The leading cause of adult disability in the US, stroke has an annual incidence of 780,000 with over 5.8 million stroke survivors. Most stroke survivors have some degree of spontaneous recovery, typically occurring in the first weeks to months after stroke; however this recovery is highly variable and in many cases incomplete. Much of our understanding of recovery mechanisms has focused on local cellular and molecular mechanisms involved in brain remodeling. More recent work has examined recovery after stroke at the network level- examining distributed patterns of synchronized neural activity throughout the brain during rest-and has revealed that global patterns of functional network connectivity are altered after focal stroke. Moreover, shortly after ischemic stroke, disrupted interhemispheric homotopic functional connectivity (fc), in particular, predicted poor performance. In a rat focal ischemia model, homotopic fc was found to recover in parallel with behavioral improvement. There is substantial indirect evidence that homotopic interhemispheric fc may be important to recovery, and has given rise to the concept of interhemispheric competition. This hypothesis holds that an equilibrium between excitation and inhibition across hemispheres may be important for normal unilateral function (e.g. unilateral hand movement). If this interhemispheric balance is disrupted (for example by stroke), local ipsilesional inhibitory influences may exacerbate deficits, worsening functional impairment. This concept has served well to explain the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) to restore interhemispheric balance and improve sensorimotor function. However, there are conflicting reports in humans and animal models regarding the impact of contralateral homotopic influence on functional recovery. In this grant, we will test the hypothesis that interhemispheric connectivity directly influences brain plasticity and behavioral recovery after focal ischemia. To visualize fc, we will take advantage of a novel imaging modality, fcOIS (functional connectivity optical intrinsic signal imaging) developed by Dr. Culver (Co-PI), which for the first time permits fc imaging in mice. We will manipulate interhemispheric connectivity using optogenetic excitation/inhibition and the I/LnJ strain of acallosal mice, to examine their effects on cortical plasticity (brain remapping) and behavioral recovery, in the following aims: 1. To determine the relationship between fc, cortical remapping, and behavioral recovery following focal ischemia in mice. 2. To determine the influence of transcallosal interhemispheric connectivity on cortical remapping and behavioral recovery following focal ischemia. 3. To determine the effect of homotopic nodal excitation/inhibition on somatosensory cortical remapping following focal ischemia. 4. To determine if chronic physiological stimulation/deprivation using vibrissal manipulation alters cortical remapping and interhemispheric fc.
The leading cause of adult disability in the US, stroke has an annual incidence of 780,000 with over 5.8 million stroke survivors. Most stroke survivors have some degree of spontaneous recovery, typically occurring in the first weeks to months after stroke; however this recovery is highly variable and in many cases incomplete. Understanding how brain networks can influence recovery may be important for the development of therapies that enhance brain plasticity. This R01 grant proposes to study the role of functional connectivity within these brain networks in brain plasticity and recovery after ischemic stroke.
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