Neural, Anti-Inflammatory, and Clinical Effects of Transauricular Vagus Nerve Stimulation in Major Depressive Disorder: A Systematic Review

Abstract

Objectives The discovery of effective treatments for major depressive disorder (MDD) may help target different brain pathways. Invasive vagus nerve stimulation (VNS) is an effective neuromodulation technique for the treatment of MDD; however, the effectiveness of the noninvasive technique, transauricular VNS (taVNS), remains unknown. Moreover, a mechanistic understanding of the neural effects behind its biological and therapeutic effects is lacking. This review aimed to evaluate the clinical evidence and the neural and anti-inflammatory effects of taVNS in MDD. Review Methods Two searches conducted using a systematic search strategy reviewed the clinical efficacy and neural connectivity of taVNS in MDD in humans and evaluated the changes in inflammatory markers after taVNS in humans or animal models of depression. A risk of bias assessment was performed in all human studies. Results Only five studies evaluated the effects of taVNS in patients with depression. Although the studies demonstrated the efficacy of taVNS in treating depression, they used heterogeneous methodologies and limited data, thus preventing the conduct of pooled quantitative analyses. Pooled analysis could not be performed for studies that investigated the modulation of connectivity between brain areas; of the six publications, five were based on the same experiment. The animal studies that analyzed the presence of inflammatory markers showed a reduction in the level of pro-inflammatory cytokines or receptor expression. Conclusion Data on the clinical efficacy of taVNS in the treatment of MDD are limited. Although these studies showed positive results, no conclusions can be drawn regarding this topic considering the heterogeneity of these studies; as in the case of functional connectivity studies. Based on animal studies, the application of taVNS causes a decrease in the level of inflammatory factors in different parts of the brain, which also regulate the immune system. Therefore, further studies are needed to understand the effects of taVNS in patients with MDD.

Transcutaneous vagus nerve stimulation effects on chronic pain: systematic review and meta-analysis

“…Vagal electrical stimulation is known to modulate various cortical and subcortical areas, including vagal projections, the locus coeruleus, parabrachial area, hypothalamus, amygdala, anterior cingulate cortex, nucleus accumbens, thalamus, prefrontal cortex, postcentral gyrus, posterior cingulate cortex, and anterior insula. 34 It also influences several neural networks, such as the default mode network, executive network, and emotional and reward circuits. In addition, this stimulation affects the release of neurotransmitters, including GABA, norepinephrine, opioids, and serotonin, and it has demonstrated anti-inflammatory effects.…”

“…Transcutaneous auricular VNS stimulates the afferent fibers of the vagus nerve that travel to the NTS and subsequently to locus coeruleus, periaqueductal gray, cortical and subcortical areas such as hypothalamus, amygdala, hippocampus, and frontal lobe, and from these areas to descending pain pathways. 34 In addition, taVNS may trigger neuroplastic signaling mechanisms such as BDNF expression and RNA expression, 10 which may have a significant effect counteracting pain circuits with maladaptive plasticity. However, ongoing research continues to investigate these mechanisms, and conflicting evidence exists.…”

“…For example, 1 alternative and complementary hypothesis is that concurrent activation of the anti-inflammatory system cascade may account for the measurable reduction in pain intensity. 5,7,14,34,42…”

Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD)

“…Current understandings of the anti-inflammatory effects of VNS are typically derived from animal models, in vitro experiments, or transcutaneous VNS [14,23,24], yielding inconclusive results. However, data from long-term studies involving real world patients, both for invasive and transcutaneous VNS, are sparse.…”