Paired motor cortex and cervical epidural electrical stimulation timed to converge in the spinal cord promotes lasting increases in motor responses

Abstract

Key points Pairing motor cortex stimulation and spinal cord epidural stimulation produced large augmentation in motor cortex evoked potentials if they were timed to converge in the spinal cord.The modulation of cortical evoked potentials by spinal cord stimulation was largest when the spinal electrodes were placed over the dorsal root entry zone.Repeated pairing of motor cortex and spinal cord stimulation caused lasting increases in evoked potentials from both sites, but only if the time between the stimuli was optimal.Both immediate and lasting effects of paired stimulation are likely mediated by convergence of descending motor circuits and large diameter afferents onto common interneurons in the cervical spinal cord. AbstractConvergent activity in neural circuits can generate changes at their intersection. The rules of paired electrical stimulation are best understood for protocols that stimulate input circuits and their targets. We took a different approach by targeting the interaction of descending motor pathways and large diameter afferents in the spinal cord. We hypothesized that pairing stimulation of motor cortex and cervical spinal cord would strengthen motor responses through their convergence. We placed epidural electrodes over motor cortex and the dorsal cervical spinal cord in rats; motor evoked potentials (MEPs) were measured from biceps. MEPs evoked from motor cortex were robustly augmented with spinal epidural stimulation delivered at an intensity below the threshold for provoking an MEP. Augmentation was critically dependent on the timing and position of spinal stimulation. When the spinal stimulation was timed to coincide with the descending volley from motor cortex stimulation, MEPs were more than doubled. We then tested the effect of repeated pairing of motor cortex and spinal stimulation. Repetitive pairing caused strong augmentation of cortical MEPs and spinal excitability that lasted up to an hour after just 5 min of pairing. Additional physiology experiments support the hypothesis that paired stimulation is mediated by convergence of descending motor circuits and large diameter afferents in the spinal cord. The large effect size of this protocol and the conservation of the circuits being manipulated between rats and humans makes it worth pursuing for recovery of sensorimotor function after injury to the central nervous system.

Spinal associative plasticity in depth: evidence from animal model

“…The specific ISI of 10 ms between M1 and spinal cord activation fully agrees with the observation that, in rats, M1 stimulation evokes excitatory postsynaptic potentials (EPSPs) with a similar latency in C5–C6 anterior‐horn α‐motoneurons (Mishra et al . ). Concerning the exact site of interaction, the authors demonstrated that DREZ was the most effective site for spinal cord stimulation able to trigger LTP‐like plasticity when activated 10 ms later than M1.…”

“…We therefore believe that non‐synaptic plasticity should not be fully excluded as a physiological process possibly contributing to the findings observed by Mishra et al . (). Another comment concerns the observation that none of the ISIs used during spinal PAS elicited LTD‐like plasticity (as reflected by long‐term inhibition of MEPs).…”

“…The study of Mishra et al . (), recently published in The Journal of Physiology , is relevant since it provides new helpful insights into the physiological bases of spinal associative plasticity in animals. In the first set of experiments, the authors examined the exact timing and site of interaction between two stimuli, the first delivered over M1 and the second given over specific regions of the cervical spinal cord.…”

“…In conclusion the present work of Mishra et al . () provides new helpful information on the physiology of spinal associative plasticity. These experiments overall are certainly useful to better understand the physiology of spinal cord plasticity and to design new non‐pharmacological strategies based on non‐invasive neurostimulation protocols for symptomatic improvement in patients with several post‐traumatic or neurodegenerative neurological disorders.…”

“…Understanding the precise neurophysiological basis of spinal associative plasticity is the necessary precondition of development of new non-invasive neurostimulation strategies in human neurological disorders. The study of Mishra et al (2017), recently published in The Journal of Physiology, is relevant since it provides new helpful insights into the physiological bases of spinal associative plasticity in animals. In the first set of experiments, the authors examined the exact timing and site of interaction between two stimuli, the first delivered over M1 and the second given over specific regions of the cervical spinal cord.…”