Examining the impact of lesion location and extent on post-stroke neuroplasticity

About This Grant

PROJECT SUMMARY Stroke is the most common neurological disorder and leading cause of long-term disability in the US. While some recovery occurs spontaneously and can be facilitated by rehabilitation, recovery is often incomplete. Therefore, there is a need to better understand the mechanisms of post-stroke recovery in order to develop more targeted interventions. In the past, efforts to examine the mechanisms of stroke recovery have utilized animal models with focal and homogeneous cortical lesions. In contrast, human patients present with lesions in a range of locations and sizes, limiting our ability to translate findings from experimental models into human patients. The overall objective of this project is to better understand the impact of lesion location and extent on the mechanisms of post-stroke recovery. Specifically, we will seek to determine whether the role of the contralesional hemisphere after stroke is dependent upon lesion location and extent. We will seek to address this objective by examining rats randomized to receive four distinct stroke models that will independently vary lesion size relative to the corticospinal tract and lesion location in the cortex or internal capsule. We will examine these animals using a complimentary combination of methods including electrophysiology, functional imaging, and cortical inactivation to test our central hypothesis that corticospinal tract integrity will determine the specific neural circuits associated with recovery. Specifically, we will test the bimodal balance recovery model which posits that the mechanisms of recovery will depend upon corticospinal tract integrity with recovery from an incomplete infarct facilitated by restoring interhemispheric balance and recovery from a complete infarct facilitated by the unaffected hemisphere. Initially, we will examine the difference in longitudinal changes in task-related neural activity associated with lesion location and extent (Aim 1). Next, we will examine the impact of different lesion locations and sizes on changes in corticocortical connectivity (Aim 2). We will use both an assessment of direct effective connectivity as a longitudinal surrogate for anatomical connectivity (Aim 2A) as well as a measure of resting- state functional connectivity that is similar to assessments of resting state functional connectivity MRI scans in human patients (Aim 2B). Finally, we will use chemogenetic techniques to determine whether cortical inactivation reinstates deficits following recovery (Aim 3). If successful, the project will provide evidence for patient-specific mechanisms of recovery that primarily depend upon corticospinal tract integrity. The novelty and potential impact of the project stems from the use of multiple distinct lesions that seek to better model clinical stroke, and the combination of longitudinal measures that will allow us to assess the functional relevance of potential recovery mechanisms. Achieving these goals will ultimately allow us to design more personalized therapies seeking to maximize post-stroke recovery by applying patient-specific neurorehabilitation strategies.