Transcutaneous Vagus Nerve Stimulation (tVNS) Reduces Depressive Symptoms

Clinical Data 


Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis.

DOI: 10.1097/MD.0000000000013845



The systematic review aimed to establish the effectiveness and safety of taVNS in major depressive disorder. A total of 4 studies with 222 individuals were included in the meta-analysis. taVNS reduced depression score significantly more than placebo treatment (measured with Hamilton Rating Scale for Depression , Self-Rating Depression Scale, Beck Depression Inventory, Self-Rating Anxiety Scale). No difference was detected in Hamilton Anxiety Rating Scale. No notable adverse effects detected.



Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder

DOI: 10.1016/j.biopsych.2015.03.025.



tVNS was used to treat patients with mild to moderate depressive disorder for one month. The results indicated that the depression score (Hamilton Rating Scale for Depression) had reduced significantly. The observation correlated with an increase in functional connectivity (FC) between the default mode network (DMN) and precuneus and orbital prefrontal cortex. Conversely, FC between the DMN and anterior insula and parahippocampus decreased after treatment.



Auricular transcutaneous electrical nerve stimulation in depressed patients: A randomized controlled pilot study  

DOI: 10.1007/s00702-012-0908-6



This clinical trial was the first to demonstrate an antidepressant effect of the transcutaneous auricular nerve stimulation in patients with major depression. A significant reduction was detected in the Beck Depression Inventory in patients who received the electrical stimulation in contrast to placebo therapy.



Transcutaneous vagus nerve stimulation (taVNS) for major depressive disorder: An open label proof-of-concept trial




The study examined the effect of taVNS in patients with major depression. 10 sessions of vagus nerve stimulation (30 minutes daily) was shown to significantly ameliorate depression symptoms, as measured by the Hamilton Rating Scale for Depression, with no significant adverse events. The clinical response had remained stable at one-month follow-up, and no adverse changes to normal cognitive functions were detected.   


Early cortical biomarkers of longitudinal transcutaneous vagus nerve stimulation treatment success in depression  

DOI: 10.1016/j.nicl.2016.12.016



The study attempted to delineate the specific neural pathways of tVNS treatment in depression as well as determining specific biomarkers of treatment success. fMRI brain scans revealed that tVNS significantly increase activities in the left anterior insula. Such an activation in the insula was significantly associated with the observed clinical improvement (Hamilton Rating Scale for Depression) at 4-week, suggesting a potential to serve as a cortical biomarker and predictor of treatment outcome.



Frequency-dependent functional connectivity of the nucleus accumbens during continuous transcutaneous vagus nerve stimulation in major depressive disorder

DOI: 10.1016/j.jpsychires.2017.12.018



tVNS treatment for 4 weeks was shown to improve the functional connectivity (FC) between the left nucleus accumbens (NAc) and left insula, occipital gyrus and right lingual/fusiform gyrus. The FC of the NAc with the medial prefrontal cortex and the rostral anterior cingulate cortex was negatively associated with the Hamilton Rating Scale for Depression score.



A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder

DOI: 10.1016/j.brs.2018.01.006



tVNS treatment for 4 weeks was associated with a significantly lowered depression score (Hamilton Rating Scale for Depression) as compared to placebo. Such a decrease was also associated with a concurrent reduction in the functional connectivity between the bilateral medial hypothalamus and rostral anterior cingulate cortex, which could serve as a potential biomarker for treatment success.



Transcutaneous vagus nerve stimulation (tVNS) protocol for the treatment of major depressive disorder: A case study assessing the auricular branch of the vagus nerve

DOI: 10.1016/j.yebeh.2015.10.002



This is the first reported case of tVNS treatment via the mastoid process. The 39-year-old male patient with major depressive disorder that was resistant to pharmacological therapy underwent ten daily tVNS sessions with 30 minutes each. The treatment successfully ameliorated depressive symptoms with a complete clinical remission, and the patient remained stable at two-month follow-up.



Optimization of transcutaneous vagus nerve stimulation using functional MRI




The study attempted to optimise the transcutaneous vagus nerve stimulation therapy by using data from fMRI brain scans. Three stimulation locations were compared to the placebo (earlobe) treatment. Brain scans revealed that stimulation of the inner tragus activated both the nucleus of solitary tract (NTS) and the locus coeruleus (LC) while stimulation at the ear canal resulted in the weakest signals. The observation could be attributed to the innervation of the inner tragus by the afferent branch of the vagus nerve, which makes this location a good candidate for tVNS treatment.



BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation

DOI: 10.1007/s00702-007-0755-z



The study provided evidence that tVNS can be effective in inducing functional changes in the brain as well as enhancing mood without using pharmaceutical drugs. fMRI scans of 22 healthy subjects who underwent stimulation of the tragus showed a reduction in signals from the limbic areas (amygdala, hippocampus, parahippocampal gyrus and the middle and superior temporal gyrus). In contrast, heighten signals were found in the insula, precentral gyrus and the thalamus. Psychometric assessment (Adjective Mood Scale) showed significant improvement in well-being after treatment when compared to placebo therapy.



Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression

DOI: 10.1016/j.jad.2016.08.003



A deficit in the amygdala-frontal functional connectivity had been implicated in major depressive disorder (MDD). This study examined the effect of a four-week tVNS treatment on patients with MDD and found a significant reduction in the Hamilton Depression Rating Scale as well as an increase in the resting state functional connectivity (rsFC) between the right amygdala and left dorsolateral prefrontal cortex, thus shedding light on a possible mechanism of action of tVNS to treat MDD.



Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study

DOI: 10.1016/j.jad.2016.02.031



This non-randomised clinical trial examined the effect of a 12-weeks transcutaneous auricular VNS (taVNS/tVNS) treatment versus a 4-week placebo followed by 8-week taVNS therapy in patients with major depressive disorder. The results indicated that just a 4-week treatment was enough to show significant reduction in the Hamilton Depression Rating Scale. Such clinical benefits also persisted until week 12 in the active taVNS group.



Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability

DOI: 10.1111/ene.12629



The review article found that both invasive VNS and non-invasive VNS (nVNS) are effective in treating depression (significant reduction in Hamilton Depression Rating Scale), However, invasive VNS was associated with more adverse events, such as infection and pain. Voice alteration was also common (20% of patients at 5 years) and may be disturbing. nVNS (non-invasive VNS; or tVNS) had a much better safety profile and could negate the negative aspects of invasive VNS entirely without diminishing the treatment efficacy.



A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI

DOI:  10.1515/BMT.2008.022



This study sought to demonstrate the ability of tVNS to induce cortical as well as subcortical brain changes that were relevant to the treatment of depression. fMRI scans of four healthy male adults showed a positive BOLD (Blood Oxygenation Level Dependent) response in key brain regions that were related to the higher order relay nuclei of vagal afferent pathways, including the left locus coeruleus, thalamus, left prefrontal cortex, the right and left postcentral gyrus, left posterior cingulate gyrus and the left insula. Deactivations of the right nucleus accumbens (NAc) and right cerebellar hemisphere were detected as well. The complex interplay of these regions is thought to affect depression where tVNS therapy was shown to tilt the balance towards favourable clinical outcomes.



CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study  

DOI: 10.1016/j.brs.2013.01.011



This study provides evidence to differentiate distinct effects on the brain caused by a variation in the location for stimulation (anterior versus posterior, or simply the front versus the back) of the left outer auditory canal. It was found that stimulation to the front side would induce opposite changes in BOLD (Blood Oxygenation Level Dependent) fMRI responses in most cortical areas compared to stimulation to the back part of the canal. Notable decreases in BOLD signals were found in the parahippocampal gyrus, posterior cingulate cortex and right thalamus following anterior (front) stimulation. A significant decrease in BOLD signals was also detected in the locus coeruleus and the solitary tract during anterior stimulation. Only in the insular cortex where positive BOLD responses were detected through both the anterior and posterior stimulation. These observations suggested successful stimulation of the vagal afferent nerve by tVNS to produce favourable brain changes to combat depression.



Transcutaneous vagus and trigeminal nerve stimulation for neuropsychiatric disorders: a systematic review

DOI: 10.1590/0004-282X20140061



The review article examined the effect of the transcutaneous vagus and trigeminal nerve stimulation in neuropsychiatric disorders. 4 clinical studies were included for the analysis of tVNS effects where 3 of them were performed on healthy volunteers and the remaining one on epileptic patients. The authors concluded that this evidence suggested that treatment with tVNS demonstrated significantly better outcome in depression treatment and could induce positive brain changes to minimise symptoms. Based on these results, the authors postulated that further development in tVNS technique could improve neuromodulation in the future.



Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: A proof of concept trial

DOI: 10.1111/j.1528-1167.2012.03492.x



The study's primary objective was to evaluate the efficacy of tVNS in epileptic patients. However, the secondary analysis indicated that self-administered daily tVNS for 9 months, performed as three separate 1-hourly sessions, did not negatively impact cognitive functions. In fact, measures of quality of life (via the Quality of Life in Epilepsy Inventory-89) and depression (via the Beck Depression Inventory) were stable or improved over time. This finding provided a foundation to further explore the therapeutic role of tVNS in both epilepsy and depression.


Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial  

DOI: 10.1186/1472-6882-12-255



This clinical trial protocol described a double-blind, randomised, sham-controlled trial to investigate the effect of direct stimulation of the afferent nerve fibres on the ear as compared to classic VNS in treating depression. The trial result was postulated to provide clarity on the clinical benefits of tVNS on major depressive disorder and extend the application to other neuropsychiatric disorders. It was possible that the trial result would also improve understanding on acupuncture point specificity, which was largely similar to tVNS in terms of mechanism of action.



Mechanism of action

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review

DOI: 10.1016/j.brs.2017.12.009



The study attempted to delineate the biologically active sites that could best stimulate the brain via taVNS (transcutaneous auricular vagus nerve stimulation) synonymous with ‘tVNS’. With the help of fMRI scans, the researchers discovered that stimulation at the tragus produced the greatest BOLD (blood oxygen level depending) signal in the cingulate gyrus, frontal cortex, cerebellum and right caudate. The study was also the first to show that taVNS led to bilateral activation of the ACC (anterior cingulate cortex) and left dorsolateral prefrontal cortex. These observations were consistent with the proposed anti-depressant effect of taVNS that had been previously reported.



Effects of Concomitant Stimulation of the GABAergic and Norepinephrine System on Inhibitory Control – A Study Using Transcutaneous Vagus Nerve Stimulation

DOI: 10.1016/j.brs.2016.07.004



The objective of this study was to examine the joint effects of GABAergic and norepinephrine (NE) system for inhibitory control via tVNS. The results indicated that tVNS was likely to affect the NE system, and could have the potential for clinical use particularly in patients with ADHD. NE was also implicated in the pathophysiology of depression and the regulation of which was the main mechanism of action of tricyclic antidepressants. The role of tVNS in modulating the NE system could be important in managing depression.



Effects of Transcutaneous Vagus Nerve Stimulation (tVNS) on the P300 and Alpha-Amylase Level: A Pilot Study

DOI: 10.3389/fnhum.2018.00202



The study examined the effect of continuous tVNS on the locus coeruleus-norepinephrine (LC-NE) system and P300 (an event-related potential across the centro-parietal brain regions tat occurred between 300-600ms after stimulus onset), Changes on the salivary alpha-amylase (sAA), a proxy to noradrenergic activation, was also investigated. Post-hoc analyses showed that tVNS increased P300 amplitude. Increased P300 amplitude had been associated with a decreased in depression symptom severity in the literature. sAA level was also increased when compared to baseline, implying a possible release of norepinephrine (NE) that, in turn, modulated changes in P300 amplitude via the LC-NE system.



The effect of transcutaneous vagus nerve stimulation on cortical excitability

DOI: 10.1007/s00702-014-1299-7



The aim of this randomised, placebo-controlled, double-blind study was to investigate the effect of tVNS on cerebral cortex excitability in healthy volunteers. tVNS treatment was delivered in pulses that lasted 60 minutes in total. The results confirmed that tVNS was as reliable as traditional (invasive) VNS in stimulating the vagus nerve. A selective and pronounced increase of intracortical inhibition, likely related to the activity of GABA-A inhibitory circuits of the motor cortex, was discovered. Additionally, the study found no significant adverse changes to other neurophysiological as well as cardiovascular measurements. The authors concluded that tVNS was a safe and effective method to support further therapeutic applications of such a technique.  



Treating Depression with Transcutaneous Auricular Vagus Nerve Stimulation: State of the Art and Future Perspectives

DOI: 10.3389/fpsyt.2018.00020



The review article summarised existing evidence of taVNS in treating depression and found that the treatment could relieve different depressive symptoms including anxiety, psychomotor impairment, sleep disturbance, and hopelessness. These effects were likely attributed to the ability of taVNS to modulate, directly and indirectly, key brain regions such as the cortical-limbic-thalamic-striatal neural circuits. Other possible mechanisms could explain the effect of taVNS too, such as the inhibition of neuro-inflammatory sensitisation, the stimulation of hippocampal neurogenesis, and possibly through the exertion of influence over the microbiome-brain-gut axis.


Vagus Nerve Stimulation, Depression, and Inflammation

DOI: 10.1038/sj.npp.1301286



The author of the commentary postulated that stimulation of the vagus nerve could be an effective treatment of depression by suppressing the production of proinflammatory cytokines, including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), high mobility group box 1 (HMGB1) and macrophage migration inhibitory factor (MIF). Elevated concentrations of these cytokines have been implicated in depression pathophysiology. As such, the inhibition of which could be a novel therapy for depression.



Vagus Nerve Stimulation

DOI: 10.1007/s40473-014-0010-5



The article provides a comprehensive review of the efficacy and safety of VNS (including tVNS) in depression treatment. tVNS is regarded as a promising option to treat the condition and utilised as a research tool because of its non-invasive nature. Evidence also suggests that tVNS could alter proinflammatory biomarkers, which is an emerging alternative to depression treatment. In short, the author believes VNS produces favourable effects that could benefit the treatment of depression.



