Restoring functional connectivity following TBI

TBI 后恢复功能连接

• 批准号: 8800582
• 负责人: Gene Gabriel Gurkoff
• 金额: $ 42.29万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800582
• 关键词: Acute; Adult; Affect; Alzheimer' s Disease; Animals; Attention; Behavior; Biological Neural Networks; Brain; Brain region; Case Series; Cell physiology; Characteristics; Chemicals; Chronic; Clinical; Cognition; Cognitive deficits; Coma; Consciousness Disorders; Coupling; Data; Deep Brain Stimulation; Depressed mood; Distal; Dystonia; Electrodes; Electrophysiology (science); Essential Tremor; Family; Frequencies; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Injury; Intervention; Intractable Epilepsy; Lateral; Learning; Lesion; Life; Liquid substance; Medial; Medial Septal Nucleus; Memory; Neurodegenerative Disorders; Neurologic; Obsessive-Compulsive Disorder; Outcome; Outcome Measure; Parkinson Disease; Patients; Percussion; Performance; Phase; Phase III Clinical Trials; Play; Prefrontal Cortex; Quality of life; Randomized; Rattus; Research Personnel; Rest; Rodent; Rodent Model; Role; Short-Term Memory; Testing; Therapeutic; Theta Rhythm; Time; Traumatic Brain Injury; chronic depression; chronic pain; cognitive function; cognitive performance; cognitive process; cognitive recovery; cognitive task; disability; economic cost; entorhinal cortex; executive function; functional outcomes; improved; information processing; injured; innovation; interest; nervous system disorder; neuronal survival; neuroregulation; novel; phase I trial; prevent; psychosocial; restoration; spatial memory; treatment strategy

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.

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，这种损害可能在受伤后持续几天到很多年。 Theta 是一种内在的振荡节律（5-12 Hz），可同步远端神经网络并在正常认知功能中发挥关键作用。我们假设 TBI 显着减少学习和记忆回路内的 θ 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 theta 振荡将改善 TBI 大鼠的认知能力。我们的初步数据表明，成年大鼠的侧向液体冲击 TBI 会导致海马 θ 振荡功率显着降低、θ 频率振荡所需的时间减少、θ 平均频率发生变化以及整个 θ 相位相干性降低。海马体、内侧隔膜和前额皮质。我们还证明，在巴恩斯迷宫中的每次试验之前立即刺激内侧隔膜一分钟，可以显着改善动物搜索策略并缩短找到目标的潜伏期。行为的改善与内侧隔膜和海马体之间相位一致性的显着改善相关。 这项研究提出了一种新颖的神经调节方法，用于治疗 TBI 后严重的、使人衰弱的慢性神经功能缺损，这种缺损目前仅在美国就影响了数百万人。对 TBI 后的振荡进行更彻底的分析，特别是对特征良好的回路内的 θ 活动进行分析，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，为深部脑刺激提供了目标，以恢复更正常的回路功能，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，目的是确定最大化认知恢复的范式。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出现不良结果很重要，但我们为数百万存活下来的患者制定治疗策略也很重要 他们可能会在 TBI 的急性期度过，并可能在慢性残疾中度过余生。