Physiologic And Pharmacologic Studies In Epilepsy

癫痫是最常见的神经系统疾病之一，癫痫发作不受控制的患者会遭受许多不良影响。本研究的目的是研究癫痫对大脑结构和功能的影响，并在现有方法无法控制癫痫发作时测试创新的治疗方法。方法：对患者进行视频脑电图监测，确定癫痫发作类型和病灶定位。正电子发射断层扫描（PET）和磁共振成像（MRI）用于研究脑代谢、血流和结构。测定抗癫痫药物血药浓度。最近的神经影像学研究发现：中枢5-羟色胺（5-HT）1A受体在脑干中叶、海马和颞叶新皮层中高密度激活，在各种实验性癫痫发作模型中发挥抗惊厥作用。先前，我们发现5-HT1A沉默拮抗剂[18F]FCWAY在颞叶癫痫灶同侧的颞外侧新皮质区和内侧颞区结合减少。我们现在报告基于磁共振（MR）的部分体积校正（PVC）结果。13例患者和10例对照组在大剂量注射[18F]FCWAY后获得2小时动态PET图像。将图像帧注册到分割的t1加权MR体积上，并使用灰质和白质掩膜应用PVC。校正了像素数据的血管内放射性、标记代谢物摄取和颅骨18f -氟化物活性的溢出。原始和PVC像素数据使用代谢物校正输入函数拟合到2组织室模型中，以产生分布体积(V)图像。将MR体积上绘制的roi应用于V图像。只采样了灰质体素。结合电位（BP） （mL/mL）计算为[V(ROI)-V（小脑）]/血浆游离分数。在PVC前后，患者的血压明显降低，同侧海马、海马副和梭状回的侧侧不对称性明显大于对照组（p< 0.05，经多次比较校正）。PVC前后对侧无差异。PVC前海马血压不对称为64？27%与11%相比？FDG占9%。PVC后，值为51？B25%和11？分别b12%。5-HT1A BP在颞叶内侧颞区显著降低，但在外侧新皮层无显著降低。这种减少不是部分体积平均的伪影。这些发现支持了我们在颞叶癫痫灶中减少5-HT1A受体结合的假设。5-HT1A活性降低可能导致局部高兴奋性。

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.