A mechanism for stunted map plasticity after TBI

TBI 后地图可塑性发育不良的机制

• 批准号: 8860908
• 负责人: Neil Harris
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860908
• 关键词: Acute; Address; Adult; Affect; Agonist; Automobile Driving; Behavior; Behavioral; Brain; Brain Concussion; Brain region; Caring; Cerebrum; Chronic; Clinical; Cognitive; Cognitive deficits; Communication; Data; Diffusion Magnetic Resonance Imaging; Electrophysiology (science); Equilibrium; Evoked Potentials; Forelimb; Functional Magnetic Resonance Imaging; Functional disorder; Global Change; Hippocampus (Brain); Human; Individual; Injury; Intervention; Learning; Limb structure; Maps; Measures; Medical; Modeling; Monitor; Motor; Motor Cortex; Muscimol; Nerve Degeneration; Neurons; Outcome; Patients; Pharmaceutical Preparations; Physiologic pulse; Prognostic Marker; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Research; Rest; Rodent Model; Role; Sensory; Silver Staining; Staging; Stroke; Symptoms; Synaptic plasticity; Testing; Therapeutic Intervention; Time; Traumatic Brain Injury; Traumatic Brain Injury recovery; Walking; Work; base; behavioral outcome; clinically relevant; cohort; constraint induced movement therapy; controlled cortical impact; cortex mapping; design; functional outcomes; functional plasticity; improved; injured; innovation; intervention effect; mild traumatic brain injury; motor deficit; motor skill learning; neuroimaging; prevent; public health relevance; receptor; research study; response; restoration; somatosensory; therapy design; young adult

 DESCRIPTION (provided by applicant): In addition to the well-known cognitive deficits that result from traumatic brain injury (TBI) motor weakness is also a significant, yet understudied problem that occurs in over half of injured individuals. Beyond acute interventions, there are currently no generally accepted medical treatments for promoting functional recovery after TBI. Although brain regions may spontaneously reorganize to restore some lost function after injury, it is not clear which components of this plasticity may serve as a prognostic biomarker of good recovery, and which result from behavioral compensatory mechanisms that are not beneficial to outcome. Motor cortex excitability is impaired after concussion in athletes and can persist to nearly 30 years since the last concussion. This dysfunction is associated with compromised synaptic plasticity and reductions in motor learning skills, as well as reduced inhibition from the opposite cortex. In fact, neuroimaging studies after TBI have documented post-injury somatosensory cortical map changes where stimulation of the affected limb leads to activation within the intact, contra- lesional hemisphere, rather than the normal activation of cortex opposite to the limb. It is still unknown however, whether contra-lesional activation is performing a temporary, beneficial role, or whether it is interfering with recovery of ipsi-lesional plasticit. We show preliminary data using a unilateral concussive rat model of TBI that indicates an ipsi- to-contra-lesional shift of the affected forelimb cortical map occurs during alterations in trans- hemispheric excitability. We also show that early, but not delayed, temporary silencing of the contra-lesional cortex promotes recovery of affected forelimb function and recovery of the ipsi-lesional cortical map, suggesting that contra-lesional cortex prevents map reorganization and recovery of limb function. Based upon these data, the central hypothesis of the proposed research is that: unilateral TBI induces hyper-excitability in the contra-lesional cortex and alter the hemispheric balance of excitation-inhibition, such that the intact cortex remotely confers an increased inhibitory drive upon the injured cortex, preventing ipsi-lesional cortical map reorganization and the recovery of forelimb function. We propose proof-of-concept experiments to test this hypothesis using pharmacologic and rehabilitative interventions, as well as a clinically-relevant aim designed to test whether the combination of a properly timed, pharmacological intervention to promote a period of greater cortical map plasticity together with rehabilitation, will result in a persistent recovery of the affected forelimb deficits. We will use quantitative evoked and resting state functional magnetic resonance imaging and forelimb reaching tasks, together with paired-pulse sensory-evoked potential electrophysiology as readouts to determine the effect of intervention. Alterations in the excitatory-inhibitory balance have also previously been shown in the hippocampal-prelimbic circuit so that the proof-of-concept approaches that we take in this proposal to learn how to reestablish a more normal excitatory-inhibitory balance are likely to be generalizable to cognitive circuit dysfunction that are also a major hall mark of TBI.

 描述（由申请人提供）：除了由创伤性脑损伤（TBI）引起的众所周知的认知缺陷之外，运动无力也是一个重要的，但研究不足的问题，发生在超过一半的受伤个体中。除了急性干预之外，目前还没有普遍接受的用于促进TBI后功能恢复的医学治疗。虽然脑区可能会自发重组，以恢复一些损伤后失去的功能，目前尚不清楚这种可塑性的组成部分可能作为良好恢复的预后生物标志物，并导致行为代偿机制，是不利于结果。运动员脑震荡后运动皮层的兴奋性受损，并且自上次脑震荡以来可以持续近30年。这种功能障碍与受损的突触可塑性和运动学习技能的降低以及来自神经元的抑制减少有关。 对侧皮质事实上，TBI后的神经影像学研究已经记录了损伤后躯体感觉皮层地图的变化，其中对受影响肢体的刺激导致完整的对侧半球内的激活，而不是肢体对侧皮层的正常激活。然而，目前尚不清楚是否对病灶激活正在进行 暂时的、有益的作用，或者是否干扰同病灶可塑性的恢复。我们使用单侧脑震荡大鼠TBI模型显示了初步数据，表明在跨半球兴奋性改变期间发生了受影响前肢皮层地图的同侧到对侧损伤转移。我们还表明，早期，但不是延迟，临时沉默的contrasionalcortex促进恢复受影响的前肢功能和恢复的issi-lesionalcortex地图，这表明contrasionalcortex防止地图重组和肢体功能的恢复。基于这些数据，所提出的研究的中心假设是：单侧TBI诱导对侧损伤皮层的过度兴奋性并改变兴奋-抑制的半球平衡，使得完整的皮层远程赋予损伤皮层增加抑制驱动，阻止同侧损伤皮层地图重组和前肢功能的恢复。我们提出概念验证实验，使用药理学和康复干预措施来测试这一假设，以及临床相关目标，旨在测试是否将适当时机的药理干预与康复相结合，以促进一段时间更大的皮质地图可塑性，将导致受影响的前肢缺陷的持续恢复。我们将使用 定量诱发和静息状态功能性磁共振成像和前肢到达任务，以及作为读数的成对脉冲感觉诱发电位电生理学，以确定干预的效果。兴奋-抑制平衡的改变以前也曾在大脑皮层-前边缘系统回路中被证明，因此我们在本提案中采取的概念验证方法，以学习如何重建更正常的兴奋-抑制平衡，可能适用于认知回路功能障碍，这也是TBI的主要标志。