternatively, the increased BG activation seen in the baseline state without rTMS may reflect a compensatory strategy that saturates a BG contribution to this task.
Multiple Sclerosis
Leon Ruiz and colleagues (2018) stated that a growing number of studies have examined the effects of TMS for the symptomatic treatment of multiple sclerosis (MS). These researchers performed a PubMed search for articles, recent books, and recommendations from the most relevant clinical practice guidelines and scientific societies regarding the use of TMS as symptomatic treatment in MS. The authors concluded that excitatory electromagnetic pulses applied to the affected cerebral hemisphere allow researchers to optimize functional brain activity, including the transmission of nerve impulses through the demyelinated cortico-spinal pathway. Various studies into TMS have shown statistically significant improvements in spasticity, fatigue, lower urinary tract dysfunction, manual dexterity, gait, and cognitive deficits related to working memory in patients with MS; however, the exact level of evidence has not been defined as the results have not been replicated in a sufficient number of controlled studies. These investigators stated that further well-designed randomized controlled trials (RCTs) involving a greater number of subjects are needed to attain a higher level of evidence in order to recommend the appropriate use of TMS in MS patients across the board. They noted that TMS acts as an adjuvant with other symptomatic and immunomodulatory treatments; additional studies should specifically examine the effect of conventional rTMS on fatigue in these patients, something that has yet to be explored.
In a review and meta-analysis, Chen and colleagues (2022) examined the effectiveness of rTMS in the treatment of patients with MS. The PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, CBM, CNKI, and Wanfang databases were searched for RCTs from their inception through July 10, 2021. RCTs that met the inclusion criteria were included in the study, and RevMan software was used for meta-analysis. Outcome indicators included scores on the Fatigue Severity Scale (FSS), the Modified Ashworth Scale (MAS), and the H/M amplitude ratio of the Soleus H reflex. When p < 0.05, the difference was considered significant. A total of 10 articles were included in this study, with 8 of them in the quantitative synthesis. The meta-analysis showed that the short-term effect of rTMS treatment for the MAS was better than that of the control treatment (95% CI: -1.27 to -0.25, p = 0.004); and compared with the control group, the effect of rTMS treatment for the H/M ratio showed a significant effect (95% CI: -0.12 to -0.03, p = 0.002); while the treatment effect for the FSS was not significant (95% CI: -4.87 to 1.28, p = 0.25). The authors concluded that since the quality of the evidence was limited by considerable heterogeneity, small sample size, and differences in parameters across these protocols, these findings were inadequate to support the use of rTMS to treat fatigue associated with MS; however, they do support its use in the management of spasticity in MS patients. These researchers stated that in the future, the maintenance of the positive effect on spasticity and the exact effect on fatigue require more large-scale RCTs with increased follow-up durations to verify.
Musical Obsession (Stuck Song Syndrome)
Stuck song syndrome (SSS), a distressing repetition of involuntary tunes persisting in one's mind, can occur independently; however, in the literature, it is often reported as a symptom of obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). Most individuals are familiar with earworms, which are experienced by up to 98% of the Western population. Earworms can become severe, resulting in the SSS diagnosis. According to the literature, SSS has often been treated using antidepressants that are used to treat MDD and OCD. As TMS has shown a positive therapeutic effect for psychiatric disorders, especially MDD and OCD, these researchers hypothesized that TMS could be an effective treatment that reduces symptoms in patients with SSS. In a first case-series study, Niyitegeka et al. (2025) examined the use of TMS for the treatment of SSS. These investigators carried out a systematic review that identified existing treatments. They presented 2 cases of TMS treatment contributing to a reduction in symptoms of SSS. Furthermore, these investigators provided a systematic review of cases where SSS has been described and compared the pharmacological or psychotherapeutic treatments used with the novel TMS interventions for SSS. This report highlighted some limitations, including patients' psychiatric co-morbidities and treatment protocol changes, which affected the findings' generalizability. The authors concluded that despite these limitations, TMS appeared promising as a treatment for SSS due to the observed effectiveness in reducing SSS symptoms and minimal side effects, especially in medication-resistant cases. Moreover, these researchers stated that the actual prevalence of SSS may be higher than reported due to under-diagnosis, highlighting the need for further research into its epidemiology and neurobiology. They stated that the novelty and scale of this exploratory study presented a necessity for larger studies to confirm these findings. These investigators noted that given TMS’s minimal side effects and lack of expected dependency, TMS presents as a potential alternative treatment modality for SSS.
The authors stated that this study had several drawbacks. First, both patients in this case-series study had multiple psychiatric co-morbidities, which could have affected their SSS in some ways. Second, the case series only included 2 patients, which limited generalizability. Third, as a consequence of Patient A’s lack of response in the initial treatment phase, modifications were made to the original treatment protocol; thus, these changes raised concerns regarding the protocol standardization. These factors could raise questions about the generalizability of the protocol. Fourth, it was not possible to examine if SSS symptoms decreased independently, or if the amelioration of SSS symptoms promoted the reduction of other symptoms, or if other symptoms' improvement influenced the attrition of SSS. In order to minimize these limitations in the future, it will be important to maintain the same protocol throughout the whole treatment to keep the protocols standardized.
Neurodevelopmental Disorders
Masuda and colleagues (2019) stated that neurodevelopmental disorders, including ASD, are common in children and adolescents, but treatment strategies remain limited. Although rTMS has been studied for neurodevelopmental disorders, there is no clear consensus on its therapeutic effects. In a systematic review, these investigators evaluated literature on rTMS for children and adolescents with neurodevelopmental disorders published up to 2018 using the PubMed database. The search identified 264 articles and 14 articles met eligibility criteria; 12 of these studies used conventional rTMS and 2 studies used theta burst stimulation. No severe AEs were reported in these studies. In patients with ASD, LF-rTMS and intermittent theta burst stimulation applied to the dorsolateral prefrontal cortex may have therapeutic effects on social functioning and repetitive behaviors. In patients with attention deficit/hyperactivity disorder (ADHD), LF-rTMS applied to the left dorsolateral prefrontal cortex and HF-rTMS applied to the right dorsolateral prefrontal cortex may target inattention, hyperactivity, and impulsivity. In patients with tic disorders, LF-rTMS applied to the bilateral supplementary motor area improved tic symptom severity. The authors concluded that the findings of this systematic review suggested that rTMS may be a promising intervention for children and adolescents with neurodevelopmental disorders. These researchers stated that these findings warrant further large RCTs of rTMS in children with neurodevelopmental disorders.
Obsessive-Compulsive Disorder
Trevizol and colleagues (2016) stated that TMS is a promising non-invasive brain stimulation intervention; it has been proposed for obsessive-compulsive disorder (OCD) with auspicious results. These investigators assessed the effectiveness of TMS for OCD in randomized controlled trials (RCTs). They performed a systematic review using Medline and Embase from the first RCT available until March 11, 2016. The main outcome was the Hedges g for continuous scores for the Yale-Brown Obsessive Compulsive Scale in a random-effects model. Heterogeneity was evaluated with the I² statistic and the χ² test. Publication bias was evaluated using the Begg funnel plot. Meta-regression was performed using the random-effects model modified by Knapp and Hartung. These researchers included 15 RCTs (n = 483), most of which had small-to-modest sample sizes. Comparing active versus sham TMS, active stimulation was significantly superior for OCD symptoms (Hedges g = 0.45; 95% CI: 0.2 to 0.71). The funnel plot showed that the risk of publication bias was low and between-study heterogeneity was low (I² = 43%, p = 0.039 for the χ² test). Meta-regression showed no particular influence of any variable on the results. The authors concluded that TMS was superior to sham stimulation for the amelioration of OCD symptoms; trials had moderate heterogeneity results, despite different protocols of stimulation used. They stated that further RCTs with larger sample sizes are needed to clarify the precise impact of TMS on OCD symptoms.
The American Psychiatric Association (APA)’s practice guideline on “The treatment of patients with obsessive-compulsive disorder” (Koran et al., 2007) stated that “Transcranial magnetic stimulation (TMS) is associated with less potential for side effects, but evidence for its efficacy is limited … Findings of the 4 published trials of repetitive TMS (rTMS) are inconsistent, perhaps because the studies differed in design, stimulation sites, duration, and stimulation parameters. The available results and the technique’s non-invasiveness and good tolerability should encourage future research, but the need for daily treatment may limit the use of TMS in practice.”
Koran and Simpson (2013) summarized new evidence and developments since the 2007 publication of the APA’s practice guideline on “The Treatment of Patients With Obsessive-Compulsive Disorder.” The authors stated that “New studies are available on repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), and other somatic treatments, but the overall strength of evidence for these treatments remains low.”
On August 17, 2018, the FDA permitted marketing of the Brainsway Deep Transcranial Magnetic Stimulation System for the treatment of OCD. Dr. Carlos Pena, director of the Division of Neurological and Physical Medicine Devices in the FDA’s Center for Devices and Radiological Health, stated that “With today’s marketing authorization, patients with OCD who have not responded to traditional treatments now have another option.” The FDA reviewed data from a randomized, multi-center study of 100 patients, of which 49 patients received treatment with the Brainsway device and 51 received treatment with a non-working (sham) device. Patients already receiving OCD treatments (medical management) were maintained at their current dosages throughout the study. The study evaluated the reduction in patients’ Yale-Brown Obsessive Compulsive Scale (YBOCS) score. The results indicated that 38% of patients responded to the Brainsway device (i.e., greater than 30% reduction in YBOCS score), whereas 11% of patients responded when using the sham device. The Brainsway device is contraindicated for patients with metallic objects or implanted stimulator devices in or near the head, including cochlear implants, deep brain stimulators, vagus nerve stimulators, other implanted electrodes or stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry, and hair barrettes. During treatment with the device, the patient must use earplugs to reduce exposure to the loud sounds produced by the device. Patients with a history of seizures should discuss their history with their healthcare provider before receiving the device. The FDA reviewed the Brainsway device through the de novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no legally marketed predicate device to which the device can claim substantial equivalence.
In a retrospective, open study, Kumar and colleagues (2018) evaluated the safety and effectiveness of low-frequency rTMS (LF-rTMS) over the left orbitofrontal cortex (Lt-OFC) as a potential augmentation strategy in the treatment of patients with medication-refractory OCD in a real-world clinical setting. This study also examined the factors affecting response to rTMS and the durability of effects produced by rTMS over a 1-month follow-up period. This was a retrospective review and analysis of clinical case files of 25 patients with medication-refractory OCD, all of whom had received 20 sessions of LF-rTMS over Lt-OFC as part of routine clinical care. A reduction of 25% and 35% in YBOCS scores was used to determine the proportion of partial and complete responders, respectively. There was a significant decrease in mean YBOCS score at the end of 20 sessions of rTMS compared with baseline (7.04 ± 5.07; p < 0.001), with no further significant change during the subsequent 1-month follow-up period (0.20 ± 1.38; p = 0.47); 13 patients (52%) met criteria for partial response (PR), and 11 patients (44%) showed complete response (CR). Furthermore, a higher number of failed medication trials was found to be significantly associated with greater chances of non-response to rTMS treatment. The authors concluded that there is a role for applying LF-rTMS over Lt-OFC as an augmentation strategy in ameliorating clinical symptoms among patients with medication-refractory OCD. This was a small study (n = 25) with short-term follow-up.
In a randomized, double-blinded, sham-controlled trial, Arumugham and associates (2018) examined the efficacy of LF-rTMS over the bilateral pre-supplementary motor area (pre-SMA) in patients suffering from OCD with partial response/poor response to pharmacotherapy. A total of 40 subjects with OCD, who were on stable medications with PR/poor response to pharmacotherapy, were randomly divided into 2 groups (n = 20 in each group) to receive either active or sham LF-rTMS over bilateral pre-SMA; 36 patients were eligible for intention-to-treat (ITT) analysis. There was no significant difference in relevant demographic and clinical variables between the 2 groups at baseline. There were no statistically significant differences between the 2 groups after 3 weeks of treatment in the YBOCS score (time*group interaction, F(2.48,84.16) = 0.80, p = 0.40) and other secondary outcome measures, including responder rates and depressive and anxiety symptoms. The authors concluded that LF-rTMS over pre-SMA may not be effective as an augmenting agent in partial/poor responders to selective serotonin reuptake inhibitors (SRIs). They stated that the findings of this study underlined the need to explore alternate rTMS protocols in OCD.
In a double-blinded, pilot study, Carmi and colleagues (2018) examined if modulation of medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) activity by deep TMS (dTMS) affects OCD symptoms. Treatment-resistant OCD subjects were treated with either high-frequency (HF; 20 Hz), low-frequency (LF; 1 Hz), or sham dTMS of the mPFC and ACC for 5 weeks. All treatments were administered following symptom provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the YBOCS. Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) for at least 1 month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that was attributed to ACC activity. The authors concluded that HF-dTMS over the mPFC-ACC alleviated OCD symptoms and may be used as a novel therapeutic intervention. Moreover, they stated that larger studies should examine if this promising technique may become an established treatment for OCD, while considering the option of an additional maintenance phase, as done for the treatment of major depression.
The authors stated that this study had several drawbacks. First, the study was considered a pilot study, and the sample size was relatively small (n = 23). As such, further studies should be conducted in order to establish this intervention for the treatment of OCD. Second, the effect of provocation was not controlled, and relevant brain activity was not recorded during the provocation. Furthermore, the extent to which the ACC and the mPFC were adequately stimulated needs to be further investigated. Consequently, the above discussion in this matter should be regarded as speculative. Finally, the total number of pulses (over the 5 weeks of treatment) that was administered was different between the LF group (22,500 pulses) and the HF group (50,000 pulses), which may stand as an alternative explanation for the superior efficacy of the HF treatment.
Lusicic and associates (2018) stated that evidence for rTMS use in OCD is accumulating and informing further developments in the neurostimulation field, the latest being dTMS, which allows direct stimulation of deeper subcortical structures and larger brain volumes than conventional rTMS. Underlying neurobiological mechanisms related to TMS are still under evaluation but appear to offer a novel "third" way of addressing symptoms via localized electrical stimulation compared to pharmacotherapy and psychotherapy approaches. This systematic review focused on the effects of rTMS and dTMS stimulation on different brain targets in OCD. Brain areas included are the dorsolateral prefrontal cortex, supplementary motor area, orbitofrontal cortex/medial prefrontal cortex, and anterior cingulate cortex (ACC). The authors concluded that as a new neurostimulation technique, rTMS showed promise as part of a toolbox of current psychiatric treatment options for OCD. Its non-invasiveness, good tolerability, and favorable side-effect profile made it an appealing treatment consideration. Underlying neurobiological mechanisms related to TMS are still under evaluation but appear to offer a novel “third” way of addressing symptoms via localized electrical stimulation compared to pharmacotherapy and psychotherapy approaches. Recent studies have considered rTMS as an adjunct treatment in treatment-resistant (TR) patients with a long duration of illness. In the future, apart from managing design and methodology issues encountered in previous studies, it will be of interest to address rTMS as an augmentation strategy earlier in the course of treatment and consider parallel stimulation of a few cortical regions. Also, rTMS could be evaluated as an option in medication-naïve patients who cannot tolerate pharmacological treatment and have limited benefits from psychotherapy approaches. Advances in targeted brain stimulation via the development of dTMS H coils paired with functional neuroimaging are offering a step further in understanding and management of OCD. However, it is yet to be determined how one can best optimize the approach via rTMS or dTMS to achieve clinically relevant results.
Rehn and co-workers (2018) stated that randomized and sham-controlled trials (RCTs) of rTMS in the treatment of OCD have yielded conflicting results, which may be due to the variability in rTMS parameters used. These researchers performed an updated systematic review and meta-analysis on the effectiveness of rTMS for the treatment of OCD and examined if certain rTMS parameters, such as cortical target, may be associated with higher treatment effectiveness. After conducting a systematic literature review for RCTs on rTMS for OCD through to December 1, 2016, using Medline, PubMed, Web of Science, PsycINFO, Google, and Google Scholar, these investigators performed a random-effects meta-analysis with the outcome measure as pre-post changes in YBOCS scores. To determine whether rTMS parameters may have influenced treatment effectiveness, studies were further analyzed according to cortical target, stimulation frequency, and length of follow-up. Data were obtained from 18 RCTs on rTMS in the treatment of OCD. Overall, rTMS yielded a modest effect in reducing YBOCS scores with Hedge's g of 0.79 (95% CI: 0.43 to 1.15, p < 0.001). Stimulation of the supplementary motor area yielded the greatest reductions in YBOCS scores relative to other cortical targets. Sub-group analyses suggested that LF-rTMS was more effective than HF-rTMS. The effectiveness of rTMS was also greater at 12 weeks follow-up than at 4 weeks follow-up. The authors concluded that the findings of this meta-analysis implied that LF-rTMS applied over the supplementary motor area may offer the greatest effectiveness in the treatment of OCD. The therapeutic effects of rTMS also appeared to persist post-treatment and may offer beneficial long-term effectiveness. They stated that with these findings, it is suggested that future large-scale studies focus on the supplementary motor area and include follow-up periods of 12 weeks or more.
Singh and co-workers (2019) examined the effectiveness of rTMS treatment targeting either the supplementary motor area (SMA) or orbitofrontal cortex (OFC) among patients with OCD in real-world clinical practice settings. These researchers also examined potential predictors of response to rTMS treatment. A retrospective review and analysis of records of 79 patients with medication-refractory OCD, all of whom had received 20 sessions of 1-Hz rTMS as part of routine clinical care. Of 79 patients, 46 received rTMS over the bilateral SMA and 33 over the left OFC. A reduction of 25% and 35% in YBOCS scores was used to classify outcomes as partial response (PR) and complete response (CR), respectively. Statistical analysis was done using SPSS version 23.0. There was a significant decrease in mean YBOCS score from baseline to the end of treatment (7.68 ± 5.62; t = 12.14, p < 0.001); 45 patients (57%) met criteria for PR, of which 32 patients (40.5%) showed CR. There was no significant difference in outcomes between patients receiving rTMS over SMA or OFC. Binary logistic regression analysis revealed the presence of co-morbid depression and higher baseline YBOCS score to be associated with a lesser likelihood of response to rTMS. The authors concluded that this study provided evidence for the overall effectiveness of adjunctive 1-Hz rTMS treatment over either SMA or OFC in patients with medication-refractory OCD and reported co-morbid depression and higher pretreatment YBOCS scores as potential predictors of poor response to rTMS. There may be overlap of patients between this study and that of the aforementioned study by Kumar et al. (2018).
Carmi et al. (2019) noted that OCD is a chronic and disabling disorder that often unsatisfactorily responds to pharmacological and psychological treatments. Converging evidence suggested a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a prior feasibility study indicated beneficial effects of dTMS targeting the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) components. In a large, multi-center, double-blind, FDA-regulated, sham-controlled study, these researchers examined the therapeutic effect of dTMS. At 11 centers, a total of 99 OCD patients were randomly allocated to either high-frequency (20-Hz) or sham dTMS and were treated daily for 6 weeks following individualized symptom provocation. Clinical response to treatment was determined using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and the primary efficacy endpoint was the change in this scale from baseline to post-treatment. Additional measures were response rates (defined as a reduction of 30% of Y-BOCS score) at post-treatment and following another month of follow-up; 98% of the active group and 92% of the sham group completed the study. Reduction in Y-BOCS scores in patients who received active dTMS treatment was significantly greater than that of patients who received sham treatment (-6.0 versus -3.3, p = 0.01), with response rates of 38.1% and 11.1%, respectively. The response rate at 1 month follow-up was 45.2% in the active versus 17.8% in the sham group. Significant differences between the groups were maintained at follow-up. The authors concluded that high-frequency dTMS over the mPFC and ACC significantly improved OCD symptoms and represented a potential intervention for patients who did not respond adequately to pharmacological and psychological interventions. These researchers noted that the intriguing finding of an additional benefit for OCD patients who did not respond adequately to pharmacological or psychological treatment suggested that this technology may involve a different mechanism. Accordingly, these researchers recommend considering, at a relatively early stage, the option of adding dTMS to treatment when the response to a proper psychological or pharmacological intervention is inadequate (this recommendation takes into consideration that the benefit-to-risk ratio of this treatment is favorable).
The authors stated that this study had several drawbacks. First, the effect of provocation was not controlled, and relevant brain activity was not recorded; hence, the exact contribution of the exposure procedure was not fully known. In addition, the extent to which the ACC and the mPFC were stimulated needs to be further examined in future functional brain imaging studies. Moreover, although the patients were asked about their past treatment history, this was not validated with source documentation such as filled prescriptions or other objective information. These investigators stated that it would be optimal if clinicians could predict the patients who are likely to respond to treatment. For example, in the pilot study (Carmi et al., 2018), the amplitude of the theta frequency band (4 to 8 Hz) in response to a Stroop task correlated with the amplitude of the change in the Y-BOCS. The possibility of corroborating such measures at baseline, following a validation study in a large sample of patients, could help predict the response and selection of the appropriate population for this 6-week treatment course. Further refinements of the stimulation and provocation parameters, treatment during a maintenance phase, and the combination of dTMS treatment with cognitive-behavioral therapy (CBT) intervention should be investigated. Studies that combine a precise behavioral challenge with neuromodulation and neuroimaging, and that attempt to identify potential responders, should also be considered.
In a “Letter to the Editor” regarding the study by Carmi et al. (2019), Harmelech et al. (2020) stated that although further research is needed to elucidate the mechanism that mediates clinical improvement with deep transcranial magnetic stimulation (dTMS) and target selection for individuals with major depressive disorder (MDD), these researchers recommended, based on the available evidence, treating co-morbid obsessive-compulsive disorder (OCD)-MDD patients with just the OCD protocol (H7 to the dorso-medial prefrontal cortex [dmPFC] / anterior cingulate cortex [ACC]).
In a “Letter to the Editor” regarding the study by Carmi et al. (2018), Alyagon et al. (2021) stated that this study included limitations of relatively medium sample sizes and the analysis method of post-correct (PC) and post-error (PE), which may be subject to potential drift bias (although alternative methods suffer from other pitfalls). Nevertheless, this behavioral analysis of objective measures derived from a computerized cognitive task further supports the clinical improvements observed and suggests that dTMS of the mPFC and ACC could induce long-term modifications to cognitive functioning associated with error monitoring.
Roth et al. (2020) stated that OCD is a chronic and disabling disease with a lifetime prevalence of 2% to 3%; approximately 40% to 60% of these patients do not adequately respond to pharmacotherapy and cognitive behavioral therapy (CBT). Deep transcranial magnetic stimulation (dTMS) has been shown to be safe and effective as a treatment alternative for OCD and recently received regulatory approvals. Yet, it is unclear whether patients who failed numerous medications and/or CBT can still benefit from dTMS. These investigators analyzed recent data from a double-blind, multi-center dTMS study; they stated that the present analysis suggested that dTMS is beneficial for OCD patients with different treatment histories, including those with unsatisfactory responses to multiple medications and CBT.
The authors stated that drawbacks of this analysis, other than the reduction of sample size to smaller cohorts, included the lack of controlled monitoring of prior pharmacological treatments and regimens. Since OCD is a chronic disorder and patients are prescribed medications from different providers over the course of their lifetime, the medication history gathered was generally an underestimation of medication exposure. Furthermore, patients who were recalling benefits from medications at a time when they were doing poorly might be underestimating those prior benefits, as those medications could have been discontinued after the patient responded and plateaued but lost perspective. There is no simple solution for this, as pharmacy records were only available for 2 years, and clinician records for 7 years. These researchers also found that the patient and therapist reports on CBT for OCD did not necessarily correlate with exposure and response prevention (ERP) for OCD. In several cases, patients were receiving reassurance or relaxation techniques on a weekly basis or were instructed to do brief exposures without the time for habituation. A formal test on the components of ERP is needed to determine that someone truly did not respond to CBT/ERP for OCD.
Roth et al. (2021) noted that dTMS with the H7-coil was FDA-cleared (not PMA-approved) for OCD in August 2018 based on multi-center sham-controlled studies. These researchers examined the efficacy of dTMS for OCD in real-world practices. All dTMS clinics were asked to supply their data on treatment details and outcome measures. The primary outcome measure was response, defined by at least a 30% reduction in the Yale Brown Obsessive Compulsive Scale (YBOCS) score from baseline to endpoint. Secondary outcome measures included first response, defined as the first time the YBOCS score met response criteria, and at least 1-month sustained response. Analyses included response rate at the endpoint (after 29 dTMS sessions), number of sessions, and days needed to reach first response and sustained response. A total of 22 clinical sites with H7-coils provided data on treatment details and outcome (YBOCS) measures from a total of 219 patients; 167 patients who had at least 1 post-baseline YBOCS measure were included in the main analyses. Overall, first and sustained response rates were 72.6% and 52.4%, respectively. The response rate was 57.9% in patients who had YBOCS scores after 29 dTMS sessions. First response was achieved on average after 18.5 sessions (SD = 9.4) or 31.6 days (SD = 25.2). Onset of sustained 1-month response was achieved on average after 20 sessions (SD = 9.8) or 32.1 days (SD = 20.5). Average YBOCS scores demonstrated continuous reduction with increasing numbers of dTMS sessions. The authors concluded that in real-world clinical practice, the majority of OCD patients benefitted from dTMS, and the onset of improvement usually occurred within 20 sessions. Extending the treatment course beyond 29 sessions resulted in continued reduction of OCD symptoms, raising the prospect of value for extended treatment protocols in non-responders.
The authors stated that this real-world analysis was primarily limited by the amount of information that sites were able to submit for analysis. A minority of the sites did not fill out demographic information and only shared the number of treatments and YBOCS scores. The main drawback was that only a small percentage of the sites took the time to participate, even though these investigators knew the utilization patterns from many more sites that were treating OCD patients with anecdotal reports of very high success rates. Their focus was on treating patients and not consistent detailed documentation or research. Potential solutions to the deficiencies in real-world evidence data collection require interoperable technologies to enable consensual effortless sharing between electronic health records, patient mobile health applications or wearables, and surveys. These researchers hope to use these in the future in order to gain information from a larger cohort of patients in a naturalistic setting, such as in the present study. Moreover, the naturalistic data is, by its nature, incomplete and may lead to bias. For example, the data on response after 29 sessions may be biased by the patients who dropped out at an earlier stage; 57.8% of those earlier quitters reached response. Hence, it was possible that the drop-out led to decreased measured response rates after 29 sessions. Likewise, data on 1-month follow-up after response or 1-month without response was available for only 63 patients. Yet, the vast majority of patients who reached response at any time point (92 of 113, 81.4%) were responders in their last YBOCS assessment. Hence, it was possible that sustained response was attained by much more than the 52.4% found in this study among the patients who had 1-month follow-up data. Another drawback was that dTMS treatment for OCD is currently not reimbursed by insurance. Hence, the patients paid out-of-pocket for the treatment. This may introduce a bias towards increased response rates due to cognitive dissonance.
