Prasad R. Shirvalkar, M.D., Ph.D - US grants

DESCRIPTION (provided by applicant): Amnestic syndromes and age-associated cognitive decline present significant morbidity, yet have few effective treatments. The long-term goals of this proposal are to characterize the neurobiological substrates of cognitive decline associated with aging and to develop therapeutic strategies to treat such decline. These goals dovetail with the NIH mission to support innovative research, extend healthy life and reduce the burdens of illness and disability The project will study fundamental mechanisms of brain rhythm interactions relevant to episodic memory coding using a rat model of amnesia and cognitive aging. The specific aims will test a novel strategy to improve memory performance, and evaluate potential episodic memory encoding mechanisms. In normal rats, memory performance is impaired by disrupting medial septal function, and conversely, improved by electrical stimulation of the septum. By simultaneously recording hippocampal EEG, stimulating the fornix, and tracking behavior in a Radial Arm Water Maze (RAWM), we will directly evaluate the physiological and behavioral consequences of different patterns of electrical stimulation. The specific aims are to ameliorate memory in rats made amnestic by medial septal inactivation, and to improve memory in aged rats who have naturally occurring spatial deficits. We will test the hypothesis that coherent activity between theta (4-10 Hz) and gamma (30-50 Hz) frequencies are crucial for memory encoding or retrieval. We predict that theta-gamma coherence will predict memory performance, and that stimulation patterns that increase such coherence will concomitantly enhance memory mechanisms. The results of the proposed experiments will elucidate the influence of endogenous synchronous rhythmicity in memory, and may lead to therapeutic interventions for improving memory in people. Cognitive decline and memory impairments often occur during old age, despite the absence of Alzheimer's disease or other illness. This project tests an approach to repair learning deficits in both young rats with amnesia and old rats with natural memory impairments using electrical stimulation in the brain. As the population of the US aged 65 and over increases over the next decade, such treatments will become a more urgent need in our aging society.

PROJECT SUMMARY A diverse array of chronic pain syndromes are refractory to almost all treatment but involve pathological activity in similar brain regions. This suggests therapeutic potential for deep brain stimulation (DBS) for refractory pain disorders, but despite early promise, long-term efficacy is lacking. Current DBS devices are limited in anatomical reach, targeting only a subset of the distinct brain regions known to be important. Further, DBS therapy is bluntly applied in an ?open-loop,? continuous fashion without regard to underlying physiology. As a result of these shortcomings, DBS for pain is often ineffective or shows diminished effect over time. Loss of therapeutic effect may be due to nervous system adaptation or a failure of stimulation to accommodate patient- specific dynamics of pain processing. DBS could be significantly improved by seeking individually optimized brain targets or by using neural biomarkers of pain to selectively control stimulation when it is needed (?closed-loop? DBS). Better brain targets would also address the different dimensions of pain such as somatosensory (location, intensity and duration), affective (mood and motivation) and cognitive (attention and memory). The main goal of this study is to test the feasibility of personalized targeting of brain regions that support multiple pain dimensions and to develop new technology for ?closed-loop? DBS for pain. We will develop data-driven stimulation control algorithms to treat chronic pain using a novel device (Medtronic Summit RC+S) that allows longitudinal intracranial signal recording in an ambulatory setting. By building this technology in an implanted device, we will tailor chronic pain DBS to each patient and advance precision methods for DBS more generally. Beginning with an inpatient trial period, subjects with various refractory chronic pain syndromes will undergo bilateral surgical implant of temporary electrodes in the thalamus, anterior cingulate, prefrontal cortex, insula and amygdala. These regions have been implicated in the multiple dimensions of pain. The goal of the trial period is to identify candidate biomarkers of pain and optimal stimulation parameters for each individual, and to select subjects who show likelihood to benefit from the trial. A subgroup of 6 such patients will then proceed to chronic implantation of up to 3 ?optimal? brain regions for long-term recording and stimulation. We will first validate biomarkers of low- and high-pain states to define neural signals for pain prediction in individuals (Aim 1). We will then use these pain biomarkers to develop personalized closed-loop algorithms for DBS and test the feasibility of performing closed-loop DBS for chronic pain in weekly blocks (Aim 2). We will then assess the efficacy of closed-loop DBS algorithms against traditional open-loop DBS or sham in a double-blinded cross- over trial (Aim 3) and measure mechanisms of DBS tolerance. Our main outcome measures will be a combination of pain, mood and functional scores together with quantitative sensory testing. Successful completion of this study would result in the first algorithms to predict real-time fluctuations in chronic pain states and development of a new therapy for currently untreatable diseases.