Percutaneous Trigeminal Nerve Stimulation Induces Cerebral Vasodilation in a Dose-Dependent Manner

Abstract

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.

Keywords: Calcitonin gene-related peptide; Cerebral blood flow; Cerebral vasodilation; Infraorbital nerve; Trigeminal nerve stimulation; Trigemino-cerebrovascular network.

FIGURE 1.

Effects of electrical stimulation of the infraorbital nerve (pTNS) on cerebral hemodynamics in central nervous system-intact rats. Representative changes in CBF, MAP, and CVR at different stimulus intensity A, C, and E. Summarized graph of relationships between stimulus intensity and magnitude of increase B, D, and F. A and B, CBF. C and D, MAP. E and F, CVR. Data were expressed as mean ± SD. *P < .001 vs baseline, n = 10/group.

FIGURE 2.

Effects of electrical stimulation of the infraorbital nerve (pTNS) on cerebral hemodynamics in spinalized rats. Representative changes in CBF, MAP, and CVR at different stimulus intensity after spinal transection at the C5-C6 level A, C, and E. Summarized graph of relationships between stimulus intensity and magnitude of changes B, D, and F. A and B, CBF. C and D, MAP. E and F, CVR. Data were expressed as mean ± SD. *P < .001 vs baseline, n = 8/group.

FIGURE 3.

Effects of electrical stimulation of the infraorbital nerve (pTNS) on CSF CGRP. CSF CGRP levels increased with increasing stimulus intensity. Application of local anesthesia (lidocaine) or destruction of the infraorbital nerve fibers (Tx) abolished the CGRP release to the pTNS. Data were expressed as mean ± SD. ***P < .001 vs sham, n = 4-9/group.

FIGURE 4.

Effects of electrical stimulation of the infraorbital nerve (pTNS) on CPP. CPP levels increased with increasing stimulus intensity of pTNS. A, Relationship between stimulus intensity and magnitude of CPP. B, Frequency-dependent increase in CPP at the same stimulus intensity. Low-frequency stimulation (50 Hz) better improves CPP than high-frequency stimulation (133 Hz). Data were expressed as mean ± SD (n = 10). *P < .001 vs baseline, ^#P < .001 vs 50 Hz group, n = 10/group.

FIGURE 5.

Effects of pTNS on cerebral vasospasm in the ICA. Cerebral vasospasm in the ICA. A, Representative microscopic images of hematoxylin-and-eosin-stained cross sections of the ICA are shown after 48 h (scale bar = 100 μm). B, Inner diameter in the ICA. Data were expressed as mean ± SD (n = 4). *P < .05 vs sham, ^#P < .05 vs control group.