Storch et al. (2021) stated that dTMS has emerged as a therapeutic option for adults with OCD who continue to exhibit impairing symptoms following an adequate response to first-line interventions. Currently, little is known about the predictors or moderators of dTMS outcome for OCD. These researchers examined if several theoretically relevant variables may predict and moderate treatment effects, including OCD symptom severity, functional impairment, co-occurring depressive symptoms, age, gender, age of OCD onset, and family history of OCD. As part of a previously reported study, 100 patients received 29 dTMS or sham stimulation treatments over 6 weeks. dTMS was administered using a Magstim Rapid2 TMS stimulator equipped with an H-shaped coil design, which was specifically designed to stimulate the dmPFC-ACC bilaterally. Findings suggested that older subjects and those with lower OCD severity and disability responded faster to both dTMS and sham stimulation. dTMS of the dmPFC/ACC appeared to have larger benefits for individuals with greater OCD severity, whereas the difference between treatment arms was minimal in those with lower severity.
The authors stated that this study had several drawbacks. First, the sample was mostly White and non-Hispanic, and no information was collected on socioeconomic status (SES), which limited the ability to generalize findings. Second, brain activity in the target brain regions was not recorded; this prevented the authors from determining the extent to which the mPFC and ACC were stimulated as well as the association of changes in brain activity with the different predictors and moderators of outcome. Finally, some factors significantly associated with outcomes of other treatment forms, such as OCD symptom dimensions and family accommodation, were not measured in this study; thus, it was impossible to determine their association with dTMS outcomes. These investigators stated that future studies should include measures of brain activity before and after treatment to examine potential treatment-related changes and their associations with the different predictors and moderators of outcome.
Harmelech et al. (2022) shed some light on the potential durability of dTMS for the treatment of OCD. Clinical sites that participated in the OCD multi-center trial, as well as those that contributed the post-marketing data, were contacted (n = 16). All sites were provided with a list of their patients who met response criteria at their last Y-BOCS evaluation following the dTMS treatment course (overall n = 108) and were compensated for contacting these patients and reporting whether each of them had, since the end of their treatment, any medication change/CBT/hospitalization/dTMS retreatment. If so, on what date did the change in treatment occur, and was it due to an exacerbation of the patient's OCD or due to a desire for greater improvement? Sites were also requested to inquire about functional disability, days lost, and days unproductive per week. The patient populations were previously described. Moreover, these researchers stated that as with any registry-based study, the primary limitations to this study were incomplete data due to a lack of follow-up or continued care with the dTMS provider following the treatment course. Many patients only went to the dTMS center for the treatment and not their ongoing psychiatric care, which limited the analysis set to 60/108 (55.6%) responders and 7/16 (43.8%) centers. Furthermore, as the Y-BOCS is not used in routine clinical practice, this resulted in a “durability” definition as elapsed time from the last dTMS session until any change in treatment was necessary. Ideally, this would be corroborated by Y-BOCS scores, a more standardized metric administered every few months. The authors concluded that confirmatory and mechanistic studies examining the response “durability” of dTMS therapy for OCD with standardized measures are needed.
Gregory et al. (2022) examined the cost-effectiveness of dTMS for treatment-refractory OCD relative to other established therapeutic options, including antidepressant medication (ADM), ADM + antipsychotic augmentation, real-world cognitive-behavioral therapy (CBT), clinical trial CBT, intensive outpatient program (IOP), partial hospitalization program (PHP), and PHP to IOP step-down. A decision analytic model was developed to evaluate the cost-effectiveness of dTMS relative to other established treatment alternatives for adults (18 to 64 years old) with refractory OCD. Building on Gregory et al. (2018), the model was parameterized with probabilistic and deterministic parameters from the literature and an outcomes database to perform a Monte Carlo simulation of a hypothetical cohort of 100,000 adults with OCD to estimate costs and incremental cost-effectiveness ratio (ICER) for dTMS relative to each treatment strategy. Encounters took place from 2012 to 2015. Data for dTMS were taken from a recent multi-site study. Although dTMS fit between ADM and ADM + CBT in overall costs, ADM + CBT had the lowest ICER and thus would be chosen before dTMS. dTMS was determined to be more cost-effective relative to PHP/IOP step-down, PHP, and IOP. The authors concluded that these findings suggested that dTMS was cost-effective along the treatment trajectory from outpatient medication management and CBT to more intensive, facilities-based approaches, and may afford an incremental strategy to employ when higher intensity strategies are either not available, not financially feasible, or while on extended waits for admission to these higher levels of care. In the latter scenario, dTMS may be appropriate for those with significant obsessive-compulsive symptomology to potentially receive benefit while they wait. These researchers stated that future studies should incorporate robust naturalistic data into dTMS estimates to confirm placement on the treatment continuum.
The authors stated that this study had several drawbacks. First, cost-effectiveness results were included from a broad array of studies characterized by differences in treatment history, period of time sampled, and OCD symptom severity. For example, there may be differences in clinical severity between individuals who participated in clinical trials versus those receiving naturalistic intensive treatment. Alternatively, estimates from naturalistic open-label treatment may be greater than those from clinical research studies given the flexibility in treatment of the former (e.g., duration, co-commitment interventions). Second, these investigators were unable to include additional adjustments for health status for individuals receiving antipsychotic treatments, which have documented weight gain and other metabolic issues. On balance, some of the individuals across clinical trials and higher levels of care would be on conjoint antipsychotic treatment; thus, balancing out additional effects. Third, these researchers only had short-term estimates for cost and treatment response and could not parameterize estimates over longer durations. Fourth, these investigators sourced cost estimates from a variety of sources. Rates within the specialty IOP/PHP programs likely reflected proportionally higher rates than cost estimates derived from Truven, which reflected non-specialty care; this may have resulted in cost-effectiveness estimates being biased against the specialty IOP/PHP programs. Fifth, published data examining real-world effectiveness of CBT (relative to that provided in clinical trials) may represent lower estimates of potential effects. Sixth, data on age, race/ethnicity, and other potentially important demographic variables were not consistently available for analysis. Finally, the outcomes database relied on consensus diagnostic procedures (versus through structured interviews) and used self-reported Y-BOCS versus the clinician-rated Y-BOCS used in research studies.
In a case-series study, Niyitegeka et al. (2025) reported the use of TMS for the treatment of musical obsessions or stuck song syndrome (SSS). These investigators noted that SSS can occur independently, but in the literature, it is commonly reported as an OCD or MDD symptom. Most individuals are familiar with earworms, which are experienced by up to 98% of the Western population. Earworms can become severe, leading to the SSS diagnosis. SSS is a distressing repetition of involuntary tunes persisting in one's mind. According to the literature, SSS has often been treated using antidepressants that are used to treat MDD and OCD. As TMS has shown a positive therapeutic effect for psychiatric disorders, especially MDD and OCD, these researchers hypothesized that TMS could be an effective treatment that reduces symptoms in patients with SSS. The authors presented 2 cases of TMS treatment contributing to a reduction in symptoms of SSS. In addition, they provided a systematic review of cases where SSS has been described and compared the pharmacological or psychotherapeutic treatments used with their novel TMS interventions for SSS. This report highlighted some limitations, including patients' psychiatric co-morbidities and treatment protocol changes, which affect the findings' generalizability. The authors concluded that despite these limitations, TMS appears promising as a treatment for SSS due to the observed effectiveness in reducing SSS symptoms and minimal side effects, especially in medication-resistant cases.
Rech et al. (2025) proposed a theoretical protocol based on previous findings to better evaluate the effect of low-frequency rTMS (LF-rTMS) for treatment-resistant OCD patients. For a randomized, sham-controlled, phase-II clinical trial, these investigators will recruit patients with moderate-to-severe OCD and limited response to previous treatments from inpatient and outpatient clinics. These researchers will employ fMRI for precise localization of the right dorsolateral prefrontal cortex (dlPFC) and application of 1-Hz stimulation of a total of 2,000 pulses with three times 40-second inter-train intervals, 5 days a week, for 6 consecutive weeks. The primary outcome will be the mean reduction in YBOCS at the end of this study. The authors concluded that this trial highlights rTMS's potential to reform OCD treatment, accentuate safety, accessibility, clinical integration, and future research foundations.
Joseph et al. (2025) noted that OCD is a chronic condition with limited therapeutic options. Standard TMS has shown moderate effectiveness but requires 6 to 8 weeks of daily sessions. These investigators examined the safety, effectiveness, and feasibility of accelerated TMS (aTMS) for faster treatment response. They systematically searched PubMed, Web of Science, and Embase databases for RCTs comparing aTMS to placebo or once-daily TMS, conducting a meta-analysis of clinical and tolerability outcomes. The Cochrane Risk of Bias tool and GRADE approach were used to assess the quality and strength of evidence. Of 97 screened records, 7 RCTs were included in the review; and 6 were analyzed quantitatively, showing that aTMS significantly reduced OCD symptoms (SMD 0.63), depressive symptoms (SMD 0.52), as well as increased response rate (OR 4.28) compared to sham aTMS. Adverse effects were higher in the aTMS group (OR 5.16), though mild, and drop-out rates were similar (OR 0.74). At follow-ups, aTMS sustained significant reductions in depressive symptoms (SMD 0.74), but not in OCD or anxiety symptoms. On risk of bias assessment, there were "some concerns" for all included studies. GRADE assessment showed moderate certainty for the primary outcome. The authors concluded that accelerated TMS offered promising, faster treatment for OCD and significantly reduced depressive symptoms, although it has no effect on anxiety. Moreover, these researchers stated that further studies are needed to examine optimal protocols and long-term effects.
Maciaszek et al. (2025) noted that there are very few studies exploring neuroplasticity impairments and neurodegeneration processes in OCD. Furthermore, the peripheral blood levels of neuroplasticity biomarkers in individuals with OCD and their associations with treatment outcomes remain largely unexplored. In an open-label study, these researchers compared peripheral blood levels of biomarkers reflecting neuroplasticity and neurodegenerative processes between patients with OCD and healthy controls (HC) and examined if accelerated continuous theta-burst stimulation (cTBS) would influence the levels of these biomarkers in OCD. A total of 33 OCD patients participated in this study of cTBS. During the treatment, serum levels of 10 biomarkers of neuroplasticity and neurodegenerative processes were assessed at 3 time points. In addition, 42 HCs were enrolled. The cTBS treatment was associated with significant improvements in OCD and depressive symptoms. Baseline levels of all biomarkers, except myeloperoxidase (MPO), were significantly lower in OCD patients compared to HCs after adjustment for covariates and multiple testing. The levels of platelet-derived growth factor (PDGF)-AA increased considerably following the cTBS treatment; however, they remained significantly lower than in HCs at the follow-up. In turn, the levels of MPO significantly decreased during cTBS treatment and were substantially lower 1 month after the cTBS stimulations compared to HCs. A reduction in MPO levels was significantly and positively correlated with a reduction of OCD and depressive symptoms. The authors concluded that the findings of this study suggested that neuroplasticity biomarkers were reduced in patients with OCD, and cTBS treatment was associated with symptom improvement, albeit with a limited impact on peripheral blood biomarkers reflecting neuroplasticity and neurodegenerative processes.
Arunachalam Sakthiyendran et al. (2025) stated that despite advancements in psychiatric treatments, many patients with treatment-resistant disorders are turning to neurosurgical interventions. These include neuromodulation-based surgeries such as deep brain stimulation (DBS) and ablative surgeries such as cingulotomy, offering relief for severe conditions such as PTSD, depression, schizophrenia, OCD, anxiety, and substance use disorder. While "psychosurgery" has sparked debate due to concerns regarding patient well-being, recent studies indicated promising symptom improvement rates across various psychiatric conditions while also demonstrating overall safety. Neuromodulation techniques, such as DBS, TMS, and electroconvulsive therapy (ECT), have evolved in regard to their sensitivity and their ability to target specific brain regions to alleviate psychiatric symptoms. Despite their benefits, these therapies have been shown to elicit side effects such as memory loss and seizures in patients, which has sparked controversy in the use of this technology among clinicians and patients. Ablative therapies, on the other hand, are concerning for being overly invasive in their approach toward psychiatric care. Despite the stigma associated with these neurosurgical interventions for psychiatric care, these procedures often remain a last resort for many patients, highlighting the need for continued research to improve these treatments and expand options for those in need.
Tang et al. (2025) noted that limited data are available to inform clinicians on how to manage concurrent substance use in the context of rTMS for the treatment of depressive, obsessive-compulsive, psychotic, or trauma-related disorders. These investigators convened an international panel of 24 rTMS experts, representative of different geographic regions and sub-specialties, and created a consensus guideline for clinicians and researchers on approaches to concurrent substance use in patients receiving rTMS as treatment for primary psychiatric disorders. These researchers carried out a Delphi method survey, and expert opinion elicited over consecutive rounds of surveys was used, with feedback and discussion after each round. Recommendation statements were established upon very high (80% or higher) agreement. A total of 3 rounds of surveys and feedback were sufficient to reach a consensus for most topics; where consensus could not be reached, the panel discussed limitations in the current evidence base. Informed by a synthesis of the literature and practice-based evidence, the expert panel provided several consensus recommendations on the topics of screening, monitoring, risk assessment, and mitigation associated with various degrees of substance use, and specific considerations for alcohol, cannabis, stimulants, and opioids. Instead of excluding all people who use substances, a nuanced approach should be taken based on an assessment of risk factors for clinical instability and severity of use. The most important safety risk with substance use is the presence of intoxication or withdrawal states, with the most data supporting seizure risk in unstable alcohol or non-medical stimulant use. Although there is no evidence of reduced rTMS efficacy for a psychiatric disorder in the presence of concurrent substance use, the lack of data in this area warrants caution. The authors concluded that these recommendations can be readily implemented clinically and provided a framework for future research. In patients receiving rTMS for a primary psychiatric disorder, assessment and management of co-occurring substance use is complex, requiring greater attention, standardization, and further investigations.
Parkinson Disease
Wagle-Shukla et al. (2007) examined the effectiveness of rTMS for the treatment of patients (n = 6) with levodopa-induced dyskinesias (LID). They reported that a 2-week course of low-frequency rTMS reduced LID as indexed by both objective and subjective evaluations, with no change in parkinsonism as evaluated by Unified Parkinson Disease Rating Scale motor scores. The benefit was observed 1 day after treatment, but not 2 weeks later. The drawbacks of this study were its small sample size and open-label design. Furthermore, benefits were not sustained. More research is needed to ascertain the clinical value, if any, of rTMS in the treatment of LID.
An assessment of rTMS by the Health Council of the Netherlands (2008) stated that the use of rTMS to treat patients with Parkinson’s disease has produced some encouraging results, and that this technology could be useful in identifying the best site for deep brain stimulation. The assessment stated that it is "still open to question" whether or not rTMS has the potential to reduce tremors.
In a randomized, double-blind, sham-controlled study, Benninger and colleagues (2011) examined the safety and effectiveness of intermittent theta-burst stimulation (iTBS) in the treatment of motor symptoms in Parkinson's disease (PD); iTBS of the motor and dorsolateral prefrontal cortex (DLPFC) was investigated in 8 sessions over 2 weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, the Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neuropsychological, and neurophysiological measures. These researchers investigated 26 patients with mild-to-moderate PD: 13 received iTBS and 13 received sham stimulation. They found beneficial effects of iTBS on mood, but no improvement in gait, bradykinesia, UPDRS, and other measures. Electroencephalography/electromyography monitoring recorded no pathological increase in cortical excitability or epileptic activity. Few reported discomfort or pain, and 1 subject experienced tinnitus during real stimulation. The authors concluded that iTBS of the motor and prefrontal cortices appears safe and improves mood, but failed to improve motor performance and functional status in PD.
There are 2 non-invasive methods to stimulate the brain: TMS and transcranial direct current stimulation (tDCS). Compared to the former approach, the latter does not directly lead to neuronal discharges; tDCS only modulates the excitability level of brain tissue. Furthermore, tDCS can be employed in a dual mode— increasing excitability on one hemisphere and decreasing excitability on the other hemisphere. In a randomized, double-blind, sham-controlled study, Benninger and colleagues (2010) examined the effectiveness of tDCS in the treatment of PD. The effectiveness of anodal tDCS applied to the motor and prefrontal cortices was investigated in 8 sessions over 2.5 weeks. Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey, and self-assessment of mobility. A total of 25 PD patients were investigated, with 13 receiving tDCS and 12 receiving sham stimulation. Transcranial direct current stimulation improved gait by some measures for a short time and improved bradykinesia in both the on and off states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well-being, and self-assessed mobility did not differ between the tDCS and sham interventions. The authors concluded that tDCS of the motor and prefrontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.
In a randomized, double-blind, sham-controlled, multi-center study with a parallel design, Shirota et al. (2013) examined the effectiveness and stimulation frequency dependence of rTMS over the supplementary motor area (SMA) in PD. A weekly intervention was performed 8 times, and the effects were monitored for up to 20 weeks. By central registration, participants were assigned to 1 of 3 arms of the study: low-frequency (1-Hz) rTMS, high-frequency (10-Hz) rTMS, and realistic sham stimulation. The primary endpoint was the score change of the UPDRS part III from baseline. Several non-motor symptom scales, such as the Hamilton Rating Scale for Depression, apathy score, and non-motor symptoms questionnaire, were defined as secondary endpoints. Of the 106 patients enrolled, 36 were allocated to 1-Hz rTMS, 34 to 10-Hz rTMS, and 36 to realistic sham stimulation. Results showed a 6.84-point improvement in the UPDRS part III in the 1-Hz group at the last visit of the 20th week. Sham stimulation and 10-Hz rTMS improved motor symptoms transiently, but their effects disappeared during the observation period. Changes in non-motor symptoms (NMS) were not clear in any group. No severe adverse events were reported. The authors concluded that 1-Hz rTMS over the SMA was effective for motor, but not non-motor, symptoms in PD. Moreover, they stated that rTMS is a promising add-on therapy for motor symptoms of PD, whereas the establishment of an adequate protocol for NMS treatment using rTMS requires further study. They noted that the present findings warrant a confirmatory clinical trial for SMA rTMS on PD, undertaken on a larger scale.
In a systematic review, Chung and Mak (2016) evaluated the effectiveness of rTMS on improving physical function and motor signs over the short- and long-terms in people with PD. A total of 5 electronic databases were systematically searched for English language full-text articles using relevant search terms. Only randomized placebo-controlled trials investigating the effects of rTMS in PD were considered. The primary outcomes were walking performance, upper limb function, and UPDRS section III. Trials with similar outcomes were pooled by calculating Hedges' g using a random-effects model. A total of 22 trials comprising 555 people with PD were included. Pooled estimates of the effect of rTMS indicated significantly improved short-term upper limb function (Hedges' g, 0.40, p = 0.007), short-term (Hedges' g, 0.61, p = 0.03) and long-term walking performance (Hedges' g, 0.89, p = 0.03), short-term (Hedges' g, 0.31, p = 0.003) and long-term (Hedges' g, 0.54, p = 0.003) UPDRS III scores. Subgroup analyses suggested a more prominent effect for M1 stimulation. Meta-regression revealed that a greater number of total stimulation pulses were associated with more UPDRS III improvements over the long term. The authors concluded that the pooled evidence suggested that rTMS improves upper limb function in the short term, walking performance, and UPDRS III in the short- and long-terms in PD sufferers. Moreover, they stated that further studies are needed to develop optimal rTMS therapeutic protocols for PD.
Peri-Partum Depression
Cox and co-workers (2020) noted that postpartum depression (PPD) is a common and gravely disabling health concern, and rTMS is an FDA-approved treatment for major depression that may be a valuable tool in the treatment of PPD. In an exploratory study, a total of 6 women with PPD received 20 sessions of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) over a 4-week period. Psychiatric rating scales (Beck Depression Inventory [BDI], Edinburgh Postnatal Depression Scale [EPDS], State-Trait Anxiety Inventory [STAI]), cognitive assessments (Mini-Mental State Examination [MMSE], Trails B, List Generation), and breastfeeding practices were surveyed at baseline and post-rTMS treatment. BDI and EPDS were obtained weekly, as well as 3 months and 6 months post-study conclusion. Average BDI, EPDS, and STAI scores declined over the 4-week duration of rTMS treatment. Of the 6 patients, 4 achieved remission as evaluated by EPDS, and 1 achieved remission while 2 responded as assessed by BDI. Mean BDI and EPDS scores at 3- and 6-month follow-ups remained below levels at study entry. There was no evidence of cognitive changes or breastfeeding disruptions. The authors concluded that rTMS was safe and well-tolerated among women, with evidence of sustained improvements in depression and anxiety scores. This study supported rTMS as a promising non-pharmacologic treatment modality for perinatal depression. However, this was an exploratory study with a small sample size (n = 6) and no sham control arm. Daily administration of rTMS provided potential for confounding of behavioral activation in the otherwise often isolative postpartum period.
Liu and associates (2020) systematically reviewed the safety and efficacy of rTMS for women with PPD. Several databases (WanFang, CNKI, VIP, CBM, PubMed, Embase, Cochrane Library, PsycINFO, Web of Science, and Clinical Trial) were searched from inception until April 12, 2020. A total of 10 randomized controlled trials (RCTs) met the eligibility criteria and were included in this systematic review. These investigators calculated the combined effect size (standardized mean difference [SMD] and odds ratio [OR]) for the corresponding effects models. The aggregated result of 10 trials indicated a significant benefit of rTMS on PPD, and the aggregated result of remission showed significantly positive effects of the test group versus the control group. In terms of treatment adverse effects, the aggregated result showed no statistical significance of headache and dry mouth between the two groups. The results of the meta-analysis suggested that rTMS was a safe and effective intervention for PPD. Moreover, these researchers stated that owing to poor methodological quality among the included studies, high-quality multi-center RCTs are needed to further verify the effects of this treatment.
Lee and colleagues (2021) noted that PPD is a common disorder with very high potential hazards for both the patients and their babies. The typical therapeutic options include antidepressants and electroconvulsive therapy (ECT); however, these approaches do not ensure the safety of the fetus. Recently, rTMS has emerged as a promising treatment for neuropathies as well as depression. Nevertheless, many studies excluded pregnant women. In a systematic review and meta-analysis, these researchers examined if rTMS was a suitable therapeutic option for women with PPD. They carried out a systematic review that followed the PRISMA guidelines. These investigators searched for studies in the Medline, PsycINFO, Embase, and Cochrane Library databases published until the end of September 2020. A total of 11 studies were selected for the systematic review, and 5 were selected for quantitative synthesis. Data analysis was performed using Comprehensive Meta-Analysis 3 software. The effect size was analyzed using the SMD, and the 95% confidence interval (CI) was determined by the generic inverse variance estimation method. The therapeutic effect size of rTMS for PPD was 1.394 (95% CI: 0.944 to 1.843), and the sensitivity analysis effect size was 1.074 (95% CI: 0.689 to 1.459), indicating a significant effect. The side effect size of rTMS for PPD was 0.346 (95% CI: 0.214 to 0.506), a meaningful result. There were no severe side effects reported for the mothers or fetuses. The authors concluded that from various perspectives, rTMS could be considered an alternative treatment for PPD to avoid exposure of fetuses to drugs and the severe side effects of ECT. Moreover, these researchers stated that further research is needed to increase confidence in these findings.
The authors stated that this meta-analysis had several drawbacks. The findings showed high heterogeneity, which may be due to methodological diversity because the parameters of rTMS varied from study to study, or heterogeneity due to coincidence because the analysis was conducted with small sample-sized studies. However, because the parameters varied according to the patient’s situation (e.g., the stimulation site changes according to symptoms and the frequency changes according to the stimulation site), it should be judged as clinical heterogeneity. The lack of patients and studies might also constrain these findings; therefore, the effects of rTMS on PPD should be interpreted with caution. They noted that future research should focus on the effects in the prenatal and infancy periods and establish parameters for rTMS, such as the site of stimulation or frequency.
Phantom Pain
Nardone and colleagues (2019) noted that several studies have applied TMS to examine the pathophysiological mechanisms of phantom-limb pain (PLP) and non-painful phantom sensations (PS). These researchers performed a systematic review of the available evidence of this emerging technology in this indication. They identified studies that reported reduced intra-cortical inhibition and increased intra-cortical facilitation in the hemisphere contralateral to the PLP; TMS mapping revealed a significant lateralization of the center of gravity and an enlargement of the excitable area in the hemisphere contralateral to the amputation. N-methyl-d-aspartate-mediated mechanisms influence the changes in intra-cortical inhibition and facilitation occurring after limb amputation; however, these cortical excitability changes and PLP were independent of each other. TMS could also influence brain function if applied repetitively. A few studies have begun to therapeutically use rTMS to relieve PLP and non-painful PS; rTMS of the contralateral parietal cortex resulted in a transient reduction in pain intensity, while high-frequency rTMS (HF-rTMS) applied over the contralateral motor cortex (M1) or low-frequency rTMS (LF-rTMS) over the unaffected hemisphere might also induce significant clinical improvement in PLP. On the other hand, serum beta-endorphin levels increased significantly after real stimulation over contralateral M1. The authors concluded that the findings of this systematic review showed that the TMS technique is an emerging tool to gain insights into the pathophysiological aspects of PLP and non-painful PS. These researchers stated that TMS could support appropriate patient selection for different therapies and may also have therapeutic utility in subjects with PLP or PS, although the evidence is still very preliminary, and well-designed studies in larger cohorts of patients are needed.
Knorst et al. (2024) stated that phantom limb pain (PLP) occurs following amputations and can persist in a chronic and debilitating way; rTMS is a non-invasive neuromodulation method capable of influencing brain function and modulating cortical excitability. Its effectiveness in treating chronic pain is promising. In a systematic review, these investigators examined the evidence on the safety and effectiveness of rTMS in the treatment of PLP, observing the stimulation parameters used, side effects, and benefits of the therapy. This review included scientific articles published in national and international literature using electronic platforms. A total of 252 articles were identified; 246 publications were removed because they were duplicates or met the exclusion criteria. After selection, 6 studies were reviewed—2 randomized clinical trials and 4 case reports. All evaluated studies indicated some degree of benefit of rTMS to relieve painful symptoms, even temporarily. Pain perception was lower at the end of treatment when compared to the period prior to the sessions and remained during patient follow-up. There was no standardization of the stimulation parameters used. There were no reports of serious adverse events (AEs), and the effects of long-term therapy have not been evaluated. The authors concluded that there were some benefits, even if temporary, in the use of rTMS to relieve painful symptoms in PLP. High-frequency stimulation at M1 showed a significant analgesic effect. Moreover, these researchers stated that given the potential that has been revealed, but limited by the paucity of high-quality studies, further controlled studies are needed to establish and standardize the clinical use of the method.
The authors stated that this study had several drawbacks. First, the number of studies that examined the use of rTMS in the management of PLP was very small. In the past 7 years, only 2 randomized clinical trials have been published. The additional data came from case reports or estimates based on other painful conditions. As is known, chronic pain is a broad and heterogeneous condition, being subdivided into several syndromes and sub-categories, and presenting different responses to treatment in each of them. Second, there was non-standardization between the studies regarding the modulation parameters used. Although high-frequency stimulation in M1 is widely used, other parameters such as intensity, number of induction and maintenance sessions, and number of pulses were usually not standardized. Such parameters are also extremely important for the effectiveness of the therapy. The results of the studies also did not allow conclusions regarding the long-term analgesic effect of rTMS, given that most studies only assessed the short-term response and did not perform follow-up over a longer period of time. It should be noted that studies also did not usually describe pharmacological and non-pharmacological therapies that were being used concomitantly with stimulation. The evaluation of these parameters is important, since in clinical practice, rTMS is not usually used as a single therapy in the treatment of painful processes but is associated with other therapies.
