4) transcutaneous Vagus Nerve Stimulation (tVNS)

is  a very new and exciting treatment for medical and psychiatric conditions.

Before transcutaneous Vagus Nerve Stimulation (tVNS)
there was a Surgical Vagus Nerve Stimulation (VNS).
In 1997 the FDA cleared the surgical implantation of a vagus nerve stimulator (pacemaker) for the treatment of Seizures (epilepsy). Then it was cleared for depression in 2005 and for weight loss in 2015 

The non-surgical (transcutaneous) version takes advantage of the fact that a small area of skin on the outer ear is innervated by the vagus nerve. Gentle stimulation of that skin has been shown to produce similar fMRI brain activity changes  (Kraus 2007, Dietrich 2008) as the surgical version.

2017 saw two tVNS devices cleared for use in the US.  One for headaches (GammaCore)  and one for opiate withdrawal (Bridge NSS-2). The GammaCore device delivers a stimulation to the neck so it is a cervical transcutaneous Vagus Nerve Stimulation (ctVNS). The Bridge is a “percutaneous nerve field stimulator (PNFS)” device which is different in 2 ways: i) it has tiny sharp electrodes which embed into the skin. It is therefore not transcutaneous, but by definition it is percutaneous. The prefix per- means through, trans- means across. There may or may not be a difference. ii) the Bridge also stimulates the Trigeminal Nerve (CrN-V) at or near the preauricular point, and the great auricular nerve (C2&3). This is quite different than a localized stimulation at skin innervated by only the Vagus Nerve.

In Europe three tVNS devices have been cleared for use -  for Epilepsy (seizures) in 2010 and Pain in 2012 (CerboMed-Nemos), another device for headaches (GammaCore) and a third device for ringing in the ears - tinnitus  (SaluStim).

GammaCore is also approved for the acute and prophylactic treatment of primary headaches (cluster headache, migraine, hemicrania continua), and reactive airway disease (asthma, exercise- induced bronchospasm, COPD), as well as adjunctive therapy for epilepsy prevention and reducing the symptoms of certain anxiety/depression conditions (eg, panic disorder, posttraumatic stress disorder, major depressive disorder, obsessive- compulsive disorder), gastric mobility disorders, and irritable bowel syndrome

OTHER  USES  of Transcutaneous Vagus Nerve Stimulation (tVNS):

It is used off label and being investigated (and appears to be effective and safe) for many conditions including:

CARDIAC: Atrial Fibrillation, Heart Failure & MI (heart attack)

HEADACHE: Cluster & Migraine

DEPRESSION

PAIN

TINNITUS (Ringing in the Ears)

STROKE

In our experience, it is effective for Anxiety

(Generalized Anxiety, Panic Disorder and Social Anxiety) and Insomnia.

 

 REFERENCES

Heart

1. Atrial Fibrillation

Chen 2015 Low level tragus nerve stimulation is a non- invasive approach for anti-atrial fibrillation via preventing the loss of connexins

Kapa 2015 Looking Beyond the Ablation Shore, Treating Atrial Fibrillation From Afar

Kreuzer 2012 Transcutaneous Vagus Nerve Stimulation- Retrospective Assessment of Cardiac Safety in a Pilot Study

Li, Shu 2015 2015 Low level non-invasive vagus nerve stimulation- a novel feasible therapeutic approach for atrial fibrillation.

Stavrakis 2015 Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation.

Yu 2013 Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve- a noninvasive approach to treat the initial phase of atrial fibrillation.

 2. Heart Failure

Fan 2010 Transvenous Vagus Nerve Stimulation/ A Potential Heart Failure Therapy Is Feasible In Humans

Wang 2014 Transcutaneous electrical stimulation of auricular branch of vagus nerve- A noninvasive therapeutic approach for post-ischemic heart failure

Wang 2015 Noninvasive vagal nerve stimulation for heart failure- Was it practical or just a stunt?

 3. Heart Attack (myocardial infarction)

Wang 2014 Chronic Intermittent Low-Level Transcutaneous Electrical Stimulation of Auricular Branch of Vagus Nerve Improves Left Ventricular Remodeling in Conscious Dogs With Healed Myocardial Infarction

Wang 2014 Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor β1.

