Technology Research and Development Project 1 (Guiding Beneficial Plasticity)

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Spinal cord injury (SCI), stroke, cerebral palsy and other chronic neuromuscular disorders impair important functions such as walking. Current therapies are seldom fully effective. Recent advances enable powerful new therapies that target beneficial change to key nervous system pathways. Among the first of these therapies are operant conditioning protocols that modify a specific spinal reflex pathway. The reflex is elicited, and the person is rewarded if reflex size satisfies a criterion. The person learns to modify the brain's control over the pathway to increase rewards. This control gradually changes the spinal pathway itself. Furthermore, the beneficial change (i.e., plasticity) in this pathway leads to wider beneficial plasticity elsewhere. This wider effect is predicted by the new negotiated equilibrium model of spinal cord function. The result is that, in rats or people with incomplete SCI, operant conditioning of a spinal reflex increases walking speed and reduces limping. TR&D1 is developing and translating into clinical use operant conditioning protocols that induce beneficial plasticity in the nervous system. It includes animal and human studies. The animal studies reveal mechanisms and principles that guide the human studies, which develop therapeutic protocols and translate them into clinical use. Aim 1 will develop a fully implanted telemetry-based system for long-term 24/7 operant conditioning in freely moving rats. By simplifying and facilitating operant conditioning and other long-term studies, this new lab system will make it possible for many other researchers to engage in these important studies. In addition, this aim will use this new system for the first studies of the molecular biology of spinal reflex conditioning. Aim 2 will develop and validate a general-purpose operant conditioning system suitable for widespread clinical use. Full achievement of the therapeutic promise of operant conditioning and related protocols requires a clinically practical system that supports a broad range of protocols and can change a variety of nervous system pathways. The new general-purpose clinical system will be tested, optimized, and validated with clinical collaborators. Additional collaborations with colleagues at major rehabilitation centers will explore the efficacy of reflex operant conditioning for improving function in people with cerebral palsy, stroke, and other disorders. This work will define dose-response curves for key functional measures and will include functional imaging studies to characterize the underlying plasticity. It will delineate the range of potential clinical applications and help improve the design and implementation of conditioning protocols. These studies are expected to lead to larger clinical trials to establish the value of specific conditioning protocols for enhancing recovery of function for specific groups of patients. By creating, validating, and disseminating these new animal and human systems, and by conducting studies with them, TR&D1 will accelerate development and clinical translation of operant conditioning and related protocols that can complement other therapies and enhance functional recovery for people with spinal cord injury, stroke, cerebral palsy, and other devastating neuromuscular disorders.