Epilepsy is one of the most common neurological disorders, and patients whose seizures are not controlled suffer from many adverse effects. The goal of this study is to investigate the effects of epilepsy on brain structure and function, and to test innovative approaches to treatment when seizures cannot be controlled by currently available approaches. Methods: Patients undergo video-EEG monitoring to determine seizure type and focus localization. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are used to study cerebral metabolism, blood flow, and structure. Antiepileptic drug blood levels are obtained. Recent neuroimaging study findings: Activation of central serotonin (5-HT)1A receptors, found in high density in brainstem raphe, hippocampus and temporal neocortex, exerts an anticonvulsant effect in various experimental seizure models. Previously, we found reduced 5-HT1A silent antagonist [18F]FCWAY binding in both lateral temporal neocortical and mesial temporal regions ipsilateral to temporal lobe epileptic foci. We now report magnetic resonance (MR)-based partial volume corrected (PVC) results. Two-hour dynamic PET images were acquired in 13 patients and 10 controls after bolus [18F]FCWAY injection. Image frames were registered to segmented T1-weighted MR volumes, and PVC applied using gray and white matter masks. Pixel data were corrected for intravascular radioactivity, labeled metabolite uptake, and spill-in of skull 18F-fluoride activity. Original and PVC pixel data were fitted to a 2-tissue compartment model using the metabolite-corrected input function to produce volume of distribution (V) images. ROIs drawn on MR volumes were applied to V images. Only gray matter voxels were sampled. Binding potential (BP) (mL/mL) was calculated as [V(ROI)-V(CEREBELLUM)]/ plasma free fraction. Both before and after PVC, patients had significantly lower BP, as well as greater side-side asymmetry than controls in ipsilateral hippocampus, parahippocampus and fusiform gyrus (p<.05, corrected for multiple comparisons). There were no contralateral differences before or after PVC. Hippocampal BP asymmetry before PVC was 64?b27% compared to 11?b9 % for FDG. After PVC, values were 51?b25% and 11?b12%, respectively. 5-HT1A BP is significantly reduced in TLE mesial temporal regions but not lateral neocortex. This reduction is not partial volume averaging artifact. These findings support our hypothesis of reduced 5-HT1A receptor binding in temporal lobe epileptic foci. Reduced 5-HT1A activity may contribute to regional hyperexcitability. Glutamatergic receptors may play a significant role in epileptogenesis in the amygdala. The role of GluR receptor subtypes has not been elucidated. Agents such as kainic acid (KA) activate multiple glutamatergic receptors. Preliminary studies with amygdalar infusion of the specific KAr GluR5 agonist ATPA ((RS-2-amino-3-(3-hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid) led to prolonged limbic seizures (10 mins ? 4hrs ) monitored behaviorally (Racine stages 1 ? 5 ) and by EEG, suggesting that the KAr GluR5 receptor subtype could mediate ictal activity. In order to evaluate the physiologic effects of specific GluR5 activation, we used KA, AMPA and ATPA, and functional MRI to map the cerebral blood flow (CBF) response to seizures induced by amygdalar injection in rats. METHODS: Rats were anesthetized with ketamine / xylazine and MR-compatible cannula was placed stereotactically in basolateral amygdala. After several days rest, they were intubated under isoflurane anesthesia. Body core temperature was maintained at 37 degrees with a heated water pad. Lines were placed in femoral artery to monitor blood pressure, and femoral vein for drug and fluid administration. Blood gas was analyzed at frequent intervals. MRI was performed on a horizontal 7T Bruker Avance scanner using a 72mm diameter transmit-receive coil. A 2mm axial slice containing the cannula was scanned for 10 minutes before and for approximately two hours after 10 nanomoles (5uL) infusion of each convulsant. Regional cerebral perfusion was measured using arterial spin labeling techniques. MRI parameters: matrix size : 64x64, TR : 2 s, TE: 6.5 ms, 2 ms labeling pulse with power of 81 mG/cm. Field of View= 3.2 cm, Time per scan : 4.5 min. T2 weighted and Diffusion weighted images (in read) were acquired for five 1mm slices centered around the cannula. Parameters: 128x128, TR = 3000 ms, TE = 10 (T2) and 20 ms, (DWI), ? = 20 ms, FOV = 3.2 cm. RESULTS: The perfusion images for each drug showed bilateral cortical and subcortical increases in cerebral blood flow (CBF) beginning approximately 10 minutes after infusion, lasting up to 2 hours. The time course of activation was similar in widely separated brain regions. Normal saline had no effect. CONCLUSION: Focal Amgydalar infusion of glutamatergic agonists leads to rapid widespread bilateral cerebral activation. Selective GluR5 activation is sufficient to produce this response. The pattern of activation is unlikely to have been due to physical diffusion of the infused agent. Background: Previous reports characterized the effects of administration of single oral doses of antiepileptic drugs (AED) on cortical excitability. However, AED effects on cortical excitability, and their relationship to plasma blood levels, during chronic drug administration at therapeutic doses are not known. The objective of the study was to determine whether plasma blood levels during chronic administration at therapeutic doses would accurately predict changes in corticomotor excitability. Methods: We used transcranial magnetic stimulation (TMS) to measure cortical excitability during 5 weeks administration of carbamazepine (CBZ) and lamotrigine (LTG), and subsequent AED withdrawal in 20 healthy volunteers. Data were analyzed using ANOVARM and regression analysis. Results: Resting motor thresholds (r-MT) increased with increasing total and free CBZ and LTG levels during drug administration, but not drug withdrawal. After acute AED withdrawal, r-MT elevation persisted in most individuals with CBZ despite undetectable plasma levels, compared to a rapid normalization with LTG. In contrast, acute drug withdrawal resulted in a transient decrease in r-MT in 3/10 individuals with CBZ and 2/10 with LTG. Conclusions: Plasma levels provide information on motor cortical function during active treatment phases but not during AED withdrawal. Significance: The transient decrease in r-MT associated with acute AED withdrawal could represent a physiological substrate contributing to AED withdrawal seizures.
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