fMRI shows atypical language lateralization in pediatric epilepsy patients

PURPOSE: The goal of this study was to compare language lateralization between pediatric epilepsy patients and healthy children. METHODS: Two groups of subjects were evaluated with functional magnetic resonance imaging (fMRI) by using a silent verb-generation task. The first group included 18 pediatric epilepsy patients, whereas the control group consisted of 18 age/gender/handedness-matched healthy subjects. RESULTS: A significant difference in hemispheric lateralization index (LI) was found between children with epilepsy (mean LI =-0.038) and the age/gender/handedness-matched healthy control subjects (mean LI=0.257; t=6.490, p<0.0001). A dramatic difference also was observed in the percentage of children with epilepsy (77.78%) who had atypical LI (right-hemispheric or bilateral, LI<0.1) when compared with the age/gender/handedness-matched group (11.11%; chi(2)=16.02, p<0.001). A linear regression analysis showed a trend toward increasing language lateralization with age in healthy controls (R(2)=0.152; p=0.108). This association was not observed in pediatric epilepsy subjects (R(2)=0.004, p=0.80). A significant association between language LI and epilepsy duration also was found (R(2)=0.234, p<0.05). CONCLUSIONS: This study shows that epilepsy during childhood is associated with neuroplasticity and reorganization of language function.     

Ambiguous Language in Wada Evaluations

Summary:  A case is presented with ambiguous cerebral language lateralization, as determined by the intracarotid amobarbital test. Reasons for ambiguous language findings for this test are discussed.     

Functional MRI and Wada studies in patients with interhemispheric dissociation of language functions

Rare patients with chronic epilepsy show interhemispheric dissociation of language functions on intracarotid amobarbital (Wada) testing. We encountered four patients with interhemispheric dissociation in 490 consecutive Wada language tests. In all cases, performance on overt speech production tasks was supported by the hemisphere contralateral to the seizure focus, whereas performance on comprehension tasks was served by the hemisphere with the seizure focus. These data suggest that speech production capacity is more likely to shift hemispheres than is language comprehension. Wada and fMRI language lateralization scores were discordant in three of the four patients. However, the two methods aligned more closely when Wada measures loading on comprehension were used to calculate lateralization scores. Thus, interhemispheric dissociation of language functions could explain some cases of discordance on Wada/fMRI language comparisons, particularly when the fMRI measure used is not sensitive to speech production processes.     

Language lateralization in left-handed patients with schizophrenia

We evaluated hemispheric lateralization of language production in non-right-handed (NRH) patients with schizophrenia compared with matched right-handed (RH) patients, NRH control, and RH control subjects. First, the ability to generate verbs during overt training trials was checked in 78 subjects. They were then evaluated with functional magnetic resonance imaging (fMRI) while performing a covert verb generation task. No significant interactions between illness and handedness and no illness effect were observed in functional asymmetry. There was significantly less leftward asymmetry of the inferior frontal, precentral, and supramarginal gyri as well as the intra-parietal sulcus in non-right-handers compared to right-handers taking into account the task performances. Our findings suggested that decreased lateralization for language production was more closely related to handedness than to schizophrenia.     

Atypical language lateralization in epilepsy patients

Purpose:   To investigate whether atypical language dominance in epilepsy patients is related to localization and type of lesions.
Methods:   Four hundred and forty-five epilepsy patients received bilateral Wada testing. Language was classified as left (L), right (R), bilateral-dependent (BD, speech arrest after left and right injections), or bilateral-independent (BI, no speech arrest after either injection). Groups were compared regarding handedness and magnetic resonance imaging (MRI) lesions. Lesions were classified as "early" (congenital), "late" neocortical (acquired after birth), and hippocampal sclerosis (HS).
Results:   Of all patients, 78% were L, 6% R, 7% BD, and 9% BI. Right-handers with left lesions did not differ from those without lesions. Left-handers with normal MRI did not differ from right-handers. Left-handers with early left lesions were most likely R (46%). Left-handers with late neocortical left lesions were most likely BD (37%); those with left HS were most likely BD (33%) or L (33%). In both latter groups, R language was rare (13% and 11%, respectively).
Discussion:   The data support the notion that R dominance may indicate development of functional language areas in the right hemisphere following an early insult. BD language may signal defective maintenance of right hemispheric language caused by a late left hemispheric insult at a time when left dominance has already started to develop. In contrast, BI language may represent a variant with functional language representation in both hemispheres.     

