Bethea, T. | Search bioRxiv

bioRxiv2025

Hyperreflexia after corticospinal tract lesion reflects 1A afferent circuit changes not increased KCC2 hyperexcitability

Hyperreflexia is a consequence of spinal cord injury (SCI) and motor system lesions in the brain Two major mechanisms underpinning hyperreflexia have been reported: proprioceptive afferent (PA) circuit changes produced by 1A fiber sprouting, which could enhance reflex signaling, together with reduced GABAergic inhibitory presynaptic regulation (GABApre); and increased intrinsic motor neuron excitability, for example, produced by reduced motor neuron membrane-bound potassium-chloride co-transporter2 (KCC2). Here we examine how selective unilateral CST injury in the medullary pyramid (PTX), which eliminates the CST from one hemisphere, allows for specific investigation of the different mechanisms to determine their contributions to hyperreflexia. We used rate-dependent depression (RDD) of the Hoffmann (H)-reflex for the forelimb and hindlimb 5th-digit abductor muscles to assess hyperreflexia on both the contra-and ipsilesional sides. We compared RDD in naive and unilateral-PTX rats at 7-dpi and 42-dpi, supplemented with additional timepoints to examine hyperreflexia development. Immunohistochemistry was used to identify PA synapses (VGlut1), GABA presynaptic boutons (GABApre), motor neurons (ChAT), and to measure KCC2. Following unilateral PTX, we observed significant hyperreflexia in the contralesional forelimb only. Membrane-bound KCC2 was unchanged in contralesional cervical motor neurons. Whereas both cervical and lumbar motor neurons showed increased PA sprouting contralesionally, there was a concomitant increase in GABApre terminals for the lumbar not cervical cord, which associated with a normal hindlimb H-reflex. Our findings show that KCC2 is disassociated from hyperreflexia in the uniPTX model. Instead, forelimb hyperreflexia can be explained by cervical motor neuron PA sprouting and an uncompensated GABApre regulation.

neuroscience↗

bioRxiv2020

Paired motor cortex and spinal cord epidural stimulation strengthens sensorimotor connections and improves forelimb function after cervical spinal cord injury in rats.

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 (SCAP), 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 (SCI). 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. SCAP, repetitive pairing of these pathways for 5 or 30 minutes in awake rats, increased spinal excitability for hours after pairing ended. To apply SCAP 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 uninjured rats, demonstrating that spared connections after moderate SCI were sufficient to support plasticity. In a blinded trial, rats received a moderate C4 contusive SCI. Ten days after injury, they were randomized to 30 minutes of SCAP each day for 10 days or sham stimulation. Rats with SCAP had significantly improved function on the primary outcome measure, a test of dexterity during manipulation of food, at 50 days after SCI. In addition, rats with SCAP had persistently stronger responses to cortical and spinal stimulation than sham stimulation rats, indicating a spinal locus of plasticity. SCAP rats had lasting improvements in H-reflex modulation. The groups had no difference in the rat grimace scale, a measure of pain. We conclude that SCAP strengthens sensorimotor connections within the spinal cord, resulting in improved reflex modulation and forelimb function after moderate SCI. Since both motor cortex and spinal cord stimulation are performed routinely in humans, this approach can be trialed in people with SCI or other disorders that damage sensorimotor connections and impair dexterity.

neuroscience↗