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Background
Functional magnetic resonance imaging (fMRI) is a type of functional brain imaging technology. It localizes regions of activity in the brain by measuring blood flow and/or metabolism following task activation, and is generally used to identify areas of language (e.g., Broca's area, Wernicke's area) and sensorimotor function (e.g., sensorimotor cortex). Functional MRI has been employed for the diagnosis, monitoring, prognosis, or surgical management of many diseases/conditions (e.g., Alzheimer's disease, brain tumors, coma/vegetative state, epilepsy, multiple sclerosis (MS), Parkinson's disease, stroke, trauma, and vascular malformations).
The bulk of published evidence concerning the clinical applications of fMRI centers on its use in pre-surgical planning. In particular, studies involving language fMRI mainly address its use in pre-surgical planning for epilepsy, arterio-venous malformations (AVMs), and brain tumors (Bookheimer, 2007). It has been suggested that fMRI of the brain reduces the need for invasive testing of seizure disorder patients being considered for surgical treatment. Woermann et al (2003) compared the determination of language dominance using fMRI with results of the Wada test in 100 patients with different localization-related epilepsies. These investigators found 91 % concordance between both tests. The overall rate of false categorization by fMRI was 9 %, ranging from 3 % in left-sided temporal lobe epilepsy (TLE) to 25 % in left-sided extra-temporal epilepsy. The authors noted that language fMRI might reduce the necessity of the Wada test for language lateralization, especially in TLE.
Sabsevitz and colleagues (2003) examined whether pre-operative fMRI predicts language deficits in patients with epilepsy undergoing left anterior temporal lobectomy (L-ATL). A total of 24 patients with L-ATL underwent pre-operative language mapping with fMRI, pre-operative intra-carotid sodium amobarbital (Amytal)/Wada testing for language dominance, as well as pre- and post-operative neuropsychological testing. Functional MRI laterality indexes (LIs), reflecting the inter-hemispheric difference between activated volumes in left and right homologous regions of interest, were calculated for each patient. Relationships between the fMRI LI, Wada language dominance, and naming outcome were examined. Both the fMRI LI (p < 0.001) and the Wada test (p < 0.05) were predictive of naming outcome. Functional MRI showed 100 % sensitivity and 73 % specificity in predicting significant naming decline. Both fMRI and the Wada test were more predictive than age at seizure onset or pre-operative naming performance. The authors concluded that pre-operative fMRI predicted naming decline in patients undergoing L-ATL surgery.
Medina et al (2005) prospectively evaluated effect of fMRI on diagnostic work-up and treatment planning in patients with seizure disorders who are candidates for surgical treatment. A total of 60 consecutively enrolled patients (27 females and 33 males; mean age of 15.8 +/- 8.7 years; range of 6.8 to 44.2 years) were examined. Forty-five (75 %) patients were right-handed, 9 (15 %) were left-handed, and 6 (10 %) had indeterminate hand dominance. Prospective questionnaires were used to evaluate diagnostic work-up, counseling, and treatment plans of the seizure team before and after fMRI. Confidence level scales were used to determine effect of fMRI on diagnostic and therapeutic thinking. Paired-t test and 95 % confidence interval analyses were performed. In 53 patients, language mapping was performed; in 33, motor mapping; and in 7, visual mapping. The study revealed change in anatomical location or lateralization of language-receptive area -- (Wernicke's area) (28 % of patients) as well as language-expressive area (Broca's area) (21 % of patients). Statistically significant increases were found in confidence levels after fMRI in regard to motor and visual cortical function evaluation. In 35 (58 %) of 60 patients, the seizure team thought that fMRI results altered patient and family counseling. In 38 (63 %) of 60 patients, fMRI results helped to avoid further studies, including the Wada test. In 31 (52 %) and 25 (42 %) of 60 patients, intra-operative mapping and surgical plans, respectively, were altered because of fMRI results. In 5 (8 %) patients, two-stage surgery with extra-operative direct electrocortical stimulation mapping (ESM) was averted, and resection was accomplished in one-stage. In 4 (7 %) patients, extent of surgical resection was altered because eloquent areas were identified close to seizure focus. The authors concluded that fMRI results influenced diagnostic and therapeutic decision making of the seizure team; results indicated a change in language dominance, an increase in confidence level in identification of critical brain function areas, alterations in patient and family counseling as well as intra-operative mapping and surgical approach.