Lateralizing language with magnetic source imaging: Validation based on the Wada test

Purpose:   Magnetoencephalography (MEG)/magnetic source imaging (MSI) is a noninvasive functional neuroimaging procedure used to localize language-specific regions in the brain. The Wada test, or intracarotid amobarbital procedure (IAP), is the gold standard in determining speech/language lateralization for presurgical planning, although it is invasive and associated with morbidity. The purpose of this study is to provide further validation on the use of MSI for presurgical language lateralization by comparing results against the IAP.
Methods:   The sample consisted of 35 patients with epilepsy and/or brain tumor undergoing presurgical evaluation at the Minnesota Epilepsy Group. All patients received both an IAP and MSI to determine hemispheric language dominance. For MSI, a 148-channel MEG system was used to record activation of language-specific cortex by an auditory word-recognition task.
Results:   The MSI and IAP were concordant in determining language in the hemisphere to be treated in 86% of the cases with sensitivity and specificity values of 80% and 100%, respectively.
Conclusions:   The results from this study are consistent with prior research findings comparing functional neuroimaging procedures to the IAP in determining language lateralization in presurgical patients. The current study provides an important replication and support for Papanicolaou et al.'s findings in 2004 using a consecutive clinical sample from a different institution. An unusually high rate of atypical IAP language cases in this sample and differences between the two procedures are believed to explain the noted discrepancies. MSI is a viable noninvasive alternative to the IAP in the presurgical determination of language lateralization.     

Language lateralization in temporal lobe epilepsy: a comparison between fMRI and the Wada Test

PURPOSE: Recent studies have claimed that language functional magnetic resonance imaging (fMRI) can identify language lateralization in patients with temporal lobe epilepsy (TLE) and that fMRI-based findings are highly concordant with the conventional assessment procedure of speech dominance, the intracarotid amobarbital test (IAT). METHODS: To establish the power of language fMRI to detect language lateralization during presurgical assessment, we compared the findings of a semantic decision paradigm with the results of a standard IAT in 68 patients with chronic intractable right and left temporal lobe epilepsy (rTLE, n=28; lTLE, n=40) who consecutively underwent a presurgical 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. RESULTS: 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 temporoparietal or combined regions of interest (ROIs). Because of methodologic problems, recognition of bilateral speech was difficult. CONCLUSIONS: 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. Further refinements regarding the paradigms and analysis procedures will be needed to improve the contribution of language fMRI for presurgical assessment.     

Language assessment in Wada test: Comparison of methohexital and amobarbital

IntroductionMethohexital has replaced amobarbital during Wada testing at many centers. The objective of our study was to compare the use of methohexital and amobarbital during Wada testing regarding language and memory lateralization quotients as well as speech arrest times.MethodsA chart review of 582 consecutive patients undergoing 1041 Wada-procedures was performed (left = 60, right = 63, bilateral = 459). Language lateralization was calculated based on duration of speech arrest using a laterality index, defined as (L ? R)/(L + R). Memory lateralization was expressed as percentage of retained objects and laterality quotient.ResultsLanguage and memory lateralization revealed a similar distribution with amobarbital and methohexital. Speech arrest after left and right-sided injection was significantly longer in the amobarbital group as compared to the methohexital group. Language lateralization did not differ in the two groups. Percentage of retained memory items was higher in the methohexital group and there were fewer presented test items in the methohexital group.DiscussionLanguage and memory testing during the Wada test can successfully be performed with methohexital instead of amobarbital. The shorter half-life of methohexital allows repeated injections and shorter interhemispheric testing intervals, but also shortens the testing window.     

Language lateralization by Wada test and fMRI in 100 patients with epilepsy

Comparing the determination of language dominance using fMRI with results of the Wada test in 100 patients with different localization-related epilepsies, the authors 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 extratemporal epilepsy. Language fMRI might reduce the necessity of the Wada test for language lateralization, especially in TLE.     

Atypical language representation in epilepsy: implications for injury-induced reorganization of brain function

This review addresses language function and reorganization associated with various forms of epilepsy. Longstanding epilepsy, particularly types with onset early in life, may be associated with changes in the representation of language function in the brain. As a result of this reorganization, language function may be relatively spared despite injury to areas of the brain that normally subserve these functions. We examine the changes seen in language function in two types of epilepsy: hemispheric epilepsy of childhood and focal epilepsies. Findings from behavioral studies, intracarotid amytal testing, intraoperative cortical testing, and more recent functional imaging studies are reviewed. Studying changes in the representation of language function seen in some forms of epilepsy provides information about brain plasticity with implications for other neurologic diseases, as well as for the neuroscientific understanding of how and when functional reorganization may occur.     

