(I-338) Direct Modulation of Spinal Pain Pathways by Targeted Intraspinal Microstimulation

Introduction: Spinal cord injury (SCI) often results in debilitating sensorimotor consequences. Weakness, impaired voluntary movement, spasticity, and spasms in muscles innervated by spinal segments below the lesion are near-ubiquitous features. Less widely recognized, however, is the prevalence of SCI-related neuropathic pain (SCI-NP), which by some estimates impacts up to 80% of individuals living with sensorimotor incomplete SCI (1). The neural mechanisms underlying SCI-NP are unknown, leading to treatment strategies that rarely afford satisfactory relief and are frequently accompanied by deleterious side effects; opioids remain a common, if ineffective, management strategy.

Recently, it has been demonstrated that electrical intraspinal microstimulation (ISMS) delivered amidst the spinal motor pools deep inside the spinal gray matter causes an unexpected depression of the responsiveness of spinal sensory neurons to nociceptive sensory feedback. Many of these neurons exhibit pathologically elevated responses to sensory feedback after SCI, reinforcing the neuropathic pain state. Given the relative lack of efficacious therapies ameliorating SCI-NP, a depressive effect of ISMS would be a welcome advance. However, the depressive effects of ‘motor-targeted’ ISMS on spinal pain transmission were not unequivocal; indeed, some neurons were potentiated by the stimulation.

Here, we asked whether ISMS delivered in a region of the spinal cord dense with sensory neurons, the deep dorsal horn of the L5 spinal segment, could drive more robust depressive effects on pain-related neural transmission than ISMS delivered distantly amongst the motor pools.


Materials and Methods: All experiments were approved by the Institutional Animal Care and Usage Committees of Florida International University and Washington University in St. Louis. In-vivo electrophysiological recordings were performed in 8 neurologically intact adult male Sprague-Dawley rats . Following a laminectomy of the T13-L2 vertebrae, a 2-shank, 32-channel microelectrode array was implanted into the gray matter at the L5 dorsal root entry zone. The array enabled direct access to neural transmission spanning the dorso-ventral extent of the gray matter of the L5 spinal segment. It also permitted ISMS to be delivered during electrophysiological recordings. Natural nociceptive and non-nociceptive cutaneous feedback was induced by mechanically probing the L5 dermatome while simultaneously recording neural data before, during, and after ISMS. ISMS was delivered in the deep dorsal horn (dISMS) as a series of discrete biphasic current pulses, ~90% resting motor threshold, 7Hz. Primary outcome measures centered about changes in firing rates of individually identified nociceptive specific (NS) and wide dynamic range (WDR) neurons associated with ISMS.


Results, Conclusions, and Discussions: Short epochs of dISMS (2, 10 min) did not significantly impact the mean firing rate of NS or WDR neurons during non-noxious or noxious transmission. Likewise, 30 min of dISMS was not associated with significant changes in NS firing rate. However, WDR neurons exhibited progressively depressed firing rates during ISMS and induced nociceptive transmission that remained depressed following termination of stimulation (p=0.0470).

The mechanisms underlying the anti-nociceptive effect of dISMS on WDR neurons are unclear, as is why the effect was not observed in NS neurons. However, it is to some degree surprising that neither neural population was potentiated by dISMS, given the injection of depolarizing current into a region containing many of their cell bodies and dendritic arbors. Additional parameter optimization studies will be required to systematically characterize the modulatory capacity of dISMS on spinal nociceptive transmission and to determine the extent to which this approach holds translational potential.
If borne out by additional experiments, these results could highlight a novel platform for developing spinal stimulation-based therapies that afford multi-modal rehabilitation benefits for people living with SCI.




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References (Optional):

1. University of Sydney. (2023, January 30). Trial uses cannabis for spinal cord injury pain. [News release]. Retrieved from https://www.sydney.edu.au/news-opinion/news/2023/01/30/trial-uses-cannabis-for-spinal-cord-injury-pain.html


2. Bandres, M. F., Gomes, J. L., & McPherson, J. G. (2022). Spinal stimulation for motor rehabilitation immediately modulates nociceptive transmission. Journal of Neural Engineering, 19(5), 056046.