Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS), a neuroinflammatory disease, has few treatment options, none entirely adequate. We studied whether prolonged electrical stimulation of a hindbrain region (the nucleus raphe magnus) can attenuate experimental autoimmune encephalomyelitis, a murine model of MS induced by MOG35-55 injection. Eight days after symptoms emerged, a wireless electrical stimulator with a connectorless protruding microelectrode was implanted cranially, and daily intermittent stimulation of awake, unrestrained mice began immediately. The thoracic spinal cord was analyzed for changes in histology (on day 29) and gene expression (on day 37), with a focus on myelination and cytokine production. Controls, with inactive implants, showed a phase of disease exacerbation on days 19–25 that stimulation for >16 days eliminated. Prolonged stimulation also reduced infiltrating immune cells and increased numbers of myelinated axons. It additionally lowered gene expression for some pro-inflammatory cytokines (interferon gamma and tumor necrosis factor) and for platelet-derived growth factor receptor alpha, a marker of oligodendrocyte precursors, while raising it for myelin basic protein. Restorative treatments for MS might profitably consider ways to stimulate the raphe magnus, directly or via its inputs, or to emulate its serotonergic and peptidergic output.

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

“…7 Beyond mechanical trauma, we recently found that prolonged NRM stimulation in mice attenuates some signs of experimental autoimmune encephalomyelitis, a model of human multiple sclerosis, while blocking production of inflammatory cytokines as well as the underlying myelin-related pathology. 8 Here, we study some visceral deficits of midline cervical contusion injuries (C5 segment) at both acute and chronic stages, mainly using the midbrain's periaqueductal gray (PAG) as the stimulation target. As we reported previously, PAG stimulation produces a similar set of beneficial effects to NRM stimulation in the rat thoracic (T8) contusion model.…”

A novel wireless brain stimulation device for long-term use in freely moving mice

“…The ability to stimulate constantly, as is done in patient population, is critical as different durations of exposure are known to have different consequences. For example, an almost instantaneous onset of clinical benefit is observed for essential and resting tremors associated with Parkinson’s disease, while a month or more may be required to see improvement in dystonia 16,17 . The overall consistency of our findings with clinical data is of critical importance as brain stimulation has been used as a therapy for different disorders.…”

“…While important for clinical DBS research, our novel stimulator also opens up a wide range of research opportunities as exogenous brain stimulation has been shown to influence all aspects of behaviour with effects on obesity 20 , sleep-wake cycle 21 , movement 17 , mood 22 , and cognition 23 in both pathological and normal conditions 24 . At a cellular level, brain stimulation has been shown to alter inflammation, release of neurotransmitters 25,26 and differentiation of neuronal precursor cells to neurons and oligodendrocytes 16,27 . However, all techniques have their limitations, and the technology described in this article is no exception.…”

Cellular Changes in Injured Rat Spinal Cord Following Electrical Brainstem Stimulation

“…The NRM provides a major spinal projection for this system. In support of the generality of this proposed repair model, LFS in the midbrain raphe has been found to improve outcomes in a rat model of traumatic brain injury while LFS in the mouse’s NRM ameliorates experimental autoimmune encephalitis (EAE) [14,17].…”

“…We have previously shown that 2 h of NRM LFS three days after incomplete SCI restores cyclic adenosine monophosphate (cAMP), an intracellular signaling molecule implicated in inflammation and repair, to pre-injury levels [19]. This effect on cAMP is blocked by the non-specific 5-HT 7A antagonist pimozide and is accompanied by increases in phosphorylated PKA and CREB, as well as changes in the expression of various genes implicated in inflammation and repair [6,17,19]. We hypothesize that the result is an activation of conserved pathways that blunt secondary injury and enhance restorative processes.…”