Lesion lateralization in patients with epilepsy and precocious destructive insults

Destructive brain lesions that occur early in development are often unilateral or asymmetric. We analyzed the lateralization of lesions among a previously reported series of 51 patients with three kinds of destructive lesions based on their topography: specific arterial territory (AT), arterial borderzone territory (Bdz), hemispheric (H). Five patients (all from group Bdz) had bilateral nonlateralizing lesions. The distributions of left- and right-sided lesions were distinct among the groups (P=0.014): in group H, all patients except one presented with right-sided lesions (89%); in group Bdz, left-sided lesions (53%) were more frequent than right-sided lesions (17.7%); in group AT, left- and right-sided lesions were more equally distributed (56 and 44%). Our study suggests that there is a trend toward lesion lateralization among patients with different patterns of precocious destructive lesions. Differences in cerebral maturation and vulnerability between the hemispheres is a possible factor explaining lesion lateralization in early life insults.     

Left-sided interictal epileptic activity induces shift of language lateralization in temporal lobe epilepsy: an fMRI study

PURPOSE: By using speech-activated functional MRI (fMRI), we investigated whether the frequency of left-sided interictal epileptic activity (IED: spikes or sharp waves on the EEG) is associated with atypical speech lateralization. METHODS: We investigated 28 patients (13 men, aged 17-59 years) with left-sided mesial temporal lobe epilepsy (MTLE) and 11 patients with right-sided MTLE as a control population. Only patients with unilateral hippocampal sclerosis with unilateral IED were included. For fMRI of individual patients, we contrasted images sampled during covert word generation with a low-level rest condition. With SPM99, an individual comparison for the contrast "word generation versus resting inactivity" was conducted. To characterize speech lateralization in individual patients, we calculated asymmetry indexes (AIs): the difference between activated left-sided and right-sided voxels was divided by all activated voxels. Analyzing long-term EEG, the first 2 min of each hour were evaluated for the frequency of IED. Univariate associations with AIs were assessed by Pearson's correlation and by t test. When testing the independent associations, multivariate linear regression was performed. RESULTS: The AIs in patients with left-sided MTLE were 0.40 +/- 0.53 on average (range, -0.83 to +1.0), whereas in right-sided MTLE, they were 0.78 +/- 0.15 (p = 0.029). For the further investigations, we included left-sided MTLE patients only. The median frequency of IED was six per hour (range, 0-240). Higher IED frequency was correlated with left-right shift of lateralization of speech fMRI activity (p = 0.002). CONCLUSIONS: Higher left-sided spike frequency in MTLE was associated with a left-right shift of speech representation, suggesting that chronic frequent interictal activity may induce a reorganization of speech lateralization.     

Pediatric language mapping: sensitivity of neurostimulation and Wada testing in epilepsy surgery

PURPOSE: Functional mapping of eloquent cortex with electrical neurostimulation is used both intra- and extraoperatively to tailor resections. In pediatric patients, however, functional mapping studies frequently fail to localize language. Wada testing has also been reported to be less sensitive in children. METHODS: Thirty children (4.7 - 14.9 years) and 18 adult controls (18-59 years) who underwent extraoperative language mapping via implanted subdural electrodes at the NYU Comprehensive Epilepsy Center were included in the study. Ten children and 14 adults underwent preoperative Wada testing. Success of the procedures was defined as the identification of at least one language site by neurostimulation mapping and determination of hemispheric language dominance on the Wada test. RESULTS: In children younger than 10.2 years, cortical stimulation identified language cortex at a lower rate than was seen in children older than 10.2 years and in adults (p<0.05). This threshold, demonstrated by survival and chi2 analysis, was sharply defined in our data set. Additionally, Wada testing was more likely to be successful than was extraoperative mapping in this younger age group (p<0.05). CONCLUSIONS: Analysis of our series demonstrates that language cortex is less likely to be identified in children younger than 10 years, suggesting that alternatives to the current methods of cortical electrical stimulation, particularly the use of preoperative language lateralization, may be required in this age group.     

Functional MRI reveals an interhemispheric dissociation of frontal and temporal language regions in a patient with focal epilepsy

We report the case of a patient with frontal lobe epilepsy in whom the Wada test failed to lateralize representation of language (fluent speech was observed after amobarbital injection on both the right and left side). Functional magnetic resonance imaging (fMRI) during a lexical processing task revealed an atypical organization of language represented by an interhemispheric dissociation of language regions with a right frontal dominance and a left temporal dominance. Consistent with the fMRI results, the patient's ability to name pictures was not reliably impaired by electrocortical stimulation (ECS) of left frontal cortex. The findings from Wada, fMRI, and ECS were confirmed by a lack of language impairment after left frontal lobectomy for seizures. This case illustrates that fMRI can precisely map cortical language networks in epileptic patients and that fMRI may be used to help interpret laterality results provided by the Wada procedure.     

