INFLUENCE OF INTERHEMISPHERIC CONNECTIVITY ON RECOVERY AFTER FOCAL ISCHEMIA

描述（由申请人提供）：中风是美国成年人残疾的主要原因，每年有78万人中风，超过580万中风幸存者。大多数中风幸存者都有一定程度的自发恢复，通常发生在中风后的最初几周到几个月；然而，这种恢复是高度可变的，在许多情况下是不完整的。我们对恢复机制的理解主要集中在参与大脑重塑的局部细胞和分子机制上。最近的研究在网络水平上研究了中风后的恢复——检查休息时整个大脑同步神经活动的分布模式——并揭示了局部中风后功能性网络连接的整体模式发生了改变。此外，在缺血性中风后不久，半球间同位功能连接（fc）的中断尤其预示着表现不佳。在大鼠局灶性缺血模型中，发现同位fc的恢复与行为改善并行。有大量的间接证据表明，同位半球间fc可能对恢复很重要，并引起了“半球间竞争”的概念。这一假设认为，在两个半球之间的兴奋和抑制之间的平衡可能对正常的单侧功能（例如单侧手部运动）很重要。如果这种半球间平衡被破坏（例如中风），局部同脑抑制影响可能会加剧缺陷，使功能损害恶化。这个概念很好地解释了重复经颅磁刺激（rTMS）和经颅直流电刺激（tDCS）在恢复半球间平衡和改善感觉运动功能方面的潜在功效。然而，关于对侧同位影响对功能恢复的影响，在人类和动物模型中有相互矛盾的报道。在这次授权中，我们将测试

DESCRIPTION (provided by applicant): 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.