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，这些损害可以在受伤后持续几天到多年。 Theta是一种内在的振荡节律（5-12 Hz），它刺激远端神经网络，并在正常的认知功能中发挥关键作用。我们假设TBI显著降低了学习和记忆回路中的θ振荡，导致认知功能障碍。此外，我们假设使用电神经调节刺激θ振荡将改善TBI大鼠的认知表现。我们的初步数据表明，在成年大鼠的横向液压冲击TBI的结果在海马θ振荡功率显着减少，花在θ频率振荡的时间更少，θ的平均频率的变化，和减少θ相位相干性在海马，内侧隔和前额叶皮层。我们还证明，一分钟的刺激内侧隔之前，立即在巴恩斯迷宫中的每次试验显着提高动物的搜索策略，并改善潜伏期找到目标。改善的行为与内侧隔和海马之间的相位相干性的显著改善相关。 这项研究提出了一种新的神经调节方法来治疗TBI后显著的、使人衰弱的慢性神经功能缺损，目前仅在美国就有数百万人受到影响。对TBI后的振荡进行更彻底的分析，特别是在一个特征良好的回路中的θ活动，将提高我们对与持续性认知缺陷相关的潜在关键机制的理解。特定的回路功能障碍，例如振荡节律的减少，为脑深部刺激提供了目标，以在TBI后恢复更正常的回路功能，并最终恢复认知表现。因此，我们还建议在五个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重症监护室时对其进行治疗以防止不良结局很重要，但我们为数百万存活时间超过20年的患者制定治疗策略也至关重要。 创伤性脑损伤的急性期，并可能在慢性残疾中度过余生。

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.