IL‐6 levels decrease with SSRI treatment in patients with major depression

DOI: 10.1002/hup.717



The study investigated the serum concentration of proinflammatory cytokines, interleukin-6 (IL-6), in patients with major depression and the subsequent changes during treatment with serotonin reuptake inhibitor (SSRI). The results revealed that SSRI therapy significantly reduced IL-6 level in patients which could be attributed to the ability of SSRI to modulate the immune system. Such an anti-inflammatory effect was also found in individuals who underwent tVNS, suggesting a possible mechanism that mimicked the SSRI in ameliorating depressive symptoms.


Cholinergic Control of Inflammation

DOI: 10.1111/j.1365-2796.2009.02098.x



The cholinergic anti-inflammatory pathway is an important mechanism to regulate local and systemic inflammation. It consists of the vagus nerve and its major neurotransmitter, acetylcholine. The paper described VNS as a precise approach to treating inflammatory diseases including depression as it takes advantage of the nervous distribution to reach specific target organs. Regulating the tones of the vagus nerve could indirectly influence cytokine productions and restore balance to the dysfunctional parasympathetic system that is found in individuals with altered mental states (such as depression and anxiety).



Cytokines and Major Depression

DOI: 10.1016/j.pnpbp.2004.11.003



This review article examined the role of proinflammatory cytokines (interleukin (IL)-1, tumour necrosis factor (TNF)-α, and interferon (IFN)-γ) in major depression. The hypothesis where cytokines are involved in depression is supported by various empirical findings, such as the co-existence of chronic inflammatory diseases with depression, and the inducement of depression by the administration of proinflammatory cytokines (in cancer or hepatitis C). On the other hand, VNS has demonstrated its ability to downregulate cytokines production and represents a promising new therapy to treat depression.



Vagus Nerve Stimulation Attenuates the Systemic Inflammatory Response to Endotoxin

DOI: 10.1038/35013070



In this study, the authors described a parasympathetic anti-inflammatory mechanism where the brain attenuated inflammatory response via acetylcholine, the primary neurotransmitter of the vagus nerve. The study revealed that acetylcholine significantly reduced the release of several proinflammatory cytokines (interleukin (IL)-1β, IL-6, IL-18, and tumour necrosis factor), which have been implicated in various diseases including depression.



Cerebrospinal Cytokine Levels in Patients with Acute Depression

DOI: 10.1159/000026615



The study investigated the association between the increased proinflammatory cytokines (interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α) in the cerebrospinal fluids (CSF) and depression. The finding showed that patients with severe depression but who were unmedicated had a higher concentration of IL-1β in their CSF, which correlated positively with the severity of depression. This study provides a unique profile of CSF proinflammatory cytokines in depression that could be beneficial for the future treatment of the condition.



Noninvasive VNS Decreases Whole Blood Culture‐Derived Cytokines and Chemokines

DOI: 10.1111/ner.12398



The study examined the effect of transcutaneous non-invasive vagus nerve stimulation (nVNS) in modulating the peripheral immune system in this randomised, placebo-controlled, blinded trial. A significant reduction in the release of proinflammatory cytokines was detected in the nVNS group, including interleukin (IL)-1β, tumour necrosis factor, and chemokines such as the IL-8, macrophage inflammatory protein-1α and monocyte chemoattractant protein-1. The down-regulation of these inflammatory cytokines could be beneficial in depression treatment where nVNS could serve as a viable alternative to conventional therapy.



Depression as a Secondary Outcome

Efficacy and Safety of Treatment with Transcutaneous Vagus Nerve Stimulation in 17 Patients with Refractory Epilepsy Evaluated by Electroencephalogram, Seizure Frequency, and Quality of Life

DOI: 10.12659/MSM.910689



In this study, the safety and efficacy of tVNS treatment over a six-month period were examined in seventeen patients. The study team found that the ratings for both the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were reduced for most of the patients, while overall quality of life also improved. No adverse events or side effects were reported during the treatment period.




The Allure of Transcutaneous Vagus Nerve Stimulation as a Novel Therapeutic Modality

DOI: 10.1016/j.biopsych.2015.11.016



This commentary provides an overview of existing evidence on the use of tVNS to treat depression. The authors noted that the afferent fibres of the vagus nerve, which had direct and indirect ascending projections to many key brain regions, could effectively regulate mood and emotion. Beneficial clinical outcomes with tVNS treatment were observed in two trials, where significant reductions in the Beck Depression Inventory and the Hamilton Depression Rating Scale were recorded. Notable alteration of the functional connectivity between the default mode network and depression-related brain regions was observed as well, providing a plausible explanation of the underlying antidepressant mechanisms of tVNS.





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