Over 5.3 million patients live with chronic neurological disabilities related to traumatic brain injury (TBI). Of particular interest are impairments in shot-term memory, attention, and executive functions, which can last anywhere from several days to many years following injury. Theta is an intrinsic oscillatory rhythm (5-12 Hz) that synchronizes distal neural networks and plays a critical role in normal cognitive function. We hypothesize that TBI significantly reduces theta oscillations within a learning and memory circuit, leading to cognitive dysfunction. Furthermore, we hypothesize that stimulation of the theta oscillations using electrical neuromodulation will improve cognitive performance in TBI rats. Our preliminary data demonstrates that lateral fluid percussion TBI in the adult rat results in a significant reduction in hippocampal theta oscillatory power, less time spent oscillating in the theta frequency, a change in the average frequency of theta, and a reduction of theta phase coherence across the hippocampus, medial septum and prefrontal cortex. We also demonstrate that one minute of stimulation of the medial septum immediately prior to each trial in the Barnes maze significantly improves animals search strategy and improves latency to find the target. The improved behavior correlates with a significant improvement in phase coherence between the medial septum and the hippocampus. This study presents a novel neuromodulatory approach to treat significant, debilitating chronic neurological deficits following TBI that currenly affect millions of people in the US alone. A more thorough analysis of oscillations after TBI, specifically theta activity within a well-characterized circuit, will improve our understanding of potential critical mechanism related to persistent cognitive deficit. A specific circuit dysfunctio, such as a decrease in oscillatory rhythms, provides a target for deep brain stimulation to restore more normal circuit function, and ultimately cognitive performance, following TBI. We also propose, therefore, to test four different stimulation paradigms across five different cognitive tasks with the goal of identifying the paradigm that maximizes cognitive recovery. While it is important to treat patients as they come into the ER and ICU to prevent poor outcome, it is also critical that we develop treatment strategies for the millions of patients that survive well beyond the acute phase of TBI and spend, potentially, the rest of their lives living with chronic disabiliy.

Public Health Relevance

Over 5.3 million patients suffer chronic neurological deficits after TBI, including deficits in learning and memory. We propose that cognitive deficits after TBI result from a reduction in the intrinsic oscillatory rhythm, theta, known to coordinate hippocampal activity across distal neural networks. Furthermore, we propose that electrical neuromodulation, using deep brain stimulation, will enhance theta oscillations and restore cognitive function. This proposal represents an innovative approach to improve quality of life for millions of patients suffering chronic disability following TBI;a novel mechanism involved in post-TBI cognitive dysfunction and an innovative therapeutic strategy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BINP-Y (08))
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Hicks, Ramona R
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University of California Davis
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Pevzner, Aleksandr; Izadi, Ali; Lee, Darrin J et al. (2016) Making Waves in the Brain: What Are Oscillations, and Why Modulating Them Makes Sense for Brain Injury. Front Syst Neurosci 10:30
Lee, Darrin J; Gurkoff, Gene G; Izadi, Ali et al. (2015) Septohippocampal Neuromodulation Improves Cognition after Traumatic Brain Injury. J Neurotrauma 32:1822-32