Timing dependent synergies between motor cortex and posterior spinal stimulation in humans

Electrical stimulation of the brain and spinal cord can strengthen sensorimotor circuits and improve movement through associative plasticity. Current paired stimulation paradigms target the motor system alone or sensorimotor connections in cortex. We developed a paired stimulation approach in rats that targets sensory and motor connections in the cervical spinal cord. Since the circuits necessary for paired stimulation are conserved between species, we hypothesized that paired stimulation of motor cortex and posterior cervical spinal cord in humans would produce synergistic muscle responses but only when stimulation is properly timed. In 59 individuals undergoing clinically indicated cervical spine surgery, the motor cortex was stimulated with scalp electrodes and the spinal cord with epidural electrodes while muscle responses were recorded in arm and leg muscles. Spinal electrodes were placed over either the posterior or anterior spinal cord, and the interval between cortex and spinal cord stimulation was varied. Pairing stimulation between the motor cortex and posterior, but not anterior, spinal cord stimulation produced motor evoked potentials that were over five times larger than brain stimulation alone. This strong augmentation occurred when descending motor and spinal afferent stimuli were timed to converge in the cervical spinal cord. Paired stimulation also increased the selectivity of muscle responses relative to unpaired brain or spinal cord stimulation. Finally, paired stimulation effects were present regardless of the severity of myelopathy as measured by clinical signs or spinal cord imaging. The large effect size of this paired stimulation makes it a promising candidate for therapeutic neuromodulation.