Paired brain and spinal cord stimulation to strengthen spinal sensorimotor circuits

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SUMMARY Experience leads to behavioral change through the associated activity of neural circuits. Using this principle, paired stimulation has been used to selectively strengthen circuits, targeting either the relatively sparse connections between motor cortex and motoneurons or sensory and motor connections in cortex. In contrast, we propose to target the spinal cord through the strong interaction of descending motor connections and large diameter afferents, which mediate the senses of joint position and muscle tension. In rats, sub- threshold spinal cord stimulation, which activates afferents, strongly augments motor cortex evoked muscle responses when timed to converge in the spinal cord. When pairing is performed repeatedly, there is robust augmentation of muscle responses from stimulation of both cortex and spinal cord and improved forelimb function after cervical spinal cord injury (SCI). We hypothesize that pairing motor cortex and sensory spinal cord stimulation will promote sensorimotor plasticity in the cervical spinal cord and functional recovery after SCI. Aim 1 tests the timing of pairing and the source of cortical activity, key issues for proper targeting. Timing to converge in the spinal cord, as opposed to cortex, is predicted to be strongest. We will also test, for the first time, spinal stimulation triggered by endogenous cortical activity before voluntary movement versus exogenous cortical stimulation. Endogenous activity is predicted to be more specific for a targeted muscle. Aim 2 tests the necessity and sufficiency of specific motor and sensory pathways for the paired stimulation effect in rats with SCI. Inactivation with chemogenetic is predicted to show necessity, and paired optogenetic or electrical stimulation to show sufficiency. Finally, Aim 3 tests whether repetitive motor cortex and dorsal cervical spinal cord over 10 days in rats with SCI will lead to lasting increases in cortical and spinal excitability and improved forelimb skill. Together, these studies will fill critical gaps about the nature of associative plasticity in the sensorimotor system and test a new strategy to repair connections after SCI. Our novel strategy will be tested with innovative tools. To chronically stimulate the cervical spinal cord in awake rats, we have developed thin (<50μm) electrodes that soften when placed into the epidural space and have proved safe and effective over 4 months. Cortical and spinal electrodes enable both potentially therapeutic paired stimulation and longitudinal interrogation of the targeted circuits. Forelimb skill will be measured with a forelimb supination task we invented, as well as tests of skilled walking and food manipulation. Inputs to the spinal cord will be manipulated with circuit-specific viral tools. Thus, we intend to close gaps in our understanding of how paired stimulation of sensorimotor circuits should be targeted to the spinal cord and whether it is effective for recovery. This knowledge can change how we target electrical stimulation to induce associative plasticity. Motor cortex and cervical spinal cord stimulation are safe, so paired stimulation could be translated quickly to clinical trials.