Spinal cord associative plasticity improves forelimb sensorimotor function after cervical injury

Abstract

Associative plasticity occurs when two stimuli converge on a common neural target. Previous efforts to promote associative plasticity have targeted cortex, with variable and moderate effects. In addition, the targeted circuits are inferred, rather than tested directly. In contrast, we sought to target the strong convergence between motor and sensory systems in the spinal cord. We developed spinal cord associative plasticity, precisely timed pairing of motor cortex and dorsal spinal cord stimulations, to target this interaction. We tested the hypothesis that properly timed paired stimulation would strengthen the sensorimotor connections in the spinal cord and improve recovery after spinal cord injury. We tested physiological effects of paired stimulation, the pathways that mediate it, and its function in a preclinical trial. Subthreshold spinal cord stimulation strongly augmented motor cortex evoked muscle potentials at the time they were paired, but only when they arrived synchronously in the spinal cord. This paired stimulation effect depended on both cortical descending motor and spinal cord proprioceptive afferents; selective inactivation of either of these pathways fully abrogated the paired stimulation effect. Spinal cord associative plasticity, repetitive pairing of these pathways for 5 or 30 min in awake rats, increased spinal excitability for hours after pairing ended. To apply spinal cord associative plasticity as therapy, we optimized the parameters to promote strong and long-lasting effects. This effect was just as strong in rats with cervical spinal cord injury as in uninjured rats, demonstrating that spared connections after moderate spinal cord injury were sufficient to support plasticity. In a blinded trial, rats received a moderate C4 contusive spinal cord injury. Ten days after injury, they were randomized to 30 min of spinal cord associative plasticity each day for 10 days or sham stimulation. Rats with spinal cord associative plasticity had significantly improved function on the primary outcome measure, a test of dexterity during manipulation of food, at 50 days after spinal cord injury. In addition, rats with spinal cord associative plasticity had persistently stronger responses to cortical and spinal stimulation than sham stimulation rats, indicating a spinal locus of plasticity. After spinal cord associative plasticity, rats had near normalization of H-reflex modulation. The groups had no difference in the rat grimace scale, a measure of pain. We conclude that spinal cord associative plasticity strengthens sensorimotor connections within the spinal cord, resulting in partial recovery of reflex modulation and forelimb function after moderate spinal cord injury. Since both motor cortex and spinal cord stimulation are performed routinely in humans, this approach can be trialled in people with spinal cord injury or other disorders that damage sensorimotor connections and impair dexterity.

Intraoperative electrical stimulation of the human dorsal spinal cord reveals a map of arm and hand muscle responses

“…Electrical stimulation of afferents activates motoneurons through circuits involved in reflexes ( 19 , 20 ). This mechanism has been corroborated by mathematical modeling of current flow ( 21 – 23 ) as well as in inactivation studies ( 14 ). Consistent with this model, we have shown that stimulating near the dorsal root entry zone is more effective than stimulating at midline in the cervical spinal cord of rats ( 24 ).…”

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

“…In previous work we found that the facilitatory effects of combined brain and spinal stimulation were strong in both uninjured (Mishra et al 2017) and spinal cord injured (Pal et al 2022) rats. Consistent with this, there was no relationship between MEP augmentation and radiographic (T2 signal) or clinical evidence of myelopathy (mJOA, reflexes).…”

“…Epidural spinal cord stimulation recruits a large number of sensory axons as they enter the spinal cord (Capogrosso et al 2013; Liang et al 2023; McIntosh et al 2023). In one preclinical study, our group showed that timing motor cortex and dorsal epidural spinal stimulation to converge in the spinal cord markedly increased the motor evoked potential (MEP) (by 155%), while convergence in motor cortex resulted in a much smaller effect (17%) (Pal et al 2022). We have shown this method of paired stimulation targeted at sensorimotor interactions in the spinal cord to induce plasticity (Mishra et al 2017) and improve dexterity in rats with spinal cord injury (Pal et al 2022).…”

Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury

“…After all, maladaptive neural activity was allowed to develop unchecked and to chronify naturally, resulting in a 'worst case scenario' for plasticity-promoting interventions. And whereas preclinical and clinical studies have repeatedly demonstrated the ability of motor-dominant circuits below a lesion to beneficially and durably reorganize (25)(26)(27)(28)(29)(30)(31)(32), neural transmission in spinal pain pathways has been comparatively difficult to shape. Indeed, interventions explicitly designed to promote functionally-relevant neural plasticity as well as those that attempt to pharmacologically rebalance spinal excitability have been met with variable and generally nominal successespecially when initiated after establishment of the neuropathic pain state (33,34).…”

“…As a result, the ISMS paradigm made no explicit attempts to restore or reinforce natural, appropriate patterns of neural transmission in the modulated networks. Previously, it has been shown that activity-dependent spinal stimulation leads to functional gains that far exceed those afforded by open-loop stimulation, presumably by more optimally engaging circuits below the injury to promote beneficial neural plasticity (25,27,39,40).…”