Wang 2015 Unilateral low-level transcutaneous electrical vagus nerve stimulation- A novel noninvasive treatment for myocardial infarction.

STROKE

Ay 2015 The effect of transcutaneous vagus nerve stimulation on inflammatory markers in acute stroke

Ay 2016 Transcutaneous Cervical Vagus Nerve Stimulation Ameliorates Acute Ischemic Injury in Rats

Cai 2014 Vagus Nerve Stimulation in Ischemic Stroke- Old Wine in a New Bottle

Capone 2017 Transcutaneous Vagus Nerve Stimulation Combined with Robotic Rehabilitation Improves Upper Limb Function after Stroke

Redgrave 2018 Transcutaneous Auricular Vagus Nerve Stimulation with Concurrent Upper Limb Repetitive Task Practice for Poststroke Motor Recovery- A Pilot Study

Ay 2015 Electrical Stimulation of the Vagus Nerve Dermatome in the External Ear is Protective in Rat Cerebral Ischemia

DEPRESSION

Fang 2015 Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder

Fang 2016 Early cortical biomarkers of longitudinal transcutaneous vagus nerve stimulation treatment success in depression 

Fang 2017 Early cortical biomarkers of longitudinal transcutaneous vagus nerve stimulation treatment success in depression 

Hein 2013 Auricular transcutaneous electrical nerve stimulation in depressed patients- a randomized controlled pilot study.

Kong 2018 Treating Depression with transcutaneous Auricular vagus Nerve stimulation- state of the Art and Future Perspectives 

Li 2018 The effect of transcutaneous auricular vagus nerve stimulation on treatment-resistant depression monitored by resting-state fMRI and MRS- The first case report 

Li, Sha 2014 Therapeutic Effect of Vagus Nerve Stimulation on Depressive-Like Behavior, Hyperglycemia and Insulin Receptor Expression in Zucker Fatty Rats

Li, Sha 2014 Transcutaneous Auricular Vagus Nerve Stimulation Triggers Melatonin Secretion and Is Antidepressive in Zucker Diabetic Fatty Rats

Liu 2016 Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression

Polak 2013 Vagus somatosensory evoked potentials are delayed in Alzheimer’s disease, but not in major depression

Rong 2012 Transcutaneous vagus nerve stimulation for the treatment of depression- a study protocol for a double blinded randomized clinical trial.

Rong 2016 Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder- a nonrandomized controlled pilot study

Trevizol 2015 Transcutaneous vagus nerve stimulation (tVNS) protocol for the treatment of major depressive disorder/ A case study assessing the auricular branch of the vagus nerve

Trevizol 2016 Transcutaneous Vagus Nerve Stimulation (taVNS) for Major Depressive Disorder- an Open Label Proof-of-Concept Trial 

Tu 2018 A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder 

Wang 2017 Frequency-dependent functional connectivity of the nucleus accumbens during continuous transcutaneous vagus nerve stimulation in major depressive disorder 

Yu 2016 Transcutaneous Auricular Vagus Nerve Stimulation/ A Novel Non-Invasive Non-Pharmacologic Treatment for Major Depressive Disorder

please note, in our clinic we have not seen antidepressant effects of tVNS, we do not know why

EPILEPSY (Seizure disorders)

Aihua 2014 A controlled trial of transcutaneous vagus nerve stimulation for the treatment of pharmacoresistant epilepsy.

Barbella 2018 Transcutaneous vagal nerve stimulation (t-VNS)- An adjunctive treatment option for refractory epilepsy

Bauer 2016 Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy- A Randomized, Double-Blind Clinical Trial (cMPsE02)

DeGiorgio 2013 Neurostimulation for Drug-Resistant Epilepsy

Fischenich 2010 Transcutaneous vagus nerve stimulation- A treatment option in drug resistant epilepsy? (Slides)

He 2009 A new concept of transcutaneous vagus nerve stimulation for epileptic seizure

He 2013 Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy- a pilot trial

He 2013 The auriculo-vagal afferent pathway and its role in seizure suppression in rats

He 2015 Transcutaneous auricular vagus nerve stimulation for pediatric epilepsy- study protocol for a randomized controlled trial

Liu 2018 Efficacy and Safety of Treatment with Transcutaneous Vagus Nerve Stimulation in 17 Patients with Refractory Epilepsy Evaluated by Electroencephalogram

Rong 2015 Transcutaneous vagus nerve stimulation for refractory epilepsy- a randomized controlled trial.