Functional MRI has been used in pre-surgical planning for patients with brain tumors as well as vascular malformations. Pouratian and colleagues (2002) evaluated the utility of pre-operative fMRI to predict if a given cortical area would be deemed essential for language processing by ESM. These investigators studied patients with vascular malformations, specifically AVMs and cavernous angiomas, in whom blood-flow patterns are abnormal and in whom a perfusion-dependent mapping signal may be questionable. A total of 10 patients were studied (7 with AVMs and 3 with cavernous angiomas). These researchers used a battery of linguistic tasks, including visual object naming, word generation, auditory responsive naming, visual responsive naming, and sentence comprehension, to identify brain regions that were consistently activated across expression and comprehension linguistic tasks. In a comparison of ESM and fMRI activations, the researchers varied the matching criteria (overlapping activations, adjacent activations, and deep activations) and the radii of influence of ESM (2.5, 5, and 10 mm) to determine the effects of these factors on the sensitivity and specificity of fMRI. The sensitivity and specificity of fMRI were dependent on the task, lobe, and matching criterion. For the population studied, the sensitivity and specificity of fMRI activations during expressive linguistic tasks were found to be up to 100 % and 66.7 %, respectively, in the frontal lobe, and during comprehension linguistic tasks up to 96.2 % and 69.8 %, respectively, in the temporal and parietal lobes. The sensitivity and specificity of each disease population (AVMs and cavernous angiomas) and of individuals were consistent with those values reported for the entire population studied. The authors concluded that pre-operative fMRI is a highly sensitive pre-operative planning tool for identifying cortical areas that are essential for language; and that this imaging modality may play a future role in pre-surgical planning for patients with vascular malformations.
Anderson et al (2006) examined the utility of fMRI as a determinant of lateralization of expressive language in children with cerebral lesions. Functional MRI language lateralization was attempted in 35 children (29 with epilepsy) aged 8 to 18 years with frontal or temporal lobe lesions (28 left hemisphere, 5 right hemisphere, and 2 bilateral). Axial and coronal fMRI scans through the frontal and temporal lobes were acquired at 1.5 Tesla (T) by using a block-design, covert word-generation paradigm. Activation maps were lateralized by blinded visual inspection and quantitative asymmetry indices (hemispheric and inferior frontal regions of interest, at p < 0.001 uncorrected and p < 0.05 Bonferroni corrected). A total of 30 children showed significant activation in the inferior frontal gyrus. Lateralization by visual inspection was left in 21, right in 6, and bilateral in 3, and concordant with hemispheric and inferior frontal quantitative lateralization in 93 % of cases. Developmental tumors and dysplasias involving the inferior left frontal lobe had activation overlying or abutting the lesion in 5 of 6 cases. Functional MRI language lateralization was corroborated in 6 children by frontal cortex stimulation or intra-carotid Amytal testing (IAT) and indirectly supported by aphasiology in a further 6 cases. In 2 children, fMRI language lateralization was bilateral, and corroborative methods of language lateralization were left. Neither lesion lateralization, patient handedness, nor developmental versus acquired nature of the lesion was associated with language lateralization. Involvement of the left inferior or middle frontal gyri increased the likelihood of atypical language lateralization. The authors concluded that this study suggests that fMRI lateralizes language in children with cerebral lesions.
