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.
Transcranial magnetic stimulation 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 major depression or any other psychiatric disorders. 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 depression and other psychiatric disorders.
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 remain active avenues 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 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 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 2 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 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.
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 1 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-min 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 more clear answer, the National Institutes of Health has an independent study under way 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. 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 3 scales at weeks 4 and 6. Remission rates were approximately 2-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 (HAMD8) 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 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 2 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 end point 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 as 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 mins (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 2 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.
There are several limitations with the afore-mentioned study: (i) 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, (ii) 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 (iii) 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 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, can not 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 Agency for Healthcare Research and Quality's review (Gaynes et al, 2011) reported that there is insufficient evidence to evaluate whether non-pharmacological treatments are effective for TRD. The review summarized evidence of the effectiveness of 4 non-pharmacological treatments: (i) ECT, (ii) rTMS, (iii) VNS, and (iv) 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. With regard to 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.
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, cross-over 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 out-matched 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 modify specifically any of the pain subscores that were separately tested (ongoing, paroxysmal, stimulus-evoked, or disesthesic 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 of any particular submodality, but rather reduced the global pain sensation whatever its type. Moreover, they stated that these findings were driven from a small number of subjects; thus they need to be replicated.
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 mins, while in migraineurs 1 session of 10-Hz rTMS replaces the abnormal VEP potentiation by a normal habituation for 9 mins. These investigators examined if 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 between 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 thus induce long-lasting changes in cortical excitability and VEP habituation pattern. However, whether this effect may be useful in preventing migraines remains to be determined.
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 as well as subjective evaluations, with no change in parkinsonism as evaluated by Unified Parkinson Disease Rating Scale motor scores. The benefit was observed at 1 day after treatment, but not 2 weeks later. The drawbacks of this study were its small sample size and the open labeled 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 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 change 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 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. W ith 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.
Prasko et al (2007) examined if rTMS would facilitate 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 to sham rTMS. The objective of the study was to compare the 2- and 4-weeks effectiveness of the 10 sessions low-frequency rTMS with sham rTMS add on SRI therapy. These researchers used 1-Hz, 30-min rTMS, 110 % of motor threshold administered over the right dorso-lateral 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 dorso-lateral prefrontal cortex after 10 sessions did not differ from sham rTMS add on SRIs in patients with panic disorder.
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 TMS technique need a high level of vigilance.
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.
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 authros 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.
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 Hamilton Depression Rating Scale (HDRS), the Beck Depression Inventory (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.
Freitas and colleagues (2009) performed meta-analyses of all prospective studies of 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 (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 for 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.
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: (i) 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 (ii) 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 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.
In a review on autism, Levy et al (2009) stated that biologically based treatments include anti-infectives, chelation medications, gastro-intestinal medications, hyperbaric oxygen therapy, off-label drugs (e.g., secretin), and intravenous immunoglobulins. Non-biologically based treatments include auditory integration training, chiropractic therapy, cranio-sacral manipulation, facilitated communication, interactive metronome, and transcranial stimulation. However, few studies have addressed the safety and effectiveness of most of these treatments.
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 being connected and related to emotion and behavior. Researchers found selective cognitive improvement after high-frequency (HF) stimulation specifically over the left dorso-lateral pre-frontal 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".
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 disease (PD); iTBS of the motor and 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, Unified Parkinson's Disease Rating Scale (UPDRS), and additional clinical, neuropsychological, and neurophysiologic measures. These researchers investigated 26 patients with mild-to-moderate PD: 13 received iTBS and 13 sham stimulation. They found beneficial effects of iTBS on mood, but no improvement of gait, bradykinesia, UPDRS, and other measures. Electroencephalography/electromyography monitoring recorded no pathologic increase of 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 pre-frontal cortices appears safe and improves mood, but failed to improve motor performance and functional status in PD.
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 can not 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".
In a prospective, randomized, sham-controlled, observer-blinded study, Kranz et al (2010) examined the effects of rTMS on benign essential blepharospasm (BEB). In 12 patients with BEB, these investigators evaluated the effects of a 15-min session of low-frequency (0.2 Hz) rTMS over the anterior cingulate cortex (ACC) with stimulation intensities at 100 % active motor threshold with 3 stimulation coils: (i) a conventional circular coil (C-coil), (ii) a sham coil (S-coil), and (iii) 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.
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 assessing also 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 as 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. 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.
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.
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 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 fo 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.
There are 2 non-invasive methods to stimulate the brain: (i) TMS, and (ii) 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 pre-frontal 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, 13 receiving tDCS and 12 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 pre-frontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.
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 the expectation, 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.