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. 2024 Feb 29;5(1):150-158.
doi: 10.1089/neur.2023.0058. eCollection 2024.

Non-Invasive Vagal Nerve Stimulation Pre-Treatment Reduces Neurological Dysfunction After Closed Head Injury in Mice

Andreia Morais  1 , Joon Yong Chung  2 , Limin Wu  2 , Cenk Ayata  1 , Bruce Simon  3 , Michael J Whalen  2
Affiliations

Non-Invasive Vagal Nerve Stimulation Pre-Treatment Reduces Neurological Dysfunction After Closed Head Injury in Mice

Andreia Morais et al. Neurotrauma Rep. .

Abstract

Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1β) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1β activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.

Keywords: closed head injury; inflammation; vagus nerve stimulation.

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Figures

FIG. 1.
FIG. 1.
Neurological dysfunction after CHI and nVNS evaluated by MWM. (A) nVNS pre-treatment timeline (n = 12 CHI and 16 sham per group). (B) Compared to sham injury, CHI increased latency to the hidden and visible platforms (#vs. sham, p < 0.001 for group, two-way RM ANOVA). nVNS pre-treatment ameliorated the CHI effect in hidden (*nFNS, p < 0.05, two-way RM ANOVA), but not visible, platform trials. There was no difference in the probe trial among the groups. (C) nVNS post-treatment timeline (n = 10 per group). (D) Compared to sham, CHI increased latency to hidden and visible platform trials (#p < 0.01, two-way RM ANOVA), but nVNS presented similar latencies to nFNS in both CHI and sham-injured groups. Probe trial performance did not differ among the experimental groups. CHI, closed head injury; MWM, Morris water maze; nFNS, non-invasive femoral nerve stimulation; nVNS, non-invasive vagus nerve stimulation; RM ANOVA, repeated-measures analysis of variance.
FIG. 2.
FIG. 2.
Qualitative (A) and quantitative (B) effect of nVNS on IL-1b activation after CHI in neurons and CD31+ endothelial cells. Cleaved IL-1b was not detected in shams, but was robustly induced by CHI (#p < 0.01, two-way ANOVA) in neurons and endothelium. In neurons, nVNS significantly prevented CHI-associated upregulation of cleaved IL-1b expression (**p < 0.01, two-way ANOVA), but had no impact over endothelial cleaved IL-1b. Pro-IL-1b expression was upregulated in neurons in CHI-nFNS compared to sham-nFVS (#p < 0.05, non-parametric t-test) in brain endothelium and was not modulated by nVNS. N = 3 sham and 5 CHI/group. ANOVA, analysis of variance; CHI, closed head injury; IL, interleukin; nFNS, non-invasive femoral nerve stimulation; nVNS, non-invasive vagus nerve stimulation.
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