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, binding of neurotransmitter receptors, and structure. Antiepileptic drug blood levels are obtained. Studies are performed in collaboration with NIMH and the NIH Clinical Center PET Department.&#8232; We perform PET with several ligands, including 11CDASB, for serotonin transporter activity estimation, PET with FCWAY for 5HT1A receptor visualization, and 11CPBR28 for TSPO binding, fluorodeoxyglucose, a clinical marker of epileptogenic regions, as well as structural MRI both for partial volume correction of PET data and detection of epileptogenic lesions. In recent studies we compared data from 13 patients and 16 healthy volunteers who had PET with 11CDASB for 5HTT, and 18FFCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. We used a reference tissue model to estimate 11CDASB binding. 18FFCWAY volume of distribution was corrected for plasma free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relatively reduced binding (reflecting transporter activity) ipsilateral to epileptic foci. The results showed that mean regional 11CDASB binding and asymmetry did not differ between patients and controls. 18FFCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On ANOVA with region as a repeated measure, depression diagnosis had a significant effect on 11CDASB asymmetry, with significantly higher 11CDASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between 18FFCWAY asymmetry and 11CDASB asymmetry. Increased 11CDASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implies reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss, and provides additional evidence of an important role for serotonergic mechanisms in TLE and concomitant depression. In order to compare 5HT1A receptor PET and cerebral glucose metabolism (CMRglc) PET for temporal lobectomy planning, we performed preoperative 5HT1A receptor binding estimation with 18FFCWAY PET and CMRglc measurement with 18FFDG in regions drawn on coregistered qMRI after partial volume correction, in 41 patients who had anterior temporal lobectomy, with at least one-year follow-up. Surgery was tailored to individual preresection evaluations as well as intraoperative electrocorticography. Mean regional asymmetry values, and the number of regions with asymmetry exceeding 2 standard deviations in 16 healthy volunteers were compared between seizure-free and not seizure-free patients. 18FFCWAY but not 18F-FDG18FFDG and MRI data were masked for surgical decisions and outcome assessment. Twenty-six of 41 (63 %) patients seizure-free since surgery had significantly different mesial temporal asymmetries compared to 15 not seizure=free patients for both 18FFCWAY (F1,39 = 5.87, p = 0.02) and 18FFDG PET (F1,38 = 5.79, p =0.021). The probability of being seizure-free was explained by both 18FFDG and 18FFCWAY PET, but not MRI, with a significant additional 18FFCWAY effect (chi-square =9.8796, p=0.0072) after the probability of being seizure free was explained by FDG. Although MRI alone was not predictive, any combination of two lateralizing imaging studies was highly predictive of seizure-freedom. Our study suggests that both 5HT1A receptor PET and CMRglc PET can make a contribution to temporal lobectomy planning. Additional studies should explore the potential for temporal lobectomy based on interictal EEG and minimally invasive imaging studies. The PET data suggest as well that treatment with an experimental 5HT1A agonist might reduce seizures.&#8232;&#8232; We have started a double-blind placebo-controlled cross-over trial of an experimental 5HT1A agonist in patients with epilepsy, to test the hypothesis that increased activation of this receptor may ameliorate both seizures and mood disorders. &#8232;&#8232; In order to study the role of inflammation in epilepsy, in collaboration with Dr Robert Innis of NIMH, 11CPBR28 PET and MRI in 16 patients with unilateral temporal lobe epilepsy and 30 healthy subjects. Uptake of radioactivity after injection of 11CPBR28 was measured from regions of interest drawn bilaterally on MRI images. Brain uptake from ipsilateral and contralateral hemispheres was compared using a paired samples t-test. We found that brain uptake was higher ipsilateral to the seizure focus in the hippocampus, parahippocampal gyrus, amygdala, fusiform gyrus, and choroid plexus, but not in other brain regions. This asymmetry was more pronounced in patients with hippocampal sclerosis than in those without. These results are consistent with increased expression of TSPO. We are performing additional studies in patients with other epileptogenic lesions, as well as studying tissue for the presence of HHV6 in collaboration with Dr Steven Jacobson of NINDS.