PROJECT SUMMARY Our long-term goal is to identify neural mechanisms and the functional roles of sensorimotor signals in health and disease as needed to guide mechanistically targeted diagnoses, assessments, and treatments for neurological movement disorders. Here we address the scientific barriers to understanding and treating a broad class of movement disorder symptoms recently defined as joint hyper-resistance, which encompass spasticity in stroke, spinal cord injury, or cerebral palsy; parkinsonian rigidity, and hypertonia. The objective of this collaborative, interdisciplinary proposal is to identify neural mechanisms of hyper-resistance and dissociate their relative roles in abnormal movement. We will focus on the neural mechanisms underlying two clinically- defined neural contributions to hyper-resistance: non-velocity dependent involuntary background activation and velocity-dependent stretch hyper-reflexia. We hypothesize that increased spinal excitability in many neurological disorders causes involuntary background activation and velocity-dependent stretch hyper-reflexia via three dissociable neural mechanisms: 1) alpha-drive to extrafusal muscle fibers increasing background muscle tension, 2) gamma-drive to specialized intrafusal muscle fibers in muscle spindles sensory organs, increasing their sensitivity to muscle stretch, and 3) sensorimotor gain of the spinal transformation of monosynaptic sensory input into motor output. Our proposed tests of this hypothesis will advance understanding of the important, yet still unresolved relative contributions made by these neural mechanisms to hyper-resistance. Based on our neuromechanical and multiscale modeling advances in the prior funding period, in Aim 1 we will develop a multiscale in silico neuromuscular circuit model to predict how independent changes in alpha- drive, gamma-drive, and sensorimotor gain differentially affect clinically-relevant movements such as the tendon tap and pendulum test. In Aim 2, we will characterize the relative increases in alpha-drive, gamma-drive, and sensorimotor gain across clinically-relevant spinal excitability levels in a living biological neuromuscular circuit in vivo using a decerebrate rat preparation. In Aim 3 we will identify clinically-relevant movement abnormalities across spinal excitability levels in a novel biohybrid robotic system coupling the living neuromuscular circuit (in vivo) to a virtual biomechanical limb (in silico). A robotic controller will enforce the physics of dynamically changing inertial and gravitational forces, allowing movement to emerge from the causal interaction between the in vivo neuromuscular circuit and the virtual limb. Through the close coordination of these Aims, we will establish a computational and experimental framework to address clinical barriers (1) to determine how changes in neural mechanisms and the inertial properties of the limb could correct movement abnormalities, (2) to provide insight into how these m...