Progressive Supranuclear Palsy
In a double-blinded, sham-controlled, crossover study, Valero-Cabre and colleagues (2019) examined whether transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) could improve language capacities in patients with progressive supranuclear palsy (PSP). These researchers assessed the efficiency of tDCS over the DLPFC in a cohort of 12 patients with PSP. In 3 separate sessions, they evaluated the ability to boost the left DLPFC via left-anodal (excitatory) and right-cathodal (inhibitory) tDCS, while comparing them to sham tDCS. Tasks evaluating lexical access (letter fluency task) and semantic access (category judgment task) were applied immediately before and after the tDCS sessions to provide a marker of potential language modulation. The comparison with healthy controls showed that patients with PSP were impaired on both tasks at baseline. Contrasting post-stimulation versus pre-stimulation performance across tDCS conditions revealed language improvement in the category judgment task following right-cathodal tDCS, and in the letter fluency task following left-anodal tDCS. A computational finite element model of current distribution corroborated the intended effect of left-anodal and right-cathodal tDCS on the targeted DLPFC. The authors concluded that these findings demonstrated tDCS-driven language improvement in PSP. Level of Evidence = III. This was a proof-of-concept study. Moreover, these researchers stated that double-blinded and sham-controlled trials with multi-day tDCS regimens engaging enduring plasticity phenomena are needed to confirm therapeutically meaningful long-lasting effects in large PSP cohorts or in other prefrontal pathologies affecting language processing.
In an editorial that accompanied the aforementioned study by Valero-Cabre et al. (2019), Vanacore and Canevelli (2019) noted that the study was carried out in a sample that was likely poorly representative of real-world populations of patients with PSP. In particular, subjects were excluded if they were taking psychotropic medications or if they had major depression or cognitive impairment. These “ideal” conditions are hardly transferable to routine clinical practice and would limit the external validity of the findings. The generalizability of the study is also influenced by the marked heterogeneity of language profiles in the different PSP variants. In this regard, a detailed phenotyping of language abilities and disturbances in affected individuals could help to identify the best candidates for specific non-invasive brain stimulation protocols. Moreover, these editorialists noted that the study by Valero-Cabre et al. reaffirmed the difficulty of combining, especially in this experimental field, the lenses of statistical significance (i.e., how likely it is that any apparent between-group difference in outcome is real and not due to chance) and clinical significance (i.e., how large such a difference is in clinical practice) when interpreting the study findings. In fact, the clinical meaningfulness of the observed clinical benefits was not measured or discussed in the study and could only be inferred. In other words, was the 33% average improvement at the adopted letter fluency task clinically evident and relevant besides being statistically significant (and apparently important)? Along the same lines, how could researchers clinically judge the observed average increase of 3.9 points at the category judgment test? These questions assume special relevance considering that language assessment was based on experimental tasks lacking robust clinical validation. Vanacore and Canevelli were aware that investigators still faced proof-of-concept (or pre-therapeutic) evidence and that more detailed information on the clinical relevance of these interventions will surely be provided by future studies enrolling large cohorts of patients and investigating longer protocols. Nevertheless, they were convinced that, despite these drawbacks, these exploratory studies will increase interest and lead to additional exciting discoveries.
Restless Legs Syndrome
The American Academy of Neurology (AAN)’s practice guideline on “Treatment of restless legs syndrome” (Winkelman et al., 2016) stated that “rTMS is possibly effective in the treatment of primary moderate to severe RLS …. Cathodal and anodal transcranial direct current stimulation are probably ineffective for improving RLS symptoms in women with RLS who were drug-naive”. It stated that “When non-pharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C)”.
Schizo-Affective Disorder and Psychosis
Lajoie et al. (2021) stated that individuals with a psychotic disorder suffer from major cognitive impairments that prevent their functional recovery. Source memory (SM) impairments have been shown to be associated with psychotic symptoms and even to precede their onset; thus, SM has been hypothesized as a cognitive precursor of psychosis. However, few interventions targeting SM are included in current therapeutic approaches for early psychosis. In a systematic review, these investigators examined non-pharmacological interventions for early psychosis that have impacted SM processes. Studies were selected from 9 databases when they included a non-pharmacological intervention involving a sample of patients with early-onset psychotic disorder or sub-clinical psychotic symptoms, and effects on SM processes, measured directly or inferred via an episodic memory task. A total of 13 studies were identified, including 2 cognitive remediation programs and 1 rTMS treatment that reported beneficial effects on SM. The authors concluded that relevant intervention strategies for SM impairments were identified. This review highlighted a need to further develop interventions targeting theoretically defined SM concepts and examine their effects with specific and valid tasks. Recommendations regarding underlying mechanisms that could have a beneficial impact on SM may provide guidance for the future advent of early psychosis interventions.
The authors described a single case study that examined the effect of rTMS on cerebral processes. The rTMS was used in conjunction with functional magnetic resonance imaging (fMRI) guidance in an 11-year-old with severe early-onset psychosis. The stimulation was applied to the temporo-parietal junction (TPJ), a brain structure previously shown to be associated with SM. The right TPJ was stimulated for 5 days, followed by stimulation to the left TPJ for 5 additional days. Using 2 specific source monitoring tasks, the authors showed a significant decrease in internal and external source attribution errors following rTMS. In addition, a significant decrease in verbal hallucinations and normalization of neuronal activity levels were observed after treatment. These researchers stated that cognitive remediation of episodic memory using retrieval and meta-memory strategies and rTMS to the TPJ showed promising effects on SM functioning and need further investigation in patients with an early course of psychosis.
Hua et al. (2022) stated that cerebellar structural and functional abnormalities underlie widespread deficits in clinical, cognitive, and motor functioning that are observed in schizophrenia. Consequently, the cerebellum is a promising target for novel schizophrenia treatments. These researchers carried out an updated systematic review examining the literature on cerebellar stimulation effectiveness and tolerability for mitigating symptoms of schizophrenia. They discussed the purported mechanisms of cerebellar stimulation, current methods for implementing stimulation, and future directions of cerebellar stimulation for intervention development with this population. Two independent authors identified 20 published studies (7 RCTs, 7 open-label studies, 1 pilot study, 4 case reports, and 1 pre-clinical study) that described the effects of cerebellar circuitry modulation in patients with schizophrenia or animal models of psychosis. Published studies up to October 11, 2022, were identified from a search within PubMed, Scopus, and PsycInfo. Most studies stimulating the cerebellum used TMS or tDCS, specifically targeting the cerebellar vermis/midline. Accounting for levels of methodological rigor across studies, these studies detected post-cerebellar modulation in schizophrenia as indicated by the alleviation of certain clinical symptoms (mainly negative and depressive symptoms), as well as increased frontal-cerebellar connectivity and augmentation of canonical neuro-oscillations known to be abnormal in schizophrenia. In contrast to a prior review, these investigators did not find consistent evidence for cognitive improvements following cerebellar modulation stimulation. Modern cerebellar stimulation methods appeared tolerable for individuals with schizophrenia, with only mild and temporary side effects. The authors concluded that cerebellar stimulation is a promising intervention for individuals with schizophrenia that may be more relevant to some symptom domains than others. Initial results highlighted the need for continued research using more methodologically rigorous designs, such as additional longitudinal and randomized controlled trials.
Moreover, these researchers stated that it has also been argued that research linking clinical symptoms to neurobiological measures is hampered by research design obstacles, many of which were present across these studies. Notably, larger sample sizes with greater power are needed to establish the reliability of cerebellar stimulation effects. Most studies to date included fewer than 20 patients with schizophrenia. Alternatively, standardization across sites and studies would allow for the pooling of data. This point is made not only for the stimulation methods/parameters but also for the assessments, especially cognitive batteries (as there is more consistency in the clinical symptom inventories used). In addition, pre-clinical models of psychosis are needed to test mechanistic hypotheses of cerebellar stimulation. Furthermore, these investigators stated that additional research is needed to understand who will likely benefit from cerebellar stimulation. Many studies recruited individuals who were treatment-resistant or who had at least moderate symptoms; however, it is unclear if these individuals were more likely to benefit from treatment than those with fewer symptoms. Evaluating patients across the psychosis spectrum could aid in elucidating if less symptomatic individuals or those earlier in the illness course could similarly benefit from cerebellar stimulation.
Tang et al. (2023) noted that cognitive deficits in visuo-spatial learning (VSL) are highly associated with an increased risk of developing psychosis among individuals with clinical high-risk (CHR) for psychosis. Early interventions targeting VSL enhancement are needed in CHR but remain rudimentary. These investigators examined if personalized TMS over the left parieto-hippocampal network could improve VSL performance in CHR patients and if it could reduce the risk of psychosis conversion within 1 year. A total of 65 CHR patients were randomized to receive active or sham TMS treatments using an accelerated TMS protocol, consisting of 10 sessions of 20-Hz TMS treatments within 2 days. The TMS target was defined by individual parieto-hippocampal functional connectivity and precisely localized by individual structural magnetic resonance imaging (MRI). VSL performance was measured using the Brief Visuospatial Memory Test-Revised included in the measurement and treatment research to improve cognition in schizophrenia consensus cognitive battery (MCCB); 58 CHR patients completed the TMS treatments and MCCB assessments and were included in the data analysis. These researchers observed significant VSL improvements in the active TMS subgroup (Cohen's d = 0.71, p < 0.001) but not in the sham TMS subgroup (Cohen's d = 0.07, p = 0.70). Furthermore, active TMS improved the precision of VSL performance. At a 1-year follow-up, CHR patients who received active TMS showed a lower psychosis conversion rate than those who received sham TMS (6.7% versus 28.0%, χ² = 4.45, p = 0.03). The authors concluded that these findings showed that personalized TMS in the left parieto-hippocampal network may be a promising preventive intervention that improved VSL in CHR patients and reduced the risk of psychosis conversion at follow-up.
Walther et al. (2024) stated that psychomotor slowing is a frequent symptom of psychosis, impairing gross and fine motor behavior. It is associated with poor outcomes and functioning, and no treatment is available. In a 4-arm, randomized, double-blind, sham-controlled study, these researchers examined if 15 sessions of inhibitory rTMS would reduce psychomotor slowing. Enrollment of participants took place from March 2019 to August 2022. Adults aged 18 to 60 years with schizophrenia spectrum disorders and severe psychomotor slowing were eligible. All patients continued existing medications, including antipsychotics and benzodiazepines. Those with substance misuse (other than nicotine), conditions associated with impaired or aberrant movement, convulsions, a history of hearing problems, other conditions typically excluded from MRI or TMS, any TMS treatment in the past 3 months, or those who were pregnant or breastfeeding were excluded. Of 615 patients screened for eligibility, 103 were randomized, and 88 received at least 1 session of rTMS: 22 were assigned to 1-Hz rTMS, 22 to iTBS, 22 to sham, and 22 to the waiting group. Follow-up was carried out at 6 weeks and 24 weeks following the week 3 assessments, including clinical, functional, and motor measures. A total of 15 sessions of rTMS in 3 weeks over the supplementary motor area: 1-Hz rTMS, iTBS, sham, or no treatment (waiting). After 3 weeks, the waiting group received 15 sessions of 1-Hz rTMS over the supplementary motor area. The main outcome was the proportion of responders at week 3 in the Salpetriere Retardation Rating Scale (SRRS), defined as a 30% or greater reduction from baseline (last-observation-carried-forward). The SRRS has 15 items and a maximum total score of 60. Of the 88 participants analyzed, 45 were men and 43 were women. The mean (SD) age was 36.3 (12.4) years, and the mean (SD) SRRS score was 24.0 (5.9). A total of 69 participants completed the study. At week 3, response rates differed between groups: 15 of 22 (68%) in the 1-Hz rTMS group, 8 of 22 (36%) in the iTBS group, 7 of 22 (32%) in the sham group, and 4 of 22 (18%) in the waiting group (χ²₃ = 12.1; p = 0.007). The 1-Hz rTMS group had more responders than sham (OR, 0.13; 95% CI: 0.02 to 0.65; p = 0.03), iTBS (OR, 0.12; 95% CI: 0.02 to 0.61; p = 0.02), and waiting (OR, 0.04; 95% CI: 0.01 to 0.22; p = 0.003). In the waiting group, 10 of 16 participants (63%) responded after receiving 15 sessions of 1-Hz rTMS. No serious adverse events occurred. The authors concluded that in this study, inhibitory add-on rTMS safely alleviated psychomotor slowing in psychosis compared with iTBS, sham, and no treatment; the treatment was also effective with delayed onset. Moreover, these researchers stated that future, larger studies are needed to examine the neural changes associated with supplementary motor area rTMS in psychosis.
The authors stated that the use of a 4-arm parallel design allowed these investigators to test multiple stimulation types for psychomotor slowing in psychosis, especially the inclusion of a waiting group in addition to sham offered valuable insights. However, several drawbacks require consideration when interpreting these findings. First, the choice of 2 primary outcomes was made during clinical trial registration and was a deviation from the study protocol. Second, blinding was challenging in rTMS trials. Duration, machinery, and setup were identical across study arms. Most subjects were unable to identify the rTMS protocol received at week 3; however, the waiting group was aware of their treatment regimen. Third, randomization was performed before baseline assessments; thus, the intention-to-treat (ITT) population included all patients with at least 1 rTMS session. This was in line with rTMS studies in psychiatry but slightly different from drug trials. Results might indicate greater effects than analyses including individuals who had never received the assigned treatment. Fourth, randomization skewed the distribution of medication regimens and sex between the 4 groups; thus, these variables were included as covariates. Fifth, the sample size was calculated for the continuous primary outcomes and fell short in achieving sufficient power for the secondary outcomes. Sixth, randomization also resulted in some variance in the levels of catatonia severity, suggesting floor effects of the treatment in some groups. Seventh, 14 subjects (16% of the ITT population) dropped out in the first 3 weeks, which was comparable to other trials. Last observation carried forward analysis accounted for dropouts.
Schizophrenia
Freitas and colleagues (2009) performed meta-analyses of all prospective studies on the therapeutic application of rTMS in refractory schizophrenia, assessing the effects of high-frequency rTMS to the left dorsolateral prefrontal cortex (DLPFC) to treat negative symptoms, and low-frequency rTMS to the left temporo-parietal cortex (TPC) to treat auditory hallucinations (AH) and overall positive symptoms. When analyzing controlled (active arms) and uncontrolled studies together, the effect sizes showed significant and moderate effects of rTMS on negative and positive symptoms (based on PANSS-N or SANS, and PANSS-P or SAPS, respectively). However, the analysis for the sham-controlled studies revealed a small non-significant effect size for negative symptoms (0.27, p = 0.417) and for positive symptoms (0.17, p = 0.129). When specifically analyzing AH (based on AHRS, HCS, or SAH), the effect size for the sham-controlled studies was large and significant (1.04; p = 0.002). The authors concluded that these meta-analyses support the need for further controlled, larger trials to assess the clinical efficacy of rTMS on negative and positive symptoms of schizophrenia, while suggesting the need for exploration of alternative stimulation protocols.
An assessment by the Health Council of the Netherlands (2008) stated that studies of rTMS for hallucinations in schizophrenic patients are both fewer in number and more restricted in scope than in the case of depression.
Slotema et al. (2012) provided an update of the literature on the efficacy of rTMS for auditory verbal hallucinations (AVH) and investigated the effect of rTMS 1 month after the end of treatment. A literature search was performed from 1966 through August 2012 using the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Embase Psychiatry, Ovid Medline, PsycINFO, and PubMed. Randomized, double-blind, sham-controlled studies with severity of AVH or severity of psychosis as an outcome measure were included. Data were obtained from 17 randomized studies of rTMS for AVH; 5 studies fulfilled the criteria for the meta-analysis on the effect of rTMS 1 month after the end of treatment. Standardized mean weighted effect sizes of rTMS versus sham were computed on pre- and post-treatment comparisons. The mean weighted effect size of rTMS directed at the left temporo-parietal area was 0.44 (95% CI: 0.19 to 0.68). A separate meta-analysis including studies directing rTMS at other brain regions revealed a mean weighted effect size of 0.33 (95% CI: 0.17 to 0.50) in favor of real TMS. The effect of rTMS was no longer significant at 1 month of follow-up (mean weighted effect size = 0.40, 95% CI: -0.23 to 0.102). Side effects were mild, and the number of dropouts in the real TMS group was not significantly higher than in the sham group. The authors concluded that with the inclusion of studies with larger patient samples, the mean weighted effect size of rTMS directed at the left temporo-parietal area for AVH has decreased, although the effect is still significant. The duration of the effect of rTMS may be less than 1 month. Moreover, they stated that more research is needed in order to optimize parameters and further evaluate the clinical relevance of this intervention.
Smell and Taste Disorders
Henkin et al. (2011) evaluated the effectiveness of rTMS treatment in patients with phantosmia and phantageusia. A total of 17 patients with symptoms of persistent phantosmia and phantageusia with accompanying loss of smell and taste acuity were studied. Before and after treatment, patients were monitored by subjective responses and with psychophysical tests of smell function (olfactometry) and taste function (gustometry). Each patient was treated with rTMS that consisted of 2 sham procedures followed by a real rTMS procedure. After sham rTMS, no change in measurements of distortions or acuity occurred in any patient; after initial real rTMS, 2 patients received no benefit; but in the other 15, distortions decreased and acuity increased. Two of these 15 exhibited total inhibition of distortions and return of normal sensory acuity that persisted for over 5 years of follow-up. In the other 13, inhibition of distortions and improvement in sensory acuity gradually decreased; but repeated rTMS again inhibited their distortions and improved their acuity. Eighty-eight percent of patients responded to this therapeutic method, although repeated rTMS was necessary to induce these positive changes. The authors concluded that these results suggested that rTMS is a potential future therapeutic option to treat patients with the relatively common problems of persistent phantosmia and phantageusia with accompanying loss of taste and smell acuity. Moreover, they stated that additional systematic studies are necessary to confirm these results.
Smoking Cessation / Tobacco Use Disorder
Young et al. (2024) noted that tobacco-related deaths remain the leading cause of preventable death in the U.S. Veterans suffering from PTSD—approximately 11% of those receiving care from the Department of Veterans Affairs (VA)—have three times the risk of developing tobacco use disorder (TUD). The most effective strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate; thus, there is a need to develop more effective treatments for smoking cessation. Recent studies suggested that the insula is integrally involved in the neurocircuitry of TUD. These researchers proposed a feasibility phase-II randomized controlled trial (RCT) to study a form of rTMS called iTBS, which has the advantage of allowing for a patterned form of stimulation delivery that these investigators will administer at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. They hypothesized that by increasing functional connectivity between the right post-central gyrus and the right posterior insula, withdrawal symptoms and short-term smoking cessation outcomes will improve. A total of 50 eligible veterans with co-morbid TUD and PTSD will be randomly assigned to active iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n = 25) or sham iTBS + CBT + NRT (n = 25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and a retention rate of 80%. The success of iTBS will be examined via self-reported nicotine use, cravings, withdrawal symptoms, as well as abstinence following the quit date (confirmed by bio-verification), along with evaluation for target engagement via neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.
Iannuzzo et al. (2024) stated that non-invasive brain stimulation (NIBS) techniques appeared to be effective in treating tobacco use disorder (TUD). In a systematic review, these investigators examined what kinds of protocols are used to treat nicotine addiction in terms of cessation and/or reduction and assessed the long-term effectiveness of NIBS techniques. They searched PubMed, Scopus, and Web of Science for studies published, using combinations of the following search terms: "Non-invasive brain stimulation OR TMS OR transcranial magnetic stimulation OR tDCS OR transcranial direct current stimulation OR transcranial electrical stimulation OR TES AND Nicotine addiction." These researchers carried out a preliminary search, which showed papers on the topic. Articles were included in the review according to the following inclusion criteria: English language, publication in peer-reviewed journals, articles about studies performed on NIBS techniques, and RCT studies. Studies involving clinical populations with organic or psychiatric diseases were excluded. The authors found 280 studies. Of these, at the first screening conducted by title and abstract, 63 studies were excluded after duplicates were removed. After the second screening conducted by full-text examination, 45 articles were excluded. A total of 10 studies met the inclusion criteria and were included in the review. The clinical benefits of NIBS, including the fast onset and minor side effects, showed that this kind of treatment could be helpful in patients with a long history of smoking in terms of cessation and abstinence rates. These researchers stated that the clinical application of neuromodulation techniques in nicotine addiction is a promising field of study that needs further investigation.
The authors stated that this study had several drawbacks. Despite an effective search strategy for research, few studies were included. This may be explained by the relative novelty of the topic, as further investigations are needed to determine the effects of NIBS on smoking and tobacco addiction. Most of the included studies have small sample sizes (only 3 studies counted more than 100 patients). Among studies, the risk of bias was relatively high; thus, the overall quality of the presented studies resulted low. In general, studies were affected by great heterogeneity, not only in terms of NIBS protocols used (treatment duration, stimulation site and parameters employed, use of cue provocation) but also in terms of baseline severity of smoking, outcome evaluation, and duration of follow-up period. The major source of heterogeneity among treatment protocols regarded rTMS protocols, particularly the choice of stimulation frequency (ranging between 10 and 20 Hz for high-frequency protocols), the number of pulses, and the stimulation intensity, expressed in terms of percentage of resting motor threshold (RMT). Heterogeneity in baseline severity was also particularly relevant for study protocols employing cue provocation, which has been shown to have different effects on high-dependent versus low-dependent smokers. Lastly, only a few studies used smoking cessation as a primary outcome, while most of the investigations examined effectiveness in terms of surrogate endpoint measures such as reduction of cigarette intake or decrease in measures of craving and addiction. Taken together, these drawbacks may reduce the interpretability of results; in general, care is recommended as further rigorous and high-quality investigations are needed to ascertain the effectiveness of NIBS techniques in reducing smoke-related behavior.
The authors noted that NIBS techniques "seem to be safe and well-tolerated compared with other possible treatments." The analyzed studies show that smoking reduction outcomes are better than the sham treatment and comparable to other interventions such as bupropion.
Solano (2025) noted that electronic cigarettes (e-cigarettes) are the most commonly used tobacco product by adolescents. This article described the harmful effects of e-cigarette use in adolescents and how to assess the severity of nicotine dependence. It also provided an overview of treatment approaches, including behavioral interventions, contingency interventions, pharmacotherapies, school-based programs, combination and emerging approaches, and TMS. Moreover, the author stated that TMS is not indicated for adolescent smoking cessation but is indicated for treating adolescent depression and has shown some benefit in younger patients with major depressive disorder and those with severe depression.
Li et al. (2025) stated that rTMS is a non-invasive brain stimulation method that has been increasingly used to treat psychiatric disorders, including TUD; however, the neural mechanisms underlying the effects of rTMS remain unclear. These investigators evaluated the effectiveness of rTMS in smoking cessation and examined the underlying neural mechanism of the treatment effect. In Experiment 1, these researchers recruited 60 participants who smoked cigarettes and 60 healthy controls (HC) and used their baseline cerebral blood flow (CBF) measured by arterial spin labeling perfusion to determine the group-level difference in CBF. In Experiment 2, these investigators used the left dorsolateral prefrontal cortex (DLPFC) as the target for subsequent 5-day rTMS treatment at a frequency of 10 Hz with 2,000 pulses to observe the impact of rTMS on CBF, Fagerstrom test for nicotine dependence scores, and Tiffney questionnaire on smoking urges scores. In Experiment 3, these researchers measured functional connectivity to monitor the functional changes induced by rTMS and assessed their associations with smoking cravings and nicotine dependence scores. In Experiment 1, participants who smoked cigarettes presented significantly higher CBF in the left DLPFC and bilateral anterior cingulate cortex than HC. In Experiment 2, rTMS significantly decreased CBF in the DLPFC and reduced Fagerstrom test for nicotine dependence scores and Tiffney questionnaire on smoking urges scores. In Experiment 3, rTMS increased functional connectivity between the left DLPFC and the bilateral superior frontal gyrus, right DLPFC, bilateral precuneus, and bilateral para-hippocampus in participants who smoked cigarettes. The authors concluded that rTMS of the left DLPFC has the potential to serve as an effective tool for smoking cessation. Furthermore, CBF could serve as a valuable means of quantifying treatment effects.
The authors stated that this trial had several limitations. First, females who smoke cigarettes were not examined in the study. In China, the prevalence of females who smoke cigarettes is less than 1%, and most of them prefer to conceal their smoking status because of social stigmas. Therefore, further studies should examine the effect of rTMS on females who smoke cigarettes. Second, the relatively small sample size in Experiments 2 and 3 was mainly attributed to the long treatment cycle, resulting in the loss of participants. Third, due to the necessary safety checks and preparation before the MRI scan, a 1-hour gap existed between the participants’ last cigarette and the scan. The potential impact of this brief abstinence on brain activity remains unknown. Moreover, these researchers stated that future studies could examine this process in greater depth.
Spasticity
Centonze and associates (2007) examined if investigate rTMS can modify spasticity. These researchers used high-frequency (5 Hz) and low-frequency (1 Hz) rTMS protocols in 19 remitting patients with relapsing-remitting multiple sclerosis and lower limb spasticity. A single session of 1 Hz rTMS over the leg primary motor cortex increased H/M amplitude ratio of the soleus H reflex, a reliable neurophysiologic measure of stretch reflex. Five hertz rTMS decreased H/M amplitude ratio of the soleus H reflex and increased cortico-spinal excitability. Single sessions did not induce any effect on spasticity. A significant improvement of lower limb spasticity was observed when rTMS applications were repeated during a 2-week period. Clinical improvement was long-lasting (at least 7 days after the end of treatment) when patients underwent 5 Hz rTMS treatment during a 2-week protocol. No effect was obtained after a 2-week sham stimulation. The authors concluded that rTMS may improve spasticity in multiple sclerosis. The findings of this study need to be validated by prospective RCTs with larger patient numbers.
Spinal Cord Injury
Awad et al. (2015) reviewed the basic principles and techniques of TMS and provided information and evidence regarding its applications in spinal cord injury (SCI) clinical rehabilitation. A review of the available current and historical literature regarding TMS was conducted, and a discussion of its potential use in SCI rehabilitation is presented. Transcranial magnetic stimulation provides reliable information about the functional integrity and conduction properties of the cortico-spinal tracts and motor control in the diagnostic and prognostic assessment of various neurological disorders. It allows one to follow the evolution of motor control and to evaluate the effects of different therapeutic procedures. Motor-evoked potentials can be useful in the follow-up evaluation of motor function during treatment and rehabilitation, specifically in patients with SCI and stroke. Although studies regarding somato-motor functional recovery after SCI have shown promise, more trials are needed to provide strong and substantial evidence. The authors concluded that TMS is a promising non-invasive tool for the treatment of spasticity, neuropathic pain, and somato-motor deficits after SCI. They stated that further investigation is needed to demonstrate whether different protocols and applications of stimulation, as well as alternative cortical sites of stimulation, may induce more pronounced and beneficial clinical effects.
