William Theodore - US grants
Affiliations: | National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States |
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High-probability grants
According to our matching algorithm, William Theodore is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1992 — 2012 | Theodore, William H | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Neuropsychological and Cognitive Studies in Epilepsy @ Neurological Disorders and Stroke Methods: We use positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)to map language and memory neuroimaging in patients with temporal lobe epilepsy to perform non- invasive evaluation of functional cortex, and study the effect of epilepsy on cognitive anatomy in children and adults with seizures. This information is crucial as well for surgical planning in patients with intractable epilepsy.Our studies in both normal volunteers and patients with uncontrolled seizures have shown that imaging evaluation compares well with more invasive procdures such as electrostimulation mapping and the intracarotid sodium amytal test. We also evaluate the effect of seizures on the development of functional cognitive anatomy. Recent findings: We used fMRI to compare activation on a verbal fluency task in children and adults. In both groups, left inferior frontal cortex and left middle frontal gyrus (dorsolateral prefrontal cortex)were activated. Children had, on average, 60% more activation than adults. The degree of laterality was less in children than for adults in IFG and MFG. The greater activation found in children may reflect developmental plasticity for the ongoing organization of neural networks which underlie language capacity. We also used PET to study word rhyming and pseudoword rhyming, which activated the same brain regions, suggesting conjoint neural networks for phonological processing of words and pseudowords. However, pseudoword rhyming also recruited more cortical tissue in the left posterior prefrontal cortices and the left ventral occipital-temporal junction. In addition, pseudoword rhyming activated the left supramarginal gyrus which was not actively engaged in word rhyming. These results suggest that rhyming pseudowords requires extended neural systems and networks unnecessary for rhyming words. Current studies: We are using several new tasks to investigate functional reorganization in patients with epileptic foci in langauge processing regions. - Epilepsy, cognitive function, language, memory - Human Subjects |
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1998 — 2013 | Theodore, William | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Physiologic and Pharmacologic Studies in Epilepsy @ Neurological Disorders and Stroke 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 neurtransmitter receptors, and structure. Antiepileptic drug blood levels are obtained. Studies are performed in collaboration with NIMH and the NIH Clinical Center PET Department. We perform PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (11C-DASB), for serotonin transporter activity estimation, and PET with FCWAY for 5HT1A receptor visualization. We perform structural MRI for partial volume correction of PET data. We perform PET with fluorodeoxyglucose in order to study the relation cerebral glucose metabolism to depression in epilepsy, and characterize the degree of hippocampal dysfunction. We expect to find reduced 5HT1A receptor binding and reduced transport after partial volume correction, whether or not hypometabolism or hippocampal structural changes are present. We plan to study four subject groups: healthy controls;TLE patients with depression;TLE patients without depression;generalized epilepsy patients without depression. Inclusion of patients with generalized epilepsy will help us to isolate any effect of the seizure disorder itself, in the absence of a temporal lobe focus or depression, on serotonergic neurotransmission in people with epilepsy. We are not planning to study patients with generalized epilepsy and depression, as the incidence of the latter is expected to be lower in this epilepsy syndrome. The diagnosis of depression will be based on the Research Version of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) including the detailed assessment of the course of both epilepsy and depressive symptoms, as well as the family history of medical and psychiatric conditions, as well as the BDI. This study will test the following hypotheses: 1: 5HTT concentration, as measured by 11C-DASB specific binding, is significantly reduced in TLE patients compared to normal controls in mesial temporal structures, thalamus, striatum and raphe;this is not an artifact of brain atrophy. 2: Reduction of 18F-FCWAY and 11C-DASB specific binding will be greater in TLE patients with concurrent depression (or history of major depressive disorder) than in patients without concomitant depression (or history of depressive disorders). 3: Reductions of 18F-FCWAY specific binding will be greater than 11C-DASB in cortical ROIs, suggesting that reduced post-synaptic, rather than pre-synaptic, serotonergic function plays a greater role for development of depression. The laboratory of Dr David Goldman performed genotyping for the 5HT transporter gene some of our previous patients. There were strong trends for subjects with the SS or SL allele to have a higher BDI, and also to have mesial temporal sclerosis on MRI scan. At present the data are too limited to draw strong conclusions, but provide additional support for the role of serotonergic mechanisms in the etiology of depression in epilepsy, and possibly in the development of MTS. We are planning a a randomized blinded cross-over design of SGS-742 versus placebo in up to 12 patients age 12 years and older with SSADH deficiency. The study will be carried out in collaboration with Dr