Restoring functional connectivity following TBI

描述（由申请人提供）：超过530万患者患有与创伤性脑损伤（TBI）相关的慢性神经功能障碍。特别令人感兴趣的是短期记忆、注意力和执行功能的损害，这些损害可能在受伤后持续几天到多年。θ波是一种内在的振荡节律（5-12 Hz），可以同步远端神经网络，在正常认知功能中起关键作用。我们假设创伤性脑损伤显著降低了学习和记忆回路中的θ波振荡，从而导致认知功能障碍。此外，我们假设使用电神经调节刺激θ波振荡将改善脑外伤大鼠的认知表现。我们的初步数据表明，成年大鼠的外侧液体冲击TBI导致海马θ波振荡功率显著降低，θ波频率振荡时间减少，θ波平均频率发生变化，海马、中隔和前额叶皮层的θ波相一致性降低。我们还证明，在巴恩斯迷宫的每次试验之前，对内侧隔膜进行一分钟的刺激，可以显著改善动物的搜索策略，并改善寻找目标的潜伏期。行为的改善与内侧隔和海马体之间相一致性的显著改善有关。这项研究提出了一种新的神经调节方法来治疗创伤性脑损伤后严重的、使人衰弱的慢性神经功能障碍，目前仅在美国就有数百万人受到这种疾病的影响。对脑外伤后的振荡进行更彻底的分析，特别是在一个特征明确的回路内的θ波活动，将提高我们对与持续认知缺陷相关的潜在关键机制的理解。一种特殊的电路功能障碍，如振荡节律的减少，为深部脑刺激提供了一个目标，以恢复更正常的电路功能，并最终恢复TBI后的认知能力。因此，我们还建议在五种不同的认知任务中测试四种不同的刺激范式，以确定最大限度地提高认知恢复的范式。虽然在患者进入急诊室和ICU时进行治疗以防止不良结果很重要，但我们为数百万存活的患者制定治疗策略也很重要

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.