Nardone and colleagues (2014) reviewed the literature on brain neurostimulation techniques in patients with chronic neuropathic pain due to traumatic SCI and evaluated the current evidence for their effectiveness. A MEDLINE search was performed using the following terms: "spinal cord injury," "neuropathic pain," "brain stimulation," "deep brain stimulation" (DBS), "motor cortex stimulation" (MCS), "transcranial magnetic stimulation" (TMS), "transcranial direct current stimulation" (tDCS), and "cranial electrotherapy stimulation" (CES). Invasive neurostimulation therapies, in particular DBS and epidural MCS, have shown promise as treatments for neuropathic and phantom limb pain. However, the long-term effectiveness of DBS is low, while MCS has a relatively higher potential with fewer complications than DBS. Among the non-invasive techniques, there is accumulating evidence that repetitive TMS can produce analgesic effects in healthy subjects undergoing laboratory-induced pain and in chronic pain conditions of various etiologies, at least partially and transiently. Another very safe technique of non-invasive brain stimulation—tDCS—applied over the sensory-motor cortex has been reported to decrease pain sensation and increase pain threshold in healthy subjects. Cranial electrotherapy stimulation has also proved to be effective in managing some types of pain, including neuropathic pain in subjects with SCI. The authors concluded that a number of studies have begun to use non-invasive neuromodulatory techniques therapeutically to relieve neuropathic pain and phantom phenomena in patients with SCI. Moreover, they stated that further studies are needed to corroborate the early findings and confirm different targets and stimulation paradigms. The utility of these protocols in combination with pharmacological approaches should also be explored.
Moreno-Duarte et al. (2014) reviewed initial safety, effectiveness, and potential predictors of response by assessing the effects of neural stimulation techniques to treat SCI pain. A literature search was performed using the PubMed database, including studies using the following targeted stimulation strategies: tDCS, high-definition tDCS (HD-tDCS), rTMS, CES, transcutaneous electrical nerve stimulation (TENS), spinal cord stimulation (SCS), and MCS, published prior to June of 2012. These investigators included studies from 1998 to 2012. A total of 8 clinical trials and 1 naturalistic observational study met the inclusion criteria. Among the clinical trials, 3 studies assessed the effects of tDCS, 2 of CES, 2 of rTMS, and 1 of TENS. The naturalistic study investigated the analgesic effects of SCS. No clinical trials for epidural MCS or HD-tDCS were found. Parameters of stimulation and clinical characteristics varied significantly across studies. Three out of 8 studies showed larger effect sizes (0.73, 0.88, and 1.86, respectively) for pain reduction. Classical neuropathic pain symptoms such as dysesthesia (defined as an unpleasant burning sensation in response to touch), allodynia (pain due to a non-painful stimulus), pain in paroxysms, location of SCI in thoracic and lumbar segments, and pain in the lower limbs seem to be associated with a positive response to neural stimulation. No significant adverse effects were reported in these studies. The authors concluded that chronic pain in SCI is disabling and resistant to common pharmacologic approaches. Electrical and magnetic neural stimulation techniques have been developed to offer a potential tool in the management of these patients. Although some of these techniques are associated with large standardized mean differences to reduce pain, the authors found important variability in these results across studies. They stated that there is a clear need for the development of methods to decrease treatment variability and increase response to neural stimulation for pain treatment.
Gao and colleagues (2017) noted that the evidence regarding the effectiveness of rTMS on the relief of neuropathic pain (NP) in patients with prior SCI is controversial. In a meta-analysis, these researchers evaluated the effectiveness of rTMS in pain relief in patients suffering from SCI-associated NP. Medline, PubMed, Cochrane, Embase, and Google Scholar databases were searched for clinical studies on the effects of rTMS treatment on NP caused by prior SCI published before March 14, 2016, with various combinations of the following keywords: transcranial magnetic stimulation, spinal injury, and pain. Standardized difference in means with 95% CI was calculated for the change of pain scores after rTMS or sham rTMS treatments. A total of 2 RCTs and 4 crossover RCTs were included for the meta-analysis. The RCTs recruited a total of 27 patients. The crossover RCTs recruited a total of 100 patients. The combined standardized difference in means indicated that patients who received rTMS intervention had better pain relief than those who received sham rTMS intervention; however, the results did not reach statistical significance (standardized difference in means = -0.607, 95% CI: -1.29 to 0.075, p = 0.081). The authors concluded that rTMS might reduce SCI-associated neuropathic pain; however, further studies are needed to support this conclusion.
In a systematic review, Saleh and colleagues (2022) examined the effectiveness of rTMS in neuropathic pain secondary to SCI. These researchers carried out a systematic review using the PubMed/Medline, Embase, and PsycInfo (via OVID) databases up to April 2021; only RCTs were included. Results regarding the pain intensity scores were pooled using a random-effects model. The search identified a total of 203 potential articles. Of these, 8 RCTs met the eligibility criteria for qualitative synthesis, providing the total data of 141 patients. All studies employed high-frequency rTMS. In 7 studies, rTMS was applied over the motor cortex, and in 1 study over the left dorsolateral prefrontal cortex; 5 studies reported a significant improvement in baseline pain scores after treatment, and 3 studies found a significant difference between sham versus non-sham stimulation at any time. Six RCTs were included in the quantitative synthesis and showed a significant overall reduction of pain intensity in the rTMS groups compared with the sham groups (MD -0.81, 95% CI: -1.45 to -0.17). The authors concluded that these findings indicated that high-frequency rTMS of the primary motor cortex and left dorsolateral prefrontal cortex might be promising stimulation targets for neuropathic pain in SCI.
Stroke
Khedr et al. (2009a) examined the therapeutic effect of rTMS on post-stroke dysphagia. A total of 26 patients with post-stroke dysphagia due to mono-hemispheric stroke were randomly allocated to receive real (n = 14) or sham (n = 12) rTMS of the affected motor cortex. Each patient received a total of 300 rTMS pulses at an intensity of 120% hand motor threshold for 5 consecutive days. Clinical ratings of dysphagia and motor disability were assessed before and immediately after the last session and then again after 1 and 2 months. The amplitude of the motor-evoked potential (MEP) evoked by single-pulse TMS was also assessed before and at 1 month in 16 of the patients. There were no significant differences between patients who received real rTMS and the sham group in age, hand grip strength, Barthel Index, or degree of dysphagia at the baseline assessment. Real rTMS led to a significantly greater improvement compared with sham in dysphagia and motor disability that was maintained over 2 months of follow-up. This was accompanied by a significant increase in the amplitude of the esophageal MEP evoked from either the stroke or non-stroke hemisphere. The authors concluded that rTMS may be a useful adjunct to conventional therapy for dysphagia after stroke. These findings need to be validated by well-designed studies.
Regarding the use of rTMS in stroke, the Health Council of the Netherlands (2008) found that few articles have been published on this topic, and that this limited amount of published data reveals only short-term, marginal improvements.
Avenanti et al. (2012) examined the long-term behavioral and neurophysiologic effects of combined time-locked rTMS and physical therapy (PT) intervention in chronic stroke patients with mild motor disabilities. A total of 30 patients were enrolled in a double-blind, randomized, single-center clinical trial. Patients received 10 daily sessions of 1 Hz rTMS over the intact motor cortex. In different groups, stimulation was either real (rTMS(R)) or sham (rTMS(S)) and was administered either immediately before or after PT. Outcome measures included dexterity, force, inter-hemispheric inhibition, and corticospinal excitability and were assessed for 3 months after the end of treatment. Treatment induced cumulative rebalance of excitability in the 2 hemispheres and a reduction of inter-hemispheric inhibition in the rTMS(R) groups. Use-dependent improvements were detected in all groups. Improvements in trained abilities were small and transitory in rTMS(S) patients. Greater behavioral and neurophysiologic outcomes were found after rTMS(R), with the group receiving rTMS(R) before PT (rTMS(R)-PT) showing robust and stable improvements and the other group (PT-rTMS(R)) showing a slight improvement decline over time. The authors concluded that these findings indicated that priming PT with inhibitory rTMS is optimal to boost use-dependent plasticity and rebalance motor excitability and suggest that time-locked rTMS is a valid and promising approach for chronic stroke patients with mild motor impairment. Furthermore, the authors stated that "[f]urther studies are needed to evaluate the effect of intervention order of time-locked rTMS in the same patients. Moreover, future studies should assess whether the present findings can be extended to stroke patients with moderate to severe motor impairments."
Corti et al. (2012) stated that conceptually, rTMS could be used therapeutically to restore the balance of inter-hemispheric inhibition after stroke. Repetitive TMS has been used in 2 ways: low-frequency stimulation (less than or equal to 1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or high-frequency stimulation (greater than 1 Hz) to the motor cortex of the affected hemisphere (AH) to increase excitability of the ipsilesional hemisphere. These investigators reviewed evidence regarding the safety and effectiveness of high-frequency rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. The findings of this review suggested that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. The authors concluded that although the studies included in this review provided important information, double-blinded, sham-controlled phase II and phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.
In a comparative case study, Plow et al. (2011) attempted to standardize a protocol for promoting visual rehabilitative outcomes in post-stroke hemianopia by combining occipital cortical tDCS with vision restoration therapy (VRT). Two patients, both with right hemianopia after occipital stroke damage, were included in this study. Both patients underwent an identical VRT protocol that lasted 3 months (30 mins, twice-daily, 3 days/week). In patient 1, anodal tDCS was delivered to the occipital cortex during VRT training, whereas in patient 2, sham tDCS with VRT was performed. The primary outcome, visual field border, was defined objectively by using high-resolution perimetry. Secondary outcomes included subjective characterization of visual deficit and functional surveys that assessed performance on activities of daily living. For patient 1, the neural correlates of visual recovery were also investigated by using functional magnetic resonance imaging. Delivery of combined tDCS with VRT was feasible and safe. High-resolution perimetry revealed a greater shift in visual field border for patient 1 versus patient 2. Patient 1 also showed greater recovery of function in activities of daily living. Contrary to expectations, patient 2 perceived greater subjective improvement in visual field despite objective high-resolution perimetry results that indicated otherwise. In patient 1, visual function recovery was associated with functional magnetic resonance imaging activity in surviving peri-lesional and bilateral higher-order visual areas. The authors concluded that these findings of preliminary case comparisons suggested that occipital cortical tDCS may enhance recovery of visual function associated with concurrent VRT through visual cortical re-organization. They stated that future studies may benefit from incorporating protocol refinements such as those described here, which include global capture of function, control for potential confounds, and investigation of underlying neural substrates of recovery.
Szaflarsk et al. (2011) stated that aphasia affects 1/3 of stroke patients, with improvements noted only in some of them. The goal of this exploratory study was to provide preliminary evidence regarding the safety and effectiveness of functional magnetic resonance imaging (fMRI)-guided excitatory rTMS applied to the residual left-hemispheric Broca's area for chronic aphasia treatment. These researchers enrolled 8 patients with moderate or severe aphasia of more than 1 year after left middle cerebral artery stroke. A linguistic battery was administered pre-/post-rTMS; a semantic decision/tone decision (SDTD) fMRI task was used to localize left-hemispheric Broca's area. The repetitive TMS protocol consisted of 10 daily treatments of 200 seconds each using an excitatory stimulation protocol called intermittent theta burst stimulation (iTBS). Coil placement was targeted individually to the left Broca's area. A total of 6 patients showed significant pre-/post-rTMS improvements in semantic fluency (p = 0.028); they were able to generate more appropriate words when prompted with a semantic category. Pre-/post-rTMS fMRI maps showed increases in left fronto-temporo-parietal language networks with a significant left-hemispheric shift in the left frontal (p = 0.025), left temporo-parietal (p = 0.038) regions, and global language LI (p = 0.018). Patients tended to report subjective improvement on the Communicative Activities Log (mini-CAL; p = 0.075). None of the subjects reported ill effects of rTMS. The authors concluded that fMRI-guided, excitatory rTMS applied to the affected Broca's area improved language skills in patients with chronic post-stroke aphasia; these improvements correlated with increased language lateralization to the left hemisphere. They stated that this rTMS protocol appears to be safe and should be further tested in blinded studies assessing its short- and long-term safety/effectiveness for post-stroke aphasia rehabilitation.
Kakuda et al. (2012a) stated that both low-frequency rTMS (LF-rTMS) and intensive occupational therapy (OT) have been recently reported to be clinically beneficial for post-stroke patients with upper limb hemiparesis. Based on these reports, these researchers developed an inpatient combination protocol of these 2 modalities for the treatment of such patients. In a pilot study, these investigators examined the safety and feasibility of the protocol in a large number of patients from different institutions and identified predictors of the clinical response to the treatment. The study subjects were 204 post-stroke patients with upper limb hemiparesis (mean age at admission of 58.5 ± 13.4 years, mean time after stroke of 5.0 ± 4.5 years, ± SD) from 5 institutions in Japan. During a 15-day hospitalization, each patient received 22 treatment sessions of 20-min LF-rTMS and 120-min intensive OT daily. Low-frequency rTMS of 1 Hz was applied to the contralesional hemisphere over the primary motor area. The intensive OT, consisting of 60-min 1-on-1 training and 60-min self-exercise, was provided after the application of LF-rTMS. Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT) were performed serially. The physiatrists and occupational therapists involved in this study received training prior to the study to standardize the therapeutic protocol. All patients completed the protocol without any adverse effects. The FMA score increased, and WMFT log performance time decreased significantly at discharge, relative to the respective values at admission (change in FMA score: median at admission, 47 points; median at discharge, 51 points; p < 0.001; change in WMFT log performance time: median at admission, 3.23; median at discharge, 2.51; p < 0.001). These changes were persistently seen up to 4 weeks after discharge in 79 patients. Linear regression analysis found no significant relationship between baseline parameters and indexes of improvement in motor function. The authors concluded that the 15-day inpatient rTMS plus OT protocol is a safe, feasible, and clinically useful neuro-rehabilitative intervention for post-stroke patients with upper limb hemiparesis. The response to the treatment was not influenced by age or time after stroke onset. They stated that the effectiveness of the intervention should be confirmed in a randomized controlled study including a control group.
Kakuda et al. (2012b) noted that for spastic upper limb hemiparesis after stroke, they developed a triple-element protocol of botulinum toxin type A (BoNTA) injection, LF-rTMS, and intensive OT. These researchers investigated the safety and feasibility of the protocol. A total of 14 post-stroke patients with spastic upper limb hemiparesis (mean age of 54.9 ± 9.2 years, time after onset: 87.1 ± 48.2 months, ± SD) were included in this study. In all patients, BoNTA was injected into spastic muscles of the affected upper limb (maximum total dose: 240 units). Four weeks later, they were hospitalized to receive 22 sessions of 20-min LF-rTMS and 120-min intensive OT daily over 15 days. Motor function of the affected upper limb was evaluated mainly using FMA, WMFT, motor activity log (MAL), and the severity of spasticity was measured with the modified Ashworth scale (MAS) at BoNTA injection, discharge, and 4 weeks post-discharge. All patients completed the protocol without any adverse effects. The FMA score and MAL scores, but not WMFT performance time, improved significantly at discharge. The MAS score of all examined muscles decreased significantly between BoNTA and discharge. The beneficial effect of the protocol on motor function and spasticity was almost maintained until 4 weeks after discharge. The authors concluded that the protocol is safe and feasible, although further larger studies are needed to confirm its effectiveness.
Ayache et al. (2012) stated that non-invasive cortical stimulation (NICS) has been used during the acute, post-acute, and chronic post-stroke phases to improve motor recovery in stroke patients having upper- and/or lower-limb paresis. These investigators reviewed the rationale for using the different NICS modalities to promote motor stroke rehabilitation. A number of open and placebo-controlled trials have investigated the clinical effect of rTMS or tDCS of the primary motor cortex in patients with motor stroke. These studies attempted to improve motor performance by increasing cortical excitability in the stroke-affected hemisphere (via HF-rTMS or anodal tDCS) or by decreasing cortical excitability in the contralateral hemisphere (via LF-rTMS or cathodal tDCS). The goal of these studies was to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and to then restore a normal balance of inter-hemispheric inhibition. All these NICS techniques administered alone or in combination with various methods of neuro-rehabilitation were found to be safe and equally effective in the short term on various aspects of post-stroke motor abilities. However, they stated that the long-term effect of NICS on motor stroke needs to be further evaluated before considering the use of such a technique in the daily routine management of stroke.
Corti et al. (2012) stated that rTMS is known to modulate cortical excitability and has thus been suggested to be a therapeutic approach for improving the efficacy of rehabilitation for motor recovery after stroke. In addition to producing effects on cortical excitability, stroke may affect the balance of trans-callosal inhibitory pathways between motor primary areas in both hemispheres: the affected hemisphere (AH) may be disrupted not only by the infarct itself but also by the resulting asymmetric inhibition from the unaffected hemisphere, further reducing the excitability of the AH. Conceptually, therefore, rTMS could be used therapeutically to restore the balance of inter-hemispheric inhibition after stroke. Repetitive TMS has been used in 2 ways: LF stimulation (less than or equal to 1 Hz) to the motor cortex of the unaffected hemisphere to reduce the excitability of the contralesional hemisphere or HF stimulation (greater than 1 Hz) to the motor cortex of the AH to increase excitability of the ipsilesional hemisphere. These researchers collated evidence regarding the safety and efficacy of HF-rTMS to the motor cortex of the AH. The studies included investigated the concurrent effects of rTMS on the excitability of corticospinal pathways and upper-limb motor function in adults after stroke. The findings of this review suggested that rTMS applied to the AH is a safe technique and could be considered an effective approach for modulating brain function and contributing to motor recovery after stroke. The authors concluded that although the studies included in this review provided important information, double-blinded, sham-controlled phase II and phase III clinical trials with larger sample sizes are needed to validate this novel therapeutic approach.
In an evidence-based review, Wong and Tsang (2013) reported an updated evaluation and critical appraisal of available studies that investigated the effectiveness of rTMS on post-stroke aphasia rehabilitation. A literature search was performed to identify studies that investigated the therapeutic effects of rTMS on post-stroke aphasia in various electronic databases, from their inception to 2011. The selected studies were classified according to the types of participants, types of interventions, outcome measures, and results. The methodological qualities of the selected studies were evaluated using the Physiotherapy Evidence Database scale. The current review was based on 12 studies, including open-label designs and controlled trials, which showed a positive effect of rTMS, with or without conventional rehabilitation, on post-stroke aphasia compared with sham or conventional rehabilitation alone. About 41% of the selected studies reported the long-term effect of rTMS on aphasia recovery. No adverse effects were reported. The authors concluded that the current review revealed that rTMS with or without conventional rehabilitation has positive effects on post-stroke aphasia. The studies also contributed to the plausible mechanisms of stroke recovery. However, they stated that with the concerns over the methodology of the selected studies in this review, a larger-scale, multi-center, well-designed RCT involving different phases and types of aphasia needs to be carried out before recommending rTMS as a complementary treatment for post-stroke aphasia.
In a meta-analysis, Hsu et al. (2012) investigated the effects of rTMS on upper limb motor function in patients with stroke. These investigators searched for RCTs published between January 1990 and October 2011 in PubMed, Medline, Cochrane, and CINAHL using the following key words: stroke, cerebrovascular accident, and repetitive transcranial magnetic stimulation. The mean effect size and a 95% CI were estimated for the motor outcome and motor threshold using fixed and random effect models. Eighteen of the 34 candidate articles were included in this analysis. The selected studies involved a total of 392 patients. A significant effect size of 0.55 was found for motor outcome (95% CI: 0.37 to 0.72). Further subgroup analyses demonstrated more prominent effects for subcortical stroke (mean effect size, 0.73; 95% CI: 0.44 to 1.02) or studies applying low-frequency rTMS (mean effect size, 0.69; 95% CI: 0.42 to 0.95). Only 4 patients of the 18 articles included in this analysis reported adverse effects from rTMS. The authors concluded that rTMS has a positive effect on motor recovery in patients with stroke, especially for those with subcortical stroke. Low-frequency rTMS over the unaffected hemisphere may be more beneficial than high-frequency rTMS over the affected hemisphere. Recent limited data suggested that intermittent theta-burst stimulation over the affected hemisphere might be a useful intervention. They stated that further well-designed studies in a larger population are needed to better elucidate the differential roles of various rTMS protocols in stroke treatment.
In a Cochrane review, Hao and colleagues (2013) evaluated the safety and effectiveness of rTMS for improving function in people with stroke. These investigators searched the Cochrane Stroke Group Trials Register (April 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), the Chinese Stroke Trials Register (April 2012), MEDLINE (1950 to May 2012), EMBASE (1980 to May 2012), Science Citation Index (1981 to April 2012), Conference Proceedings Citation Index-Science (1990 to April 2012), CINAHL (1982 to May 2012), AMED (1985 to May 2012), PEDro (April 2012), REHABDATA (April 2012), and CIRRIE Database of International Rehabilitation Research (April 2012). In addition, they searched 5 Chinese databases, ongoing trials registers, and relevant reference lists. These researchers included RCTs comparing rTMS therapy with sham therapy or no therapy. They excluded trials that reported only laboratory parameters. Two review authors independently selected trials, assessed trial quality, and extracted the data. They resolved disagreements by discussion. A total of 19 trials involving a total of 588 participants were included in this review. Two heterogeneous trials with a total of 183 subjects showed that rTMS treatment was not associated with a significant increase in the Barthel Index score (mean difference (MD) 15.92, 95% CI: -2.11 to 33.95). Four trials with a total of 73 participants were not found to have a statistically significant effect on motor function (standardized mean difference (SMD) 0.51, 95% CI: -0.99 to 2.01). Subgroup analyses of different stimulation frequencies or duration of illness also showed no significant difference. Few mild adverse events were observed in the rTMS groups, with the most common events being transient or mild headaches (2.4%, 8/327) and local discomfort at the site of the stimulation. The authors concluded that current evidence does not support the routine use of rTMS for the treatment of stroke. Moreover, they stated that further trials with larger sample sizes are needed to determine a suitable rTMS protocol and the long-term functional outcome.
In a Cochrane review, Elsner et al. (2013a) examined the effects for improving aphasia in patients after stroke. These investigators searched the Cochrane Stroke Group Trials Register (April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, March 2012), MEDLINE (1948 to March 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012), AMED (1985 to April 2012), Science Citation Index (1899 to April 2012), and 7 additional databases. They also searched trials registers and reference lists, hand-searched conference proceedings, and contacted authors and equipment manufacturers. These researchers included only RCTs and randomized controlled cross-over trials (from which they only analyzed the first period as a parallel group design) comparing tDCS versus control in adults with aphasia due to stroke. Two review authors independently assessed trial quality and extracted the data. If necessary, they contacted study authors for additional information. These investigators collected information on drop-outs and adverse events from the trials. They included 5 trials involving 54 participants. None of the included studies used any formal outcome measure for measuring functional communication, which is measuring aphasia in a real-life communicative setting. All 5 trials measured correct picture naming as a surrogate for aphasia. There was no evidence that tDCS enhanced speech and language therapy outcomes. No adverse events were reported, and the proportion of drop-outs was comparable between groups. The authors concluded that currently there is no evidence of the effectiveness of tDCS (anodal tDCS, cathodal tDCS) versus control (sham tDCS). Moreover, they stated that it appears that cathodal tDCS over the non-lesioned hemisphere might be the most promising approach.
In a Cochrane review, Elsner et al. (2013b) examined the effects of tDCS on generic activities of daily living (ADLs) and motor function in people with stroke. These investigators searched the Cochrane Stroke Group Trials Register (March 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, May 2013), MEDLINE (1948 to May 2013), EMBASE (1980 to May 2013), CINAHL (1982 to May 2013), AMED (1985 to May 2013), Science Citation Index (1899 to May 2013), and 4 additional databases. In an effort to identify further published, unpublished, and ongoing trials, these investigators searched trials registers and reference lists, hand-searched conference proceedings, and contacted authors and equipment manufacturers. They included only RCTs and randomized controlled cross-over trials (from which they analyzed only the first period as a parallel-group design) that compared tDCS versus control in adults with stroke for improving ADL performance and function. Two review authors independently assessed trial quality and extracted data. If necessary, these researchers contacted study authors to ask for additional information. They collected information on drop-outs and adverse events from the trial reports. These researchers included 15 studies involving a total of 455 participants. Analysis of 6 studies involving 326 participants regarding the primary outcome, ADL, showed no evidence of an effect in favor of tDCS at the end of the intervention phase (mean difference (MD) 5.31 Barthel Index points; 95% CI: -0.52 to 11.14; inverse variance method with random-effects model), whereas at follow-up (MD 11.13 Barthel Index points; 95% CI: 2.89 to 19.37; inverse variance method with random-effects model), these investigators found evidence of an effect. However, the CIs were wide, and the effect was not sustained when only studies with low risk of bias were included. For the secondary outcome, upper limb function, these investigators analyzed 8 trials with 358 participants, which showed evidence of an effect in favor of tDCS at the end of the intervention phase (MD 3.45 Upper Extremity Fugl-Meyer Score points (UE-FM points); 95% CI: 1.24 to 5.67; inverse variance method with random-effects model) but not at the end of follow-up 3 months after the intervention (MD 9.23 UE-FM points; 95% CI: -13.47 to 31.94; inverse variance method with random-effects model). These results were sensitive to the inclusion of studies at high risk of bias. Adverse events were reported, and the proportions of drop-outs and adverse events were comparable between groups (risk difference (RD) 0.00; 95% CI: -0.02 to 0.03; Mantel-Haenszel method with random-effects model). The authors concluded that evidence of very low to low quality is available on the effectiveness of tDCS (anodal/cathodal/dual) versus control (sham/any other intervention) for improving ADL performance and function after stroke. Moreover, they stated that future research should investigate the effects of tDCS on lower limb function and should address methodological issues by routinely reporting data on adverse events and drop-outs and allocation concealment, and by performing intention-to-treat analyses.
In a RCT with a 4-week follow-up, Barros Galvao et al. (2014) examined the effectiveness of inhibitory rTMS for decreasing upper-limb muscle tone after chronic stroke. Patients with stroke (n = 20) with post-stroke upper limb spasticity were enrolled in this study. The experimental group received rTMS to the primary motor cortex of the unaffected side (1,500 pulses; 1 Hz; 90% of resting motor threshold for the first dorsal interosseous muscle) in 10 sessions, 3 days/week, and physical therapy (PT). The control group received sham stimulation and PT. Main outcome measures were MAS, upper-extremity Fugl-Meyer assessment, FIM, range of motion, and stroke-specific quality-of-life scale. All outcomes were measured at baseline, after treatment (post-intervention), and at a 4-week follow-up. A clinically important difference was defined as a reduction of greater than or equal to 1 in the MAS score. The Friedman test revealed that PT is efficient for significantly reducing the upper limb spasticity of patients only when it is associated with rTMS. In the experimental group, 90% of the patients at post-intervention and 55.5% at follow-up showed a decrease of greater than or equal to 1 in the MAS score, representing clinically important differences. In the control group, 30% of the patients at post-intervention and 22.2% at follow-up experienced clinically meaningful changes. There were no differences between the groups at any time for any of the other outcome measures, indicating that both groups demonstrated similar behaviors over time for all variables. The authors concluded that rTMS associated with PT can be beneficial in reducing post-stroke spasticity. Moreover, they stated that more studies are needed to clarify the clinical changes underlying the reduction in spasticity induced by non-invasive brain stimulations.
- modest sample size (n = 24),
- single-center setting, and
- examination of sustainability was limited to 2 months.
