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)发生在颅脑损伤的急性期，这损害了神经元的回路能力 为了满足当地的活动需求，这反过来又可能限制康复战略的成功，以及 结果。尽管大多数神经元在轻度或中度脑损伤中存活下来，至少是急性损伤，但它们不能有效地运作。 这严重损害了大脑功能，可能导致持续的行为缺陷。这体现了 作为使用静息状态功能磁共振成像(RsFMRI)的相关功能活动的丧失 通常使用脑网络功能的连接分析进行报道。还有很多东西需要学习 关于如何治疗受伤的大脑，神经元的功能轨迹如何随时间演变，以及 依赖于最初损伤的程度和主要病理亚型。我们提出了组合rsFMRI， 代谢和突触可塑性的行为和分子研究将提供对 研究MD如何表现为慢性的功能连接改变和脑重组。我们 将利用所获得的信息来深入了解TrkB受体的小分子激动剂-7，8- 二羟基黄酮(DHF)将通过急剧减少MD改变受损脑的功能轨迹， 随之而来的是突触可塑性和认知功能的慢性增强。通过对临床情况进行建模 伤后早期康复与因额外受伤而延迟的康复相比，我们将确定 DHF的干预是否会减轻急性MD的影响，随后是，还是与 通过提前或推迟一段时间的锻炼来恢复机能。我们提出的研究将测试 无论是单独干预还是联合干预，都可以推迟，但仍能显著促进大脑功能 连通性和功能结果。我们将在雄性和雌性大鼠身上进行这些研究，并将使用 新的统计驱动型方法，可提供一定程度的置信度，以实现对以下各项的主题级别分析 区分组织损伤的负担，而不考虑实际的损伤严重程度。我们将使用这些 MD、组织肿胀和萎缩以及运动水平的协变量，以得出统计上可靠的分析 能否敏锐地抵消MD，将增强康复效果。