Midbrain Raphe Stimulation Improves Behavioral and Anatomical Recovery from Fluid-Percussion Brain Injury

Abstract

The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4-6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In watermaze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested.

Pathophysiology and Treatment of Memory Dysfunction After Traumatic Brain Injury

“…Another deep brain stimulation study showed an increased exploration time when animals were exposed to new objects [126]. Furthermore, theta stimulation of the midbrain medial raphe and dorsal raphe showed a decreased learning peak during reference memory acquisition, and theta-burst stimulation of the fornix demonstrated improved working memory performance [40,127]. Clinically, there have been a few studies where stimulation electrodes have been successfully implanted in severe TBI patients chronically [128–132].…”

Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

“…The ascending systems of the median or dorsal raphe of the midbrain, when stimulated intermittently for one week (8 Hz, 5 minutes on-off cycling, 12 hours daily) beginning several hours after traumatic brain injury, enhanced both behavioral and gross anatomical recovery (Carballosa Gonzalez et al, 2013). The hindbrain’s nucleus raphe magnus (NRM), a major source of spinal cord serotonin, similarly improved motor recovery from spinal cord injury (Hentall and Burns, 2009; Hentall and Gonzalez, 2012) while augmenting myelin sparing and serotonergic innervation around the injury site.…”

Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury

“…An exception is the work of Lee et al, in which DBS of the septum using a theta-band frequency temporarily improved hippocampal theta activity and even was associated with increased performance in the Barnes maze, if the DBS was timed appropriately [46]. Likewise, Carballosa Gonzalez et al reported that long-term low-frequency stimulation (8 Hz) of the serotonergic cell groups of the midbrain improved the rate memory acquisition for a hidden platform in the Morris water maze [47]. …”