Philip Pearl of CNMC, and Dr Mike Gibson of Children's Hospital Pittsburgh. SGS-742 is a GABABR antagonist that has demonstrated good safety and tolerability in clinical trials of cognitive impairment. In a phase II double-blind, placebo-controlled study in 110 patients with mild cognitive impairment, oral administration of SGS-742 (600 mg t.i.d. for 8 weeks) significantly improved attention, reaction time, visual information processing, and working memory. Additionally, pre-treatment with SGS-742 antagonized GHB-induced effects on behavior and motor function in baboons. Since GHB has agonist GABAB effects, this effect of SGS-742 may also be contributory in SSADH deficient patients who have markedly elevated levels of both GABA and GHB. Our study will use neurological and neuropsychiatric evaluations, TMS and PET/MRI as biomarkers. We predict that patients will show: 1) improvement in the areas of attention, reaction time, visual information handling, and working memory, and 2) improvement in baseline abnormalities in cortical silent period and long-interval intracortical inhibition as measured by TMS. The trial will be carried out in collaboration with DR Philip Pearl of CNMC, who will ascertain and screen patients, drawing from the database maintained at Childrens Hospital, and Dr K Michael Gibson of the University of Pittsburgh. Screening may be performed at the NIH Clinical Center or at CNMC Washington DC. The study itself, including TMS, imaging, and clinical aspects, will be performed at the NIH Clinical Center. Additional parallel studies in the SSADH Aldh5a1-/- mouse model will be carried out by Dr Gibson. Previous work by Dr Gibson has shown improvement in baseline abnormalities in GABAB receptor (GABABR) binding, electrophysiology and structure in Aldh5a1-/- mice following application of SGS-742. SGS-742 led to a dose-dependent improvement in ECoG tracings, and significantly reduced spike-wave discharge (SWD) duration. The GABABR is the pharmacological target of SGS-742. Alterations of GABABR structure/function have been documented in, both prior to, and after, the onset of lethal status epilepticus (Wu et al 2006;Buzzi et al 2006). The inclusion criteria will be persistent -hydroxybutyric aciduria, documented succinic semialdehyde dehydrogenase enzyme deficiency and/or molecular analysis showing a mutation in the Aldh5a1gene, and parents or guardians available as contact persons. Patients already receiving drugs with GABAergic effects will not be included. At baseline, neurological examination, neuropsychological evaluation, TMS, and FMZ-PET with co-registered MRI will be performed. Patients will be are randomized into a six month trial of treatment versus placebo. Following a two-month washout period, patients will enter the other treatment arm. Patients and examining physicians will be blinded as to the treatment arm in which the patient is enrolled. At 2 months and 6 months of treatment, and at the start of the second six-month arm, patients receive repeat neurological and neuropsychological evaluations, and repeat TMS. PET will be done at the conclusion of each six month treatment phase. Studying a new treatment option in a yet untreatable disorder indicates that this research study has enormous potential benefit to SSADH-deficient patients and may provide a model for approaches to similar disorders. Evidence of SGS-742 efficacy in human or murine Aldh5a1 deficiency will provide insight into underlying pathophysiology and further rationale for expanded clinical intervention. This study has more general relevance for epilepsy. The neuropsychological and psychiatric symptoms of people with SSADH deficiency mirror in more severe form cognitive and behavioral co-morbidities of patients with other epilepsy syndromes. Studying GABAergic neurotransmission in this syndrome may provide more generalizable data. Moreover, we will be able to test the effect of modulatory intervention on clinical, neurophysiologic, and imaging parameters. |
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2007 — 2008 | Theodore, William | Z01Activity Code Description: Undocumented code - click on the grant title for more information. |
Ion Channels in Epilepsy and as Targets For Antiepileptic Drugs @ Neurological Disorders and Stroke Cellular electrophysiological recording techniques are used to study drug modulation of neurotransmitter-gated and voltage-activated ion channels in brain slices, cultured neurons and heterologous cells transfected with cloned ion channel subunit genes. Correlative studies are carried out in animal models. [unreadable] [unreadable] In a series of experiments we revealed the roles of kainate receptors (KAR) that contain the GluR5 subunit (KAR-G5) in seizure induction and epileptogenesis. These receptors are a subgroup of ionotropic glutamate receptors which are distinguishable from NMDA and AMPA receptors. We used KAR-G5 receptor knockout mice and the KAR-G5 agonist ATPA to determine the behavioral, clinical seizure and electrophysiological effects of KAR-G5 receptor activation. By performing slow tail vain infusion of the selective GluR 5 agonist ATPA during Video-EEG recordings we demonstrated that the selective activation of KAR-G5 mediates a behavioral arrest followed by myoclonic jerks which show a sharp wave as EEG correlate. Clonic and tonic seizures occurring at higher doses of ATPA are not mediated by KAR-G5 and are most likely due to AMPA receptor activation as ATPA loses its selectivity at higher concentrations. These data were confirmed in in vitro slice recordings and behavioral testing for locomotor activity. [unreadable] [unreadable] In a different approach we triggered epilepsy in rats by induction of SE with intraperitoneal injections of kainic acid. Seven to thirteen days after SE we performed 24h Video-EEG monitoring, which revealed signs of epileptogenesis in all animals (EEG seizures, clinical seizures, sharp waves). The following day the rats were sacrificed for in vitro slice recordings (whole cell patch clamp, extracellular recordings) to characterize potential changes in the functional effects of KAR-G5 activation on GABA transmission. GABA is the main inhibitory neurotransmitter in the adult brain of humans as well as rodents.