Resting State Connectivity in Primate Spinal Cord

摘要/总结 该提案旨在继续我们的研究，以确定和表征静息态功能MRI 脊髓灰质内的信号，并验证静息状态功能的解释 脊柱中的rsFC网络似乎反映了特定的行为相关功能。在 在目前的研究期间，我们发现脊髓内的静息态网络表现出更复杂的连通性。 比以前报告的，无论是内部和跨部门，包括显着的相关性， 中间区域和灰色连合与自主功能和左右协调相关。 重要的是，通过对非人类灵长类动物的颈椎实施背柱损伤， 证实，这些网络内的连接强度一般与功能有关， 性能，并且网络中的变化对应于例如熟练的手使用中的行为变化。 接下来，我们的目标是充分表征rsFC的子组件，并将它们与更具体的功能联系起来。我们 将在松鼠猴体内以高场（9.4 T）采集亚毫米、多参数MR图像并解决 三大目标。(1)我们将使用选择性损伤识别和区分脊髓内的rsFC网络 和药物干预，以确定哪些组件和网络连接受到影响， 正常感觉或运动通路的特定中断。我们将隔离受（a）可逆 用药理学试剂阻断运动或感觉输入;（B）永久性消融运动或感觉输入的驱动， 来自腹角中的初级运动皮层的神经元;以及（c）通过以下方式破坏对背角神经元的感觉信号： 切断背脊神经根。我们将使用CEST和DTI跟踪每个损伤的演变， 测量损伤的范围和严重程度，以及DTI和qMT以验证损伤严重程度并量化变化 轴突完整性和髓鞘形成(2)我们将通过与以下各项的比较来验证来自MRI的rsFC测量结果： 电生理学、微刺激和束追踪组织学。我们将（a）直接刺激特定的节点 同时用电生理学和fMRI监测下游活动;（B）进行纵向fMRI， 微阵列记录每只接受特定干预的猴子的电相干性（目标1）;以及 (c)确定功能性磁共振成像显示的功能性连接区域是否也显示出强烈的解剖学特征， 通过注射示踪剂和死后进行组织学评估来建立连接。(3)我们将确定 rsFC的功能和行为相关性，通过破坏每个回路，识别相应的变化， 在rsFC中，并将这些变化与熟练的手感觉运动行为的表现相关联。通过完成 在这项研究中，我们将验证rsFC测量作为脊髓功能的指标，并建立精细的 脊髓内回路的颗粒状内在结构。这些研究将为神经系统的研究提供新的信息。 脊髓的组织，验证连接性BOLD测量的解释，并提供 使用功能磁共振成像研究人类脊髓功能的路线图。

ABSTRACT / SUMMARY This proposal aims to continue our research to identify and characterize resting state functional MRI signals within the grey matter of the spinal cord, and to validate the interpretation of resting state functional connectivity (rsFC) networks in the spine that appear to reflect specific, behaviorally-relevant functions. In the current funding period we have found resting state networks within the cord exhibit more complex connectivity than previously reported, both within and across segments, including significant correlations with the intermediate region and grey commissure that are relevant for autonomic functions and left-right coordination. Importantly, by implementing a dorsal column injury to the cervical spine in a non-human primate, we have confirmed that the strengths of connectivity within these networks are in general related to functional performance, and changes in the networks correspond to behavioral changes in, for example, skilled hand use. We next aim to fully characterize the sub-components of rsFC and relate them to more specific functions. We will acquire sub-millimeter, multi-parametric MR images at high field (9.4T) in squirrel monkeys and address three main aims. (1) We will identify and differentiate rsFC networks within spinal cord using selective lesions and pharmacological interventions to determine which components and network connectivities are affected by specific disruptions of normal sensory or motor pathways. We will isolate circuits affected by (a) reversible block of motor or sensory inputs with pharmacological agents; (b) permanently ablating the drive of motor neurons from primary motor cortex in ventral horn; and (c) disrupting sensory signals to dorsal horn neurons by sectioning dorsal spinal nerve roots. We will follow the evolution of each injury using CEST and DTI to measure the extent and severity of the injury, and DTI and qMT to validate injury severity and quantify changes in axonal integrity and myelination. (2) We will validate the rsFC measures from MRI by comparisons with electrophysiology, micro-stimulation and tract-tracing histology. We will (a) directly stimulate specific nodes while monitoring down-stream activity with electrophysiology and fMRI; (b) perform longitudinal fMRI and microarray recordings of electrical coherences in each monkey subjected to specific interventions (Aim 1); and (c) determine whether regions which appear to be functionally connected by fMRI also show strong anatomical connections by injecting tracers and performing histological assessments post mortem. (3) We will determine the functional and behavioral relevance of rsFC by disrupting each circuit, identifying corresponding changes in rsFC, and relating these changes to performance of skilled hand sensorimotor behavior. By the completion of the study, we will validate rsFC measurements as indicators of spinal cord functions, and establish the fine- grained intrinsic architecture of intra-spinal circuits. These studies will provide new information on the neural organization of the spinal cord, validate the interpretation of BOLD measurements of connectivity, and provide a roadmap for the use of fMRI for studying human spinal cord functions.