Date of Award

12-20-2024

Author's School

McKelvey School of Engineering

Author's Department

Biomedical Engineering

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Spinal cord injury (SCI) generally leads to numerous physiological consequences, including impaired voluntary motor output, dysregulation of reflexes, autonomic dysreflexia, bladder, bowel, and sexual dysfunction and SCI-related neuropathic pain (SCI-NP). Electrical spinal stimulation (ESS) approaches have been successful at treating several of these consequences. However, most therapies focus on treating one consequence of SCI at a time and rarely report potential off-target effects on other functions or systems. We argue that ESS approaches could leverage the high interconnectivity and plastic capacity of spinal networks to drive multi-modal therapies for SCI rehabilitation – i.e., therapies that simultaneously treat more than one consequence of SCI. As a result, multi-modal therapies hold the promise of being more optimal and efficacious at driving rehabilitation than conventional, uni-modal approaches. Thus, the main purpose of this dissertation is to evaluate whether ESS approaches that leverage the intrinsic properties of spinal networks can deliver multi-modal therapeutic benefits after chronic SCI. We approached this main question through two lines of research. The first line of research investigates whether intraspinal microstimulation (ISMS) parametrized for enhancing voluntary motor output (motor-targeted ISMS) after SCI can simultaneously modulate spinal sensory transmission. If so, this may serve as evidence that ISMS could enhance voluntary motor output and ameliorate symptoms of SCI-NP, delivering multi-modal therapeutic benefits for two of the most common and functionally limiting SCI-related impairments. We tested this hypothesis in vivo, using neurologically intact rats and rats with chronic SCI that also presented moderate to severe sensorimotor impairments. Using multielectrode arrays that spanned the sensory-dominant and motor-dominant regions of the spinal gray matter, we found (1) that motor-targeted ISMS decreases spinal nociceptive transmission while apparently not impacting non-nociceptive transmission, both in neurologically intact animals and animals with chronic SCI; (2) that the antinociceptive effects of motor-targeted ISMS increase with stimulation duration and persist after ISMS is discontinued, suggesting that stimulation led to plastic changes in synaptic transmission in the affected spinal networks; and (3) motor-targeted ISMS was more efficacious at reducing nociceptive transmission in animals manifesting behavioral signs of SCI-NP compared to animals with SCI that lacked behavioral signs of SCI-NP. These results supported our hypothesis that motor-targeted ISMS can be used to deliver multi-modal therapeutic benefits after chronic SCI. Next, we conducted two studies to explore potential neural mechanisms that could be driving the antinociceptive effects of motor-targeted ISMS. First, we explored whether bulbospinal monoaminergic pathways may be associated with the modulatory effects of motor-targeted ISMS in spinal sensory circuits using a pharmacological approach. We found that the antinociceptive effects of motor-targeted ISMS could be partially explained by the engagement of spinal noradrenergic alpha-2 receptors. Second, we explored whether the antinociceptive effects of motor-targeted ISMS could be driven by the induction of short-term plastic changes in spinal networks located in both the sensory- and motor-dominant regions of the spinal gray matter. We found evidence of plastic changes in both motor-dominant and sensory-dominant spinal networks within 10 minutes of motor-targeted ISMS, which could facilitate the modulatory effects of ISMS. The main purpose of the second line of research was to elucidate additional properties of spinal networks that could be leveraged by ESS intended to deliver multi-modal therapeutic benefits for SCI rehabilitation. We chose to investigate spontaneous neural transmission in the adult spinal cord, which is a comparably less understood component of spinal networks. We implanted microelectrode arrays spanning sensory- and motor-dominant regions of the spinal gray matter in vivo in neurologically intact rats and rats with chronic SCI. In both cohorts we found vigorous spontaneous neural transmission across the spinal gray matter even during anesthesia-induced unconsciousness. In neurologically intact animals, we found that spontaneous neural transmission supported functional connections that linked sensory-dominant and motor-dominant anatomical regions during unconsciousness. We also found that this type of transmission included a diverse mixture of neurons with distinct biophysical and phenomenological properties that involved multi-modal transmission consistent with sensorimotor behaviors. These findings support two hypothetical functions of spinal spontaneous transmission: (1) the spontaneous, unconscious functional connectivity could reflect consolidation of patterns of neural transmission experienced during behavior, somewhat analogous to the hippocampal replay mechanism integral to memory consolidation during sleep, and (2) spontaneous neural transmission could serve to maintain a state of readiness to execute sensorimotor behaviors during unconsciousness (i.e., a framework to go from rest to action). Lastly, we explored if and how SCI alters spontaneous neural transmission in spinal networks and whether any such changes could contribute to the sensorimotor consequences of chronic SCI. We found exacerbated discharge rates in most spinal neurons, and particularly in nociceptive specific neurons, which could contribute to SCI-NP. Specifically, this finding suggests that altered spontaneous neural transmission may be associated with spontaneous neuropathic pain after SCI, an enigmatic, poorly understood aspect of SCI-NP. We also found that chronic SCI impacted neuronal variability in spinal networks below the lesion. We hypothesize that these changes in variability may alter the fidelity of information transmission in spinal networks and reduce the repertoire of available movement patterns under volitional control.

Language

English (en)

Chair

Jacob McPherson

Committee Members

Daniel Moran; Gretchen Meyer; Megan Detloff; Robert Gereau

Available for download on Saturday, December 19, 2026

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