Promotion of Recovery From Thoracic Spinal Cord Contusion in Rats by Stimulation of Medullary Raphe or Its Midbrain Input

Abstract

Background. Brainstem regions with descending axons could influence recovery after spinal cord injury, thus presenting potential targets for treatment. Neurons in the hindbrain raphe magnus respond to sensory and chemical concomitants of trauma (eg, pain, circulating cytokines) and release trophic substances (serotonin, neuropeptides) in widespread spinal regions. Objectives. The authors tested in rats whether intermittent stimulation of the raphe magnus or its major midbrain input, the periaqueductal gray, influences recovery from incomplete thoracic (T8) injury. Methods. After a moderate weight-drop injury, an implanted wireless stimulator intermittently delivered cathodal pulses (8 Hz, 30 µA) through a microelectrode for 12 hours daily over multiple days. Stimulators in controls were inactive or not implanted. Results. Raphe magnus stimulation, started 1 to 2 hours after injury, enduringly improved open-field motor performance (measured weekly for 8 weeks) and footprint and gridwalk performance (measured in the 9th week). These improvements increased with days of stimulation (1-7). Myelinated axons in perilesional white matter and serotonin-containing terminals in gray matter, quantified 14 weeks postinjury, also increased. In separate parametric studies that examined open-field behavior following 14 days of stimulation, starting 2 days after injury was better than 7 days or 2 hours; starting at 8 weeks appeared ineffective. The periaqueductal gray, an established, safe stimulation target in man, similarly facilitated recovery of motor performance and myelination (but not serotonergic terminals) when stimulated for 4 to 7 days. Conclusions. Raphe magnus neurons mediate restorative feedback in acute spinal cord injury. Their interim activation, direct or indirect (via periaqueductal gray), offers a basis for possible treatments in patients.