Robert Fisher - US grants

electrophysiology; epilepsy; neurotransmitter metabolism; neural plasticity; convulsants; afferent nerve; aging; gamma aminobutyrate; electroencephalography; biological models; electrostimulus; electrical potential;

A new radionuclide scintigraphic technique will be employed to study the regulation of gallbladder emptying. The aims of this study will address the following questions. 1) What are the effects of chemical and physical composition of meals on gallbladder emptying responses? Monocomponent and multicomponent meals will be studied. The effects of solid versus liquid meals and isotonic versus hypertonic meals will be determined. 2) What are the effects of pharmacologic agents on gallbladder emptying? Alpha and beta adrenergic and cholinergic agonists and antagonists will be evaluated. 3) Can gallbladder emptying be stimulated or inhibited by administration of gastrointestinal peptides? Dose-responses to cholecystokinin, secretin, glucagon and somatostatin will be studied. 4) Is gallbladder emptying affected by endogenous autonomic stimulation? Vagal cholinergic responses will be stimulated by sham feeding and insulin-induced hypoglycemia and an alpha adrenergic response, by cold-pressor testing. 5) Does alcohol affect gallbladder emptying? Both the gallbladder response to oral alcohol and the effect of oral alcohol on the gallbladder emptying response to meals will be investigated. Dose-response curves will be established. 6) Is gallbladder emptying abnormal in patients with selected disorders? Patients with cholelithiasis, diabetes mellitus, vagotomy, and biliary dyskinesia will be tested. The mechanism of abnormal emptying, if observed, will be studied.

Colonic transit, psychiatric factors and dietary intolerance will be evaluated in patients with the irritable colon syndrome. Normal subjects and matched psychoneurotic patients will serve as controls. Patients with the irritable colon syndrome will be recruited based on a negative "routine" evaluation and symptoms including abdominal pain, constipation, diarrhea, abdominal bloating and flatulence. Each of these symptoms will be scored for severity. Colonic scintigraphy will be employed to quantitate cecal-ascending colon emptying and the progression of luminal contents through the colon. Time distribution histograms, time activity curves and progression of the geometric center of the cecal instillate will be determined for each study subject. Psychiatric evaluations will include a psychiatric interview (DIS) and psychometric testing (MMPI, Beck Depression Inventory, Spielberger State/Trait Anxiety Inventory, Vocabulary Subtest of WAIS-R), and a special questionnaire. Dietary intolerances will be established by a comprehensive interview, symptom-diet checklist and completion of a home diary. An attempt will be made to correlate abnormalities in colonic transit with clinical symptoms and/or psychiatric and dietary factors. The effects of "provocative" and "bland" films on colonic transit will be compared in normal subjects, patients with the irritable colon syndrome and psychoneurotics. Provocation of anxiety will be documented by the Spielberger State Anxiety Inventory and measurements of urinary and plasma catecholamines. The effects of provocative meals on colonic transit will be compared in normal subjects and patients with the irritable colon syndrome. The mechanisms of provoked changes in colonic transit will be studied using pharmacologic interventions, such as adrenergic, cholinergic and opiate receptor blockers, prostaglandin inhibition and somatostatin to prevent the release of GI peptides.

Glutamate (GLU), or a closely related compound, is believed to be the primary excitatory neurotransmitter in mammalian brain. A better understanding of the glutamatergic system could influence treatment for epilepsy, brain ischemia and several other important neurological diseases. This project proposes exploration of new concepts pertaining to the physiology of glutamate (GLU) and related amino acids in vertebrate brain, using intracellular recordings in rat hippocampal slice. Section 1 will investigate endogenous dipeptides containing glutamate (GLU), recently shown by the P.I. to be physiologically active in regions of presumed glutamatergic synapses. The candidicy of these dipeptides as CNS neurotransmitters or neuromodulators will be studied by ascertaining ionic dependencies, pharmacology and action on hippocampal neurons. Section 2 will examine how glutamatergic transmission is regulated in the presence of excessive GLU (1-2 mM for 1-5 minutes), reflecting a type of "desensitization". This will be among the first detailed studies of GLU desensitization in mammalian brain using intracellular techniques. First, we will establish that GLU desensitization occurs, and specify the experimental parameters needed to produce it. Second, we will document that evoked EPSPs decline concurrently with desensitization to GLU. This EPSP decline will be shown to result from a block in synaptic transmission at specific excitatory, but not inhibitory, hippocampal pathways. Miniature EPSP analysis will indicate if the block of the EPSP by exposure to GLU is mediated pre- or post-synaptically. The contributions of the receptor subtype agonists, N-methyl-D-aspartate, quisqualate and kainate, to GLU desensitization will be studied. Agents that enhance GLU desensitization in invertebrate systems (such as lectins) will be studied in hippocampus.

gastric acid; esophagogastric junction; patient monitoring device; bilirubin; diagnostic catheterization; acidity /alkalinity; esophagus; acid base balance; clinical research; human subject;

DESCRIPTION (Applicant's Abstract): This application proposes a clinical pilot study of anterior nucleus thalamic stimulation (ANTS) as a treatment for intractable epilepsy, in order to lay the groundwork for a larger randomized, controlled clinical trial. Studies by the principal investigator and others have suggested that thalamic stimulation is useful for treatment of seizures in animal models and potentially in patients. Epilepsy affects about 1% of the U.S. population, and approximately 25% are not helped by existing therapies. Therefore, the need for new therapies is great. Study subjects will have partial epilepsy with or without secondarily generalized seizures, at least 10 per month, and not responsive to standard medical or surgical therapies. Stimulating electrodes will be implanted bilaterally in the anterior nucleus of thalamus and connected subcutaneously to subclavicular stimulators. A combination of physiological and anatomical techniques will be used to verify proper electrode placements. Stimulation will be delivered continuously as 90 microsecond pulses at 100/s, for one minute on and five minutes off, at five Volts amplitude. A blinded lead-in design will be used to establish safety and a preliminary evaluation of efficacy of this therapy. Specific aims of the pilot trial will be to establish that ANTS targeting can be accomplished in the operating room with accuracy of 5 mm or better. The pilot will show that it is possible to develop a suitable double-blind test protocol. The study will establish that a high level of stimulation at 5 V, 90 us, 100 Hz is as well-tolerated as is a low level of stimulation at 1 V, 90 us, 100 Hz, thereby allowing future trials to use high levels of stimulation. Sub-projects to be done at selected study sites will determine whether PET scans can provide metabolic maps of brain sites activated by thalamic stimulation, whether EEG spikes and seizures can be recorded from ANT, whether unit recording increases accuracy of electrode placement, and whether ANTS affects neuropsychologic testing. The pilot study will serve to develop a group of investigators experienced with ANTS for future trials, to identify institutions at which the protocol successfully can be completed, and to provide an accurate sample size estimate for a definitive trial. A consortium of centers experienced in epilepsy research will collaborate on this project, which will move brain stimulation for epilepsy into the realm of a testable new therapy for intractable seizures.