[unreadable] [unreadable] Experiments published by our collaborator Maria Braga showed that activation of KAR-G5 in the amygdala slice preparation of healthy rats has a bidirectional effect. Low concentrations of ATPA (1uM) increase GABAergic transmission but higher doses (10uM) rather decrease GABAergic transmission. We found that in the epileptic amygdala the response to low concentrations of ATPA is reduced, reflecting less enhancement of GABAergic transmission ( disinhibition). However, 10 uM ATPA did still induce bursting activity in the slices of epileptic animals. This suggests that the function of KARG5 receptors may be changed in a way that excitation outweighs inhibition. Further studies investigating the cellular location and detailed subunit composition that may have changed during epileptogenesis are underway. [unreadable] [unreadable] Furthermore we performed a therapeutic study using a competitive antagonist at the AMPA receptor, also an ionotropic glutamate receptor. AMPA receptors carry the vast majority of the fast excitatory currents induced by glutamate (main excitatory neurotransmitter). This makes them a promising target as treatment for status epilepticus. The study was performed in mice under Video-EEG recordings. We chose two arbitrary time points (early and late) for treatment with the AMPA antagonists and compared it with vehicle and diazepam.[unreadable] [unreadable] At both time points early (after the first 5 min of continuous EEG seizure activity) and late (25 min later) the AMPA antagonist was superior to both vehicle and diazepam in successfully interrupting the ongoing seizure activity without later reoccurrence of seizures. We did not see any mortality after the AMPA antagonist treatment. The mortality rate in the diazepam group (57%) exceeded even the vehicle group what is most likely due to the depressant effect on the respiratory and cardiovascular system.[unreadable] [unreadable] The potential antiepileptogenic (protection against epilepsy after SE) effect of the AMPA antagonist treatment is currently being evaluated by screening for the occurrence of spontaneous seizures with 24h Video-EEG- monitoring sessions up to 20 weeks after SE. |
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2014 — 2018 | Theodore, William | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Evaluation and Treatment of Drug-Resistant Epilepsy @ Neurological Disorders and Stroke 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. Antiepileptic drug blood levels are obtained. Studies are performed in collaboration with NIMH and the NIH Clinical Center PET Department. The rate of atypical language was 2.5%) among healthy volunteers and 24.5% for patients. There was agreement between several classification methods, yet cluster analysis revealed novel correlations with clinical features. 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. Based on our previous PET studies showing reduced 5HT1A receptor binding in TLE, 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. We used Freesurfer to segment cortical structures and obtain hippocampal volumes in 39 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volume ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real time PCR specific for HHV-6A and HHV-6B. For 14 patients, viral DNA detection was performed using digital droplet PCR (DdPCR) specific for HHV-6A and HHV-6B. HHV-6B was detected in 16 of 25 patients studied in the laboratory of Dr Steve Jacobson NINDS with quantitative real time PCR. For 14 studied with digital droplet PCR, one had HHV-6A, six HHV-6B, and three both viruses. On both Freesurfer and manual tracing, HHV-6-negative patients had significantly greater AI and lower ipsilateral volume than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. Our data suggest multiple potential etiologies for MTS. HHV-6 negative hippocampi had significantly greater preoperative atrophy than hippocampi positive for virus. HHV6 may have a less severe effect on hippocampus than other etiologies. 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. Anti-inflammatory therapy may have a role in treating drug-resistant epilepsy. We collaborated with Childrens National Medical Center in a trial of taurine for SSADH Deficiency. 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. NCS-382, a GHB receptor antagonist, had the highest survival rate of all interventions in the mutant animal model. However, there were significant alterations in blood chemistries found in NCS-382-treated mice. 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 (del Olmo et al 2000). The neuroprotective action of taurine against beta-amyloid and glutamate receptor agonists in chick retinal neurons is blocked by the GABAA antagonist picrotoxin (Louzada et al 2004). 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. We initiated a trial of SGS-742, a GABAB receptor antagonist that has demonstrated good safety and tolerability in clinical trials of cognitive impairmen in patients age 8 years and older with SSADH deficiency. There is no proven therapy for this disorder. 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 is relevant to conditions beyond SSADH deficiency, and will enhance our ability to understand inborn metabolic errors that present with phenotypes such as intellectual disability or autism spectrum disorder, and to make optimal therapeutic decisions in SSADH deficiency patients. |
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