Song 2018 A retrospective study of transcutaneous vagus nerve stimulation for poststroke epilepsy

Stefan 2011 First experiences with transcutaneous vagus nerve stimulation (t"VNS) in epilepsy treatment

Stefan 2012 Transcutaneous vagus nerve stimulation (t- VNS) in pharmacoresistant epilepsies/ A proof of concept trial Epilepsia

Yuen 2017 Can natural ways to stimulate the vagus nerve improve seizure control?

HEADACHE

  1. Cluster

Barbanti 2015 Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine- an open-label study. 

Garcia 2015 Trigeminal sensory nucleus connectivity is modulated by respiratory-gated auricular vagus nerve stimulation in migraine patients

Gaul 2011 Cluster Headache Clinical Features and Therapeutic Options

Gaul 2014 EHMTI-0362. Non-invasive vagus nerve stimulation with gammacore for prevention and acute treatment of chronic cluster headache- report from the extension phase of the preva study

Gaul 2015 Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA)- A randomised controlled study

Gaul 2017 Effects of non-invasive vagus nerve stimulation on attack frequency over time and expanded response rates in patients with chronic cluster headache: a post hoc analysis of the randomised, controlled PREVA study.

Holle-Lee 2014 Noninvasive vagus nerve stimulation in the management of cluster headache/ clinical evidence and practical experience

Kinfe 2013 Partial Response of Intractable Cluster-Tic Syndrome Treated by Cervical non-invasive Vagal Nerve Stimulation 

Lavano 2015 Neurostimulation for the Treatment of Cluster Headache

Nesbitt 2015 Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment

2. Migraine

Goadsby 2014 Effect of noninvasive vagus nerve stimulation on acute migraine- An open-label pilot study 

Grimsrud 2018 Emerging Treatments in Episodic Migraine 

Kinfe 2015 Cervical non-invasive vagus nerve stimulation (nVNS) for preventive and acute treatment of episodic and chronic migraine and migraine-associated sleep disturbance- a prospective observational cohort study. 

Schoenen 2016 Noninvasive neurostimulation methods for migraine therapy/ The available evidence

Silberstein 2016 Chronic migraine headache prevention with noninvasive vagus nerve stimulation The EVENT study

Straube 2015 Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS)- a randomized, monocentric clinical trial

3. Other or not specified headaches

Jurgens 2013 Pearls and pitfalls- neurostimulation in headache

h Lambru 2014 Peripheral neurostimulation in primary headaches

Magis 2012 Transcutaneous Vagus Nerve Stimulation (tVNS) for headache prophylaxis/ initial experience

h Martelletti 2013 Neuromodulation of chronic headaches- position statement from the European Headache Federation

Zhu 2016 Non-Invasive Neuromodulation for Headache Disorders

Yuan 2015 Vagus Nerve Stimulation and Headache 

Zhu 2016 Non-Invasive Neuromodulation for Headache Disorders

TINNITUS (Ringing in the ears)

Hyvarinen 2014 Transcutaneous Vagus Nerve Stimulation Modulates Tinnitus-Related Beta- and Gamma-Band Activity (EEG)

Kreuzer 2014 Feasibility, Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation in Chronic Tinnitus- An Open Pilot Study

Kreuzer 2014 Feasibility, Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation in Chronic Tinnitus- An Open Pilot Study

Lehtimaki 2013 Transcutaneous vagus nerve stimulation in tinnitus- a pilot study.

