The Physiological and Psychological Effects of Electrical Vagus Nerve Stimulation in Patients with Refractory Epilepsy

The vagus nerve is the longest cranial nerve in the body and has innervations and influence on many organs, yet the mechanisms that mediate these effects are still to be fully understood. Electrical stimulation of the vagus nerve has been used to treat refractory epilepsy for over 30 years despite an incomplete understanding of how it produces anti-epileptic effects. More recently, vagus nerve stimulation (VNS) has gained huge attention after the discovery that it may also have therapeutic benefit in mood and inflammatory disorders. This thesis explored the possible mechanisms that mediate the beneficial effects of VNS with a particular focus on the immune system in patients with refractory epilepsy. We also explored other potential therapeutic effects of VNS on anxiety, fatigue and perceived stress as well as heart rate variation As a non-invasive biomarker for the associated beneficial effects. By 6 months post-VNS implantation, a trend in reduced perceived stress was observed and was independent of changes in seizure frequency, seizure severity, mood, age, and gender. In heart rate variation studies, a significant decrease in high frequency relative power was seen at 6 months after VNS implantation, suggesting a reduction in sympathetic tone. This however did not correlate with other measures tested in the thesis. Flow cytometry analysis did not identify a trend in increasing Treg frequency following VNS treatment. However, functional analysis suggests a reduction in Treg function in response to anti-CD3 antibody which mimics antigen-presenting cell mediated expansion of T cells. Finally, cytokine array assays identified a significant reduction in the expression of BDNF, FGF-7, FGF-9, IL-1α, IL-1β, and MDC from plasma 3 months following VNS implantation. In summary, this thesis has identified novel findings which open additional avenues for exploring the therapeutic potential of VNS to treat stress disorders and its effects on Tregs for anti-inflammatory effects.