Strategy to Potentiate Rehabilitation after TBI

加强 TBI 后康复的策略

• 批准号: 10308503
• 负责人: Fernando Gomez-Pinilla
• 金额: $ 60.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308503
• 关键词: Acute; Adult; Agonist; Animals; Atrophic; Behavior; Behavioral; Bioenergetics; Brain; Brain Concussion; Brain Injuries; Brain imaging; Brain-Derived Neurotrophic Factor; Cells; Cellular Metabolic Process; Cerebrovascular Circulation; Chronic; Clinical; Cognitive; Convalescence; Data; Dependence; Diffuse; Diffusion; Discrimination; Dose; Early Intervention; Elements; Exercise; Exercise Physiology; Female; Flavonoids; Functional Magnetic Resonance Imaging; Hippocampus (Brain); Image; Impairment; Injury; Intervention; Lead; Learning; Link; Magnetic Resonance Imaging; Maps; Measures; Memory; Metabolic Marker; Metabolism; Methods; Modeling; Molecular; Monitor; Motor Cortex; Network-based; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Pathologic; Pathology; Patients; Pharmacology; Physical Rehabilitation; Physical activity; Play; Rattus; Recovery; Recovery of Function; Rehabilitation Outcome; Rehabilitation therapy; Reporting; Rest; Severities; Soldier; Swelling; Synapses; Synaptic plasticity; TBI Patients; Testing; Therapeutic; Time; Tissues; Training; Traumatic Brain Injury; Traumatic Brain Injury recovery; Treatment Efficacy; anxiety-like behavior; base; behavioral outcome; brain cell; brain metabolism; cognitive function; energy balance; experience; experimental study; functional outcomes; gain of function; improved; improved outcome; in vivo; indexing; insight; limb injury; longitudinal analysis; male; metabolic abnormality assessment; metabolic depression; neural circuit; neuronal circuitry; novel; pre-clinical; protein biomarkers; rehabilitation strategy; small molecule; success; synaptic function

Abstract Metabolic depression (MD) occurs during the acute period of TBI and this impairs the ability of neuronal circuits to meet local activity demand, which in turn could limit the success of rehabilitative strategies, and functional outcome. Although most neurons survive mild or moderate TBI, at least acutely, they cannot operate efficiently and this severely compromises brain function, which may lead to persistent behavioral deficits. This manifests as a loss of correlated functional activity using resting state functional magnetic resonance imaging (rsFMRI) and is typically reported using a connectomic analysis of brain network function. There remains much to learn about how to treat the injured brain, how the functional trajectory of neurons evolves with time, and the dependence on the extent and major pathologic subtype of the initial injury. We propose combined rsFMRI, behavior and molecular studies of metabolism and synaptic plasticity that will provide a longitudinal analysis of injury to investigate how MD manifests in altered functional connectivity and brain reorganization chronically. We will use the information gained to provide insight on how the small molecule agonist of TrkB receptors - 7,8- dihydroxyflavone (DHF) will alter the functional trajectory of the injured brain through reduction of MD acutely, followed by enhancement of synaptic plasticity and cognitive outcome chronically. By modelling clinical situations of early post-injury rehabilitation versus rehabilitation that is delayed due to additional injuries, we will determine whether an intervention with DHF will mitigate the effects of acute MD, followed by, or simultaneously with the reinstitution of function using a period of early or delayed exercise. We propose studies that will test whether either intervention, alone or in combination, can be delayed but still provide a significant boost to brain connectivity and functional outcome. We will conduct these studies in both male and female rats, and will use new statistically-driven methods that provide a level of confidence to enable subject-level analysis for discrimination of burden of tissue damage, regardless of the actual injury severity. We will employ these covariates of MD, tissue swelling and atrophy, as well as exercise level, to derive a statistically robust analysis of whether off-setting MD acutely, will potentiate the effects of rehabilitation.

摘要 代谢抑制（MD）发生在TBI的急性期，这损害了神经元回路的能力 满足当地活动需求，这反过来又可能限制康复战略的成功， 结果。尽管大多数神经元在轻度或中度TBI中存活，至少在急性TBI中存活，但它们不能有效地工作 这会严重损害大脑功能，可能导致持续的行为缺陷。这表现 使用静息态功能性磁共振成像（rsFMRI） 并且通常使用脑网络功能的连接组学分析来报告。还有很多东西要学 关于如何治疗受伤的大脑，神经元的功能轨迹如何随着时间的推移而演变， 依赖于初始损伤的程度和主要病理亚型。我们提出结合rsFMRI， 代谢和突触可塑性的行为和分子研究，将提供一个纵向分析， 研究MD如何长期表现为改变的功能连接和大脑重组。我们 将利用获得的信息提供关于TrkB受体的小分子激动剂-7，8- 二羟基黄酮（DHF）可通过急性减少MD改变受损脑的功能轨迹， 随后是突触可塑性和认知结果的慢性增强。通过模拟临床情况 伤后早期康复与因额外伤害而延迟的康复，我们将确定 DHF干预是否会减轻急性MD的影响，随后或同时 通过早期或延迟的锻炼来恢复功能。我们建议进行研究， 无论是单独的干预还是联合的干预，都可以推迟，但仍然可以显著促进大脑 连接性和功能性结果。我们将在雄性和雌性大鼠中进行这些研究， 新的实验驱动方法，提供一定程度的置信度，以实现受试者级别的分析， 区分组织损伤的负担，而不考虑实际损伤的严重程度。我们将利用这些 MD、组织肿胀和萎缩以及运动水平的协变量，以得出统计学稳健的分析 急性偏置MD是否会增强康复的效果。