Peter 2018 Neuromodulation for tinnitus treatment/ an overview of invasive and non-invasive techniques

Shim Feasibility and Safety of Transcutaneous Vagus Nerve Stimulation Paired with Notched Music Therapy for the Treatment of Chronic Tinnitus

30Hz SUK 2018 Characteristics of Stimulus Intensity in Transcutaneous Vagus Nerve Stimulation for Chronic Tinnitus

Yakunina 2018 BOLD fMRI effects of transcutaneous vagus nerve stimulation in patients with chronic tinnitus

How transcutaneous Vagus Nerve Stimulation Works (Mechanism of Action)

1) stimulating the skin of the ear, 

2) stimulates the Auricular Branch of the Vagus Nerve

3) the stimulation goes to a nucleus (cluster of nerve cells) called the Nucleus Tractus Solitarius (NTS)

4) the NTS receives information from the body (heart, lungs, intestines, immune system) and

5) sends output to several structures including the Locus coeruleus and indirectly to the Dorsal raphe nucleus.

6) Locus Ceruleus is the brain's primary source of norepinephrine (aka noradrenaline) 

7) Dorsal Raphe nucleus is the brain's primary source of serotonin

8) so those two structures influence alertness/energy (norepinephrine) and confidence (serotonin)

9) those two then send those chemicals (neurotransmitters) to the whole brain, especially parts for thinking and feeling.  Serotonin (Calm Confidence) & Norepinephrine (Relaxed Energy) - are sent more to the thinking, deliberate, newer Prefrontal Cortex, and less to the Amygdala (Hippocampus and Anterior Thalamus). This reduces anxiety and panic (fight or flight response).

 

• How Does tVNS Work?

 

Fig. 6: The vagus nerve sends afferents to the nucleus tractus solitarius (NTS), which in turn projects to the locus coeruleus .... Vagus nerve stimulation (VNS) facilitates the excitatory pathway of neurons in the locus coeruleus more than the inhibitory one. The locus coeruleus then modifies the firing rate of serotonin (5-HT) neurons in the dorsal raphe nucleus. Therefore, VNS is believed to change the locus coeruleus activity, and then indirectly the serotoninergic neurons in the dorsal raphe nucleus. It leads to a change of norepinephrine (NE) and serotonin (5-HT) transmission. (after Manta 2009 Enhancement of the Function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation)

••How Does tVNS Work?

2) BETTER RELATIONSHIP WITH SELF & LESS RUMINATION- Transcutaneous vagus nerve stimulation increases the functional connectivity (the way parts of the brain connect and communicate) of the default mode network (DMN) structures. The DMN is a set of brain areas that are more active when you are not focused on outside things or activities, awake and at rest, like when the mind wanders. The DMN is related to our relationship with ourself, our thoughts about our feelings, and emotion control (Connolly 2013, Berman 2011 & Nejad 2013). People who are depressed tend to have more self-focus and sensitivity to stress (Rodriguez 2012). Part of the DMN (medial) is activated during focus on self and part (Lateral) is activated when the focus is on others. tVNS shifts the focus (Fang 2015) "The Functional Connectivity between the DMN and anterior insula and parahippocampus decreased; the FC between the DMN and precuneus and orbital prefrontal cortex increased" (see below).  

Figure 3. Yellow indicates brain regions that showed significant functional connectivity increase with default mode network in the transcutaneous vagus nerve stimulation group as compared with sham transcutaneous vagus nerve stimulation. Blue indicates brain regions whose default mode network functional connectivity changes (posttreatment minus pretreatment) were negatively correlated with the corresponding Hamilton Depression Rating Scale score changes across all subjects. L, left; OPFC, orbital prefrontal cortex; Precu, precuneus; rACC, rostral anterior cingulate cortex. (Fang 2016 transcutaneous vagus nerve stimulation Modulates Default Mode Network in Major Depressive Disorder. )

 

3) LESS STRESS MORE RELAXATION - Transcutaneous vagus nerve stimulation may improve heart rate variability (Clancy 2014, Leeds, UK), reduce sympathetic tone (adrenalin, fight or flight), and increase parasympathetic tone (rest, digest, attend and befriend). Vagus (parasympathetic) activity is related to better health and outcomes in many conditions including heart disease, high blood pressure, sleep apnea and obesity.