Spinal stimulation for motor rehabilitation immediately modulates nociceptive transmission

Abstract

Objective: Spinal cord injury (SCI) often results in debilitating movement impairments and neuropathic pain. Electrical stimulation of spinal neurons holds considerable promise both for enhancing neural transmission in weakened motor pathways and for reducing neural transmission in overactive nociceptive pathways. However, spinal stimulation paradigms currently under development for individuals living with SCI continue overwhelmingly to be developed in the context of motor rehabilitation alone. The objective of this study is to test the hypothesis that motor-targeted spinal stimulation simultaneously modulates spinal nociceptive transmission. Approach: We characterized the neuromodulatory actions of motor-targeted intraspinal microstimulation (ISMS) on the firing dynamics of large populations of discrete nociceptive specific and wide dynamic range neurons. Neurons were accessed via dense microelectrode arrays implanted in vivo into lumbar enlargement of rats. Nociceptive and non-nociceptive cutaneous transmission was induced before, during, and after ISMS by mechanically probing the L5 dermatome. Main results: Our primary findings are that (1) sub-motor threshold ISMS delivered to spinal motor pools immediately modulates concurrent nociceptive transmission; (2) the magnitude of anti-nociceptive effects increases with longer durations of ISMS, including robust carryover effects; (3) the majority of all identified nociceptive-specific and wide dynamic range neurons exhibit firing rate reductions after only 10 min of ISMS; and (4) ISMS does not increase spinal responsiveness to non-nociceptive cutaneous transmission. These results lead to the conclusion that ISMS parameterized to enhance motor output results in an overall net decrease in spinal nociceptive transmission. Significance: These results suggest that ISMS may hold translational potential for neuropathic pain-related applications and that it may be uniquely suited to delivering multi-modal therapeutic benefits for individuals living with SCI.

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

“…2C, right). This trend in WDR neurons was qualitatively similar to that previously reported in neurologically intact animals (10).…”

“…This outcome was unexpected, as the proportion of ISMS-depressed NS neurons in a recently reported cohort of neurologically intact rats exhibited a ~25% decrease upon cessation of 30 min of stimulation. More surprisingly still, the proportion of NS neurons exhibiting persistent depression after discontinuation of ISMS was also greater in animals with chronic SCI (~61%) than that reported in animals without neurological injury (~55%) (10). Together, these findings reveal unexpectedly robust carryover effects.…”

“…In neurologically intact rats, brief periods of motor-targeted ISMS -that is, ISMS delivered directly in the vicinity of spinal motor pools -can immediately and persistently modulate intraspinal nociceptive transmission (10). However, it is difficult to generalize these findings to sensorimotor networks below an SCI given the maladaptive plasticity and profound alterations in neural excitability that occur during the chronification process.…”

“…Previous work has shown that population-level neural trends (or lack thereof) often belie easily separable subgroups that reveal more granular insights into the state of spinal networks (10,(19)(20)(21)(22)(23). Thus, we speculated that for both the NS and the WDR populations, it would be possible to identify subpopulations that exhibited either ISMS-induced potentiation or depression of discharge rate during nociceptive transmission.…”

“…However, recent studies have hinted that the neuromodulatory profile of electrical spinal stimulation may be considerably more nuanced than this canonical understanding. In neurologically intact rats, direct electrical stimulation in the vicinity of spinal motor pools has revealed a different set of actions: a predictable increase in net spinal motor excitability coupled with a net decrease in high-threshold nociceptive transmission and minimal effects on lowthreshold sensory transmission (10). Such a profile would be highly advantageous for spinal cord injury (SCI)-related applications, in which reduced voluntary motor output is frequently accompanied by pathologically elevated spinal responses to sensory feedback resulting in SCIrelated neuropathic pain (SCI-NP), spasms, and spasticity (11)(12)(13)(14).…”