Strategy to Potentiate Rehabilitation after TBI

加强 TBI 后康复的策略

基本信息

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
项目类别：
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

项目摘要

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.

抽象的代谢性抑郁症（MD）发生在TBI的急性期间，这会损害神经元电路的能力满足当地活动需求，这反过来可能限制康复策略的成功和功能结果。尽管大多数神经元在轻度或中度的TBI中生存，但至少急性化，它们无法有效运行这严重损害了大脑功能，这可能导致持续的行为缺陷。这表现出来作为使用静止状态功能磁共振成像（RSFMRI）的相关功能活性的丧失并且通常使用大脑网络功能的连接分析进行报告。还有很多要学习的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流逝而演变对初始损伤的程度和主要病理亚型的依赖性。我们提出了RSFMRI的组合，代谢和突触可塑性的行为和分子研究将提供纵向分析损伤研究MD如何长期表现在功能连通性和大脑重组中。我们将使用所获得的信息来洞悉TRKB受体的小分子激动剂-7,8-- 二羟基氟氟酮（DHF）将通过急性减少MD，改变受伤大脑的功能轨迹，然后长期增强突触可塑性和认知结果。通过建模临床情况由于额外的伤害，我们将确定早期伤害后的康复与康复的康复。与DHF的干预是否会减轻急性MD的影响，然后与使用早期或延迟运动时期恢复功能。我们提出的研究将测试是否干预措施，单独或组合都可以延迟，但仍然可以显着增强大脑连通性和功能结果。我们将在雄性和雌性大鼠中进行这些研究，并将使用新的统计驱动方法提供了一定的信心，以实现主题级分析无论实际伤害严重程度如何，歧视组织损伤负担。我们将采用这些 MD的协变量，组织肿胀和萎缩以及运动水平，以得出统计上强大的分析偏离脱离MD的MD是否会增强康复的影响。