Stancanello et al (2007) attempted to validate a method to exploit functional information for the identification of functional organs at risk (fOARs) in CyberKnife radiosurgery treatment planning. Five patients affected by AVMs and scheduled to undergo radiosurgery were scanned prior to treatment using computed tomography (CT), three-dimensional rotational angiography (3D-RA), T2 weighted and blood oxygenation level dependent echo planar imaging MRI. Tasks were chosen on the basis of lesion location by considering those areas which could be potentially close to treatment targets. Functional data were superimposed on 3D-RA and CT used for treatment planning. The procedure for the localization of fMRI areas was validated by direct ESM on 38 AVM and tumor patients undergoing conventional surgery. Treatment plans studied with and without considering fOARs were significantly different, in particular with respect to both maximum dose and dose volume histograms; consideration of the fOARs allowed quality indices of treatment plans to remain almost constant or to improve in 4 out of 5 cases compared to plans with no consideration of fOARs. The authors concluded that the presented method provides an accurate tool for the integration of functional information into AVM radiosurgery, which might help to minimize undesirable side effects and to make radiosurgery less invasive.
Stippich and colleagues (2007) prospectively evaluated the feasibility of standardized pre-surgical fMRI for localizing the Broca and Wernicke areas as well as for lateralizing language function. A total of 81 patients (36 females, 45 males; aged 7 to 75 years) with different brain tumors underwent blood oxygen level-dependent fMRI at 1.5 T with two paradigms: (i) sentence generation (SG), and (ii) word generation (WG). Functional MRI measurements, data processing, and evaluation were fully standardized by using dedicated software. Four regions of interest were evaluated in each patient: the Broca and Wernicke areas and their anatomical homologs in the right hemisphere. The SG and WG paradigms were successfully completed by all (100 %) and 70 (86 %) patients, respectively. Success rates in localizing and lateralizing language were 96 % for the Broca and Wernicke areas with the SG paradigm, 81 % for the Broca area and 80 % for the Wernicke area with the WG paradigm, and 98 % for both areas when the SG and WG paradigms were used in combination. Functional localizations were consistent for SG and WG paradigms in the inferior frontal gyrus (Broca area) and the superior temporal, supra-marginal, and angular gyri (Wernicke area). Surgery was not performed in 7 patients (9 %) and was modified in 2 patients (2 %) because of fMRI findings. The authors concluded that fMRI proved to be feasible during routine diagnostic neuro-imaging for localizing and lateralizing language function pre-operatively.
There is evidence for the use of fMRI in pre-surgical planning for epilepsy and monitoring of language function during tumor resection.
Roux et al (2003) analyzed the usefulness of pre-operative language fMRI by correlating fMRI data with intra-operative ESM results for patients with brain tumors. Naming and verb generation tasks were used, separately or in combination, for 14 right-handed patients with tumors in the left hemisphere. Acquired fMRI data were analyzed with statistical parametric mapping software, with two standard analysis thresholds (p < 0.005 and then p < 0.05). The fMRI data were then registered in a frameless stereotactic neuro-navigational device and correlated with direct brain mapping results. These researchers used a statistical model with the fMRI information as a predictor, spatially correlating each intra-operatively mapped cortical site with fMRI data integrated in the neuro-navigational system (site-by-site correlation). Eight patients were also studied with language fMRI post-operatively, with the same acquisition protocol. These investigators observed high variability in signal extents and locations among patients with both tasks. The activated areas were located mainly in the left hemisphere in the middle and inferior frontal gyri (F2 and F3), the superior and middle temporal gyri (T1 and T2), and the supra-marginal and angular gyri. A total of 426 cortical sites were tested for each task among the 14 patients. In frontal and temporo-parietal areas, poor sensitivity of the fMRI technique was observed for the naming and verb generation tasks (22 % and 36 %, respectively) with p < 0.005 as the analysis threshold. Although not perfect, the specificity of the fMRI technique was good in all conditions (97 % for the naming task and 98 % for the verb generation task). Better correlation (sensitivity, 59 %; specificity, 97 %) was achieved by combining the two fMRI tasks. Variation of the analysis threshold to p < 0.05 increased the sensitivity to 66 % while decreasing the specificity to 91 %. Post-operative fMRI data (for the cortical brain areas studied intra-operatively) were in accordance with brain mapping results for 6 of 8 patients. Complete agreement between pre- and post-operative fMRI studies and direct brain mapping results was observed for only 3 of 8 patients. The authors concluded that with the paradigms and analysis thresholds used in this study, language fMRI data obtained with naming or verb generation tasks, before and after surgery, were imperfectly correlated with intra-operative brain mapping results. A better correlation could be obtained by combining the fMRI tasks. The overall results of this study showed that language fMRI could not be used to make critical surgical decisions in the absence of direct brain mapping. Other acquisition protocols are needed for evaluation of the potential role of language fMRI in the accurate detection of essential cortical language areas.
