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.

Associative plasticity occurs when two stimuli converge on a common neural target. We sought to use the strong convergence between motor and sensory systems in the spinal cord to restore movement after spinal cord injury (SCI). We developed a paired motor cortex and dorsal spinal cord stimulation protocol to target this interaction called spinal cord associative plasticity (SCAP). Subthreshold spinal cord stimulation strongly augments motor cortex evoked potentials at the time they are paired, but only when they arrive synchronously in the spinal cord. We tested the hypothesis that this paired stimulation effect depended on cortical descending motor and spinal cord proprioceptive afferents. Selective inactivation of either of these pathways fully abrogated the paired stimulation effect. We then found that repetitive pairing in awake rats increased spinal excitability for hours after pairing ended. To apply this protocol as therapy, we optimized the parameters to promote strong and long-lasting effects. This effect was just as strong in rats with cervical SCI as in un-injured rats, demonstrating that spared connections after SCI are sufficient to support this plasticity. When 30 minutes of paired stimulation was done over 10 days, the effect of pairing was sustained for weeks. In addition, H-reflex modulation improved, showing decreased hyperreflexia that also persisted for weeks. Importantly, repetitive paired stimulation supported enhanced recovery of forelimb dexterity in rats after SCI with no augmentation of injury-induced neuropathic pain. We conclude that SCAP strengthens sensory-motor connections within the spinal cord, resulting in decreased hyperreflexia and improved forelimb function after SCI.Significance StatementDespite evidence that electrical stimulation of spared nervous system connections can facilitate recovery after SCI, strongly overlapping sensory and motor connections in the spinal cord have not been targeted for therapy. Here we demonstrate a robust paired stimulation paradigm that depends on corticofugal and proprioceptive afferent convergence in the spinal cord. The paradigm, termed SCAP for spinal cord associative plasticity, produced large-scale physiological changes in a preclinical model of cervical SCI. Importantly, SCAP caused lasting improvements in dexterity and decreased hyperreflexia in rats with SCI. Thus, we have determined the neural circuits that drive SCAP and have preclinical evidence for its efficacy to restore function after incomplete cervical SCI, the most common SCI in people.

Background and Purpose— Lacunar strokes are subcortical infarcts with small size and high disability rates, largely due to injury of the corticospinal tract in the internal capsule (IC). Current rodent models of lacunar infarcts are created based on stereotactic coordinates. We tested the hypothesis that better understanding of the somatotopy of the IC and guiding the lesion with electrical stimulation would allow a more accurate lesion to the forelimb axons of the IC. Methods— We performed electrophysiological motor mapping and viral tracing to define the somatotopy of the IC of Sprague Dawley rats. For the lesion, we used an optrode, which contains an electrode to localize forelimb responses and an optical fiber to deliver light. The infarct was induced when light activated the photothrombotic agent Rose Bengal, which was administered systemically. Results— We found largely a separate distribution of the forelimb and hindlimb axons in the IC, both by microstimulation mapping and tract tracing. Microstimulation-guided IC lesions ablated the forelimb axons of the IC in rats and caused lasting forelimb impairments while largely preserving the hindlimb axons of the IC and surrounding gray matter. Conclusions— Stimulation guidance enabled selective and reproducible infarcts of the forelimb axons of the IC in rats. Visual Overview— An online visual overview is available for this article.