Vagal Nerve Stimulation

This research focused on investigating the biological pathways that are involved in the antidepressant effects of vagal nerve stimulation (VNS), an FDA-approved therapeutic intervention for patients with treatment-resistant depression (TRD) i.e those who do not respond to multiple trials with antidepressant medications or electroconvulsive therapy. Clinical data showed that VNS is effective in TRD patients; yet, the biological rationale behind its beneficial effects were unclear. To address this gap in knowledge, we conducted preclinical studies using stimulators and settings that were similar to those used clinically.

First, we demonstrated that repeated administration of VNS produced positive behavioral effects in rats. Short-term VNS treatment had an antidepressant-like effect whereas long-term VNS treatment reduced both, anxiety- and depression-like, symptoms. We then used toxins or inhibitors to block or destroy one neurobiological system at a time and assessed if this interfered with the beneficial behavioral effects produced in rats treated with 1) VNS or 2) classical AD drugs, like Prozac, to evaluate if VNS recruited biological systems beyond those used by these classical drugs. Our study was the first to demonstrate that VNS produces its antidepressant effects via the serotonergic system and anxiolytic effects via the serotonergic as well as noradrenergic systems. By contrast, classical antidepressants primarily recruit only one of these neurotransmitter systems.

One of the most widely accepted theories for the pathophysiology of depression is the neurotrophin theory, which suggests that stress causes reduction of brain derived neurotrophic factor (BDNF) in certain brain areas. BDNF binds to its receptor and promotes survival and proliferation of brain cells. Our study was the first to demonstrate that VNS treatment recruits this system to produce its beneficial behavioral effects whereas a classical AD drug called desipramine, does not. Collectively, these studies show that unlike AD drugs, VNS therapy recruits multiple biological pathways, which may begin to explain why it is effective for TRD.