A mechanism for stunted map plasticity after TBI

 描述(由申请人提供)：除了众所周知的由创伤性脑损伤(TBI)引起的认知缺陷外，运动无力也是一个严重的、但尚未得到充分研究的问题，发生在超过一半的受伤个体中。除了急性干预，目前还没有被普遍接受的促进脑损伤后功能恢复的药物治疗。尽管损伤后大脑区域可能会自发重组以恢复一些失去的功能，但尚不清楚这种可塑性的哪些成分可能作为良好恢复的预后生物标志物，哪些是由对结果不利的行为补偿机制造成的。运动皮质兴奋性在运动员脑震荡后受损，自上次脑震荡以来可持续近30年。这种功能障碍与突触可塑性受损、运动学习技能降低以及 对侧皮质。事实上，脑外伤后的神经成像研究记录了损伤后躯体感觉皮层图的变化，其中刺激受影响的肢体导致完整的对侧半球内的激活，而不是肢体对面皮质的正常激活。然而，目前尚不清楚对抗性激活是否正在进行 一种暂时的、有益的作用，或者它是否干扰自身的可塑性的恢复。我们使用单侧脑震荡的大鼠脑损伤模型显示了初步的数据，表明在跨半球兴奋性的改变过程中，受影响的前肢皮质映射发生了自对位移位。我们还发现，早期而非延迟的对侧皮质的暂时沉默促进了患侧前肢功能的恢复和患侧皮质图的恢复，这表明对侧皮质阻止了MAP的重组和肢体功能的恢复。基于这些数据，本研究的中心假设是：单侧颅脑损伤可引起对侧皮质的高兴奋性，改变大脑半球的兴奋-抑制平衡，从而使完整的皮质远程给予受损皮质更强的抑制性驱动，阻止患侧皮质地图的重组和前肢功能的恢复。我们建议进行概念验证实验，使用药理学和康复干预措施来验证这一假说，以及临床相关的目的，旨在测试适当时机的药物干预措施与康复措施的结合是否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磁共振成像和前肢到达任务，结合双脉冲感觉诱发电位电生理读数确定干预效果。兴奋-抑制平衡的改变以前也在海马体-预激回路中表现出来，因此我们在这项建议中采取的概念验证方法很可能适用于认知回路功能障碍，这也是脑外伤的一个主要标志。

 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.