Restoring functional connectivity following TBI

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DESCRIPTION (provided by applicant): 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.