Restoring functional connectivity following TBI

描述(申请人提供)：超过530万名患者患有与创伤性脑损伤(TBI)相关的慢性神经功能障碍。尤其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的任何地方持续几天到许多年。Theta是一种内在的振荡节律(5-12赫兹)，它同步远端神经网络，在正常认知功能中发挥关键作用。我们假设，TBI显著减少学习和记忆回路中的theta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theta振荡将改善脑损伤大鼠的认知能力。我们的初步数据显示，在成年大鼠中，侧向液压冲击导致海马theta振荡功率显著降低，在theta频率上振荡的时间减少，theta平均频率改变，并降低了海马区、内侧隔区和前额叶皮质的theta相一致性。我们还证明，在每一次巴恩斯迷宫试验之前对内侧隔区进行一分钟的刺激，显著改善了动物的搜索策略，并缩短了寻找目标的潜伏期。行为的改善与内侧隔和海马区之间的相位一致性显著改善有关。这项研究提出了一种新的神经调节方法来治疗脑外伤后严重的、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影响。更深入地分析脑损伤后的振荡，特别是一个特征明确的回路中的theta活动，将有助于我们更好地理解与持续性认知障碍相关的潜在关键机制。特定的回路功能障碍，如振荡节律的减少，为脑深部刺激提供了一个靶点，以恢复脑损伤后更正常的回路功能，并最终恢复认知能力。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，目的是确定最大限度地促进认知恢复的范式。虽然在患者进入急诊室和重症监护室时对他们进行治疗以防止不良结果是很重要的，但同样重要的是我们为数百万存活了很久的患者制定治疗策略 颅脑损伤的急性期，可能会在他们的余生中与慢性残疾生活在一起。

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.