George A. Ojemann - US grants

Electrocorticographic (ECoG) changes accompanying human higher functions involving language are recorded directly from cortex in awake, behaving patients during the unique opportunity that occurs with the surgical treatment of epilepsy. ECoG changes are sought that are anatomically specific to those cortical sites independently identified as essential to that function by electrical stimulation mapping, and there, behaviorally specific, that is, absent on tasks using the same sensory input but processed with different higher functions. This proposal is an extension of our previous work where changes were visually identified in the averaged ECoG that had anatomic and behavioral specificity to silent naming: slow evoked potentials (EP's) at frontal language sites and desynchronization at posterior language sites. That desynchronization has been measured with spectral density techniques on ECoG during individual trials of silent naming, and the specificity confirmed statistically. An EP of unique morphology with anatomic and behavioral specificity to short-term verbal memory has been identified, measured, and that specificity confirmed statistically. Preliminary observations of ECoG changes during silent word reading have been made with some differences compared to changes with silent naming. The present posposal extends these studies by: Measurement of EP's related to motor speech function, determining if the EP related to memory also occurs at frontal sites, confirming ECoG changes with anatomic and behavioral specificity to reading, and identifying ECoG events with such specificity to auditory naming, word repetition and speech sound identification. The population variability in the occurrence of these events (identified to date in individuals patients) will be determined. The details of the extent and behavioral correlation of these ECoG events will test the hypothesis that language cortex is organized in mosaics of considerable behavioral specificity. The timing of events at different sites in the same patient will determine the degree of serial or parallel processing of a particular function. The morphology of these events may suggest underlying neurobiologic mechanisms. These studies will increase our understanding of where in the human brain language functions occur, and the neurobiologic mechanisms operative there during those behaviors.

The central theme of this Clinical Center Grant proposal is the clinical phenomenon of Epilepsy. It is a large, complex proposal designed to indicate the interdigitations of 29 individual proposals generated by a large and broad group of multidisciplinary clinical scientists. Thus, the proposed studies include evaluations of several specific forms of pharmacological therapy in adults and children including the evaluation and clinical trial of new anticonvulsant drugs. A series of detailed pharmacokinetic studies are proposed as well as examination of several biological consequences of drugs including changes during pregnancy. Studies in clinical neurophysiology include an attempt to develop EEG predictors of seizure frequency, computer analysis of various elements of the electrophysiological discharge, behavioral activation of EEG to improve diagnostic resolution as well as EEG studies of language localization which can have important consequences in theraputic surgical judgements. Radiologic techniques to improve diagnostic capabilities include the use of the CT scan to resolve ambiguities regarding localization and hopefully to assist in the diagnosis of incisural sclerosis. Frequency of seizures raises a variety of interesting statistical questions and computer modeling of seizure frequency will be examined as well as other statistical studies in epilepsy. These extend into several field studies of epidemiological phenomena as well as the roles of specific enviornmental factors such as stress and depression as determinates of seizure frequency. Such neuropsychological investigations extend into the area of rehabilitation where controlled studies will be undertaken of optimal techniques for evaluating capabilities for job placement and the cost effectiveness of specified rehabilitation measures as well as consumer involvement. Finally, studies to determine the effectiveness of various educational techniques involving both the public as well as the medical profession are proposed including educational efforts in nursing homes and an epilepsy information line which will hopefully uncover those problems of highest priority to patients with epilepsy. Thus, there is a broad spectrum of projects ranging from biological studies to those in the psychosocial area.

DESCRIPTION: (Investigator's Abstract): Neural mechanisms of human memory are investigated utilizing a unique opportunity, craniotomy where the patient is awake under local anesthesia for a portion of the operation. During the portion of these operation, neural activity occurring with memory measures is recorded by extracellular microelectrodes in human lateral temporal and entorhinal cortex, and hippocampus. Multiple aspects or memory are evaluated during those recordings, including long-term semantic, recent explicit post-distractional, working, and implicit memory and recall and recognition modes of retrieval. These various aspects of memory are assessed for three types of verbal material, visually presented names of objects and words and auditory words. based on our previous observation, we expect to identify neurons related to the various aspects of memory in lateral temporal cortex, as well as more medial temporal structures. Individual neurons will be related to a specific aspect of memory, and for the same aspect of memory, to a specific type of verbal material. Each aspect of memory for each type of verbal material has separate neural systems in temporal lobe. This study, then, will more clearly define the subdivisions of human verbal memory and establish some of the changes in neural activity occurring with them.

DESCRIPTION (provided by applicant): The overall aim of this proposal is to establish the relationships between changes in BOLD signals obtained with functional magnetic resonance imaging (fMR) and changes in activity of neurons during the same cognitive measures, at the same sites, in the same subjects in human association cortex. The proposal utilizes a unique clinical opportunity, patients undergoing surgery for epilepsy with a technique where they are awake under local anesthesia for a portion of the operation. In that context we have previously recorded neuronal activity, both action potentials (AP) and overlying electroencephalogram (ECoG) from lateral temporal association cortex during recent verbal memory, finding that a substantial proportion of neurons changed the frequency of AP activity with that task. Both the fMR literature and our preliminary fMR data show fMR changes in lateral temporal cortex with recent memory measures. Having developed a recent verbal memory measure suitable for both fMR and intraoperative recording, we propose investigating the spatial and temporal relation between AP, local field potential (LFP), ECoG and fMR. Hypotheses to be tested include a closer relation between fMR and LFP than AP activity, based on findings reported from nonhuman studies, and specificity of fMR changes to sites with sustained patterns of AP activity during memory. These studies provide a unique window into how neural activity is reflected in changes in BOLD fMR during higher-level cognitive measures.

DESCRIPTION (provided by applicant): This proposal is a continuation of the postdoctoral training program in clinical neurosciences originally funded in July 1, 1979, and renewed July 1, 1982, 1987, 1992 and 1997. The original aim remains unchanged: To provide research training opportunities in neurosciences for both clinicians and basic scientists. The goal is to develop academic neurosurgeons and neurologists who will combine clinical and basic neuroscience and attract basic neuroscientists into areas addressing clinical problems. Thus, we propose fundamental training in the basic neurosciences areas for MDs, and for basic neuroscientists research in an environment that fosters understanding of the significant clinical problems pertinent to neuroscience. Research opportunities are available in a wide range of areas, including neurophysiology and neuroanatomy, developmental neurobiology, and neuro-oncology. Ongoing training opportunities exist in the neurobiology of cerebral cortex and hippocampus, morphology and physiology of epileptogenic tissue, developmental neurobiology (plasticity in development and deafferentation), structural and functional details of trigeminal and other pain pathologies, memory and language of the human brain, cerebrovascular physiology with special emphasis on microcirculatory regulation and fundamental studies of the genetic, cellular and molecular biology of brain tumors. Our training method emphasizes participation in research itself, with frequent interactions between investigators involved in fundamental and disease oriented aspects of neurobiology. Laboratory research experience is emphasized over didactic methods but with an organized series of conferences and seminars that promotes cross-fertilization of ideas. Post-doctoral training for a minimum of two years is proposed for MDs interested in pursuing academic careers, either in neurosurgery or neurology, and PhD trainees with interest in addressing clinically relevant issues. Pre-doctoral MD, DDS and PhD students will be selected for their promise and potential for an investigative career (for one year of training, or a short-term 3-month exposure). Four (4) post-doctoral and two (2) pre-doctoral trainees each year are requested, along with three (3) three-month short-term trainees.