Some Autonomic Deficits of Acute or Chronic Cervical Spinal Contusion Reversed by Interim Brainstem Stimulation

Abstract

Prolonged electrical stimulation of the hindbrain's nucleus raphe magnus (NRM) or of its major midbrain input region, the periaqueductal gray (PAG), was previously found in rats to promote recovery from sensory-motor and histological deficits of acute thoracic spinal cord injury (SCI). Here, some visceral deficits of acute and chronic midline cervical (C5) contusion are similarly examined. Cranially implanted wireless stimulators delivered intermittent 8 Hz, 30-70 μA cathodal pulse trains to a brainstem microelectrode. Injured controls were given inactive stimulators; rats without injuries or implants were also compared. Rectal distension or squeezing of the forepaws caused an exaggerated rise in mean arterial pressure in injured, untreated rats under anesthesia on post-injury week 6, probably reflecting autonomic dysreflexia (AD). These pressor responses became normal when 7 days of unilateral PAG stimulation was started on the injury day. Older untreated injuries (weeks 18-19) showed normal pressor responses, but unexpectedly had significant resting and nociceptive bradycardia, which was reversed by 3 weeks of PAG stimulation started on weeks 7 or 12. Subsequent chronic studies examined gastric emptying (GE), as indicated by intestinal transit of gavaged dye, and serum chemistry. GE and fasting serum insulin were reduced on injury weeks 14-15, and were both normalized by ∼5 weeks of PAG stimulation begun in weeks 7-8. Increases in calcitonin gene-related peptide, a prominent visceral afferent neurotransmitter, measured near untreated injuries (first thoracic segment) in superficial dorsal laminae were reversed by acutely or chronically initiated PAG stimulation. The NRM, given 2-3 weeks of stimulation beginning 2 days after SCI, prevented abnormalities in both pressor responses and GE on post-injury week 9, consistent with its relaying of repair commands from the PAG. The descending PAG-NRM axis thus exhibits broadly restorative influences on visceral as well as sensory-motor deficits, improving chronic as well as acute signs of injury.

Cellular Changes in Injured Rat Spinal Cord Following Electrical Brainstem Stimulation

“…The present findings as a whole provide additional support to our hypothesis that the brainstem raphe nuclei are key central links in restorative feedback responses to injury, potentially playing a role in the restorative and analgesic effects of LFS reported previously [6,14,16,17]. Consistent with this model, raphe neurons respond to physiologic correlates of injury, such as pain, low blood pressure, and circulating cytokines, and send diffuse projections to all regions of the neuraxis [26,32].…”

“…Raphe neurons also secrete several neuropeptides, including galanin, substance P, and thyrotropin-release hormone, that are potentially protective after SCI [32,33]. The relation of NRM LFS to other stimulation targets used for the management of neurotrauma (vagal nerve, periaqueductal grey, spinal cord), for which the modulation of autonomic function is a commonly proposed mechanism, is unclear [6,8,14,16,17,19,35]. However, given the established reciprocal connections between these targets, it is likely that diverse overlapping processes are elicited with each stimulation target [14,26,32].…”

“…The output consisted of fixed-amplitude 30 µA monopolar pulses with a width of 1.0 ms. The microprocessor cycled between 5 min of 8 Hz stimulation and 5 min of rest during 12 daylight hours [6,14,16,17].…”

“…We have previously shown that LFS of the nucleus raphe magnus (NRM) or its primary midbrain afferent, the periaqueductal gray (PAG), improves functional and anatomic recovery from incomplete SCI in rats, while increasing myelination and expression of serotonin- and CGRP-containing axons around the injury site [6,16]. This includes improvements in cutaneous mechanical allodynia [15].…”

“…This includes improvements in cutaneous mechanical allodynia [15]. Other sequelae of SCI, such as reduced gastric motility and autonomic dysreflexia, appear to be influenced with LFS of NRM as well [16]. This has led to the proposal that the raphe nuclei of the brainstem, which collectively constitute a system of fibers that diffusely project to most areas of the nervous system, form a key link in a centralized restorative feedback system.…”