Impact of post-stroke rehabilitation on neurophysiological dynamics - SUMMARY/ABSTRACT The long-term goal of this project is to develop a novel mechanistic framework to understand how post-stroke rehabilitative training modulates neural reorganization in sensorimotor brain regions, and whether such reorganization is associated with recovery of motor function. In a non-human primate model of capsular stroke, we will describe the time course of changes in task-related motor encoding and mesoscale cortico-cortical connectivity that occur in sensorimotor brain regions, and the time course of these changes in relation to motor recovery. These neurophysiological changes will be compared to those occurring in animals undergoing intensive rehabilitation initiated in the sub-acute stage after injury. Post-stroke neural plasticity has been demonstrated repeatedly in pre-clinical and clinical studies. Animal studies have provided key information regarding the molecular mechanisms of synaptic plasticity, and focal cortical stroke models have demonstrated that alterations in neuronal connectivity are correlated with functional recovery. However, most studies are cross- sectional and cannot address the complex temporal relationships between neural plasticity and behavioral recovery; conclusions about the impact of rehabilitation on recovery mechanisms, and ultimately on clinical recovery, are largely correlative. As a result, it is currently unknown whether plasticity mechanisms demonstrated in most clinical and preclinical studies are associated with the initiation of recovery processes or are the result of behavioral recovery. Further, when longitudinal studies in clinical populations have been done, relationships between plasticity and motor recovery have been equivocal, in part because fMRI-based approaches lack the temporal specificity to resolve the intricate patterns of communication among brain regions that are essential for normal sensorimotor function. Using chronic microelectrode arrays in a longitudinal experimental design, we will address three specific aims that examine neural activity (extracellular spikes) simultaneously recorded from multiple cortical sensorimotor areas and motor thalamus before and after capsular infarct. This will allow us to examine how stroke-like injuries disrupt task-related motor encoding in somatosensory and motor cortical areas using traditional dynamical structure models (Aim 1). Further, we will characterize the impact of capsular infarcts on mesoscale effective connectivity using a novel neurophysiological approach that we recently developed (Aim 2). Finally, we will determine whether rehabilitative training procedures initiated in the sub-acute period after neural injury influence recovery by modulating task-related activity, altering effective connectivity, or both (Aim 3). The novelty and potential impact of this project stems from the unique longitudinal design, providing us with the ability to plot the precise temporal profile of local and networked changes to determine if a particular biomarker precedes rehabilitation-aided recovery, and thus, is more likely to have a direct causal relationship with functional restoration. Achieving these goals ultimately will inform clinical studies aimed at personalizing post-stroke rehabilitation based on neurophysiological biomarkers of recovery potential.
