Leveraging behavioral state to enhance specificity of non-invasive brain stimulation on motor circuits

项目摘要 在过去的二十年里，非侵入性脑刺激技术的使用呈指数级增长， 包括重复经颅磁刺激（rTMS），在基础神经科学和临床实践。 rTMS有望用于神经系统疾病的研究和治疗。然而，人们对这一问题的理解有限， rTMS对大脑和行为的影响。我们将研究一种特殊类型的rTMS，称为θ爆发 刺激（TBS），它比其他形式的rTMS诱导更持久的效果，使TBS成为一个重要的工具 用于治疗应用。虽然TBS提供相对集中的刺激，但对大脑的影响是通过以下方式发生的： 互联网络的方式知之甚少。此外，刺激是高度依赖于状态的， 在大多数治疗环境中使用rTMS，例如治疗运动障碍， 行为不受控制。通过与行为干预相结合来增强rTMS是一个很有吸引力的想法 用于改善治疗性rTMS，但其疗效和机制尚不清楚。为了弥补这一关键差距， 这个探索性的R21建议将检验TBS和行为状态对大脑和行为的影响。我们 在拟议的工作的总体目标是（i）阐明TBS配对的神经机制， 运动任务导致手部功能的改善;（ii）开发更具针对性的网络调节rTMS 加强运动功能的干预措施。我们将重点讨论后顶叶皮层（PPC），以及相关的 顶叶运动回路，有助于熟练的抓握控制，这是一种已知在中风中受损的能力， 创伤性脑损伤、脑瘫和其他运动障碍。我们将收集功能性磁共振 在相同的受试者中进行功能磁共振成像（fMRI）、经颅磁刺激（TMS）电生理测量和行为测量。五 将对65名健康受试者进行连续的每日TBS治疗， 随后进行两次评估以评估刺激的效果。在目标1中，我们将展示改进 在PPC刺激过程中，通过操纵行为状态来控制动作表现。在目标2中，我们 证明通过操纵行为状态来调节PPC刺激的神经生理学后效。 在目标3中，我们将评估大脑连接，神经可塑性和反应行为之间的关系 大脑刺激期间的行为状态。影响：此处报告的方法可能会被修改 通过靶向残余的高级运动区域，更彻底地治疗中风后的运动障碍， 皮层通路受损研究结果将为今后的研究奠定机理基础，以显示如何控制 脑卒中后rTMS期间的行为状态可提高治疗效果。

Project Summary The last two decades have seen an exponential growth in the use of noninvasive brain stimulation techniques, including repetitive transcranial magnetic stimulation (rTMS), in both basic neuroscience and clinical practice. rTMS holds promise for the study and treatment of neurological disorders. Yet, there is a limited understanding of the effects of rTMS on brain and behavior. We will examine a particular type of rTMS, known as theta burst stimulation (TBS), which induces longer lasting effects than other forms of rTMS, making TBS an important tool for therapeutic applications. While TBS provides relatively focal stimulation, effects on the brain occur through interconnected networks in ways that are poorly understood. Moreover, stimulation is highly state-dependent, and the use of rTMS in most therapeutic settings, such as the treatment of motor disorders, leaves the behavioral state uncontrolled. Augmenting rTMS by pairing it with behavioral interventions is an attractive idea for improving therapeutic rTMS, but its efficacy and mechanisms remain unknown. To address this critical gap, this exploratory R21 proposal will examine the effects of TBS and behavioral state on brain and behavior. Our overall objectives in the proposed work are to (i) elucidate the neural mechanism by which TBS paired with a motor task leads to improvements in hand function and (ii) develop more targeted network-modulatory rTMS interventions to enhance motor function. We will focus on the posterior parietal cortex (PPC), and associated parietal-motor circuits, which subserve skilled grasp control, an ability known to be impaired in stroke, traumatic brain injury, cerebral palsy, and other motor disorders. We will collect functional magnetic resonance imaging (fMRI), electrophysiological measures with TMS, and behavioral measures in the same subjects. Five consecutive daily TBS sessions will be applied to 65 healthy subjects assigned to one of three groups, each followed by two assessments to evaluate the effects of stimulation. In Aim 1, we will demonstrate improvement in action performance by manipulating the behavioral state during PPC stimulation. In Aim 2, we will demonstrate modulation of neurophysiological aftereffects of PPC stimulation by manipulating behavioral state. In Aim 3, we will assess the relationship between brain connectivity, neural plasticity and behavior in response to the behavioral state during brain stimulation. Impact: The methods reported here potentially can be modified to more incisively treat motor disorders after stroke by targeting residual higher motor areas to improve impaired cortical pathways. Results will lay a mechanistic foundation for future studies to show how controlling behavioral state during rTMS can improve therapeutic efficacy after stroke.