Shennan A. Weiss - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] The causes of many neuorological and psychiatric illnesses remain unknown despite their widespread prevelance and cost to families and society. Electrical recordings from human and primate brains have demonstrated the sophisticated capacities of single neurons to process information and make decisions, i.e. compute. It is possible that many neurological and psychiatric diseases are caused by neurons that perform computations incorrectly. The long-term objective of the proposed project is to understand how synaptic mechanisms define the computational capacities of a single neuron. To address this question I study an identifiable neuron whose activity correlates with a stereotypic behavior. The two goldfish Mauthner (M-) cells receive auditory input, process this input, and the all-or-none result is translated in to an escape response, the C-start. Thus the M-cell(s) must deduce, from a continuous stream of sensory information, whether or not a stimulus merits the initiation of an escape, the precise timing of the escape, the initial direction of the escape, which is reflected in whether the left or right M-cell is activated. Since the M-cell soma and lateral dendrite are accessible to intracellular recordings in vivo I intend to describe how these functions are carried out by the sub-threshold interactions between sound evoked synaptic excitation and inhibition. Auditory afferents make excitatory chemical and electrical synapses on the M-cell while glycinergic feed-forward inhibitory interneurons chemically and ephaptically inhibit the M-cell. Published data indicates that the timing of sound evoked excitatory electrotonic postsynaptic potentials (PSPs) are phase locked to the sound stimulus. Aim 1 will test whether the timing of the glycinergic inhibitory PSPs are also phase locked and investigate how excitation and inhibition are integrated. Aim 2 will determine whether the phase locking of the sound evoked synaptic activity is necessary for unambiguously determining the location of a sound source underwater and Aim 3 will determine if the strength of glycinergic inhibition of the M-cell governs the probability that a stimulus will elicit a C-start. Paired intracellular recordings will be performed in immobilized fish in air, and these results will be correlated with underwater studies in behaving fish monitored with high speed video, EMG, and extracellular chronic electrodes. Strychnine applied by intramuscular injection and locally by electroporesis will disrupt glycinergic inhibition and simulate hyperekplexia, a hereditary disease resulting in spasticity and associated with mutations in the glycine receptor. The results of these experiments will clarify if glycinergic inhibition disrupted in the spinal cord or brain stem induces hyperekplexia and identify pharmacological approaches that can reduce spasticity. [unreadable] [unreadable] [unreadable]

ABSTRACT Seizures fail to respond to medication in 30-40% of patients with epilepsy, and epilepsy surgery is an effective alternative. We need better methods to identify epileptogenic cortex that must be removed to render patients seizure free. Chronic intracranial EEG (iEEG) telemetry recording is often required, and this poses risk, discomfort, inconvenience, and cost. The proposed project aims to develop a new method to more safely plan epilepsy surgery by reducing or eliminating the need for chronic intracranial monitoring. High-frequency oscillations (HFOs) are a candidate biomarker of epileptogenic brain and consist of brief (25-200 msec) EEG events with a spectral content ranging between 80-600 Hz. HFO rates are elevated in the seizure onset zone (SOZ), but HFO rates may also be elevated in the epileptogenic zone (EZ) a hypothetical concept constituting the area that must be excised to attain postoperative seizure freedom. The SOZ does not always indicate the location of the EZ. The accuracy of HFO rates for determining the location of the SOZ is not established, and whether HFO rates in resected regions have different prognostic value than HFO rates outside resected regions, also requires elucidation. I hypothesize that inter-ictal HFO rates measured during acute intra- operative recording has sufficient accuracy for localizing the EZ to justify reducing or eliminating inpatient iEEG telemetry for patients with temporal lobe epilepsy (TLE), but not for patients with extra-temporal focal epilepsy. We will test this hypothesis in an observational clinical study of diagnostic accuracy in patients with medically refractory focal epilepsy. Aim 1 of the study will determine and compare the accuracy of HFO rates to identify the SOZ and the EZ in chronic recordings during sleep and acute recordings at the time of depth electrode implantation in patients with focal epilepsy. This will be accomplished by 1) Assessing the concordance between HFO biomarker predictions and clinical outcomes to distinguish classifiers of SOZ from EZ using a receiver operating characteristic (ROC) approach, and 2) Assessing the accuracy of the rates of occurrence of the HFO biomarkers in specific neuroanatomical structures and locations. Aim 2 will determine the predictive value of resected and residual HFO biomarker rates recorded with electrocorticography (ECoG) during surgery for post-resection seizure freedom. The clinical endpoint of this aim is that the predictive value of residual HFO rates for seizure recurrence will exceed the predictive value of resected HFO rates for seizure freedom. This research study is closely integrated with my career development plan that focuses on course work in biostatistics, clinical trial design, and neuroengineering. Four mentors who are recognized leaders in clinical and translational epilepsy research, with a specific expertise in the study of HFOs, and a dedicated statistician will provide the teaching and technical expertise to assure that the study is conducted properly and that I meet the aims of my career development plan.