Benke and associates (2006) noted that recent studies have claimed that language fMRI can identify language lateralization in patients with TLE and that fMRI-based findings are highly concordant with the conventional assessment procedure of speech dominance, the IAT. These researchers attempted to establish the power of language fMRI to detect language lateralization during pre-surgical assessment and compared the findings of a semantic decision paradigm with the results of a standard IAT in 68 patients with chronic intractable right and left TLE (rTLE, n = 28; lTLE, n = 40) who consecutively underwent a pre-surgical evaluation program. The patient group also included 14 (20.6 %) subjects with atypical (bilateral or right hemisphere) speech. Four raters used a visual analysis procedure to determine the laterality of speech-related activation individually for each patient. Overall congruence between fMRI-based laterality and the laterality quotient of the IAT was 89.3 % in rTLE and 72.5 % in lTLE patients. Concordance was best in rTLE patients with left speech. In lTLE patients, language fMRI identified atypical, right hemisphere speech dominance in every case, but missed left hemisphere speech dominance in 17.2 %. Frontal activations had higher concordance with the IAT than did activations in temporo-parietal or combined regions of interest. Because of methodological problems, recognition of bilateral speech was difficult. The authors concluded that these data provide evidence that language fMRI as used in the present study has limited correlation with the IAT, especially in patients with lTLE and with mixed speech dominance. They noted that further refinements regarding the paradigms and analysis procedures will be needed to improve the contribution of language fMRI for pre-surgical assessment.
Petrella and colleagues (2006) prospectively evaluated the effect of pre-operative fMRI localization of language and motor areas on therapeutic decision making in patients with potentially resectable brain tumors. A total of 39 consecutive patients (19 men, 20 women; mean age of 42.2 years) referred for fMRI for possible tumor resection were evaluated. A pre-operative diagnosis of brain tumor was made in all patients. Sentence completion and bilateral hand squeeze tasks were used to map language and sensorimotor areas. Neurosurgeons completed questionnaires regarding the proposed treatment plan before and after fMRI and after surgery. They also gave confidence ratings for fMRI results and estimated the effect on surgical time, extent of resection, and surgical approach. The effect of fMRI on changes in treatment plan was assessed with the Wilcoxon signed rank test. Differences in confidence ratings between altered and un-altered treatment plans were assessed with the Mann-Whitney U test. The estimated influence of fMRI on surgical time, extent of resection, and surgical approach was denoted with summary statistics. Treatment plans before and after fMRI differed in 19 patients (p < 0.05), with a more aggressive approach recommended after imaging in 18 patients. There were no significant differences in confidence ratings for fMRI between altered and un-altered plans. Functional MRI resulted in reduced surgical time (estimated reduction, 15 to 60 minutes) in 22 patients who underwent surgery, a more aggressive resection in 6, and a smaller craniotomy in 2. The authors concluded that fMRI enables the selection of a more aggressive therapeutic approach than might otherwise be considered because of functional risk. In certain patients, surgical time may be shortened, the extent of resection increased, and craniotomy size decreased.
Di et al (2007) assessed the differences in brain activation in response to presentation of the patient's own name spoken by a familiar voice (SON-FV) in patients with vegetative state (VS) and minimally conscious state (MCS). By using fMRI, these investigators prospectively studied residual cerebral activation to SON-FV in 7 patients with VS and 4 with MCS. Behavioral evaluation was performed by means of standardized testing up to 3 months post-fMRI. Two patients with VS failed to show any significant cerebral activation, while 3 patients with VS showed SON-FV induced activation within the primary auditory cortex. Finally, 2 patients with VS and all 4 patients with MCS not only showed activation in primary auditory cortex but also in hierarchically higher order associative temporal areas. The 2 patients with VS showing the most widespread activation subsequently showed clinical improvement to MCS observed 3 months after their fMRI scan. The authors concluded that cerebral responses to patient's own name spoken by a familiar voice as measured by fMRI might be a useful tool to pre-clinically distinguish MCS-like cognitive processing in some patients behaviorally classified as vegetative.
