BACKGROUND The trigeminal nerve directly innervates key vascular structures both centrally and peripherally. Centrally, it is known to innervate the brainstem and cavernous sinus, whereas peripherally the trigemino-cerebrovascular network innervates the majority of the cerebral vasculature. Upon stimulation, it permits direct modulation of cerebral blood flow (CBF), making the trigeminal nerve a promising target for the management of cerebral vasospasm. However, trigeminally mediated cerebral vasodilation has not been applied to the treatment of vasospasm. OBJECTIVE To determine the effect of percutaneous electrical stimulation of the infraorbital branch of the trigeminal nerve (pTNS) on the cerebral vasculature. METHODS In order to determine the stimulus-response function of pTNS on cerebral vasodilation, CBF, arterial blood pressure, cerebrovascular resistance, intracranial pressure, cerebral perfusion pressure, cerebrospinal fluid calcitonin gene-related peptide (CGRP) concentrations, and the diameter of cerebral vessels were measured in healthy and subarachnoid hemorrhage (SAH) rats. RESULTS The present study demonstrates, for the first time, that pTNS increases brain CGRP concentrations in a dose-dependent manner, thereby producing controllable cerebral vasodilation. This vasodilatory response appears to be independent of the pressor response induced by pTNS, as it is maintained even after transection of the spinal cord at the C5-C6 level and shown to be confined to the infraorbital nerve by administration of lidocaine or destroying it. Furthermore, such pTNS-induced vasodilatory response of cerebral vessels is retained after SAH-induced vasospasm. CONCLUSION Our study demonstrates that pTNS is a promising vasodilator and increases CBF, cerebral perfusion, and CGRP concentration both in normal and vasoconstrictive conditions.

Objectives: To determine if trigeminal nerve stimulation can ameliorate the consequences of acute blood loss and improve survival after severe hemorrhagic shock. Design: Animal study. Setting: University research laboratory. Subjects: Male Sprague-Dawley rats. Interventions: Severe hemorrhagic shock was induced in rats by withdrawing blood until the mean arterial blood pressure reached 27 ± 1 mm Hg for the first 5 minutes and then maintained at 27 ± 2 mm Hg for 30 minutes. The rats were randomly assigned to either control, vehicle, or trigeminal nerve stimulation treatment groups. The effects of trigeminal nerve stimulation on survival rate, autonomic nervous system activity, hemodynamics, brain perfusion, catecholamine release, and systemic inflammation after severe hemorrhagic shock in the absence of fluid resuscitation were analyzed. Measurements and Main Results: Trigeminal nerve stimulation significantly increased the short-term survival of rats following severe hemorrhagic shock in the absence of fluid resuscitation. The survival rate at 60 minutes was 90% in trigeminal nerve stimulation treatment group whereas 0% in control group (p < 0.001). Trigeminal nerve stimulation elicited strong synergistic coactivation of the sympathetic and parasympathetic nervous system as measured by heart rate variability. Without volume expansion with fluid resuscitation, trigeminal nerve stimulation significantly attenuated sympathetic hyperactivity paralleled by increase in parasympathetic tone, delayed hemodynamic decompensation, and improved brain perfusion following severe hemorrhagic shock. Furthermore, trigeminal nerve stimulation generated sympathetically mediated low-frequency oscillatory patterns of systemic blood pressure associated with an increased tolerance to central hypovolemia and increased levels of circulating norepinephrine levels. Trigeminal nerve stimulation also decreased systemic inflammation compared with the vehicle. Conclusions: Trigeminal nerve stimulation was explored as a novel resuscitation strategy in an animal model of hemorrhagic shock. The results of this study showed that the stimulation of trigeminal nerve modulates both sympathetic and parasympathetic nervous system activity to activate an endogenous pressor response, improve cerebral perfusion, and decrease inflammation, thereby improving survival.

BACKGROUND: Delayed cerebral ischemia (DCI) is the most consequential secondary insult after aneurysmal subarachnoid hemorrhage (SAH). It is a multifactorial process caused by a combination of large artery vasospasm and microcirculatory dysregulation. Despite numerous efforts, no effective therapeutic strategies are available to prevent DCI. The trigeminal nerve richly innervates cerebral blood vessels and releases a host of vasoactive agents upon stimulation. As such, electrical trigeminal nerve stimulation (TNS) has the capability of enhancing cerebral circulation. OBJECTIVE: To determine whether TNS can restore impaired cerebral macrocirculation and microcirculation in an experimental rat model of SAH. METHODS: The animals were randomly assigned to sham-operated, SAH-control, and SAH-TNS groups. SAH was induced by endovascular perforation on Day 0, followed by KCl-induced cortical spreading depolarization on day 1, and sample collection on day 2. TNS was delivered on day 1. Multiple end points were assessed including cerebral vasospasm, microvascular spasm, microthrombosis, calcitonin gene-related peptide and intercellular adhesion molecule-1 concentrations, degree of cerebral ischemia and apoptosis, and neurobehavioral outcomes. RESULTS: SAH resulted in significant vasoconstriction in both major cerebral vessels and cortical pial arterioles. Compared with the SAH-control group, TNS increased lumen diameters of the internal carotid artery, middle cerebral artery, and anterior cerebral artery, and decreased pial arteriolar wall thickness. Additionally, TNS increased cerebrospinal fluid calcitonin gene-related peptide levels, and decreased cortical intercellular adhesion molecule-1 expression, parenchymal microthrombi formation, ischemia-induced hypoxic injury, cellular apoptosis, and neurobehavioral deficits. CONCLUSION: Our results suggest that TNS can enhance cerebral circulation at multiple levels, lessen the impact of cerebral ischemia, and ameliorate the consequences of DCI after SAH.

The trigeminal nerve, the fifth cranial nerve, is known to innervate much of the cerebral arterial vasculature and significantly contributes to the control of cerebrovascular tone in both healthy and diseased states. Previous studies have demonstrated that stimulation of the trigeminal nerve (TNS) increases cerebral blood flow (CBF) via antidromic, trigemino-parasympathetic, and other central pathways. Despite some previous reports on the role of the trigeminal nerve and its control of CBF, there are only a few studies that investigate the effects of TNS on disorders of cerebral perfusion (i.e., ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury). In this mini review, we present the current knowledge regarding the mechanisms of trigeminal nerve control of CBF, the anatomic underpinnings for targeted treatment, and potential clinical applications of TNS, with a focus on the treatment of impaired cerebral perfusion.