In a systematic review and meta-analysis, Tung and colleagues (2019) examined the effects of rTMS on the post-stroke recovery of lower limb motor function. These investigators searched the databases of PubMed, Cochrane Library, and Embase for RCTs that were published by January 25, 2019. They included RCTs that evaluated the effects of rTMS on lower limb motor recovery in patients with stroke; 2 reviewers independently screened the searched records, extracted data, and assessed the risk of bias. The treatment effect sizes were pooled in a meta-analysis by using the RevMan 5.3 software. The internal validity was assessed using topics suggested by the Physiotherapy Evidence Database (PEDro). A total of 8 studies with 169 subjects were included in the meta-analysis. Pooled estimates demonstrated that rTMS significantly improved the body function of the lower limbs (SMD = 0.66; p < 0.01), lower limb activity (SMD = 0.66; p < 0.01), and motor-evoked potential (SMD = 1.13; p < 0.01). The subgroup analyses results also revealed that rTMS improved walking speed (SMD = 1.13) and lower limb scores on the Fugl-Meyer Assessment scale (SMD = 0.63). These researchers found no significant differences between the groups in different mean post-stroke time or stimulation mode over lower limb motor recovery; only 1 trial reported mild AEs. The authors concluded that rTMS may have short-term therapeutic effects on the lower limbs of patients with stroke; the application of rTMS is safe. However, they stated that this evidence is limited by a potential risk of bias.
In a systematic review and meta-analysis, Yang et al. (2021) examined the effect of rTMS on recovery of dysphagia following stroke. These investigators searched RCTs and non-RCTs published by PubMed, the Cochrane Library, ScienceDirect, Medline, and Web of Science from inception until April 24, 2021; language was limited to English. After screening and extracting the data, and examining the quality of the selected literature, these researchers performed the meta-analysis with software RevMan 5.3 and summarized available evidence from non-RCTs. Among 205 potentially relevant articles, 189 subjects (from 10 RCTs) were recruited in the meta-analysis, and 6 non-RCTs were qualitatively described. The random-effects model analysis revealed a pooled effect size of SMD = 0.65 (95% CI: 0.04 to 1.26, p = 0.04), which indicated that rTMS therapy had a better effect than conventional therapy. However, the subgroup analysis showed that there was no significant difference between low-frequency (LF) and high-frequency (HF) groups. Even more surprisingly, there were no statistically significant differences between the 2 groups and the conventional training group in the subgroup analysis; however, the combined effect was positive. The authors concluded that the findings of this study showed that rTMS was more effective than conventional training for the recovery of dysphagia; however, subgroup analysis of HF-rTMS and LF-rTMS did not show significant effectiveness for post-stroke dysphagia when compared with conventional rehabilitation, which was probably due to a small number of included studies. Therefore, larger trials are needed for further study. These researchers noted that this study also found that both inter-hemispheric inhibition theory and compensatory model may play a role in the therapeutic effect of rTMS in treating dysphagia. More clinical studies are needed to help develop better treatment plans for these patients.
The authors stated that this study had several drawbacks. First, the main limitations of the review were the small number of studies and participants included in this review. Second, only subgroup analysis for frequency was carried out in these analyses, whereas heterogeneity was observed in both subgroups. The effectiveness of rTMS could also be affected by other parameters such as stimulation sites and locations of lesions. Third, these researchers chose the Penetration-Aspiration Scale (PAS) and dysphagia grade (DD) as evaluation criteria, but did not include other evaluation criteria, which also resulted in a certain bias in the inclusion process of the article. In order to better serve clinical practice, these investigators will sort out all commonly used clinical evaluation criteria and collect relevant literature for data analysis in the later stage. The authors stated that further clinical controlled trials should be conducted to examine the influencing factors on the effectiveness and mechanism of rTMS in treating post-stroke dysphagia.
Cerebellar Transcranial Magnetic Stimulation for Post-Stroke Limb Dysfunction Rehabilitation
In a narrative review, Wang et al. (2025) examined the emerging field of cerebellar TMS in the rehabilitation of limb dysfunction after a stroke. These investigators reviewed findings from RCTs and case studies, examining the safety, effectiveness, as well as underlying mechanisms of cerebellar TMS. This review outlined advancements in TMS technologies, such as low-frequency repetitive TMS, intermittent theta burst stimulation, and cerebello-motor paired associative stimulation, and their integration with physiotherapy. The role of the cerebellum in motor control, the theoretical underpinnings of cerebellar stimulation on motor cortex excitability, and the indirect effects on cognition and motor learning were examined. Furthermore, the authors discussed current challenges, including coil types, safety, as well as optimal timing and modes of stimulation, and suggested future research directions. These researchers stated that this comprehensive analysis highlighted cerebellar TMS as a promising approach in stroke rehabilitation, offering insights for its clinical optimization.
Post-Stroke Fatigue
Soltsov et al. (2025) noted that post-stroke fatigue (PSF) is one of the most prevalent symptoms that affects QOL as well as daily function following stroke. Despite a growing body of research, its pathophysiology is poorly understood. Non-invasive brain stimulation, such as the TMS and tDCS, can serve as a non-pharmacological intervention for PSF. In this review, these investigators examined PSF neuroimaging studies to deduce potential neural mechanisms; described NIBS as a tool to probe brain structures to further understand pathophysiology of fatigue; and evaluated NIBS as a treatment for PSF. They carried out a systematic search using the databases PubMed, Embase, Scopus, CINAHL and Cochrane. Studies were included based on the following inclusion and exclusion criteria: greater than 18 years of age with PSF, use of neuroimaging and/or NIBS for investigation or as an intervention for PSF, English language, study types including cohort, case control, or RCTs. Data extracted included participant characteristics, concept, context, study methods, and key findings relevant to the review questions. A total of 30 studies met criteria. Neuroimaging studies that examined brain structure (MRI) found conflicting associations between lesion location and PSF. Functional methods (fMRI, TMS) showed altered resting state functional connectivity (rsFC), cortical excitability, and a disruption in inter-hemispheric inhibitory balance as potential mechanisms of PSF. There were no studies using TMS as an intervention for PSF. Of the 6 studies that used tDCS, only 2 reported statistically significant reductions in the severity of PSF. The authors concluded that structural characteristics of stroke lesions had conflicting findings, while functional neuroimaging studies suggested that altered rsFC, cortical excitability and inter-hemispheric inhibitory balance contributed to the development of PSF. There were inconsistent results on the effectiveness of tDCS as an intervention for PSF, due to varying methodologies and lack of precise targeting of underlying neural mechanisms. Moreover, these researchers stated that further investigations are needed to determine if NIBS could be a potential treatment to alleviate the effects of PSF.
Post-Stroke Pain
Gurdiel-Alvarez et al. (2024) stated that although rare, central post-stroke pain (CPSP) remains one of the most refractory forms of neuropathic pain. It has been reported that rTMS may be effective in these cases of pain. In a systematic review and meta-analysis, these investigators examined the effectiveness of rTMS in patients with CPSP. They included RCTs or controlled trials published until October 3, 2022, which examined the effect of rTMS compared to placebo in CPSP. These researchers included studies of adult patients (18 years of age or older) with a clinical diagnosis of stroke, in which the intervention consisted of the use of rTMS for the treatment of CPSP. A total of 9 studies were included in the qualitative analysis; 6 studies (4 RCTs and 2 non-RCTs), with 180 participants, were included in the quantitative analysis. A significant reduction in CPSP was found in favor of rTMS compared with sham, with a large effect size (SMD: -1.45; 95% CI: -1.87 to -1.03; p < 0.001; I²: 58%). The authors concluded that the findings of this systematic review with meta-analysis suggested that there is low-quality evidence on the effectiveness of rTMS in the treatment of CPSP. Moreover, these researchers stated that future studies should consider improving methodology by blinding the therapist and taking into account patients’ characteristics and rTMS parameters to reduce heterogeneity.
The authors stated that this review had several drawbacks. First, 2 of the studies included in the meta-analysis were not RCTs; thus, there exists some risk of selection bias. Second, regarding the duration of pain, some studies did not report it, while others ranged between acute (less than 3 months) to chronic presentation (greater than 3 months). Mixing patients with acute and chronic CPSP in the study sample could account for increased variability in the results, due to differences in the underlying pathophysiological processes; therefore, future studies should consider these differences when establishing their inclusion criteria. Third, the dosage of rTMS varied between studies, with the frequency of stimulation ranging between 5 Hz and 20 Hz, the intensity of stimulation ranging between 80% and 100% resting motor threshold, and the total number of sessions ranging between 1 and 18 sessions. Analyzing together studies with different rTMS protocols could, in fact, account for differences in the measured effects, leading to increased heterogeneity in the results. Due to the scarcity of studies applying the same rTMS protocols in CPSP, future studies should take into account replicating the methodology of stimulation from previous studies to reduce this problem. Fourth, there appeared to be a common risk of bias between the included studies regarding the randomization process or the clarity in the report of the outcomes. Researchers must consider reporting clearly the randomization processes to reduce possible biases and facilitate replicability, as well as expressing measures of centralization and dispersion to improve transparency and better understanding of the results.
Treatment of Stroke - Motor Function
Wang et al. (2024) noted that lower extremity (LE) motor dysfunction is one of the most severe consequences following stroke, restricting functional mobility and impairing daily activities. Growing evidence suggests that rTMS can improve stroke patients' LE motor function; however, there is still controversy regarding the optimal rTMS protocol. In a network meta-analysis (NMA), these investigators examined the effects of different rTMS protocols on LE motor function in stroke patients. They systematically searched CNKI, WanFang, VIP, CBM, PubMed, Embase, Web of Science, and Cochrane Library databases (from inception to December 31, 2023); RCTs or cross-over RCTs on rTMS improving LE motor function in stroke patients were included. Two authors independently completed article screening, data extraction, and quality assessment. RevMan (version 5.4) and Stata (version 17.0) were used to analyze the data. A total of 38 studies with 2,022 patients were eligible for the NMA. The interventions included HFrTMS-M1, LFrTMS-M1, iTBS-Cerebellum, iTBS-M1, dTMS-M1, and placebo. The results of the NMA revealed that LFrTMS-M1 ranked 1st in FMA-LE and speed, and HFrTMS-M1 ranked 1st in BBS, TUGT, and MEP amplitude. The subgroup analysis of FMA-LE showed that HFrTMS-M1 was the best stimulation protocol for post-stroke time of over 1 month, and LFrTMS-M1 was the best stimulation protocol for post-stroke time of 1 month or less. The authors concluded that considering the impact of the stroke phase on LE motor function, the available evidence shows that HFrTMS-M1 may be the preferred stimulation protocol to improve the LE motor function of patients for post-stroke time of over 1 month, and LFrTMS-M1 for post-stroke time of 1 month or less. Moreover, these researchers stated that these conclusions require further analysis and validation by high-quality, multi-center RCTs with large samples and long-term follow-ups.
The authors stated that this NMA had several drawbacks. First, coil type, stimulation intensity, total number of pulses, and duration of intervention were not exactly the same among the included studies, resulting in potential heterogeneity. Second, despite including the full stimulation protocol in this analysis, the iTBS-M1 and dTMS-M1 groups accounted for 2.6% and 5.3% of the total data, respectively. This affected, to some extent, the quality of the conclusions of this study. Third, the age and disease severity of the included patients were slightly different, and some data indicators would be affected; therefore, subgroup analysis according to age and disease severity is needed in the future. Fourth, AEs may not be strictly reported in the included studies; thus, the safety of each intervention protocol needs to be further studied.
Visual Hallucinations after Stroke
Rafique and colleagues (2016) examined the effectiveness of multi-day rTMS to the occipital cortex in a patient with continuous visual phosphene hallucinations for more than 2 years following occipital stroke. Low-frequency rTMS (1 Hz) was applied to the lesion site for 30 minutes daily over 5 consecutive days; fMRI was performed before and after rTMS treatment. Increased application of rTMS corresponded with a reduction in intensity of visual phosphene hallucinations and was reflected in altered blood oxygen level-dependent signal; fMRI revealed focal excitatory discharges at the border of the lesion, highlighting the origin of phosphenes. Post-rTMS, rTMS did not simply suppress activity in the patient but rather re-distributed the previously imbalanced cortical activity not only at the stimulation site but in remote cortical regions so that it more closely resembled that of controls. The authors concluded that this case was rare in its presentation of chronic continuous visual phosphene hallucinations following occipital stroke. They presented a case of multi-day application of rTMS to visual cortex and demonstrated that rTMS provided a valuable therapeutic intervention in modulating visual hallucinations following occipital damage. This study provided Class IV evidence in a single-case report that multi-day rTMS reduced intra-hemispheric and inter-hemispheric imbalance and associated visual phosphene hallucinations following occipital stroke. The main drawbacks of this study were: (i) single-case design, and (ii) the inability to refine stimulation intensity and duration to attain maximal phosphine suppression.
Tinnitus
In a pilot study, Smith et al. (2007) evaluated the effectiveness of rTMS and its effects on attentional deficits and cortical asymmetry in 4 patients with chronic tinnitus using objective and subjective measures and employing an optimization technique refined in our laboratory. Patients received 5 consecutive days of active, low-frequency rTMS or sham treatment (using a 45-degree coil-tilt method) before crossing over. Subjective tinnitus was assessed at baseline, after each treatment, and 4 weeks later. Positron emission tomography/computed tomography (PET/CT) scans were obtained at baseline and immediately after active treatment to examine changes in cortical asymmetry. Attentional vigilance was assessed at baseline and after each treatment using a simple reaction time test. All patients had a response to active (but not sham) rTMS, as indicated by their best tinnitus ratings; however, tinnitus returned in all patients by 4 weeks after active treatment. All patients had reduced cortical activity visualized on PET immediately after active rTMS. Mean reaction time improved (p < 0.05) after active but not sham rTMS. The authors concluded that rTMS is a promising treatment modality that can transiently diminish tinnitus in some individuals, but further trials are needed to determine the optimal techniques required to achieve a lasting response. This is in agreement with the findings of Plewnia et al. (2007), who reported that the effects of rTMS for patients with chronic tinnitus are only moderate; inter-individual responsiveness varied; and the attenuation of tinnitus appeared to wear off within 2 weeks after the last stimulation session.
In a pilot study, Lee and colleagues (2008) examined if rTMS may suppress excessive spontaneous activity in the left superior temporal gyrus associated with tinnitus. A total of 8 patients with tinnitus received 5 consecutive days of rTMS (0.5 Hz, 20 mins) to the left temporo-parietal area. Tinnitus Handicap Inventory (THI) measures before sessions 1 and 3 and after session 5 were used to evaluate effectiveness. Patient 1's THI decreased from 40 to 34 to 26, patient 4 reported a subjective improvement, patient 8 withdrew, and the remaining patients reported no improvement. Adverse effects included temporary soreness, restlessness, and photophobia. The authors concluded that the parameters for this rTMS study are different from those that reported success with its use. With these current parameters, rTMS did not improve tinnitus. There were no permanent adverse outcomes.
Kleinjung et al. (2009) investigated if administration of the dopamine precursor levodopa before low-frequency rTMS enhances its effectiveness in tinnitus treatment. A total of 16 patients with chronic tinnitus received 100 mg of levodopa before each session of low-frequency rTMS. Results were compared with a matched control group of 16 patients who received the same treatment, but without levodopa. Treatment outcome was assessed with a standardized tinnitus questionnaire. Both stimulation protocols resulted in a significant reduction of tinnitus scores after 10 days of stimulation; however, there was no significant difference between the 2 groups. The authors concluded that these findings suggested that 100 mg of levodopa does not enhance the effect of rTMS in the treatment of tinnitus. Furthermore, they stated that "[e]ven if the available data clearly demonstrate the therapeutic potential of rTMS in tinnitus, the clinical effects are still relatively limited. A better understanding of the underlying neurobiological mechanisms will be crucial for optimizing stimulation protocols and further improving the efficacy of rTMS."
In a Cochrane review on rTMS for tinnitus, Meng et al. (2011) concluded that there is very limited support for the use of low-frequency rTMS for the treatment of patients with tinnitus. When considering the impact of tinnitus on patients' quality of life, support is from a single study with a low risk of bias based on a single outcome measure at a single point in time. When considering the impact on tinnitus loudness, this is based on the analysis of pooled data with a large confidence interval. Studies suggest that rTMS is a safe treatment for tinnitus in the short term; however, there were insufficient data to provide any support for the safety of this treatment in the long term. The authors stated that more prospective, randomized, placebo-controlled, double-blind studies with large sample sizes are needed to confirm the effectiveness of rTMS for tinnitus patients. Uniform, validated, tinnitus-specific questionnaires and measurement scales should be used in future studies.
In a systematic review, Peng et al. (2012) evaluated the effectiveness of rTMS for the treatment of chronic tinnitus. Data sources relevant electronic databases and a reference list of articles published up to January 2012 were searched. Randomized controlled clinical trials of all types of rTMS treatment for patients with chronic tinnitus were included. A total of 5 trials (160 participants) were included in this review. Repetitive TMS showed benefits in the short term, but the long-term effects are questionable. The Tinnitus Handicap Inventory (THI) and the visual analog scale (VAS) were the major assessment methods used. After active TMS stimulation, the reduction in the THI total score and VAS was significant compared with baseline at the first time point assessed and in the short term (2 weeks and 4 weeks). The longest follow-up time was 26 weeks after treatment, and the shortest follow-up time was 2 weeks. No severe side effects were reported from the use of rTMS. Differences in age, hearing level, duration of tinnitus of the included patients, and the condition of sham treatment may influence the effect. The authors concluded that rTMS could be a new therapeutic tool for the treatment of chronic tinnitus, and thus far they have not been able to demonstrate any substantial risk from rTMS treatment. However, they stated that the long-term effects of rTMS treatment for tinnitus are not clear and will require further study.
Plewnia et al. (2012) examined if 4 weeks of bilateral rTMS to the temporal or temporo-parietal cortex is effective and safe in the treatment of chronic tinnitus. In this controlled 3-armed trial, 48 patients with chronic tinnitus were treated with 4 weeks (20 sessions) of bilateral continuous theta burst stimulation (cTBS). They were randomized to stimulation above the temporal cortex, the temporo-parietal cortex, or as a sham condition behind the mastoid. Patients were masked for the stimulation condition. Tinnitus severity was assessed after 2 and primarily 4 weeks of treatment and at 3 months follow-up with the tinnitus questionnaire and by a tinnitus change score. Audiologic safety was monitored by pure-tone and speech audiometry after 2 and 4 weeks of cTBS. Tinnitus severity was slightly reduced from baseline by a mean (SD) of 2.6 (8.2) after sham, 2.4 (8.0) after temporo-parietal, and 2.2 (8.3) after temporal treatment of 16 patients each, but there was no significant difference between sham treatments and temporal (CI: -5.4 to +6.7) or temporo-parietal cTBS (CI: -5.9 to +6.3) or real cTBS (CI: -7 to +5.1). Patients' global evaluation of tinnitus change after treatment did not indicate any effects. Audiologic measures were unaffected by treatment. The authors concluded that treating chronic tinnitus for 4 weeks by applying cTBS to the temporal or temporo-parietal cortex of both hemispheres appears to be safe but not more effective than sham stimulation. However, these results are not to be generalized to all forms of rTMS treatments for tinnitus.
In an editorial that accompanied the aforementioned study, Triggs and Hajioff (2012) stated that “At present, rTMS should be classified as 'U' by the American Academy of Neurology classification of recommendation: the data are inadequate and conflicting, and the treatment is unproven.”
The American Academy of Otolaryngology - Head and Neck Surgery’s clinical practice guideline on “Tinnitus” (Tunkel et al., 2014) listed transcranial magnetic stimulation as one of the interventions considered, but no recommendation was made or were recommended against.
Liang and colleagues (2020) stated that although the clinical safety and efficacy of rTMS in the treatment of chronic tinnitus have been frequently examined, the results remain contradictory. These researchers carried out a systematic review and meta-analysis of clinical trials examining the effects of rTMS to examine its safety and efficacy. Studies of rTMS for chronic tinnitus were retrieved from PubMed, Embase, and Cochrane Library through April 2020. Review Manager 5.3 software was used for data synthesis, and Stata 13.0 software was used for analyses of publication bias and sensitivity. A total of 29 randomized studies involving 1,228 chronic tinnitus patients were included. Compared with sham-rTMS, rTMS exhibited significant improvements in the THI scores at 1 week (MD: -7.92, 95% CI: -14.18 to -1.66), 1 month (MD: -8.52, 95% CI: -12.49 to -4.55), and 6 months (MD: -6.53, 95% CI: -11.406 to -1.66) post-intervention; there were significant mean changes in THI scores at 1 month (MD: -14.86, 95% CI: -21.42 to -8.29) and 6 months (MD: -16.37, 95% CI: -20.64 to -12.11) post-intervention, and the tinnitus questionnaire (TQ) score at 1 week post-intervention (MD: -8.54, 95% CI: -15.56 to -1.52). Non-significant efficacy of rTMS was found regarding the THI score 2 weeks post-intervention (MD: -1.51, 95% CI: -13.42 to -10.40); the mean change in TQ scores 1 month post-intervention (MD: -3.67, 95% CI: -8.56 to 1.22); TQ scores 1 (MD: -8.97, 95% CI: -20.41 to 2.48) and 6 months (MD: -7.02, 95% CI: -18.18 to 4.13) post-intervention; and AEs (OR: 1.11, 95% CI: 0.51 to 2.42). Egger's and Begg's tests indicated no publication bias (p = 0.925). The authors concluded that this meta-analysis demonstrated that rTMS was effective for chronic tinnitus; however, its safety needs more validation. Moreover, these researchers stated that, restrained by the insufficient number of included studies and the small sample size, large, randomized, double-blinded, multi-center studies are needed for further verification.
The authors stated that this study had several drawbacks. First, despite the inclusion of recent large randomized trials, the limited number of enrolled subjects in the meta-analysis limited more accurate analyses, and some results were non-significant, which might be attributed to the nature of the population receiving rTMS. Second, this study only analyzed English-language references, which led to lost data from those in other languages. Third, although Egger’s and Begg’s analyses showed no publication bias in the meta-analysis, because of the limited number of studies included in this analysis, the possibility of false negatives could not be excluded.
Traumatic Brain Injury
Demirtas-Tatlidede et al. (2012) reviewed novel techniques of non-invasive brain stimulation (NBS), which may have value in the assessment and treatment of traumatic brain injury (TBI). They reviewed the following techniques: TMS, transcranial DCS (tDCS), low-level laser therapy, and transcranial Doppler sonography. Furthermore, these investigators provided a brief overview of TMS studies to date. They described the rationale for the use of these techniques in TBI, discussed their possible mechanisms of action, and raised a number of considerations relevant to the translation of these methods to clinical use. Depending on the stimulation parameters, NBS may enable suppression of the acute glutamatergic hyper-excitability following TBI and/or counter the excessive GABAergic effects in the sub-acute stage. In the chronic stage, brain stimulation coupled with rehabilitation may enhance behavioral recovery, learning of new skills, and cortical plasticity. Correlative animal models and comprehensive safety trials seem critical to establish the use of these modalities in TBI. The authors concluded that different forms of NBS techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical re-organization and enable functional restoration in TBI. They noted that future lines of safety research and well-designed clinical trials in TBI are warranted to determine the capability of NBS to promote recovery and minimize disability.
In a double-blind, sham-controlled, cross-over study, Thibaut et al. (2014) examined the effects of left dorsolateral prefrontal cortex tDCS (DLPF-tDCS) on Coma Recovery Scale-Revised (CRS-R) scores in severely brain-damaged patients with disorders of consciousness. Anodal and sham tDCS were delivered in randomized order over the left DLPF cortex for 20 minutes in patients in a vegetative state/unresponsive wakefulness syndrome (VS/UWS) or in a minimally conscious state (MCS) assessed at least 1 week after acute traumatic or non-traumatic insult. Clinical assessments were performed using the CRS-R directly before and after anodal and sham tDCS stimulation. Follow-up outcome data were acquired 12 months after inclusion using the Glasgow Outcome Scale-Extended. Patients in MCS (n = 30; interval 43 ± 63 months; 19 traumatic, 11 non-traumatic) showed a significant treatment effect (p = 0.003) as measured by CRS-R total scores. In patients with VS/UWS (n = 25; interval 24 ± 48 months; 6 traumatic, 19 non-traumatic), no treatment effect was observed (p = 0.952). Thirteen (43%) patients in MCS and 2 (8%) patients in VS/UWS further showed post-anodal tDCS-related signs of consciousness, which were observed neither during the pre-tDCS evaluation nor during the pre- or post-sham evaluation (i.e., tDCS responders). Outcome did not differ between tDCS responders and non-responders. The authors concluded that tDCS over the left DLPF cortex may transiently improve signs of consciousness in MCS following severe brain damage as measured by changes in CRS-R total scores. Moreover, they stated that the long-term non-invasive neuro-modulatory tDCS outcome clinical improvement in this challenging population remains to be shown.
In an editorial that accompanied the aforementioned study, Whyte (2014) stated that “If a longer course of tDCS can accelerate recovery for a subgroup of the DOC population, perhaps a positive response to a single session of tDCS can identify the subgroup of individuals who are treatment responders to this or to other treatments that modulate attention and working memory circuitry. If so, tDCS may provide a useful screening approach for other treatment studies, as well as a useful treatment in its own right.”
In a prospective, case series trial with follow-up at 12 months, Angelakis et al. (2014) evaluated the effectiveness of tDCS on improving consciousness in patients with persistent UWS (previously termed persistent vegetative state [PVS]) or in an MCS. Inpatients in a PVS/UWS or MCS (n = 10; 7 men, 3 women; age range of 19 to 62 years; etiology: traumatic brain injury, n = 5; anoxia, n = 4; post-operative infarct, n = 1; duration of PVS/UWS or MCS range of 6 months to 10 years). No participant withdrew because of adverse effects. All patients received sham tDCS for 20 minutes per day, 5 days per week, for 1 week, and real tDCS for 20 minutes per day, 5 days per week, for 2 weeks. An anodal electrode was placed over the left primary sensorimotor cortex or the left DLPF, with cathodal stimulation over the right eyebrow. One patient in an MCS received a second round of 10 tDCS sessions 3 months after initial participation. The main outcome measure was the JFK Coma Recovery Scale-Revised. All patients in an MCS showed clinical improvement immediately after treatment. The patient who received a second round of tDCS 3 months after initial participation showed further improvement and emergence into consciousness after stimulation, with no change between treatments. One patient who was in an MCS for less than 1 year before treatment (post-operative infarct) showed further improvement and emergence into consciousness at the 12-month follow-up. No patient showed improvement before stimulation. No patient in a PVS/UWS showed immediate improvement after stimulation, but 1 patient who was in a PVS/UWS for 6 years before treatment showed improvement and change of status to an MCS at the 12-month follow-up. The authors concluded that tDCS seems promising for the rehabilitation of patients with severe disorders of consciousness; severity and duration of pathology may be related to the degree of tDCS' beneficial effects.
