Psychiatry Advisor: What are the mechanisms by which VNS is believed to relieve depression?

Nicholson: The neural mechanisms involved in VNS and depression are not well understood. In part, this relates to the need for the neural properties of VNS to be mapped according to the evolving science surrounding the complex mechanisms that drive depression. Generally, vagus nerve function — as indexed by heart-rate variability — is associated with parasympathetic activity via sinoatrial node actions, and it has been suggested that it regulates the stress response by serving as a “braking” mechanism for the sympathetic nervous system. Chronic sympathetic dominance has been demonstrated in depression, as measured by reduced heart-rate variability, which suggests a pathologic withdrawal — simply put, an inability to successfully control the stress response — of the vagus nerve.

Studies have shown that VNS projects to the dorsolateral prefrontal cortex, anterior cingulate, insula, and precuneus, which are neural circuits specific to depression. Moreover, research suggests that VNS has connections to relevant brain stem areas — dorsal raphe, and locus coeruleus, among others — that are highly associated with neurotransmitters commonly linked to depression, such as serotonin and norepinephrine. As such, VNS is suggested to treat depression by helping establish autonomic nervous system homeostasis via its cardio-neural connections. Of note, ongoing advances in neuroimaging and functional connectivity technology will allow for more comprehensive neural mapping of VNS.

Psychiatry Advisor: What are the main takeaways of your findings for mental health clinicians?

Nicholson: Much like in the general population, approximately 30% of people with HIV-depression experience treatment-resistant depression. The use of neuromodulatory devices has progressively gained support in various mental health conditions. Non-implantable tVNS has been shown to be an effective intervention for treatment-resistant depression and is considered to have a better safety profile when compared with other traditional treatments — for example, antidepressants or off-label medications often used in treatment-resistant cases. To the best of our knowledge, tVNS has not been utilized in the HIV population for research or treatment purposes.

While research examining the potential role of the VN in HIV symptomatology is lacking, multiple studies have demonstrated its involvement in symptomatology shared by both HIV and depression alike, including metabolic disruptions; reduced heart-rate variability; proinflammatory states; gastrointestinal disturbances; cardiovascular disorders; and pain, social, emotional, and cognitive impairments). Moreover, VNS studies have demonstrated the ability of VNS to provide both protective and beneficial effects when utilized in numerous populations exhibiting these clinical symptomologies. Therefore, tVNS could provide a safe alternative treatment in HIV-depression by targeting both depression and other comorbidities that can burden people living with HIV.

Related Articles

Psychiatry Advisor: What should be next steps in terms of research in this area?

Nicholson: With regard to current science and available technology, studies are needed to determine the appropriate stimulation parameters for treating HIV-depression. This can be accomplished with pilot studies that examine the short-term effects of tVNS on depressive symptoms in HIV. Given the accessibility and affordability of these devices, long-term studies should be considered that evaluate both depressive symptomatology and the beneficial effects of tVNS as it relates to common comorbidities. While the vagus nerve’s role in the inflammatory process remains under investigation, studies examining the augmenting potential of tVNS in the presence of combination antiretroviral therapy (cART) could enhance our understanding of both the vagus nerve and antiretroviral therapy in the context of chronic inflammation mechanisms.


  1. Arseniou S, Arvaniti A, Samakouri M. HIV infection and depressionPsychiatry Clin Neurosci. 2013;68(2):96-109.
  2. Nanni MG, Caruso R, Mitchell AJ, Meggiolaro E, Grassi L. Depression in HIV-infected patients: a review. Curr Psychiatry Rep. 2014;17(1):530.
  3. Fields J, Dumaop W, Langford TD, Rockenstein E, Masliah E. Role of neurotrophic factor alterations in the neurodegenerative process in HIV-associated neurocognitive disordersJ Neuroimmune Pharmacol. 2014;9(2):102-116.
  4. Lotrich FE, Albusaysi S, Ferrell RE. Brain-derived neurotrophic factor serum levels and genotype: association with depression during interferon-α treatment. Neuropsychopharmacology. 2012;38(6):985-995.
  5. Raedler TJ. Inflammatory mechanisms in major depressive disorderCurr Opin Psychiatry. 2011;24(6):519-525.
  6. Nicholson WC, Kempf M-C, Moneyham L, Vance DE. The potential role of vagus-nerve stimulation in the treatment of HIV-associated depression: a review of literature. Neuropsychiatr Dis Treat. 2017;13:1677-1689.
  7. Fang J, Rong P, Hong Y, et al. Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorderBiol Psychiatry. 2016;79(4):266-273.
  8. Rong PJ, Fang JL, Wang LP, et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trialBMC Complement Altern Med. 2012;12:255.