Trigeminal nerve stimulation: a current state-of-the-art review

Abstract

Nearly 5 decades ago, the effect of trigeminal nerve stimulation (TNS) on cerebral blood flow was observed for the first time. This implication directly led to further investigations and TNS' success as a therapeutic intervention. Possessing unique connections with key brain and brainstem regions, TNS has been observed to modulate cerebral vasodilation, brain metabolism, cerebral autoregulation, cerebral and systemic inflammation, and the autonomic nervous system. The unique range of effects make it a prime therapeutic modality and have led to its clinical usage in chronic conditions such as migraine, prolonged disorders of consciousness, and depression. This review aims to present a comprehensive overview of TNS research and its broader therapeutic potentialities. For the purpose of this review, PubMed and Google Scholar were searched from inception to August 28, 2023 to identify a total of 89 relevant studies, both clinical and pre-clinical. TNS harnesses the release of vasoactive neuropeptides, modulation of neurotransmission, and direct action upon the autonomic nervous system to generate a suite of powerful multitarget therapeutic effects. While TNS has been applied clinically to chronic pathological conditions, these powerful effects have recently shown great potential in a number of acute/traumatic pathologies. However, there are still key mechanistic and methodologic knowledge gaps to be solved to make TNS a viable therapeutic option in wider clinical settings. These include bimodal or paradoxical effects and mechanisms, questions regarding its safety in acute/traumatic conditions, the development of more selective stimulation methods to avoid potential maladaptive effects, and its connection to the diving reflex, a trigeminally-mediated protective endogenous reflex. The address of these questions could overcome the current limitations and allow TNS to be applied therapeutically to an innumerable number of pathologies, such that it now stands at the precipice of becoming a ground-breaking therapeutic modality.

Keywords: Autonomic nervous system; Bioelectronic medicine; Cerebral blood flow; Cerebral vasodilation; Diving reflex; Neuromodulation; Neurotransmission; Trigeminal nerve; Trigeminal nerve stimulation; Vasoactive neuropeptide.

Fig. 1

A brief history of Trigeminal Nerve Stimulation. TNS was first used in 1974 to assess the neural control of cerebral blood flow. Since then, it has been applied clinically in migraine, epilepsy, depression, PTSD, fibromyalgia, SAD, cognitive/balance dysfunction, pediatric ADHD, PVS, SAH, and secondary issues due to mTBI. In 2014, Cefaly was approved by the FDA for treatment of migraine, Neurosigma was approved in 2019 for pediatric ADHD, and PoNS was approved in 2023 for cognitive/balance dysfunction. Preclinically, the efficacy of TNS has additionally been assessed in TBI, HS, TBI + HS, and ischemic stroke. In the past decade, the effects and mechanisms of TNS within the brain and throughout the body have been expanded upon. (This figure was generated using BioRender.com) (AcH: acetylcholine: ACN: anticorrelated networks; ADHD: attention deficit and hyperactivity disorder; ANS: autonomic nervous system; BBB: blood–brain barrier; BOLD: Blood Oxygenation Level Dependent; CB: cingulum bundle; CBF: cerebral blood flow; CGRP: Calcitonin gene-related peptide; CVR: cerebrovascular resistance; HR: heart rate; HS: hemorrhagic shock; mTBI: mild traumatic brain injury; PFC: prefrontal cortex; PTSD: post-traumatic stress disorder; PVS: persistent vegetative state; SAD: social anxiety disorder; SAH: subarachnoid hemorrhage; TBI: traumatic brain injury; TNS: trigeminal nerve stimulation;)

Fig. 2

PRISMA flowchart of the identification, screening, and eligibility inclusion for papers included in this assessment

Fig. 3

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)

Fig. 4

The effects, therapeutic targets, and unique properties of TNS. The effects of TNS can be separated into 3 main categories: effects on the CNS, the ANS, and the peripheral vasculature. Based on these effects, and particularly the effects on the CNS, many current therapeutic targets are focused on neurological, psychological, neuromuscular, and cerebrovascular pathologies. Already, some are approved for clinical usage, and others are in clinical testing. TNS is also currently under preclinical trials for acute/traumatic conditions, such as TBI, stroke, and hemorrhagic shock. Its multitudinous effects may allow it to be used therapeutically for the treatment of retinopathy, spinal cord injury, inflammatory dysfunctions, chronic cerebral hypoperfusion, and drug addiction. Setting it apart from other forms of bioelectronic medicine, TNS is able to cause direct cerebrovasodilation, increase hypocretin expression, and induce peripheral vasoconstriction. It is also the only one so far tried for balance difficulties due to mTBI. Uniquely, TNS also has diagnostic potentials in regard to Parkinson’s disease and hemorrhagic shock severity, which broadens its potential applications. (This figure was generated using BioRender.com) (ADHD: attention deficit and hyperactivity disorder; BBB: blood–brain barrier; CNS: central nervous system; CSD: cortical spreading depolarization; HS: hemorrhagic shock; IBD: irritable bowel disease; mTBI: mild traumatic brain injury; PNS: parasympathetic nervous system; PTSD: post-traumatic stress disorder; PVS: persistent vegetative state; SAD: social anxiety disorder; SAH: subarachnoid hemorrhage; SNS: sympathetic nervous system TBI: traumatic brain injury; TNS: trigeminal nerve stimulation)