Accelerated, Repetitive, MRI-Guided Theta-Burst Stimulation / Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT)
Cole et al. (2020) conducted an open-label clinical study to evaluate the feasibility, tolerability, safety, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose, functional connectivity MRI–guided intermittent theta-burst stimulation protocol for treatment-resistant depression. The study enrolled 23 adults with a current nonpsychotic major depressive episode who had not responded to at least one antidepressant medication; one participant was screened out after enrollment due to a very high motor threshold, resulting in 22 participants in the intent-to-treat population, and one additional participant withdrew after the first day of stimulation because of anxiety, leaving 21 participants who completed the full protocol. Participants received 50 iTBS sessions delivered as 10 sessions per day over 5 consecutive days, with 1,800 pulses per session, 50-minute intersession intervals, and stimulation at 90% resting motor threshold, individually targeted to the left dorsolateral prefrontal cortex region most anticorrelated with the subgenual anterior cingulate cortex. Outcomes assessed included depressive symptoms measured by the Montgomery-Åsberg Depression Rating Scale, Hamilton Depression Rating Scale (17-item and 6-item), Beck Depression Inventory–II, and measures of suicidal ideation, as well as neuropsychological testing before and after treatment. In the per-protocol analysis, 19 of 21 participants (90.5%) met remission criteria defined as a Montgomery-Åsberg Depression Rating Scale score less than 11, while in the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria; the mean number of days to response based on the 6-item Hamilton Depression Rating Scale was 2.30 days (SD 1.13), and the mean number of days to remission was 2.63 days (SD 1.21). No serious adverse events were reported, and neuropsychological testing showed no negative cognitive side effects. The authors acknowledged several limitations to their study, including a small sample size, an open-label design, the absence of a sham-control group, stimulation of a single brain region, fixed stimulation frequencies, fixed intersession intervals, and the lack of state-dependent stimulation. The authors concluded that SAINT is feasible, well tolerated, and safe; however, double-blinded, sham-controlled trials are needed to confirm the observed remission rates.
Cole et al. (2022) noted that depression is the leading cause of disability globally, and 50% of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the FDA for the treatment of treatment-resistant depression, but is limited by suboptimal effectiveness and a 6-week duration. These researchers addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of approximately 90% after 5 days of open-label treatment. The authors reported the results of a double-blind, sham-controlled trial of SNT for treatment-resistant depression. Participants with treatment-resistant depression currently experiencing moderate-to-severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anti-correlated with the subgenual anterior cingulate cortex. The primary outcome was the score on the MADRS 4 weeks after treatment. At the planned interim analysis, 32 subjects with treatment-resistant depression had been enrolled, and 29 subjects who continued to meet inclusion criteria received either active (n = 14) or sham (n = 15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group. The authors concluded that SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Moreover, these researchers stated that further investigations are needed to determine SNT's durability and to compare it with other treatments.
The authors stated that this trial had several drawbacks. First, the sample size was small, as the trial was ended at the planned interim analysis because of the superiority of the active treatment with a large effect size; however, the sample size was similar to those of other clinical trials in patients with severe treatment-resistant depression. Second, as with all clinical trials for major depressive disorder, this trial relied on clinical assessments to measure improvement in depressive symptoms, as there are currently no validated biomarkers of depression remission. Third, thus far this SNT protocol has been tested at a single site, in a highly educated sample. Although this limited generalizability, the absence of a significant sham response in this treatment-resistant population indicated clear effectiveness of active over sham stimulation for this patient population. Fourth, 45% of the participant sample had co-morbid psychiatric diagnoses, which could have influenced the effectiveness of the protocol. Co-morbid anxiety, in particular, has been shown to reduce rTMS efficacy, perhaps because of the need for an alternative treatment target for these patients or a higher incidence of benzodiazepine use in this population. However, the number of subjects with co-morbid psychiatric conditions was not significantly different between the active and sham treatment groups. Fifth, given the large effect size in comparison to other TMS protocols in similar populations, these researchers hypothesized that the differences between SNT and standard rTMS protocols resulted in high antidepressant effectiveness; however, SNT remains to be tested directly against another active protocol, and the unique aspects of the SNT protocol that account for improvements in effectiveness over conventional iTBS remain to be identified. Moreover, these investigators stated that further studies are needed to compare the effectiveness of SNT parameters with and without functional connectivity MRI (fcMRI)-guided targeting to determine the importance of this targeting method.
In an editorial that accompanied the aforementioned study by Cole et al. (2022), Weissman and Daskalakis (2022) noted that while the SNT protocol revealed strong treatment effects in the study, there were some questions with regard to study design and patient inclusion, which may limit the generalizability and full adoption of this treatment innovation in the treatment-resistant depression population. First, the severity of treatment-resistant depression and level of treatment resistance in the study sample appeared to be moderate, not severe, owing partially to the relatively few failed medication trials during the current episode (the mean number of adequate antidepressant trials in the current episode was 2 for the active treatment group and 1 for the sham treatment group). It remained to be seen how effective this treatment will be in patients with more severe illness in whom ECT is commonly used (e.g., inpatients or those with emergent suicidality). Nevertheless, the logistics of delivering SNT may actually be more practical for a patient who is already stationed in a hospital setting all day. It may be difficult for patients employed full-time to lose an entire work week, especially given the limited evidence on the long-term durability of response with SNT (the response and remission rates declined by week 4 in this study). Thus, it is still unclear who the optimal target population is for this treatment. The other issue with generalizability was that the authors employed an MRI-guided technique to localize treatment to the left DLPFC. Recent advances in these methods have improved the ability to optimally target specific locations within the DLPFC. What has yet to be determined is whether these methods would result in improved remission rates above standard targeting techniques. Moreover, MRI-guided targeting of the DLPFC could be prohibitive for clinics running small margins or for patients who are partially insured. Finally, only 16% of individuals screened online were included in this study, which implied that patients were carefully selected. Even so, the overall results were both exciting and compelling, and follow-up studies with the SNT approach are currently underway. Moreover, these researchers stated that with the growing acceptance of accelerated TBS treatments by physicians, researchers, and patients, a new avenue of rTMS research is now open. These investigators stated that future studies in this area should further refine treatment parameters and examine the role of accelerated protocols in other psychiatric diseases, such as bipolar depression and severe treatment-resistant depression in the inpatient setting; further investigations of these therapeutic approaches may result in improved outcomes in a substantial proportion of patients, offering hope for those who suffer from disabling conditions.
Caulfield et al. (2022) stated that accelerated TMS (aTMS) is an emerging delivery schedule of rTMS. TMS is "accelerated" by applying 2 or more stimulation sessions within a day. In a 3-part review, these investigators examined the safety/tolerability, effectiveness, and stimulation parameters affecting response across disorders. They used the PubMed database to identify studies administering aTMS, which these researchers defined as applying at least 2 rTMS sessions within 1 day. The targeted literature search identified 85 aTMS studies across 18 diagnostic and healthy control groups published from July 2001 to June 2022. Excluding overlapping populations, 63 studies delivered 43,873 aTMS sessions using low-frequency, high-frequency, and theta burst stimulation in 1,543 participants. Regarding safety, aTMS studies had similar seizure and side effect incidence rates to those reported for once-daily rTMS. One seizure was reported from aTMS (0.0023% of aTMS sessions, compared with 0.0075% in once-daily rTMS). The most common side effects were acute headache (28.4%), fatigue (8.6%), and scalp discomfort (8.3%), with all others under 5%. These investigators examined aTMS effectiveness in 23 depression studies (the condition with the most studies), finding an average response rate of 42.4% and remission rate of 28.4% (range = 0% to 90.5% for both). Regarding parameters, aTMS studies ranged from 2 to 10 sessions per day over 2 to 30 treatment days, 10 to 640 minutes between sessions, and a total of 9 to 104 total aTMS sessions per participant (including tapering sessions). Qualitatively, response rate tended to be higher with an increasing number of sessions per day, total sessions, and total pulses. The authors concluded that the available evidence suggested that aTMS was safe and well-tolerated across conditions. These investigators stated that taken together, these early studies suggested potential effectiveness even in highly treatment-refractory conditions with the added potential to reduce patient burden while also expediting response time. These researchers stated that further investigations are needed to examine how key aTMS parameters affect treatment outcome and durability.
Chen et al. (2023) stated that rTMS is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20 to 30 daily sessions over 4 to 6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a pre-defined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of inter-session intervals. In this study, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesized a consensus based on 20 years of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). These investigators proposed descriptive nomenclature for accelerated rTMS, recommended avenues to optimize therapeutic and efficiency potential, and suggested using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies demonstrated that accelerated rTMS protocols were well-tolerated and not associated with serious adverse effects. More importantly, the antidepressant effectiveness of accelerated rTMS appeared comparable to conventional, once-daily rTMS protocols. These researchers stated that whether accelerated rTMS would induce antidepressant effects more quickly remains uncertain. On present evidence, therapeutic protocols incorporating high pulse dose and multiple treatments per day show promise and improved effectiveness. These investigators stated that the durability and depression relapse patterns following accelerated rTMS remain a recognized knowledge gap. There is clear merit in the ongoing research and development of accelerated rTMS protocols for depression and other neuropsychiatric conditions. To this end, the authors provided suggestions to work towards consensus of nomenclature and the systematic investigation of protocol parameters and treatment outcomes. They noted that future neuroimaging and electrophysiology research may see translation to protocol individualization and optimization, in turn improving accelerated rTMS’s therapeutic effectiveness.
Lan et al. (2023) conducted a systematic review of RCTs and observational studies examining the safety and effectiveness of Stanford neuromodulation therapy (SNT) for patients with treatment-resistant depression (TRD). These investigators carried out a systematic search (up to September 25, 2023) of RCTs and single-arm prospective studies. A total of 1 RCT (n = 29) and 3 prospective, single-arm studies (n = 34) met the inclusion criteria. In the RCT, compared to sham, active SNT was significantly associated with higher rates of antidepressant response (71.4% versus 13.3%) and remission (57.1% versus 0%); 2 out of the 3 prospective, single-arm studies reported the percentage of antidepressant response after completing SNT, ranging from 83.3% (5/6) to 90.5% (19/21). In the 3 prospective, single-arm studies, the antidepressant remission rates ranged from 66.7% (4/6) to 90.5% (19/21); and no severe AEs occurred in all the 4 studies. The authors concluded that this systematic review found SNT significantly improved depressive symptoms in patients with TRD within 5 days, without severe AEs. Moreover, these researchers stated that further investigations are needed to confirm and expand the use of SNT as an adjunctive treatment for TRD.
The authors stated that this systematic review had several drawbacks. First, only 1 RCT was detected and the total sample size of the included studies (n = 63) was relatively small. Second, of the included 4 studies, 3 were conducted by the same team at a single site, limiting the generalizability of these findings. Third, the systematic review was not registered as this was not compulsory in most academic journals. Fourth, a long-term follow-up period (e.g., longer than 3 months) was not adopted in included studies, although the persistence of the antidepressant effect remains an important issue for TMS treatments, with several studies emphasizing the urgency of developing maintenance protocols to prevent potential relapses.
Ramasubbu et al. (2024) stated that theta burst stimulation (TBS) is approved and widely used in the treatment of treatment-resistant major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once-daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. In an open-label, pilot study, these investigators examined the safety and effectiveness of accelerated bilateral TBS in the treatment of patients with MDD. This trial included 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least 1 antidepressant, who received bilateral TBS, consisting of 5 sequential bilateral iTBS (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treatment changes at day 5 and 2 weeks in HDRS-17 scores and response (50% or more reduction from the baseline scores) and remission (7 or less) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2 weeks post-treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2 weeks post-treatment, suggesting delayed clinical effects. However, the reduction in symptom scores between the 2 post-treatment end-points was non-significant. A total of 60% of patients could not tolerate the high-intensity stimulation; no major AEs occurred. The authors concluded that these preliminary findings suggested that accelerated bilateral TBS may be safe and effective for treatment-resistant depression. Moreover, these researchers stated that RCTs are needed to establish the therapeutic role of accelerated bilateral TBS in depression. These investigators noted that the drawbacks of this study included the uncontrolled, open-label design of the trial and its small sample size (n = 25).
Taylor et al. (2025) investigated the impact of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression on healthcare resource utilization as well as commercial and Medicare Fee-for-Service payer costs. They conducted a retrospective observational analysis of claims data using Medicare Fee-for-Service datasets and commercial (Merative MarketScan Research Databases) datasets from January 2021 to September 2023. They identified two cohorts, a cohort that received rTMS and a cohort not treated with rTMS over an 18-month period. The authors used propensity score matching to balance the baseline characteristics of the cohorts, and calculated the total cost of care based on payer allowed amounts from Merative MarketScan Research Databases and Standard Analytical Files. The authors found that relative to the non-TMS cohort, the rTMS cohort incurred 37% more hospital outpatient visits (14.00 vs 10.21; p ≤ 0.0001) with 7% higher outpatient cost ($8946 vs $8363; p = 0.3400). Simultaneously, the rTMS cohort incurred 24% fewer inpatient admissions (0.25 vs 0.33; p = 0.0003) with 19% lower inpatient admission costs ($5666 vs $6978; p = 0.0392), 48% fewer emergency room visits (0.27 vs 0.53; p ≤ 0.0001) with 34% lower emergency room costs ($322 vs $487; p ≤ 0.0001), and $893 less in episode of care costs. The authors concluded that this suggests that patients who receive rTMS for treatment-resistant depression required fewer high acuity hospital visits and incurred less expensive episode-of-care costs compared with patients who do not receive rTMS. From this perspective, rTMS is an investment that returns health and economic dividends through fewer high acuity hospital visits.
Taylor and colleagues identified several limitations in their study, including the reliance on data collected during the peak of the COVID-19 pandemic, which may not accurately represent typical healthcare utilization patterns, especially for outpatient and elective services. They also pointed out challenges in inferring treatment resistance from changes in prescribing practices, as psychiatric medications might be used prophylactically, despite these changes being assumed to reflect standard clinical practice. Additional limitations included the lack of medication data for Medicare beneficiaries and the absence of psychometric severity measures, both of which are part of the Maudsley Staging Method; however, alternative utilization-based proxies were employed to evaluate treatment-resistant depression (TRD). Despite statistical adjustments, the complexity of psychiatric disorders introduces potential confounding factors that could influence interpretation, and while the dataset was geographically diverse, the findings may not be applicable across different healthcare systems due to variations in access and policy. The propensity score matching aimed to control for population differences rather than to compare payer groups. For future research, the authors recommend exploring newer repetitive transcranial magnetic stimulation (rTMS) methods, including accelerated protocols and MRI-guided systems like the FDA-cleared SAINT neuromodulation system, which may provide better response rates, enhanced cost-effectiveness, and broader application in inpatient or psychiatric observation settings compared to standard rTMS and other treatments such as esketamine or electroconvulsive therapy.
Geoly et al. (2025) conducted a retrospective exploratory clinical study to evaluate the durability of antidepressant benefit following a single 5-day course of Stanford Neuromodulation Therapy (SNT) in treatment-resistant depression. The study analyzed pooled long-term follow-up data from previously published open-label and randomized controlled trials and included 46 participants experiencing a moderate-to-severe nonpsychotic major depressive episode as part of major depressive disorder or bipolar II disorder who received active SNT. Depressive symptoms were assessed using the 6-item Hamilton Depression Rating Scale (HDRS-6) collected weekly during a 4-week controlled period and fortnightly for up to 24 weeks during a naturalistic follow-up, with remission defined as HDRS-6 scores of 4 or less and relapse defined as two consecutive HDRS-6 scores of 5 or greater. Seventy percent (32/46) of participants entered remission one week after treatment, and 33% (15/46) remained in remission at 12 weeks; among acute remitters, 46.9% (15/32) had not relapsed at 12 weeks. Kaplan–Meier analyses reported a restricted mean survival time of 105.1 days (SE 12.4) for remission-relapse among acute remitters and 126.1 days (SE 11.6) for response-relapse among acute responders. The authors concluded that a subset of participants maintained remission for at least 12 weeks following SNT without continuation treatment, indicating measurable durability of antidepressant response. Reported limitations included small sample size, limited follow-up beyond 12 weeks, retrospective pooling across study cohorts, lack of long-term MADRS data, limited demographic diversity, and allowance of medication changes after week 4.
Kratter et al. (2026) conducted a double-blind, randomized, sham-controlled trial to evaluate the antidepressant efficacy of Stanford neuromodulation therapy (SNT) and to examine associated electroencephalographic effects in individuals with treatment-resistant major depressive disorder. The study enrolled 53 participants, of whom 48 met eligibility criteria and were randomized to active SNT (n=24) or sham SNT (n=24), and participants received a 5-day course of accelerated, high-dose intermittent theta-burst stimulation targeting an individualized left dorsolateral prefrontal cortex site. Outcomes assessed included remission at 1 month, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 10 or less, response at 1 month, defined as a 50% or greater reduction in MADRS score from baseline, longitudinal changes in MADRS scores, adverse events, and pre- to post-treatment changes in resting-state electroencephalography beta power. At 1 month, remission occurred in 50.0% of participants receiving active SNT and 20.8% receiving sham SNT (χ²₁,48=4.5, p=0.035), and response occurred in 54.2% and 25.0%, respectively (χ²₁,48=4.3, p=0.039), with generalized mixed-effects models showing significant group, time, and group-by-time effects on MADRS scores. Resting-state EEG analyses showed a significant group-by-time interaction for frontal beta power, with significant reductions after treatment in the active group but not the sham group, and greater reductions in left anterior cingulate cortex beta power correlated with greater reductions in MADRS scores immediately post-treatment (rho=0.48, p=0.019) and at 1 month (rho=0.51, p=0.012), while higher baseline left anterior cingulate cortex beta power predicted greater symptom improvement immediately post-treatment (β=−10.26, p=0.0042) and at 1 month (β=−9.00, p=0.024) in the active group only. No serious adverse events were reported, and no adverse event occurred more frequently with active than sham treatment. The authors concluded that SNT achieved higher remission and response rates than sham treatment and that reductions in left anterior cingulate cortex beta activity represented a potential mechanism of action and candidate pre-treatment biomarker of efficacy. Limitations were acknowledged and included the single-site design, the modest sample size despite being the largest SNT randomized trial to date, limited demographic diversity of participants, restriction to individuals with primary major depressive disorder, absence of an active treatment comparator, and uncertainty regarding longer-term durability of antidepressant effects beyond the reported follow-up period.
Combined Transcranial Magnetic Stimulation and Electroencephalography
The evidence for combined EEG-TMS systems as diagnostic tools (e.g., Quantalx Delphi-MD) is an evolving but still early-stage field. The published literature supports the scientific rationale for TMS-EEG as a research methodology, but clinical validation of integrated commercial devices like the Delphi-MD remains limited, with only a small number of published studies directly evaluating the platform.
TMS-EEG combines transcranial magnetic stimulation (to perturb cortical circuits) with simultaneous EEG recording (to measure the evoked response), enabling direct, objective assessment of cortical excitability, inhibition, connectivity, and plasticity—independent of the patient's conscious effort (Ferrarelli et al., 2021; Ziemann et al., 2026). A 2026 international expert consensus review describes TMS-EEG as "rapidly shaping a dynamic new field in clinical neurophysiology," with emerging diagnostic and prognostic utility across psychiatric and neurological disorders (Ziemann et al., 2026). However, the same review and a 2023 expert panel both emphasize significant methodological challenges, including artifact contamination, lack of standardization across equipment and analysis pipelines, and limited reproducibility between laboratories (Ziemann et al., 2026; Hernandez-Pavon et al., 2023).
TMS-EEG has identified alterations in GABAergic inhibition and gamma oscillations in schizophrenia and mood disorders, with potential as biomarkers for treatment response prediction. A 2025 systematic review found that the most promising predictive biomarker is baseline N100 amplitude for predicting depression response to rTMS/iTBS, though sample sizes remain small (n = 113 across 2 studies) (Prokop-Millar et al., 2025).
TMS-EEG has potential application in Alzheimer’s disease and mild cognitive impairment. A systematic review of 22 TMS-EEG studies (592 MCI/AD patients, 301 controls) found specific patterns of excitability, plasticity, and connectivity distinguishing individuals on the AD spectrum from cognitively normal adults, with correlations to cognitive performance and AD biomarkers (Hall et al., 2024). Reduced short-latency afferent inhibition (reflecting cholinergic dysfunction) has been demonstrated in MCI using TMS-EEG (Mimura et al., 2024).
TMS-EEG has been investigated as a noninvasive biomarker for epilepsy, with studies demonstrating that anti-seizure medications modulate specific TEP components (increased N45, decreased N100 and P180 amplitudes). However, a 2023 systematic review of 20 articles found poor methodological uniformity and inconsistent reporting of study parameters, limiting the validity of TMS-EEG as an established epilepsy biomarker (Gefferie et al., 2023).
A 2024 study using the Delphi-MD system specifically found that TMS-EEG could detect occipital network involvement in early Parkinson's disease patients (within 5 years of diagnosis), demonstrating the platform's capability to identify neurophysiological changes beyond the motor cortex (Zifman et al., 2024).
TMS-EEG studies have shown altered cortical neuroplasticity and inhibitory function following mild traumatic brain injury (mTBI), with changes in TMS-evoked potentials persisting even after clinical symptom resolution (Coyle et al., 2023; Moore et al., 2026; Opie et al., 2019).
TMS-EEG has been used to evaluate the unconscious state. A study aimed to validate the Perturbational Complexity Index, a brain-based metric of consciousness, and apply it to stratify unresponsive patients with disorders of consciousness (Casarotto et al., 2016). The investigators first established the index in a large benchmark cohort of 150 individuals, including healthy subjects and communicative brain-injured patients assessed across conscious, unconscious, and disconnected conscious states such as sleep and anesthesia, using transcranial magnetic stimulation combined with electroencephalography to quantify cortical response complexity. They then derived an empirical cutoff via receiver operating characteristic analysis that optimally distinguished conscious from unconscious conditions based on subjective reports. This cutoff was subsequently applied to 81 noncommunicative patients, including those in minimally conscious and vegetative states, who underwent similar TMS-EEG assessments alongside behavioral evaluations using the Coma Recovery Scale-Revised. Results demonstrated that the index discriminated conscious from unconscious states in the benchmark population with 100% sensitivity and specificity, and it identified minimally conscious state patients with high sensitivity of 94.7%. Importantly, a subset of patients diagnosed as vegetative state exhibited high complexity values comparable to conscious individuals, suggesting possible covert consciousness not detectable through behavior alone. The study also revealed heterogeneity within vegetative state patients, stratifying them into no-response, low-complexity, and high-complexity subgroups with differing neurophysiological profiles and clinical trajectories. Limitations include reliance on subjective report as the gold standard in the benchmark population, which may be imperfect, potential variability in TMS targeting and EEG signal quality, heterogeneity of brain injuries limiting anatomical inference, and uncertainty regarding whether high complexity definitively indicates conscious experience in noncommunicative patients, as well as the lack of longitudinal validation for prognostic use.
Aria and colleagues (2021) noted that the unconscious state has been examined in many studies so far; however, the pathophysiology of this state is still unclear. Recently, combined electroencephalography (EEG) and TMS (TMS-EEG) has been developed to allow for non-invasive evaluation of neurophysiology in the cerebral cortex. These researchers carried out a systematic literature search for TMS-EEG studies on the human unconscious state using PubMed with cross-reference and manual searches. The initial search yielded 137 articles, and 19 of them were identified as relevant, including 1 article found by manual search. This review included 10 studies for unresponsive wakefulness syndrome (UWS), 9 for minimally conscious states (MCS), 5 for medication-induced unconscious states, and 6 for natural non-rapid eye movement states. These studies analyzed TMS-evoked potential to calculate the perturbational complexity index (PCI) and OFF-periods. In particular, PCI was found to be a potentially useful marker to differentiate between UWS and MCS. The authors concluded that this review demonstrated that TMS-EEG could represent a promising neuroscientific tool to examine various unconscious states. Moreover, these investigators stated that further TMS-EEG research may help elucidate the neural basis of the unconscious state.
Porcaro and associates (2022) stated that when treating patients with a disorder of consciousness (DOC), it is important to obtain an accurate diagnosis as soon as possible to generate individualized treatment programs. However, accurately diagnosing patients with DOCs is challenging and prone to errors when differentiating patients in a vegetative state (VS)/UWS from those in an MCS. Upwards of approximately 40% of patients with a DOC can be misdiagnosed when specifically designed behavioral scales are not employed or improperly administered. To improve diagnostic accuracy for these patients, several important neuroimaging and electrophysiological technologies have been proposed. These include PET, fMRI, EEG, and TMS. These investigators reviewed the different ways in which these techniques could improve diagnostic differentiation between VS/UWS and MCS patients. They did so by referring to studies that were carried out within the past decade, which were extracted from the PubMed database. A total of 55 studies met selection criteria (clinical diagnoses of VS/UWS from MCS as made by PET, fMRI, EEG, and TMS-EEG tools) and were included in this review. These researchers noted that by summarizing the promising results achieved in understanding and diagnosing these conditions, they aimed to emphasize the need for more such tools to be incorporated into standard clinical practice, as well as the importance of data sharing to incentivize the community to meet these goals. The authors stated that TMS-EEG in a cognitive experiment allows for the observation of event-related potentials that follow cortical stimulation from TMS, known as TMS-evoked potentials. Moreover, these researchers stated that despite these promising early results, TMS-EEG is not yet available for clinical purposes. However, further research and developments should be pursued for its eventual implementation in clinical settings.
Zifman et al. (2019) aimed to evaluate whether a novel transcranial magnetic stimulation–electroencephalography (TMS–EEG)–based method (DELPHI) could provide a direct, objective measure of brain network function and distinguish normal aging from abnormal aging, such as mild dementia. The investigators conducted a cross-sectional study including 80 healthy participants across age groups (25–85 years) and 20 older adults with mild dementia, all of whom underwent MRI, neurocognitive testing, and standardized TMS–EEG assessment; DELPHI analysis quantified multiple electrophysiological features of brain network function, including connectivity, coherence, evoked response slopes, and short-term plasticity derived from TMS-evoked potentials. Results demonstrated a progressive age-related decline in interhemispheric and regional connectivity, particularly in temporal and parietal networks, as well as reductions in evoked response slopes, indicating diminished network efficiency with aging. Compared with age-matched healthy controls, patients with mild dementia showed more pronounced reductions in global and frontal interhemispheric connectivity, altered excitatory–inhibitory balance reflected in slope changes, and distinct abnormalities in plasticity measures that enabled clear differentiation between normal and pathological aging. Additionally, DELPHI-derived measures exhibited high reproducibility (reliability coefficients ~0.9), suggesting utility as a biomarker for monitoring brain health. Key study limitations include its relatively small sample size, particularly for the dementia group; cross-sectional design limiting inference about longitudinal changes or predictive validity; lack of stratification by dementia subtype or earlier prodromal stages such as mild cognitive impairment; and potential generalizability constraints due to single-protocol TMS stimulation focused primarily on motor cortex regions, highlighting the need for larger, longitudinal studies to validate clinical applicability.
Fogel et al. (2021) sought to identify early neurophysiological biomarkers of neurodegenerative cognitive decline by examining brain network integrity and structural changes across individuals with subjective cognitive decline, mild cognitive impairment, dementia, and healthy controls. The investigators conducted a cross-sectional study involving 55 participants who underwent comprehensive evaluation, including computerized cognitive testing, magnetic resonance imaging for gray matter volume, diffusion tensor imaging for white matter integrity, and transcranial magnetic stimulation with electroencephalography using the DELPHI system to assess network connectivity, excitability, and plasticity. Results demonstrated that individuals with subjective cognitive decline, despite normal cognitive testing and preserved gray matter volume, exhibited significant reductions in white matter integrity and altered neurophysiological network measures compared with healthy controls, while similar but more pronounced abnormalities were observed in mild cognitive impairment and dementia groups. Importantly, gray matter atrophy was only evident in mild cognitive impairment and dementia, suggesting that functional and microstructural disruptions precede detectable structural brain loss and objective cognitive impairment. These findings support the concept that TMS-EEG and diffusion tensor imaging may provide sensitive early indicators of neurodegenerative processes before traditional clinical markers emerge. Study limitations include the small sample size across groups, the cross-sectional design that limits causal inference and progression assessment, potential heterogeneity within subjective cognitive decline and mild cognitive impairment populations, and the need for longitudinal studies and larger cohorts to validate the findings and determine predictive clinical utility.
