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 the functional anatomy of language and memory activation, cerebral metabolism, blood flow, binding to neurotransmitter receptors, deposition of inflammatory markers, alterations in blood-brain barrier permeability and structure. We found atypical language in 2.5% of healthy volunteers and 24.5% of patients. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning. Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for language mapping are functional MRI and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to optimize non-invasive language localization and assess its validity. We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed 4 language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether electrode pairs intersected with significant fMRI activity clusters for each language task. Sensitivity and specificity depended on electrode ROI radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description task provided the best tradeoff between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of ruling out language areas. Language fMRI is an effective tool for determining language lateralization prior to electrode implantation, and is especially useful for excluding unexpected critical language areas. It can help guide subdural electrode implantation and narrow the search for eloquent cortical areas via DCS. In collaboration with Dr Robert Innis in NIMH, we studied patients with TLE and ligands binding to the TSPO receptor, highly expressed on activated microglia and reactive astrocytes. We found that ligand binding was higher in TLE patients than in controls for all temporal regions ipsilateral to seizure foci and in contralateral hippocampus, amygdala, and temporal pole. This study shows that TSPO binding is increased both ipsilateral and contralateral to seizure foci in TLE patients, suggesting ongoing inflammation. Findings were most prominent in patients with MTS or FCD. Anti-inflammatory therapy may have a role in treating drug-resistant epilepsy. Based on our previous PET studies showing reduced 5HT1A receptor binding in TLE, 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. For unknown reasons, placebos reduce seizures in clinical trials in many patients. It is also unclear why some drugs showing statistical superiority to placebo in one trial may fail to do so in another. Using Seizuretracker.com, a patient-centered database of 684,825 seizures, we simulated placebo and drug trials, in order to clarify sources, and identify methods of diminishing placebo effects in epilepsy. Our results suggest that in addition to 'regression to the mean,' since patients tend to enter clinical trials at times of high seizure frequency, some seizure reduction traditionally attributed to placebo effect may reflect the natural course of the disease itself. Understanding these dynamics will allow future investigations into optimal clinical trial design and may lead to identification of more effective therapies. We have conducted a series of studies of SSADH Deficiency, an autosomal recessive syndrome characterized by characterized by seizures, developmental delay, hypotonia, ataxia and neuropsychiatric symptoms, in collaboration with Childrens National Medical Center. There is no established treatment for this disorder. One marketed antiepileptic drug, vigabatrin, although effective in the mouse model, is associated with substantial toxicity in man, and, moreover, has not been helpful for the patients who have tried it. Recently we performed a trial of taurine. Taurine is abundant in various tissues, and has important roles in physiologic processes such as neuromodulation and osmoregulation. It may play a role in protection against free radical damage in neural tissus. Taurine increases chloride conductance in excitable tissues and binds to GABAA receptors. The neuroprotective action of taurine against beta-amyloid and glutamate receptor agonists in chick retinal neurons is blocked by the GABAA antagonist picrotoxin. Taurine has demonstrable antiepileptic effects, and with increased seizure onset latency and reduced occurrence of tonic seizures in the parenteral kainic acid rodent epilepsy model. The mechanism was most consistent with an increase in GABA receptor function. Results did not show clinically meaningful improvement in the adaptive domains following taurine therapy. Transcranial magnetic stimulation was used to assess measures of cortical excitability found to be altered in our previous studies. We wished to test the hypothesis that patients with SSADH deficiency would have lengthening toward normal values of the cortical silent period, and return of short and long interval intracortical inhibition, during taurine treatment. We found preliminary evidence for increased cortical excitability parallels the lack of clinical effect; taurine may inhibit GABAA neurotransmission in SSADH deficiency and/or reduce the interval at which ICF occurs. Our data as well as other studies support the use of TMS as a biomarker for further clinical trials in SSADH deficiency. Subsequently, We initiated a trial of SGS-742, a GABA B receptor antagonist that has demonstrated good safety and tolerability in clinical trials of cognitive impairment, in patients age 8 years and older with SSADH deficiency. We will assess drug effects on cortical excitability as well as seizures, neuropsychological function, and other clinical parameters. We hope to establish validated markers in SSADH-deficient patients that can be measured during therapeutic intervention. The hypotheses to be tested are: 1: Patients will show improvement in the Auditory Comprehension subtest of the Neuropsychological Assessment Battery Language Module during treatment with SGS-742. 2: Patients with SSADH deficiency will have lengthening toward normal values of the cortical silent period, and return of long interval intracortical inhibition, during a therapeutic trial of SGS-742 3: Patients will show improvement on global assessment ratings Data from this study are relevant to conditions beyond SSADH deficiency, and will enhance our ability to understand inborn metabolic errors that present with phenotypes such as seizures and developmental delay.