Strongly lateralized activation in language fMRI of atypical dominant patients-implications for presurgical work-up

PURPOSE: Functional magnetic resonance imaging (fMRI) is being used increasingly for language dominance assessment in the presurgical work-up of patients with pharmacoresistant epilepsy. However, the interpretation of bilateral fMRI-activation patterns is difficult. Various studies propose fMRI-lateralization index (LI) thresholds between +/-0.1 and +/-0.5 for discrimination of atypical from typical dominant patients. This study examines if these thresholds allow identifying atypical dominant patients with sufficient safety for presurgical settings. METHODS: 65 patients had a tight comparison, fully controlled semantic decision fMRI-task and a Wada-test for language lateralization. According to Wada-test, 22 were atypical language dominant. In the remaining, Wada-test results were compatible with unilateral left dominance. We determined fMRI-LI for two frontal and one temporo-parietal functionally defined, protocol-specific volume of interest (VOI), and for the least lateralized of these VOIs ("low-VOI") in each patient. RESULTS: We find large intra-individual LI differences between functionally defined VOIs irrespective of underlying type of language dominance (mean LI difference 0.33+/-0.35, range 0-1.6; 15% of patients have inter-VOI-LI differences >1.0). Across atypical dominant patients fMRI-LI in the Broca's and temporo-parietal VOI range from -1 to +1, in the "remaining frontal" VOI from -0.93 to 1. The highest low-VOI-LI detected in atypical dominant patients is 0.84. CONCLUSIONS: Large intra-individual inter-VOI-LI differences and strongly lateralized fMRI-activation in patients with Wada-test proven atypical dominance question the value of the proposed fMRI-thresholds for presurgical language lateralization. Future studies have to develop strategies allowing the reliable identification of atypical dominance with fMRI. The low-VOI approach may be useful.     

The use of neuroimaging to study behavior in patients with epilepsy

Structural and functional neuroimaging continues to play an increasing role in the presurgical evaluation of patients with epilepsy. In addition to its value in localizing the epileptogenic zone and eloquent cortex, neuroimaging is contributing to our understanding of mood comorbidity in epilepsy. Although the vast majority of research has focused on patients with temporal lobe epilepsy (TLE), neuroimaging studies of patients with extratemporal epilepsy and primary generalized epilepsy are increasing in number. In this review, structural and functional imaging modalities that have received considerable research attention in recent years are reviewed, and their strengths and limitations for understanding behavior in epilepsy are assessed. In addition, advances in multimodal imaging are discussed along with their potential application to the presurgical evaluation of patients with seizure disorders.     

Presurgical language mapping in children with epilepsy: clinical usefulness of functional magnetic resonance imaging for the planning of cortical stimulation

Purpose: Presurgical language mapping in dominant hemisphere epilepsy to evaluate the risk of postoperative deficit is particularly difficult in children. Extraoperative invasive cortical stimulation can show some areas critical to language, but not all of them, due to scarce sampling, poor cooperation, cortical immaturity, or network reorganization, whereas functional magnetic resonance imaging (fMRI) displays entire networks involved in, but not necessarily critical to, language. In a homogeneous series of children with epilepsy, we compared the contributions of language fMRI and depth electrode stimulations to optimize language mapping. Methods: Eight children (7.5–15.5 years) with left frontal or temporal epilepsy underwent language fMRI and language stimulation with depth electrodes as part of their comprehensive presurgical workup. fMRI data collected during sentence generation were analyzed using statistical parametric mapping (SPM2) (false discovery rate [FDR] p < 0.05). Bipolar stimulations were performed during language production tasks. By coregistering fMRI and postimplantation computed tomography (CT) images, we were able to directly compare the cortical areas identified by both investigations. Key Findings: fMRI during sentence generation robustly showed activation in the whole perisylvian regions with little reorganization (left hemisphere dominant in 7). Of the 184 electrode contacts tested for language, only 8 were positive (language disruption) in three of the seven patients with periictal language impairment and left language dominance. All of the positive contacts colocalized with an fMRI activated cluster, that is, fMRI did not miss any region critical to language (sensitivity = 100%). However, 54 of the 176 negative contacts were within activated clusters (low specificity). Significance: In children with epilepsy, the sensitivity of fMRI during sentence generation allows for the detection of all critical regions displayed by cortical stimulation within the large perisylvian language network, but with a low specificity. It is, therefore, useful to optimize the placement of intracranial electrodes when language mapping is necessary. Systematic planning of the electrode placement according to language fMRI maps should increase the yield of extraoperative cortical stimulation, which appears rather low in children when compared to adults.     

Functional MRI and Wada determination of language lateralization: a case of crossed dominance

The Wada test has historically been the conventional procedure for determining language lateralization before neurosurgery. However, functional magnetic resonance imaging (fMRI) offers a less invasive alternative to the Wada procedure. Research indicates that the two techniques used together may provide comparable, and sometimes complementary, information that results in improved prediction of postsurgical language ability. We present a case in which use of fMRI in conjunction with Wada testing provided complementary information about language lateralization before neurosurgical resection of a mesial temporal subependymoma for seizure control in a patient with schizencephaly.