Zifman et al. (2024) aimed to determine whether transcranial magnetic stimulation–evoked potentials (TEPs) could identify network-level differences in Parkinson’s disease (PD), particularly across clinical subgroups, and to assess the role of occipital (visual) cortical involvement in early-stage PD. The investigators conducted a cross-sectional analysis of 62 patients with PD (within ~5 years of diagnosis) and 76 healthy controls using a TMS–EEG “Delphi” protocol that stimulated three cortical regions: primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), and primary visual cortex (V1), with measurement of four electrophysiologic metrics (wide waveform adherence [wWFA], interhemispheric connectivity, cortical excitability, and late phase latency). PD participants were stratified into tremor-dominant (TD), non–tremor-dominant (NTD), and rapid disease progression (RDP) subgroups, and analyses included ANCOVA adjusted for cognitive status, subgroup comparisons, and logistic regression for discriminatory accuracy. Results showed that, compared with controls, PD patients had significantly reduced waveform adherence and interhemispheric connectivity across all stimulation sites, indicating disrupted network integrity; notably, occipital connectivity was inversely correlated with disease severity. Among subgroups, NTD and RDP patients exhibited lower occipital wWFA than TD patients, and occipital TEP measures were most effective in distinguishing RDP cases (area under the curve ~0.85), suggesting early involvement of posterior cortical networks even in non-demented patients. The study’s limitations include its cross-sectional design, modest sample size (especially in the RDP subgroup), assessment only in the medication “ON” state, limited cognitive characterization using MoCA alone, averaging of hemispheric stimulation despite disease asymmetry, and lack of longitudinal validation of subgroup progression, all of which may restrict generalizability and causal inference.
A study by Maidan et al. (2021) investigated neurophysiological alterations in Parkinson’s disease using a multimodal transcranial magnetic stimulation combined with electroencephalography approach to characterize cortical function and connectivity. The investigators conducted a cross-sectional case-control study including 32 patients with Parkinson’s disease and 21 healthy controls, who underwent TMS-EEG stimulation of four cortical regions consisting of bilateral primary motor cortex and bilateral dorsolateral prefrontal cortex, with analysis of six TMS-evoked potential metrics including waveform adherence, early and late phase deflections, short-term plasticity, inter-trial adherence, and interhemispheric connectivity using linear mixed models and correlation analyses. The results demonstrated that patients with Parkinson’s disease exhibited significant neurophysiological abnormalities compared with controls, including reduced waveform adherence, reduced early phase deflection, lower inter-trial adherence indicating greater variability in cortical responses, and decreased interhemispheric connectivity, while short-term plasticity and late phase deflection were not significantly different between groups. Additionally, reduced inter-trial adherence correlated with longer disease duration, and combined neurophysiological measures showed high diagnostic performance with an area under the curve of 0.898 for distinguishing Parkinson’s disease from controls. These findings suggest that altered cortical excitability, disrupted connectivity, and increased variability of neural responses reflect underlying disease mechanisms and may serve as potential biomarkers of Parkinson’s disease pathophysiology. Study limitations include the modest sample size, cross-sectional design that limits inference about disease progression, potential confounding from medication effects since patients were assessed in the medicated state, and the lack of comparison across disease stages or other neurodegenerative populations, indicating that further longitudinal and comparative studies are needed.
An exploratory study aimed to evaluate whether transcranial magnetic stimulation–evoked potentials (TEPs) could serve as noninvasive neurophysiological biomarkers to diagnose idiopathic normal pressure hydrocephalus (iNPH) and predict response to ventriculoperitoneal shunt (VPS) surgery, potentially replacing invasive cerebrospinal fluid tap testing (Davidy et al., 2025). The investigators conducted a longitudinal study of 37 patients with suspected iNPH and 16 age-matched healthy controls, all of whom underwent TMS–EEG (Delphi) assessment measuring cortical responses to motor (M1) and dorsolateral prefrontal cortex (DLPFC) stimulation; baseline clinical, imaging, and functional evaluations were collected, and 16 patients proceeded to VPS with outcomes assessed at 3 months using the modified Rankin Scale (MRS), clinical global impression of change (CGIC), and timed up-and-go (TUG) testing, with statistical analyses including correlations and receiver operating characteristic (ROC) modeling. Results showed that TEP-derived metrics differed between responders and controls, with earlier M1 P60 and P180 latencies in responders, and that a composite “Delphi-NPH index” integrating multiple TEP features predicted VPS response with high accuracy (ROC AUC 0.91), outperforming conventional imaging parameters and clinical tests such as TUG and CSF tap testing. Additionally, several TEP measures correlated with post-surgical gait improvement and functional outcomes, suggesting that preserved or enhanced cortical excitability and network dynamics may underlie treatment responsiveness. However, the study has notable limitations, including its small sample size and limited number of surgical cases, short follow-up duration (3 months), reliance primarily on gait-related outcome measures rather than comprehensive cognitive and urinary assessments, use of semi-quantitative clinical scales rather than objective continuous monitoring, and lack of comparison with other invasive diagnostic procedures or long-term validation, which together constrain generalizability and highlight the need for larger, prospective studies.
Levy-Lamdan et al. (2020) evaluated whether a transcranial magnetic stimulation and electroencephalography-based system, known as DELPHI, can detect and quantify white matter connectivity damage in patients with stroke and traumatic brain injury and relate these findings to established structural imaging measures. The investigators conducted a cross-sectional analysis of 123 participants, including 53 patients with white matter pathology and 70 healthy controls, all of whom underwent DELPHI TMS-EEG assessments and diffusion tensor imaging to measure fractional anisotropy as an index of white matter integrity. DELPHI-derived features of TMS-evoked potentials, including early and late phase deflections, waveform adherence, and short-term plasticity indices, were extracted and analyzed using statistical comparisons, machine learning classification with support vector machines, and multivariate regression to assess relationships with diffusion tensor imaging metrics. Results showed significant differences in DELPHI measures between healthy controls and patients, and a multidimensional classification model distinguished patients from controls with balanced accuracy of approximately 0.81 and an area under the curve of 0.88. In addition, regression analyses demonstrated moderate to strong correlations between DELPHI outputs and fractional anisotropy values in key white matter tracts, particularly those near the stimulation site, suggesting that electrophysiological responses reflect underlying structural connectivity changes. These findings support the clinical potential of TMS-EEG as a noninvasive tool to assess brain network integrity and complement conventional imaging. Study limitations include its cross-sectional and retrospective design, heterogeneity of injury types and locations, lack of control for age-related brain changes in classification models, and limited ability to establish causality or predictive clinical outcomes, as well as the need for external validation and inclusion of broader patient populations to confirm generalizability.
A narrative review synthesized existing evidence on the clinical utility of single-pulse transcranial magnetic stimulation and electroencephalography-derived transcranial-evoked potentials for assessing brain physiology across neurological and psychiatric disorders (Fogel et al., 2024). The authors conducted a structured literature review of studies published between 2010 and 2024 using databases such as PubMed, Embase, and Google Scholar, ultimately including 55 peer-reviewed studies that examined diagnostic, prognostic, or treatment-related applications of TMS-EEG measures across conditions including Alzheimer’s disease, disorders of consciousness, stroke, major depressive disorder, Parkinson’s disease, and normal aging. The review categorized findings by clinical domain and analyzed commonly used TEP components and derived metrics such as waveform amplitudes, latencies, and perturbational complexity index to assess cortical excitability, connectivity, and network dynamics. Results across studies showed that TEP measures consistently reflect disease-specific alterations in cortical function, including reduced excitability with normal aging, early hyperexcitability in Alzheimer’s disease, simplified and low-complexity responses in disorders of consciousness, and characteristic changes associated with stroke recovery and psychiatric conditions. The evidence also demonstrated that TMS-EEG metrics can discriminate disease states, monitor treatment effects, and predict clinical outcomes in some contexts, with particularly strong support for use in disorders of consciousness and treatment monitoring in major depressive disorder. However, the review emphasized that methodological heterogeneity across studies, including variability in stimulation parameters and recording approaches, limited comparability, and that many findings remain based on relatively small or nonrandomized studies, highlighting the need for standardized protocols and larger randomized trials to confirm clinical utility.
Cranial Electrical Stimulation for Anxiety and Insomnia
Shekelle and colleagues (2018) noted that CES is increasingly popular as a treatment, yet its clinical benefit is unclear. These investigators reviewed evidence regarding the benefits and harms of CES for adult patients with chronic painful conditions, anxiety, depression, and insomnia. Data sources included several databases from inception to October 10, 2017 without language restrictions and references from experts, prior reviews, and manufacturers; RCTs of CES versus usual care or sham CES that reported pain, anxiety, depression, or sleep outcomes in any language were selected for analysis. Data extraction entailed single-reviewer extraction checked by another; dual independent quality assessment; strength-of-evidence grading by the first author with subsequent group discussion. A total of 28 articles from 26 randomized trials met eligibility criteria. The 2 trials that compared CES with usual care were small, and neither reported a statistically significant benefit in pain or anxiety outcomes for patients with fibromyalgia or anxiety, respectively; 14 trials with sham or placebo controls involving patients with painful conditions, such as headache, neuromuscular pain, or musculoskeletal pain, had conflicting results; 4 trials carried out more than 40 years ago and 1 from 2014 provided low-strength evidence of a possible modest benefit compared with sham treatments in patients with anxiety and depression. Trials in patients with insomnia (n = 2), insomnia and anxiety (n = 1), or depression (n = 3) had inconclusive or conflicting results. Low-strength evidence suggested that CES did not cause serious side effects. The authors concluded that evidence is insufficient that CES has clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia; low-strength evidence suggested modest benefit in patients with anxiety and depression. The authors stated that the main drawback of this study was that most trials had small sample sizes and short durations; all had high risk of bias due to inadequate blinding.
Magnetic e-Resonance Therapy (MeRT)
Magnetic e-Resonance Therapy (MeRT) is a personalized, non-invasive neuromodulation treatment that employs magnetic fields to stimulate specific areas of the brain. It is designed to address imbalances in brain activity and is used for the treatment of diseases/disorders such as autism, depression, PTSD, and TBI. MeRT begins with a quantitative electroencephalograph (qEEG) and electrocardiogram (EKG) to identify areas of the brain that are not communicating effectively. Based on this data, a personalized treatment plan is created using TMS to stimulate specific brain regions.
Taghva et al. (2015) noted that PTSD is a disabling and prevalent psychiatric disorder with limited effective therapeutic options. In addition to the clinical features of the disease, pathologic changes in EEG, including decreased alpha power, have been reported. In an open-label study, these researchers examined if magnetic brain stimulation can induce normalization of EEG abnormalities and improve symptoms in patients with PTSD. They reviewed prospectively collected data on 21 veterans who were consecutively treated for PTSD. Magnetic resonance therapy (MRT) was administered for 2 weeks at treatment frequencies based on frequency-domain analysis of each patient’s dominant alpha-band EEG frequencies and resting heart rate. Patients were evaluated on the PTSD checklist (PCL-M) and pre- and post-treatment EEGs before and after MRT. Of the 21 patients who initiated therapy, 16 completed treatment. Clinical improvements on the PCL-M were observed in these 16 patients, with an average pre-treatment score of 54.9 and post-treatment score of 31.8 (p < 0.001). Furthermore, relative global EEG alpha-band (8 to 13 Hz) power increased from 32.0% to 38.5% (p = 0.013), and EEG delta-band (1 to 4 Hz) power decreased from 32.3% to 26.8% (p = 0.028). The authors concluded that the findings of this study showed trends toward normalization of EEG and concomitant clinical improvement using magnetic stimulation for PTSD. These researchers stated that the drawbacks of this trial included the lack of a control arm, open-label design, lack of female participants, as well as lack of long-term treatment data. Given these limitations, randomized-controlled, double-blinded studies are underway.
Makale et al. (2023) stated that there are no FDA-approved treatments for the chronic sequelae of concussion; rTMS has been examined as a therapy, but outcomes have been inconsistent. These researchers developed a personalized rTMS (PrTMS) protocol involving continual rTMS stimulus frequency adjustment and progressive activation of multiple cortical sites, guided by spectral EEG-based analyses and psychological questionnaires. They acquired pilot clinical data for 185 symptomatic brain concussion patients who underwent the PrTMS protocol over an approximate 6-week period. The PrTMS protocol employed a proprietary EEG spectral frequency algorithm to define an initial stimulation frequency based on an anteriorly graded projection of the measured occipital alpha center peak, which was then used to interpolate and adjust regional stimulation frequency according to weekly EEG spectral acquisitions. PrTMS improved concussion indices and normalized the cortical alpha band center frequency and peak EEG amplitude. This potentially reflected changed neurotransmitter, cognitive, and perceptual status. The authors concluded that PrTMS may be a promising treatment for patients with persistent concussion symptoms. This observational study was limited in that there was no control group and a number of variables were not recorded, such as time since injury and levels of depression. These researchers noted that while these observations were preliminary and cursory, they may suggest further prospective research on PrTMS in concussion and examination of the spectral EEG as a concussion biomarker, with the objectives of confirmation and determining optimal PrTMS treatment parameters.
Makale et al. (2024) stated that autism spectrum condition (ASC) is a neurodevelopmental condition that is only partly responsive to prevailing interventions. ASC manifests core challenges in social skills, communication, as well as sensory function and repetitive stereotyped behaviors, along with imbalances in the brain's excitatory (E) and inhibitory (I) signaling. rTMS has shown promise in ASC and may be a useful addition to applied behavioral analysis (ABA), a gold-standard psychotherapeutic intervention. In an open-label, pilot study, ABA-treated ASC persons (n = 123) received PrTMS, which used low TMS pulse intensities and continuously updated multiple cortical stimulation locales and stimulation frequencies based on the spectral EEG and psychometrics. No adverse effects were observed, and 44% of subjects had ASC scale scores reduced to below diagnostic cut-offs. More importantly, in PrTMS responders, the spectral EEG regression flattened, implying a more balanced E/I ratio. Moreover, with older participants, alpha peak frequency increased, a positive correlate of non-verbal cognition. The authors concluded that PrTMS may be an effective ASC intervention, offering improved cognitive function and overall symptomatology. Moreover, these researchers stated that these preliminary findings warranted further research into PrTMS mechanisms and specific types of subjects who may benefit, along with validation of the present results and exploration of broader clinical applicability.
Ezedinma et al. (2024) noted that individual alpha frequency (IAF) is a biomarker of neurophysiological functioning. The IAF-guided rTMS (α-rTMS) is increasingly studied in diverse neurological conditions. However, there are limited data on the safety and effectiveness of α-rTMS in children with ASD. In a retrospective chart review, these investigators examined the IAF, childhood autism rating scale (CARS), Pediatric Quality of Life Inventory 4.0 (PedsQLTM 4.0), and semi-structured interview data of patients who received 19 α-rTMS sessions (4 weeks) using paired student t-test and descriptive method. Data were retrieved from 28 patients (26 males, aged 3 to 9 years (mean ± SD age: 6.1 ± 1.8 years)). The post-α-rTMS data showed a significant improvement in IAF (9.4 Hz; p ≤ 0.025) towards 10 Hz. The CARS and PedsQLTM 4.0 surveys indicated that patients' ASD symptoms and QoL improved significantly. Specifically, reports from semi-structured interviews suggested improved sleep trouble—the most significant co-morbidity. The experiences of minor side effects such as hyperactivity resolved within 2 hours following α-rTMS sessions. The authors concluded that this study presented evidence on the safety and effectiveness of α-rTMS in improving ASD symptoms, QoL, as well as co-morbid sleep troubles in children. Moreover, these researchers stated that these findings should be interpreted as preliminary pending the presentation of double-blind, randomized clinical trials. These investigators stated that as a consequence of the inherent limitations of retrospective studies, there is a need for future prospective studies to fully examine the safety and effectiveness of α-rTMS in children with ASD. Specific drawbacks of this trial entailed the small sample size (n = 28), lack of objective measures for improved sleep troubles, the influence of concurrent interventions such as speech and occupational therapies, as well as methylphenidate and melatonin on patients’ IAF and clinical outcomes, and a post-study follow-up.
Bailar-Heath et al. (2024) stated that special operations forces service members (SOF) are often exposed to traumatic and concussive events, increasing the prevalence of symptoms of PTSD and depression, shortening potential years of service. In a retrospective chart review, these investigators presented preliminary data on a Human Performance Optimization (HPO) program that provided an average of 30 sessions of α-rTMS to active-duty SOF to reduce symptoms of PTSD and depression following TBI. Scores from the PTSD Checklist for DSM-5, PROMIS Depression short form, and Perceived Deficits Questionnaire (PDQ) were reviewed. Significant reductions were noted after the HPO program in all clinical scales, with an average 37% decrease in PCL-5 (p < 0.01), 11.3% reduction in PROMIS depression T-scores (p < 0.01), and 45.5% reduction in PDQ scales by session 30 (p < 0.01), with side effects matching those commonly reported in rTMS. More importantly, the average PCL-5 score decreased from 42.9 to 27 by the end of the treatment program, which was below the clinical threshold of 33 for the presence of PTSD. For those with depression symptom scores greater than cut-off clinical thresholds at baseline, 46% resolved following treatment. The authors concluded that these findings provided preliminary support for the safe application of α-rTMS for symptom reduction in active-duty special operations military personnel. Moreover, these investigators stated that a randomized, sham-controlled study of α-rTMS is currently underway to corroborate these findings and further establish the safety and effectiveness of this approach.
Mohankumar et al. (2025) stated that PrTMS offers an individualized approach to neuromodulation via customized therapeutic protocols. In a case-series study, these researchers examined outcomes of PrTMS in 2 patients with PTSD, based on standardized rating scale scores and spectral EEG-guided alpha brain-wave activity optimization. Participants diagnosed with PTSD received PrTMS treatments informed by quantitative rating scales and weekly spectral EEG measurements. Weekly psychometric assessments showed an improvement in symptoms, as quantified by PCL-5 (Posttraumatic Stress Disorder Checklist for DSM-5), GAD-7 (Generalized Anxiety Disorder 7-item scale), PHQ-9 (Patient Health Questionnaire-9), and SCI (Sleep Condition Indicator) questionnaires. Specifically, PCL-5 scores showed an average reduction of 20.5 points by the mid-point of treatment (4 weeks), while GAD-7 and PHQ-9 scores decreased by 7 and 8.5 points, respectively, at the end of 7 weeks. Mean SCI scores increased by 6 points by the end of the 7-week treatment period. The authors concluded that while previous studies have also shown the role of spectral EEG-directed personalized PrTMS in the treatment of PTSD, further investigations, including multi-center randomized studies, are needed to examine the role of spectral EEG in the treatment of complex psychiatric disorders and the long-term effectiveness of PrTMS. These investigators noted that a drawback of this trial was the small sample size (n = 2), which restricted the ability to generalize the results. Another drawback was the absence of PCL-5 scores for patient 1 during the final 2 weeks of treatment, resulting from technical errors with the software in obtaining and saving the data. The use of patient-reported psychometric assessments may have resulted in potential subjective response bias. To mitigate this, spectral EEG measurements were used to support psychometric findings.
Frueh et al. (2025) noted that SOF are at particular risk of suffering from PTSD and TBI, and often these two conditions are co-morbid, with the inciting event causing both conditions. These conditions present with broad-band EEG abnormalities that may be amenable to neuromodulation. In a retrospective chart review, these investigators reported on preliminary safety and clinical response data of individualized neuromodulation in a cohort of SOF veterans suffering from symptoms of PTSD and TBI. A total of 33 male SOF veterans with TBI and PTSD symptoms received α-rTMS 5 days/week, with the magnetic pulse frequency set to their IAF. Data on clinical scale scores at baseline and conclusion of treatment were extracted, including Rivermead Post-Concussion Questionnaire (RPQ), PCL-5, and side effects. A total of 33 charts containing pre-post scales for at least one of the clinical measures collected were reviewed. TBI symptom severity decreased an average of 54% on the RPQ (p < 0.01), and PTSD symptom severity decreased an average of 37.6% on the PCL-5 (p < 0.01). For participants with PCL-5 scores above the screening threshold of 33, 69% no longer met clinical criteria for PTSD at the end of the human performance program. Side effects were consistent with those reported for standard TMS, most frequently headache and fatigue. The authors concluded that significant reductions in TBI clinical symptoms, as well as significant decreases in PTSD clinical severity, were reported in SOF veterans who underwent α-rTMS. Side effects were equivalent to those observed in normal TMS. These researchers stated that these findings supported the need for α-rTMS clinical trials in the SOF veteran population to further examine the clinical impact of this approach.
Navigated Transcranial Magnetic Stimulation
Navigated TMS is being studied as a diagnostic tool to stimulate functional cortical areas at precise anatomical locations to induce measurable responses. This technology is being investigated to map functionally essential motor areas for diagnostic purposes and for treatment planning.
Navigated TMS is a novel tool for pre-operative functional mapping. It has been used for motor mapping in the vicinity of rolandic brain lesions as well as for mapping human language areas.
Rossini and Rossi (2007) stated that TMS is widely used in clinical neurophysiology, including rehabilitation and intra-operative monitoring. Single-pulse TMS and other more recent versions (e.g., paired-pulse TMS, rTMS, integration with structural and functional MRI, and neuro-navigation) allow motor output to be mapped precisely to a given body district. Moreover, TMS can be used to assess excitatory/inhibitory intra-cortical circuits and to provide information on brain physiology and pathophysiology of various neuropsychiatric diseases, as well as on the mechanisms of brain plasticity and of neuroactive drugs. Transcranial magnetic stimulation applied over non-motor areas made it possible to extend research applications in several fields of psychophysiology. Being able to induce relatively long-lasting excitability changes, rTMS has made the treatment of neuropsychiatric diseases linked with brain excitability dysfunctions possible. The authors noted that these uses, however, warrant further large-scale studies. In emerging fields of research, TMS-EEG co-registration is considered a promising approach to evaluate cortico-cortical connectivity and brain reactivity with high temporal resolution. However, safety and ethical limitations of the TMS technique need a high level of vigilance.
Picht et al. (2011) compared the accuracy of a 3-dimensional MRI-navigated TMS system with the gold standard of direct cortical stimulation. The primary motor areas of 20 patients with rolandic tumors were mapped pre-operatively with navigated TMS at 110% of the individual resting motor threshold. Intra-operative direct cortical stimulation was available from 17 patients. The stimulus locations eliciting the largest electromyographic response in the target muscles ("hotspots") were determined for both methods. The navigated TMS and direct cortical stimulation hotspots were located on the same gyrus in all cases. The mean ± SEM distance between the navigated TMS and direct cortical stimulation hotspots was 7.83 ± 1.18 mm for the abductor pollicis brevis (APB) muscle (n = 15) and 7.07 ± 0.88 mm for the tibialis anterior (TA) muscle (n = 8). When a low number of direct cortical stimulations was performed, the distance between the navigated TMS and direct cortical stimulation hotspots increased substantially (r = -0.86 for APB). After exclusion of the cases with less than 15 direct cortical stimulation APB responses, the mean ± SEM distance between the hotspots was only 4.70 ± 1.09 mm for APB (n = 8). The authors concluded that peri-tumoral mapping of the motor cortex by navigated TMS agreed well with the gold standard of direct cortical stimulation. Thus, navigated TMS is a reliable tool for pre-operative mapping of motor function. These preliminary findings need to be validated by well-designed studies with a larger number of participants.
Picht et al. (2012) evaluated how much influence, benefit, and impact navigated TMS has on the surgical planning for tumors near the motor cortex. This study reviewed the records of 73 patients with brain tumors in or near the motor cortex, mapped pre-operatively with navigated TMS. The surgical team prospectively classified how much influence the navigated TMS results had on the surgical planning. Step-wise regression analysis was used to explore which factors predict the amount of influence, benefit, and impact navigated TMS has on the surgical planning. The influence of navigated TMS on the surgical planning was as follows: it confirmed the expected anatomy in 22% of patients, added knowledge that was not used in 23%, added awareness of high-risk areas in 27%, modified the approach in 16%, changed the planned extent of resection in 8%, and changed the surgical indication in 3%. The authors concluded that navigated TMS had an objective benefit on the surgical planning in 25% of the patients and a subjective benefit in an additional 50% of the patients. It had an impact on the surgery itself in just more than 50% of the patients.
Krieg et al. (2012) stated that navigated TMS is a newly evolving technique. Despite its supposed purpose (e.g., pre-operative central region mapping), little is known about its accuracy compared with established modalities like direct cortical stimulation and functional MR imaging (fMRI). These researchers compared the accuracy of navigated TMS with direct cortical stimulation and fMRI. Fourteen patients with tumors in or close to the pre-central gyrus were examined using navigated TMS for motor cortex mapping, as were 12 patients with lesions in the subcortical white matter motor tract. Moreover, pre-operative fMRI and intra-operative mapping of the motor cortex were performed via direct cortical stimulation, and the outlining of the motor cortex was compared. In the 14 cases of lesions affecting the pre-central gyrus, the primary motor cortex as outlined by navigated TMS correlated well with that delineated by intra-operative direct cortical stimulation mapping, with a deviation of 4.4 ± 3.4 mm between the two methods. In comparing navigated TMS with fMRI, the deviation between the two methods was much larger: 9.8 ± 8.5 mm for the upper extremity and 14.7 ± 12.4 mm for the lower extremity. In 13 of 14 cases, the surgeon admitted easier identification of the central region because of navigated TMS. The procedure had a subjectively positive influence on the operative results in 5 cases and was responsible for a changed resection strategy in 2 cases. One of 26 patients experienced navigated TMS as unpleasant; none found it painful. The authors concluded that navigated TMS correlates well with direct cortical stimulation as a gold standard despite factors that are supposed to contribute to the inaccuracy of navigated TMS. Moreover, surgeons have found navigated TMS to be an additional and helpful modality during the resection of tumors affecting eloquent motor areas, as well as during pre-operative planning. These findings need to be confirmed.
Frey et al. (2012) established a novel approach for fiber tracking based on navigated TMS mapping of the primary motor cortex and proposed a new algorithm for determination of an individualized fractional anisotropy value for reliable and objective fiber tracking. A total of 50 patients (22 females, 28 males; median age of 58 years, range of 20 to 80) with brain tumors compromising the primary motor cortex and the cortico-spinal tract underwent pre-operative MRI and navigated TMS mapping. Stimulation spots evoking muscle potentials (MEP) closest to the tumor were imported into the fiber tracking software and set as seed points for tractography. Next, the individual FA threshold, namely, the highest FA value leading to visualization of tracts at a pre-defined minimum fiber length of 110 mm, was determined. Fiber tracking was then performed at a fractional anisotropy value of 75% and 50% of the individual FA threshold. In addition, fiber tracking according to the conventional knowledge-based approach was performed. Results of tractography of either method were presented to the surgeon for pre-operative planning and integrated into the navigation system, and its impact was rated using a questionnaire. Mapping of the motor cortex was successful in all patients. A fractional anisotropy threshold for cortico-spinal tract reconstruction could be obtained in every case. TMS-based results changed or modified surgical strategy in 23 of 50 patients (46%), whereas knowledge-based results would have changed surgical strategy in 11 of 50 patients (22%). Tractography results facilitated intra-operative orientation and electrical stimulation in 28 of 50 (56%) patients. Tracking at 75% of the individual FA thresholds was considered most beneficial by the respective surgeons. The authors concluded that fiber tracking based on navigated TMS by the proposed standardized algorithm represents an objective visualization method based on functional data and provides a valuable instrument for pre-operative planning and intra-operative orientation and monitoring. This was a small study, and it did not validate navigated TMS findings with improved health outcomes.