The American College of Radiology (ACR)'s guideline on neurological imaging for patients with epilepsy (Karis et al, 2006) noted that the data provided by MRI are essential in the pre-surgical evaluation of patients with medically refractory epilepsy, but noted that structurally detectable abnormalities are absent in many patients. In these patients, functional studies provide useful information on localization of the seizure focus. In this regard, functional imaging techniques, including positron emission tomography, single-photon emission computed tomography, magnetic source imaging, and fMRI, have contributed to the pre-surgical evaluation of patients with epilepsy. The ACR guideline provided appropriateness ratings (1 = least appropriate; 9 = most appropriate) on fMRI for the following indications:
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Chronic epilepsy, poor therapeutic response. Surgery candidate (rating = 5; may be helpful in pre-surgical planning).
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New onset of seizure. Ethyl alcohol, and/or drug-related (rating = 2).
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New onset seizure. Aged 18 to 40 years (rating = 2).
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New onset seizure. Aged greater than 40 years (rating = 2).
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New onset seizure. Focal neurological deficit (rating = 2).
Additionally, the ACR's guideline on neurological imaging for patients with head trauma (Davis et al, 2006) provided an appropriateness rating of 2 for patients with sub-acute or chronic closed head injury with cognitive and/or neurological deficit(s).
The Ontario Ministry of Health and Long-Term Care's review on functioning brain imaging (2006) stated that there may be a role for fMRI in the identification of surgical candidates for tumor resection. The review also stated that there may be some clinical utility for fMRI in pre-surgical functional mapping.
The assessment by the Ontario Ministry of Health and Long-Term Care (2006) stated that there is limited clinical utility of functional brain imaging in the management of patients with MS at this time. This is in agreement with the European Federation of Neurological Societies' guideline on the use of neuro-imaging in the management of MS (Filippi et al, 2006), which stated that the use of non-conventional MRI techniques (e.g., fMRI, diffusion tensor MRI, magnetization transfer MRI, and MR spectroscopy) is not recommended.
Rocca and colleagues (2008) used fMRI to examine the properties of the mirror neuron system (MNS) in patients with MS. Using a 3 tesla scanner, these researchers acquired fMRI in 16 right-handed patients with relapsing-remitting MS and 14 controls. Two motor tasks were studied. The first consisted of repetitive flexion-extension of the last 4 fingers of the right hand (simple task) alternated to epochs of rest; the second (MNS task) consisted of observation of a movie showing the hand of another subject while performing the same task. During the simple task, compared to controls, patients with MS had more significant activations of the contralateral primary sensori-motor cortex and supplementary motor area. During the MNS task, both groups showed the activation of several visual areas, the infra-parietal sulcus, and the inferior frontal gyrus (IFG), bilaterally. The IFG and the visual areas were significantly more active in patients than controls. The between-group interaction analysis showed that in patients with MS, part of the regions of the MNS were more active also during the simple task. The authors concluded that the findings of this study suggested increased activation of the MNS in patients with MS with a normal level of function and widespread damage of the central nervous system. The potentialities of this system in facilitating clinical recovery in patients with MS and other neurological conditions should be investigated.
In an editorial that accompanied the afore-mentioned article, Phillips (2008) stated that fMRI has tremendous potential for assessing and better understanding MS. He noted that it is important to remember that fMRI is an indirect measurement of neuronal activity. Also, it has been reported that there is altered brain perfusion in patients with MS. Changes in perfusion may alter the sensitivity and statistical characteristics of fMRI. Currently, it is unclear to what extent altered tissue perfusion complicates the interpretation of fMRI in MS. Furthermore, theenhanced activation patterns observed in MS have also been shown in other neurological conditions such as Alzheimer's disease, Parkinson's disease, and stroke.
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