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-spina...