Transcutaneous vagus nerve stimulation relieves depression by reducing brain inflammation
There is a large body of scientific evidence validating the effectiveness of transcutaneous vagus nerve stimulation (tVNS) in the treatment of depression. tVNS is inexpensive and easy to do at home.
Numerous studies have explored the mechanisms by which transcutaneous vagus nerve stimulation (tVNS) improves depression. New research further shows that the effects of tVNS include reducing inflammation in the brain.
Neuroinflammation and depression
It is well established that neuroinflammation (brain inflammation) is a leading biological cause of depression. Neuroinflammation can impair the activity of frontal lobe neurons. Moreover, it inhibits vagal outflow resulting in numerous adverse consequences.
“A large number of evidences suggest that there is a close link between neuroinflammation and depression [17], and stress-induced neuroinflammation characterized by overproduction of inflammatory cytokines in the brain acts as an important pathogenesis of depression [10]. The preclinical studies have also shown that chronic stress can lead to the activation of the innate immune system in the brain, while the increase of inflammatory cytokines, such as IL-1β can lead to depressive-like behavior…”
Accordingly…
“Stress-induced neuroinflammation was considered to play a critical role in the pathogenesis of depression…In 2005, the US Food and Drug Administration approved vagus nerve stimulation (VNS) for refractory MDD patients [8]. Significantly, VNS produces a systemic anti-inflammatory effect which may be an important reason for its effectiveness in patients who do not respond to anti-depressants [9].”
Making vagal stimulation safe and easy
Vagus nerve stimulation (as distinguished from tVNS) requires surgery with all the risks and discomfort that entails. But the vagus nerve can be accessed at the surface of the body in the ear.
“Researches from neuroanatomy show that the only branch of the vagus nerve reaching the body surface is the auricular branch of the vagus nerve (ABVN) [11], which mainly distributes in the external auditory meatus and concha (cymba conchae and cavum conchae), and the cymba conchae is supplied exclusively by the ABVN [12]. The transcutaneous auricular vagus nerve stimulation (taVNS), as one of the promising electrotherapies, has been used in the treatment of depression [13].”
Transcutaneous auricular vagus nerves stimulation (taVNS = tVNS applied to the ear) has a fine track record for treating depression.
“Clinical studies show that taVNS can greatly improve the scores of Hamilton Depression Rating Scale (HAMD) and self-rated depression scale in patients with depression without surgery, and produce clinical efficacy similar to that of VNS [10, 14]. taVNS is frequently used in the treatment of MDD [major depressive disorder], especially for residual symptoms [15].”
taVNS reduces brain inflammation
The authors build on earlier work concerning the efficacy of immune system modulation by taVNS.
“Studies have shown that VN can serve as a bridge between the central nervous system (CNS) and the immune system, playing an important role in regulating inflammation [20]. Our previous results suggest that taVNS significantly improved depression-like behavior and pain intensity as well as decreased the release of TNF-α in plasma, hypothalamus and hippocampus of the CUMS with chronic constriction injury of the sciatic nerve (CCI) model rats [21].”
Acetylcholine is the primary neurotransmitter involved in vagus nerve function. In this study, they focus on the role of the αlpha-7 nicotinic acetylcholine receptors (α7nAChRs) that respond to acetylcholine, activating the α7nAChR-mediated cholinergic anti-inflammatory pathway (CAP). In this case, they were particularly interested in the effect of vagal stimulation on the hippocampus.
“α7nAChR plays an essential role in the central anti-inflammation process that regulates microglia function in inflammation, and distributed widely in CNS, not only in neurons, but also in glial cells [46]. The hippocampus is a key nucleus involved in the regulation of cognition and emotion, where there are expressions of many nAChR subunits. But the most highly expressed receptor is α7nAChR [49]. Acting on α7nAchR can regulate synaptic plasticity of the hippocampus [50].”
taVNS modulates the function of immune cells in the hippocampus
Microglia are the immune cells in the brain and central nervous system. Their dysregulation is a major factor in depression and other brain and neuropsychiatric disorders. The vagus nerve ‘talks’ to them to regulate their function.
