Both children and adults with epilepsy, particularly left temporal lobe foci, may have diminished language functioning. Specific naming difficulties have been reported in pediatric, and adult studies of patients with temporal lobe epilepsy. A significantly larger percentage of epilepsy patients have right or bilateral hemispheric dominance for language than normal healthy volunteers. Epilepsy offers the opportunity to examine the effects of pathological processes on language processing. The ability of language reorganization tends to diminish after language networks areas are established between ages 4-7. A large proportion of patients with left mesial temporal sclerosis (MTS) and seizure onset before five show atypical language. A dysfunctional left hippocampus can alter the development of cerebral language ability. A recent study found that atypical handedness, specific structural lesions, and age at onset were the most important factors leading to atypical language representation in patients with left hemispheric epileptic foci. It remains uncertain whether the reduced AI in patients with left TLE is due to permanent functional reorganization or temporary compensation. Advances in neuroimaging, including fMRI and MEG, provide noninvasive alternatives for language mapping in patients with uncontrolled epilepsy being considered for surgery. Functional MRI has become an established technique in the evaluation of epilepsy, with accuracy comparable to the Wada test. MEG is less well-developed, due in part to lack of clearly established methods, uncertainty over the best frequency bands to evaluate, and failure to perform careful clinical correlation. Some studies suggest that synthetic aperture magnetometry (SAM) may be superior to dipole analysis for language lateralization. One small study suggested that combined MEG and fMRI might provide more accurate language localization than either procedure alone. We used a data driven method and SPM2 to analyze a word definition language paradigm in 45 patients with a left hemisphere seizure focus and 19 normal controls, in to assess inter and intra-hemispheric reorganization of language functions. Spatially normalized individual patient and control SPM maps were compared to identify voxels with z>2, followed by a principal component analysis with hierarchical clustering of variance patterns from individual difference maps, and k-means clustering into groups. We identified four patient groups: one with no difference from normal controls;one with increased left temporal activation on the margin of regions activated in controls;and two others with recruitment in right inferior frontal gyrus, middle frontal gyrus, and temporal cortex. Right hemisphere activation in these two groups occurred in homologues of left hemisphere regions that sustained task activation. Using novel data driven methods, independent of a priori assumptions, we found evidence for constraints on inter-hemispheric reorganization of language in recruitment of right homologues, and, in a subpopulation of patients, evidence for intra-hemispheric reorganization of language limited to the margins of typical left temporal regional activation. These methods may be applied to investigate both normal and pathological variance in other developmental disorders and cognitive domains. Atypical language dominance is common in patients with temporal lobe epilepsy. We examined the association of left temporal PET hypometabolism with laterality of fMRI activation in a language task in a cross sectional study. We found that increasing left mid-temporal hypometabolism correlated with decreased MFG LI (r=-0.41, p<0.05) and showed trends with WA LI (r=-0.37, p=0.055) and IFG LI (r= -0.31, p=0.099);these relationships became more significant after controlling for age of onset. Increasing hypometabolism was associated with fewer activated voxels in WA ipsilateral to the focus and more activated voxels contralaterally, but overall, activation amount in left WA was similar to subjects without left temporal hypometabolism (t=-1.39, p>0.10). Thus, we did not find evidence of impaired BOLD response in hypometabolic cortex. Regional hypometabolism appears to be a marker for the temporal lobe dysfunction that leads to displacement of language function. Surprisingly few studies have examined the effect of epilepsy surgery on the functional anatomy of language. Our study will test several hypotheses: 1: After successful (>90% seizure frequency reduction) but not unsuccessful resection of a left hemisphere epileptic focus, the L/R activation asymmetry index (AI) will increase, reflecting normalization of left hemisphere dominance for language. 2: The increase in asymmetry index will not be seen in right-handed patients after right hemispheric epileptic focus resection. 3: The increase in asymmetry index will not be seen in patients whose seizures began before age 6, because these patients will be more likely to have had definitive language reorganization 4: MEG and fMRI will demonstrate congruent language lateralization. The study will be a collaboration with CNMC. It will include children and adults between the ages of 7-55 years with localization-related epilepsy who are surgical candidates. Each subject will have formal neuropsychological assessment using age-appropriate panels. We will use a series of fMRI activation tasks. The Word Definition task (Auditory) will be used as probe for Wernicke's area , and the Category Decision task (Auditory) will be the probe for Broca's area. Functional MRI images will be reconstructed and corrected for motion. Studies with significant motion artifact will be discarded, and the study repeated. The MEG tasks are event-related adaptations of our fMRI paradigms. EEG electrodes will be placed as part of the EEG procedure, in order to allow analysis of MEG events that occur during EEG spikes. Synthetic aperture magnetometry (SAM) will be used to localize event-related differences in oscillatory power between the experimental and control conditions. SAM, is an example of minimum-variance beamformer. SAM-estimated source activation within user-defined voxel consists of time series dipole moments with no loss of MEGs millisecond temporal resolution. The power of this activity can be computed for specified frequency which can be compared between the experimental and control conditions. Thus, the resulting SAM volumes are maps of the ratio between the power in the experimental and control conditions within a specified time/frequency window. Our preliminary data suggest that SAM may be an accurate language mapping procedure. Several approaches will be used to obviate potential confounding factors. The order of fMRI and MEG will be counterbalanced. Age-appropriate neuropsychological test results, particularly the Boston naming will be used as an explanatory variable for interpretation of changes in fMRI and MEG AI. In order to examine the effect of performance variables on fMRI and MEG activation, we will compare the relative change in AI to relative changes in neuropsychological test scores after surgery. The healthy controls will provide a measure of baseline scan to scan variability, and practice effects. They are also necessary to help establish normal MEG language measures. The primary outcome measure will be change in fMRI laterality index post-surgery in Brocas and Wernickes areas. The secondary outcome measure will be changes in MEG laterality index post-surgery in Brocas and Wernickes areas.

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Berl, Madison M; Zimmaro, Lauren A; Khan, Omar I et al. (2014) Characterization of atypical language activation patterns in focal epilepsy. Ann Neurol 75:33-42
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