Abdominal Vagus Nerve Stimulation Increases Firing in the Rat Locus Coeruleus

Abstract

Background: Cervical vagus nerve stimulation (VNS) is a clinically available treatment for refractory epilepsy and depression. Animal studies show that electrical activation of the noradrenergic brain region, locus coeruleus (LC), is essential for the therapeutic effects of cervical VNS for the treatment of these conditions. Cervical VNS often causes side effects such as coughing, headache, and apnea-hypopnea. Such side effects can be mitigated by reducing stimulation intensity; however, evidence suggests this reduces efficacy of treatment. Abdominal VNS, targeting the vagus nerve below the nerve branches that cause these side effects, is an alternative strategy to deliver VNS.

Objective: This study aimed to assess whether abdominal VNS increases spike activity in the LC without causing any off-target effects.

Materials and methods: Cervical and abdominal vagi of anesthetized male Sprague-Dawley rats were implanted with cuff electrode arrays, and a tungsten electrode was used to record neural activity in the LC. Changes in the firing rate of LC neurons and changes to the heart and breathing rate were recorded during cervical and abdominal VNS.

Results: Cervical VNS significantly reduced heart and/or breathing rate (two-way repeated measures analysis of variance, p < 0.05; n = 6) when stimulation was 0.82 ± 0.09 mA or higher. This stimulation level was termed the "off-target effect threshold." Abdominal VNS did not produce any changes in heart and breathing rate at any stimulus level tested. Cervical and abdominal VNS, delivered at 2 mA (maximum tested) significantly increased spike activity predominantly in the anteromedial LC, compared with prestimulation baseline (paired t-test, p < 0.001, n = 6). However, when "safe levels," that is, below the off-target effect threshold, of VNS were applied, only abdominal VNS increased spike activity in the LC.

Conclusion: Abdominal VNS activated the LC without causing changes to vitals and could be used as an alternative approach to providing VNS therapy for brain disorders such as drug-resistant epilepsy and depression.

Keywords: Noradrenergic nucleus; neural recordings; neuromodulation; peripheral nerve stimulation; subdiaphragmatic vagus nerve.