Tarapore et al. (2012) noted that direct cortical stimulation is the gold-standard technique for motor mapping during craniotomy. However, pre-operative non-invasive motor mapping is becoming increasingly accurate. Two such non-invasive modalities are navigated TMS and magnetoencephalography (MEG) imaging. These investigators compared the accuracy of TMS to both direct cortical stimulation and MEG imaging. Patients with tumors in proximity to the primary motor cortex underwent pre-operative TMS and MEG imaging for motor mapping. The patients subsequently underwent motor mapping via intra-operative direct cortical stimulation. The loci of maximal response were recorded from each modality and compared. Motor strength was assessed at 3 months post-operatively. Transcranial magnetic stimulation and MEG imaging were performed on 24 patients. Intra-operative direct cortical stimulation yielded 8 positive motor sites in 5 patients. The median distance ± SEM between TMS and direct cortical stimulation motor sites was 2.13 ± 0.29 mm, and between TMS and MEG imaging motor sites was 4.71 ± 1.08 mm. In no patients did direct cortical stimulation motor mapping reveal a motor site that was unrecognized by TMS. Three of 24 patients developed new, early neurological deficit in the form of upper-extremity paresis. At the 3-month follow-up evaluation, 2 of these patients were significantly improved, experiencing difficulty only with fine motor tasks; the remaining patient had improvement to 4/5 strength. There were no deaths over the course of the study. The authors concluded that maps of the motor system generated with TMS correlate well with those generated by both MEG imaging and direct cortical stimulation. Negative TMS mapping also correlates with negative direct cortical stimulation mapping.
In a feasibility study, Forster et al. (2012) examined cortical motor representation after resection of peri-rolandic World Health Organization grade II and III gliomas using navigated TMS. A total of 5 patients were examined before neurosurgery and after a follow-up period of 17.7 ± 6.8 months. As a control, 5 healthy age-matched subjects were equally studied by navigated TMS in 2 sessions spaced 12.6 (range of 2 to 35) days apart. Resting motor thresholds (RMT), hotspots, and centers of gravity (CoG) were identified for the first dorsal interosseous (FDI), APB, extensor digitorum (EXT), TA, and abductor hallucis (AH) muscles. Euclidean distances, coefficients of variance, and intra-class correlation coefficients (ICC) were calculated. Healthy subjects showed moderate-to-excellent reliability measurement of RMT (ICC = 0.69 to 0.94). Average displacement of CoGs across sessions was 0.68 ± 0.34 cm in the dominant and 0.76 ± 0.38 cm in the non-dominant hemisphere; hotspots moved 0.87 ± 0.51 cm and 0.83 ± 0.45 cm, respectively. In 1 patient, these parameters differed significantly from the control group (p < 0.05 for both CoGs and hotspots). Overall, all patients' CoGs moved 1.12 ± 0.93 cm, and hotspots were 1.06 ± 0.7 cm apart. In both patients and healthy subjects, movement of assessed parameters was more important along the X- than the Y-axis. The authors concluded that navigated TMS allows evaluating cortical re-organization after brain tumor surgery. It may contribute to the understanding of neurofunctional dynamics, thus influencing therapeutic strategy.
Makela et al. (2013) stated that navigated TMS has been suggested to be useful in pre-operative functional localization of the motor cortex in patients having tumors close to the somato-motor cortex. These researchers described functional plasticity of the motor cortex indicated by navigated TMS in 2 patients with epilepsy. Navigated TMS, fMRI, diffusion-tensor (DT)-tractography, and MEG were utilized to pre-operatively localize motor cortical areas in the work-up for epilepsy surgery. The localizations were compared with each other, with the cortical anatomical landmarks, and in 1 patient with invasive electrical cortical stimulation (ECS). In 2 out of 19 studied patients, navigated TMS identified motor cortical sites that differed from those indicated by anatomical landmarks. In 1 patient, navigated TMS activated preferentially premotor cortex rather than pathways originating from the pre-central gyrus. Functional MRI and MEG localizations conformed with navigated TMS, whereas ECS localized finger motor function into the pre-central gyrus. Resection of the area producing motor responses in biphasic navigated TMS did not produce a motor deficit. In the other patient, navigated TMS indicated abnormal ipsilateral hand motor cortex localization and confirmed the functionality of aberrant motor cortical representations of the left foot, also indicated by fMRI and DT-tractography. The authors concluded that navigated TMS may reveal the functional plasticity and shifts of motor cortical function. Epileptic foci may modify cortical inhibition, and the navigated TMS results. Thus, the authors noted that in some patients with epilepsy, the navigated TMS results need to be interpreted with caution with regard to surgical planning.
Frey et al. (2014) reported on a prospective cohort analysis designed to assess whether navigated transcranial magnetic stimulation (nTMS) improves treatment outcomes in patients with brain tumors located in motor eloquent areas. The investigators enrolled 250 consecutive patients undergoing preoperative nTMS motor mapping and compared their outcomes to a matched historical control group of 115 patients who did not receive nTMS. The primary objectives were to evaluate the impact of nTMS on surgical decision-making, extent of resection, neurological outcomes, and progression-free survival. The investigators found that nTMS mapping altered surgical strategy in a substantial proportion of cases: it ruled out suspected motor cortex involvement in 25.1%, expanded surgical indications in 14.8%, and led to more extensive resections in 35.2% and more restrictive resections in 3.5%. The gross total resection (GTR) rate increased significantly from 42% in controls to 59% in the nTMS group. For low-grade glioma, progression-free survival was significantly longer in the nTMS group (22.4 months vs. 15.4 months). The rate of new postoperative motor deficits was lower in the nTMS group (6.1% vs. 8.5%), but this difference was not statistically significant. Limitations of the study include its non-randomized design, use of a historical control group (introducing potential bias from changes in surgical technique or perioperative care over time), and single-center setting, which may limit generalizability. Additionally, while the study demonstrates improved oncological outcomes and surgical decision-making, the reduction in postoperative deficits did not reach statistical significance, and long-term functional outcomes were not fully addressed.
A commentary accompanying the study by Frey et al. noted many of these limitations (Jensen, 2014). The commentator stated that the major limitation of this study is the comparison of two cohorts with data not collected concurrently. The editorialist noted that, in comparing two groups: patients treated over two years without nTMS and patients treated over a subsequent five years with nTMS, the study design complicates interpretation, as the authors have certainly improved their technique and judgment during these time frames. Progression-free survival (PFS) was improved, but overall survival (OS) remained unchanged. The improved PFS might be explained in part by a much lower number of “biopsy-only” cases. The study did not report the mix of patient molecular profiles between the two groups, which could impact PFS or OS. The commentator noted that measurement of PFS in gliomas can be technically problematic given the reliance on imaging and the timing of imaging, as well as definitions of “progression.” The commentator noted that another of the limitations of this technique is that nTMS is still subject to interpretation by the surgeon preoperatively, but that functional MRI (fMRI) suffers from the same limitations. They found that the mean (range) distance between nTMS and intraoperative stimulating mapping hotspots for abductor pollicis brevis was 6.2 mm (0.4–14.8); however, it has been demonstrated that injury to neurological pathways occurs when tumor resection is carried out within a distance of 5–10 mm from the stimulation-positive site. The commentator noted, furthermore, that this technique is limited to motor function and is not useful for speech or language mapping, thus the need for preoperative fMRI or intraoperative mapping remains.
Krieg et al. (2016) evaluated whether preoperative navigated transcranial magnetic stimulation (nTMS) motor mapping improves surgical outcomes for patients with brain metastases in motor-eloquent (peri-Rolandic) regions. The study reported a comparison of two prospectively enrolled observational cohorts: 120 patients who underwent preoperative nTMS mapping (2010–2015) and 130 patients who did not (2006–2015). The investigators stated that the cohorts were comparable in terms of tumor location, pathology, size, and preoperative motor deficits. The investigators reported a significantly lower rate of residual tumor on postoperative MRI in the nTMS group (odds ratio 0.30, 95% CI 0.14–0.67), smaller craniotomy size (16.7 ± 8.6 cm² vs. 25.0 ± 17.1 cm²), and shorter surgical time (128.8 ± 49.4 min vs. 158.0 ± 65.8 min) compared to the non-nTMS group. Long-term follow-up showed improved surgery-related motor outcomes in the nTMS group: paresis improved in 30.8% (vs. 13.1%), was unchanged in 65.8% (vs. 73.8%), and worsened in 3.4% (vs. 13.1%) of patients (p = 0.0002). Limitations of the study include its non-randomized design, use of historical controls (raising the possibility of confounding by changes in surgical technique or perioperative care over time), and single-center setting, which may limit generalizability. The authors note that further evaluation in prospective, randomized trials is warranted to confirm these findings.
Raffa and colleagues (2019) stated that navigated TMS (nTMS) is an emerging tool for surgery of motor-eloquent intrinsic brain tumors; however, a critical re-appraisal of the literature evidence has never been performed. These researchers carried out a systematic review and meta-analysis using PubMed/Medline and the Cochrane Central Register of Controlled Trials for studies that analyzed the impact of nTMS-based motor mapping on surgery of patients affected by motor-eloquent intrinsic brain tumors, in comparison with series of patients operated without using nTMS. The impact of nTMS mapping was assessed by analyzing the occurrence of post-operative new permanent motor deficits, the gross total resection rate (GTR), the size of craniotomy, and the length of surgery. A total of 8 studies were included in the quantitative review and meta-analysis. The pooled analysis showed that nTMS motor mapping significantly reduced the risk of post-operative new permanent motor deficits (OR = 0.54, p = 0.001, data available from 8 studies) and increased the GTR rate (OR = 2.32, p < 0.001, data from 7 studies). Moreover, results from 4 studies documented that the craniotomy size was reduced in the nTMS group (-6.24 cm², p < 0.001), whereas a trend towards a reduction, even if non-significant, was observed for the length of surgery (-10.30 mins, p = 0.38; in 3 studies). The authors concluded that available literature provided data in favor of the use of nTMS motor mapping: its use appeared to be associated with a reduced occurrence of post-operative permanent motor deficits, an increased GTR rate, and a tailored surgical approach compared to standard surgery without using pre-operative nTMS mapping. Nonetheless, a growing need for high-level evidence regarding the use of nTMS motor mapping in brain tumor surgery is perceived. These researchers stated that well-designed RCTs from multiple institutions are needed to continue to shed light on this emerging topic.
Sollmann and associates (2019) stated that nTMS in combination with diffusion tensor imaging fiber tracking (DTI FT) is increasingly used to locate subcortical language-related pathways. These researchers attempted to establish nTMS-based DTI FT for pre-operative risk stratification by evaluating associations between lesion-to-tract distances (LTDs) and aphasia and by determining a cut-off LTD value to prevent surgery-related permanent aphasia. A total of 50 patients with left-hemispheric, language-eloquent brain tumors underwent pre-operative nTMS language mapping and nTMS-based DTI FT, followed by tumor resection. nTMS-based DTI FT was performed with a pre-defined fractional anisotropy (FA) of 0.10, 0.15, 50% of the individual FA threshold (FAT), and 75% FAT (minimum fiber length [FL]: 100 mm). The arcuate fascicle (AF), superior longitudinal fascicle (SLF), inferior longitudinal fascicle (ILF), uncinate fascicle (UC), and fronto-occipital fascicle (FoF) were identified in nTMS-based tractography, and minimum LTDs were measured between the lesion and the AF and between the lesion and the closest other subcortical language-related pathway (SLF, ILF, UC, or FoF). LTDs were then associated with the level of aphasia (no/transient or permanent surgery-related aphasia, according to follow-up examinations). A significant difference in LTDs was observed between patients with no or only surgery-related transient impairment and those who developed surgery-related permanent aphasia with regard to the AF (FA = 0.10, p = 0.0321; FA = 0.15, p = 0.0143; FA = 50% FAT, p = 0.0106) as well as the closest other subcortical language-related pathway (FA = 0.10, p = 0.0182; FA = 0.15, p = 0.0200; FA = 50% FAT, p = 0.0077). Patients with surgery-related permanent aphasia showed the lowest LTDs in relation to these tracts. Thus, LTDs of greater than or equal to 8 mm (AF) and greater than or equal to 11 mm (SLF, ILF, UC, or FoF) were determined as cut-off values for surgery-related permanent aphasia. The authors concluded that nTMS-based DTI FT of subcortical language-related pathways appeared suitable for risk stratification and prediction in patients suffering from language-eloquent brain tumors. Therefore, the current role of nTMS-based DTI FT might be expanded, going beyond the level of being a mere tool for surgical planning and resection guidance.
Sollmann et al. (2020) sought to determine the value of combining preoperative navigated transcranial magnetic stimulation (nTMS) mapping with nTMS-based diffusion tensor imaging fiber tracking (DTI FT) for individualized risk assessment of surgery-related motor or language deficits in patients with highly eloquent brain tumors. This retrospective analysis included 250 preoperative nTMS mappings (150 motor, 100 language) from 216 patients with predominantly high-grade gliomas. Deterministic tractography was performed using nTMS-derived cortical maps as seed regions, and lesion-to-tract distances (LTDs) were measured between the tumor and the corticospinal tract (CST), arcuate fascicle (AF), or other language-related tracts. LTDs were correlated with postoperative functional outcomes (no, transient, or permanent deficits). The results demonstrated that shorter LTDs were significantly associated with permanent postoperative deficits. Specifically, cut-off values for increased risk were ≤12 mm for LTD-CST (motor deficits), ≤16 mm for LTD-AF, and ≤25 mm for LTD to other language tracts (aphasia). There were strong negative correlations between LTD and the likelihood of permanent deficits, supporting the use of these measurements for risk stratification. Limitations of this study include the retrospective design, single-center setting, and lack of randomization. The study population was heterogeneous, and the findings may not be generalizable to all tumor types or centers. Additionally, while LTD thresholds were identified, prospective validation is needed to confirm their predictive value in clinical practice.
Hendrix et al. (2021) aimed to determine whether preoperative navigated transcranial magnetic stimulation (nTMS) improves gross total resection (GTR) rates in patients with motor-eloquent high-grade gliomas. The investigators reported on a retrospective matched cohort study including 105 patients who underwent nTMS-guided surgery and 105 matched controls who did not receive nTMS mapping. The primary outcomes were GTR rates and postoperative motor function, with subgroup analyses for WHO grade III/IV gliomas and brain metastases. Results showed that GTR was significantly more frequent in the nTMS group compared to controls (P = .02), particularly in the WHO III/IV glioma subgroup (72.3% vs. 53.2%, P = .049). There was no significant difference in postoperative motor outcomes between groups. In patients with brain metastases, GTR rates and motor outcomes were similar regardless of nTMS use. Multivariable analysis indicated that prolonged survival in high-grade glioma was associated with achieving GTR and younger age, but not directly with nTMS mapping. Limitations include the retrospective design, potential selection bias, and the use of matched historical controls rather than randomization. The study was also single-center, which may limit generalizability. Additionally, while nTMS improved GTR rates, the study did not demonstrate a direct survival benefit attributable solely to nTMS mapping, and the impact on long-term functional outcomes remains uncertain.
Narayana et al. (2021) evaluated the clinical utility of transcranial magnetic stimulation (TMS) for presurgical mapping of motor, speech, and language cortices in young children with refractory epilepsy or brain tumors. This retrospective chart review included 47 TMS mapping sessions in 36 children aged 3 years or younger for motor mapping, and 13 children aged 5–6 years for language mapping. The primary hand motor cortex was successfully identified in at least one hemisphere in 33 of 36 children, and bilaterally in 27. Leg motor cortex was mapped in 17 children. For language mapping, temporal language cortices were identified in 11 of 13 children, and frontal language areas in 6, with right hemisphere dominance for expressive language in most cases. The investigators reported that TMS mapping was feasible and safe, with seizures occurring in 10 children during or after TMS, all consistent with their baseline semiology and none requiring intervention or interrupting mapping. Postoperative outcomes showed preserved or improved motor function in 9 of 11 children who underwent surgery, and preserved language function in all 7 children with lesions near eloquent cortex. Limitations include the retrospective design (chart review), small sample size, lack of a control group, and the preliminary nature of the findings. The study population was highly selected, and results may not generalize to all pediatric patients.
Rosenstock et al. (2024) assessed the feasibility and clinical utility of bihemispheric repetitive navigated transcranial magnetic stimulation (rnTMS) for language lateralization in pediatric neurosurgical patients. Nineteen children (mean age 12.5 years, range 4–17) with language-associated lesions underwent preoperative rnTMS mapping of 100 stimulation sites per hemisphere. The primary outcome was the hemispheric dominance ratio (HDR), calculated as the ratio of left to right hemisphere error rates during language mapping. Feasibility, adverse events, surgical site, and postoperative language outcomes at 3 months were also evaluated. rnTMS mapping was feasible in all patients without relevant adverse events. Thirteen children (68%) demonstrated left hemispheric dominance (HDR > 1.1), two (11%) had right dominance (HDR < 0.9), and four (21%) had nearly equal bihemispheric involvement (HDR 0.9–1.1). Of the 16 children who underwent surgery, 25% showed improved language function, 63% remained stable, and 12.5% experienced deterioration postoperatively. Notably, none of the children with right or bihemispheric language involvement (HDR ≤ 1.1) had postoperative language decline. Right hemispheric language involvement was more common in children with glial tumors, focal cortical dysplasia, or hypoxic injury. Limitations of this study include the small sample size, single-center design, and lack of a direct comparison to gold-standard intraoperative mapping. The correlation between rnTMS findings and long-term language outcomes requires further validation.
A consensus statement (Rossi et al., 2021) was developed by the International Federation of Clinical Neurophysiology (IFCN) to update and expand safety, ethical, and operational guidelines for transcranial magnetic stimulation (TMS) use in both healthy subjects and patient populations. The objectives were to address new developments in TMS technology, applications, and safety data since the prior 2009 guidelines, and to provide updated recommendations on operator training, device safety, and ethical considerations. The methods involved a consensus process among international experts, incorporating evidence from the literature and clinical experience up to April 2020. The statement covers safety issues related to new stimulation devices and pulse configurations, responsibilities of device manufacturers, TMS in neuroimaging and robot-guided contexts, TMS combined with other neuromodulation techniques, and the use of TMS for therapeutic seizure induction (magnetic seizure therapy). It also provides updated recommendations for operator training and ethical considerations, particularly regarding neuroenhancement. Key results include the reaffirmation that, when performed within established safety parameters and with appropriate screening, TMS is associated with a low risk of serious adverse events, including seizures—even in patients taking central nervous system-active medications. The risk of seizure remains the most serious potential complication, but is rare with standard protocols and focal coils. The guidelines emphasize the importance of operator training, adherence to safety protocols, and careful subject selection. New operational guidelines are provided for planning future trials and for the safe use of both traditional and patterned TMS protocols. Limitations of the consensus statement include reliance on expert opinion where high-quality evidence is lacking, and the fact that recommendations may not cover all possible device types or emerging protocols. The document also notes that some recommendations from the 2009 guidelines remain valid and are not reiterated in detail. The consensus is intended to be updated as new evidence and technologies emerge.
Vucic et al. (2023) published an updated report of an International Federation of Clinical Neurophysiology (IFCN) committee, which aimed to provide a comprehensive review of the clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological disorders. The objectives were to update the previous 2008 IFCN report by systematically evaluating the evidence for TMS as a diagnostic tool across a broad range of neurological diseases, focusing on both established and emerging applications. The methods involved a consensus-based, narrative review of the literature, with committee members synthesizing data on TMS protocols, diagnostic performance, and clinical relevance. The review covered single- and paired-pulse TMS, threshold tracking, and advanced techniques such as the triple stimulation technique (TST), as well as the integration of TMS with neuroimaging and EEG. The results were that TMS has established diagnostic value in several contexts: (1) detecting upper motor neuron involvement in amyotrophic lateral sclerosis (ALS), where cortical hyperexcitability is a key biomarker; (2) identifying subclinical corticospinal tract lesions in multiple sclerosis, with abnormalities in central motor conduction time (CMCT) and TST correlating with disability; (3) aiding diagnosis in myelopathy and stroke, even when radiological findings are absent; (4) assessing cholinergic dysfunction in Alzheimer’s disease via short-latency afferent inhibition; and (5) mapping motor cortex for preoperative planning in brain tumor surgery. TMS also shows utility in evaluating nerve root and facial nerve function, and in localizing lesions in demyelinating neuropathies. Limitations of the evidence noted by the authors include the predominance of single-center studies, variability in TMS protocols, and limited large-scale, prospective validation for many indications. The review notes that while TMS is a valuable adjunct in several diagnostic pathways, its clinical adoption is constrained by methodological heterogeneity and the need for further standardization and multicenter trials to define its role in routine practice.
In summary, there is insufficient evidence from peer-reviewed medical literature that navigated TMS is an effective clinical diagnostic test. Most of the evidence for nTMS is derived from single-center, non-randomized, or retrospective studies, with a lack of large, multicenter randomized controlled trials, which limits the generalizability and strength of the conclusions. Well-designed studies with larger sample sizes are needed to ascertain how this test can reduce clinical diagnostic uncertainty or impact treatment planning.
Appendix
Antidepressant medication classes include:
- aminoketones (Wellbutrin/SR/XL [bupropion]);
- monoamine oxidase inhibitors (MAOIs) (e.g., Marplan, Nardil, Parnate, phenelzine, tranylcypromine);
- N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., Spravato, Auvelity);
- noradrenaline and specific serotoninergic antidepressants (NASSAs) (e.g., amoxapine, maprotiline, mirtazapine/ODT, Oleptro ER, Remeron/Solutab, trazodone);
- selective serotonin reuptake inhibitors (SSRIs) (e.g., Celexa, citalopram, escitalopram, fluoxetine, fluvoxamine, Lexapro, Luvox/CR, paroxetine, Paxil/CR, Pexeva, Prozac/Weekly, sertraline, Zoloft);
- serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., Cymbalta, desvenlafaxine/ER, duloxetine, Effexor/XR, Fetzima, Irenka, Khedezla, Pristiq, venlafaxine/ER);
- tricyclic antidepressants (TCAs) (e.g., amitriptyline, desipramine, doxepin, Elavil, imipramine, Norpramin, nortriptyline, Pamelor, Surmontil, Tofranil, trimipramine); and
- serotonin modulators (e.g., Trintellix, vortioxetine, Viibryd, vilazodone).
| Brand Name | Generic Name | Dose | Frequency |
|---|---|---|---|
| Ascendin | amoxapine | 100-600 mg | once a day |
| Anafranil | clomipramine | 100-250 mg | once a day |
| Aplenzin | bupropion HBr | 174 mg to 348 mg | once a day |
| Auvelity | dextromethorphan HBr and bupropion HCl | 45 mg/105 mg | twice per day |
| Celexa | citalopram | 20-40 mg | once a day |
| Cymbalta | duloxetine | 60-120 mg | once a day |
| Desyrel | trazadone | 150-400 mg | divided dose |
| Effexor XR | venlafaxine | 75-225 mg | once a day |
| Elavil | amitriptyline | 50-150 mg | once a day |
| Emsam | selegiline | 6-9 mg | once a day |
| Fetzima | levomilnacipran | 40-120 mg | once a day |
| Khedezla ER | desvenlafaxine | 50 mg | once a day |
| Lexapro | escitalopram | 10-20 mg | once a day |
| Ludiomil | maprotiline | 75-225 mg | once a day |
| Luvox | fluvoxamine | 50-150 mg | once a day |
| Marplan | isocarboxazid | 10-60 mg | divided dose |
| Nardil | phenlyzine | ||
| Norpramin | desipramine | 100-300 mg | once a day |
| Oleptro ER | trazodone | 150-375 mg | once a day |
| Pamelor | nortriptyline | 50-150 mg | once a day or therapeutic blood level |
| Parnate | tranylcypromine | 30-60 mg | once a day |
| Paxil CR | paroxetine CR | 25-75 mg | once a day |
| Paxil | paroxetine | 20-60 mg | once a day |
| Pexeva | paroxetine | 20-60 mg | once a day |
| Pristiq | desvenlafaxine | 50-150 mg | once a day |
| Prozac | fluoxetine | 20-80 mg | once a day |
| Remeron | mirtazapine | 30-60 mg | once a day |
| Sinequan | doxepin | 75-150 mg | once a day |
| Spravato | esketamine | 56 or 84 mg | REMS protocol Weeks 1 - 4: twice per week Weeks 5 - 8: once a week Maintenance: once a week or every 2 weeks |
| Surmontil | trimipramine | 75-200 mg | once a day |
| Symbyax | fluoxetine/olanzapine | 3/25-12/50 mg | once a day |
| Trintellix | vortioxetine | 10-20 mg | once a day |
| Tofranil | imipramine | 100-300 mg | once a day |
| Viibryd | vilazodone HCl | 20-40 mg | once a day |
| Vivactil | protriptyline | 15-60 mg | once a day |
| Wellbutrin | buproprion | 300-450 mg | three times a day |
| Wellbutrin SR | buproprion SR | 200-400 mg | twice per day |
| Wellbutrin XL | buproprion XL | 150 to 450 mg | once a day |
| Zoloft | sertraline | 50-200 mg | once a day |
Augmentation therapy is defined as any of the following:
- two FDA-approved antidepressants with different mechanisms of action used concomitantly,
- an FDA-approved antidepressant and a second-generation antipsychotic used concomitantly that is FDA approved for augmenting depression treatment,
- an FDA-approved antidepressant and lithium used concomitantly,
- an FDA-approved antidepressant and thyroid hormone T3 used concomitantly.
| Brand Name | Generic Name | Dose | Frequency |
|---|---|---|---|
| Abilify | aripiprazole | 2-15 mg | once a day |
| Caplyta | lumateperone | 42 mg | once a day |
| Rexulti | brexpiprazole | 0.5-3 mg | once a day |
| Seroquel XR | quetiapine XR | 150-300 mg | once a day |
| Spravato | esketamine | 54 mg or 84 mg nasal spray | REMS protocol Weeks 1 - 4: twice per week Weeks 5 - 8: once a week Maintenance: once a week or every 2 weeks |
| Symbyax | olanzapine and fluoxetine | 6 mg/25 mg - 12 mg/50 mg | once a day |
| Vraylar | cariprazine | 1.5-3 mg | once a day |
| Zyprexa | olanzapine | only in combination with fluoxetine within dosage range Olanzapine 6-18 mg and Fluoxetine 25-50 mg | once a day |
Source: Prescribing Information
Note: Trials of medications that have no FDA approval (i.e., drugs that are not approved for use in the United States) do not qualify as adequate trials of antidepressants/augmenting agents.
References
The above policy is based on the following references:
Cranial Electrical Stimulation
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