Fig. 3
From: Trigeminal nerve stimulation: a current state-of-the-art review
The underlying mechanisms of trigeminal nerve stimulation’s effects. The main mechanisms of TNS can be split into three main categories, 1)the release of vasoactive neuropeptides, 2)the modulation of neurotransmission, and 3)modulation of the ANS. The direct release of vasoactive neuropeptides such as CGRP, PACAP, VIP, SP, and NO from trigeminal and parasympathetic nerve fibers underlies the observed anti-inflammatory and cerebral vasodilatory effects of TNS. Via the increase of hypocretin and dopamine, there is an increase wakefulness and psychological dysfunction. The upregulation of eNOS and upregulation of NMDA receptors and glutamate result in bimodal modulation of BBB permeability, while the downregulation of NMDA receptors decreases glutamatergic transmission and increases GABA, thus modulating CSDs. Systemically, the cholinergic and catecholaminergic pathways of the ANS are harnessed by TNS. Through the cholinergic pathway of the PNS and upregulation of acetylcholine, cardiac performance is modulated when the acetylcholine binds to the muscarinic receptors on the heart. This cholinergic pathway is hypothesized to be the mechanism which gives rise to TNS’ systemic anti-inflammation as well. The released acetylcholine would stimulate α7-nicotinic receptors on splenic macrophages and decrease proinflammatory cytokine production. Concurrent upregulation of the SNS and the catecholaminergic pathway induces the release of norepinephrine peripheral vasoconstriction, leading to increased blood pressure and CBF. (This figure was generated using BioRender.com) (Ach: acetylcholine; ANS: autonomic nervous system; BBB: blood–brain barrier; CGRP: Calcitonin gene-related peptide; CO: cardiac output; CRH: corticotropin releasing hormone; DMN: dorsal motor nucleus; eNOS: endothelial nitric oxide synthase; GABA: gamma-aminobutyric acid; KF: Kölliker-FuseNO: nitric oxide; L: leukocyte; MAP: mean arterial pressure; MDH: medullary dorsal horn; MG: microglia; NA: nucleus accumbens; NE/E: norepinephrine/epinephrine; NMDA: N-methyl-d-aspartate; NTS: nucleus tractus solitarius; PACAP: pituitary adenylate cyclase-activating peptide; PNS: parasympathetic nervous system; RVLM: rostral ventrolateral medulla; SNS: sympathetic nervous system; SP: Substance P; SV: stroke volume; TG: trigeminal ganglion; TNS: trigeminal nerve stimulation; VIP: vasoactive intestinal peptide; VN: vagus nerve; VTA: ventral tegmental area)