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.

抽象的代谢抑制 (MD) 发生在 TBI 急性期，损害神经元回路的能力以满足当地的活动需求，这反过来又可能限制康复策略和功能的成功结果。尽管大多数神经元能够在轻度或中度 TBI 中幸存下来，但至少在急性损伤中，它们无法有效运作这严重损害了大脑功能，可能导致持续的行为缺陷。这体现了使用静息态功能磁共振成像 (rsFMRI) 作为相关功能活动的丧失通常使用大脑网络功能的连接组学分析来报告。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取决于初始损伤的程度和主要病理亚型。我们建议联合 rsFMRI，新陈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来研究 MD 如何在长期的功能连接改变和大脑重组中表现出来。我们将利用获得的信息深入了解 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 来改变受损大脑的功能轨迹，其次是突触可塑性和认知结果的长期增强。通过模拟临床情况受伤后早期康复与因额外受伤而延迟的康复的比较，我们将确定 DHF 干预是否会减轻急性 MD 的影响，随后或同时进行通过一段时间的早期或延迟锻炼来恢复功能。我们提出研究来测试是否单独或组合干预都可以延迟，但仍然可以显着促进大脑功能连接性和功能结果。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一定程度的置信度，以便能够进行主题级分析区分组织损伤的负担，无论实际损伤的严重程度如何。我们将采用这些 MD、组织肿胀和萎缩以及运动水平的协变量，以获得统计稳健的分析是否会严重抵消 MD 的影响，从而增强康复的效果。