“α7nAChR plays an essential role in the central anti-inflammation process that regulates microglia function in inflammation, and distributed widely in CNS, not only in neurons, but also in glial cells [46]. The hippocampus is a key nucleus involved in the regulation of cognition and emotion, where there are expressions of many nAChR subunits. But the most highly expressed receptor is α7nAChR [49]. Acting on α7nAchR can regulate synaptic plasticity of the hippocampus [50]. Microglial abnormalities have been implicated in a wide range of brain diseases, including depression [51]. Microglia exhibits a broad spectrum of activation states upon receiving various stimuli, and can be divided into the M1 phenotype that secrets the pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6 and the M2 phenotype that produces the anti-inflammatory factors such as IL-4 and IL-10 [52]. It is widely known that the vagus nerve has positive anti-inflammatory actions of regulating the function of immune cells through activation of α7nAChR. The α7nAChR is the pivotal receptor that mediates the inflammation reflex of the vagus nerve [13, 53].”
Amazingly, taVNS not only regulates the activity of these immune cells but even alters their phenotype (their observable traits, shape, etc.).
“TaVNS stimulates ABVN, and the brain receives information from the vagus afferent fibers. The afferent fibers project to the nucleus tractus solitarius (NTS) and locus coeruleus (LC) in the brainstem, and then form direct and indirect ascending projections from the NTS to hypothalamus, amygdala, hippocampus, frontal lobe, and other areas of the brain [54, 55]. In addition, taVNS can affect cholinergic anti-inflammation mediated by α7nAChR on macrophage, microglia and neuron [56]. Our studies also clarified that the morphology of microglia changed from an amoebic-like activated state to a resting state with small cell bodies, slender protrusions and free stretching and the level of IL-1β secreted by the M1 phenotype decreased after taVNS intervention of 21 days.”
Stress chemistry, brain inflammation, and depression ameliorated
They also observed the dampening of NF-κB (nuclear factor kappa beta), a core module of the chemistry of inflammation involved in depression as well as the rest of the body. ‘Stress chemistry’ increases this inflammation in a self-amplifying loop, and taVNS was shown to reduce it.
“NF-κB signal is a critical mediator of the anti-neurogenic and behavioral actions of stress. NF-κB is closely related to neuroinflammation. On one hand, NF-κB, as a multi-effect regulator, is involved in the regulation of inflammatory mediators and the transcription and expression of inflammatory cytokines; on the other hand, inflammatory factors such as IL-1β, can activate NF-κB. This cycle aggravates the inflammatory response [61]. Experiments have shown that stress inhibition of neurogenesis in the hippocampus, which has been demonstrated on the pro-depressive effects of stress, is blocked by an inhibitor of NF-κB [62].
Furthermore, the activation of α7nAChR blocked LPS-mediated NF-κB nuclear translocation, which indicated that the observed anti-inflammatory effect may be mediated through inhibition of the NF-κB pathway [63]. α7nAChR/NF-κB signal pathway is a crucial pathway to regulate CNS neuroinflammation [64], and the results of this experiment suggest that taVNS can up-regulate the expression of α7nAchR on hippocampal microglia. α7nAchR prevents the NF-κB nuclear translocation and the expression of phosphorylated-p65, thereby reducing the content of IL-1β. Therefore, the antidepressant effect of taVNS is related to hippocampal α7nAchR/NF-κB signal pathway.”
Antidepressant effect of transcutaneous auricular vagus nerve stimulation.
Growing body of knowledge for the relief of depression
This study adds to the growing body of knowledge in the functional/integrative treatment of depression using interventions that promote healthy brain biology and adds to the expanding resources used in the FM model for calming brain inflammation, and taVNS in particular. The authors conclude:
“This study shows that the taVNS alleviates depression-like behavior induced by CUMS in rats and is related to the α7nAchR-mediated neuroinflammation in the hippocampus. Importantly, our results show that taVNS intervention can effectively relieve depression-like behavior in CUMS model rats. This antidepressant effect is due to anti-inflammation by upregulation of the α7nAchR, which prevents the expression of NF-κB nuclear translocation and its phosphorylated-p65 to reduce the production of pro-inflammatory cytokines such as IL-1β. Therefore, the antidepressant-like effect of taVNS may be related to the regulation of α7nAchR/NF-κB signal pathway. We hope that this study may provide a new idea for exploring neuromodulation techniques in the treatment of depression from the perspective of anti-inflammation.”
