Functional dyspepsia : taVNS can significant improvements in stomach’s ability to accommodate and process a meal

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People who suffer frequent indigestion may find relief with a small device that hooks onto the ear known as a transcutaneous auricular vagus nerve stimulator, or taVNS.

People who used taVNS showed significant improvements in their stomach’s ability to accommodate and process a meal, according to a new study.

The research was scheduled to be presented at the American Physiological Society annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team’s abstract was published in this month’s issue of The FASEB Journal.

Up to 15% of U.S. adults suffer from indigestion, also known as functional dyspepsia. The disorder can cause a premature sensation of fullness and stomach pain after a meal.

Though its causes are not well understood, it is thought that the stomach may not stretch and contract appropriately when food is ingested, causing pressure and discomfort.

taVNS devices deliver short pulses of painless electrical current to the vagus nerve, a peripheral nerve (one outside the brain and spinal cord) that runs from the head to the abdomen.

While taVNS has been explored as a possible treatment for epilepsy, depression and a variety of other conditions, the new research study is one of the first to assess the potential benefits of auricular taVNS for gastrointestinal problems.

The study involved a particular type of taVNS device, Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS), that delivers electrical pulses in tune with the respiratory rhythm.

“Our findings suggest that RAVANS has the ability to modulate the stomach’s response to food ingestion, which may be impaired in functional dyspepsia patients,” said lead study author Roberta Sclocco, Ph.D., a postdoctoral fellow at Massachusetts General Hospital and Harvard Medical School, who is also affiliated with Logan University in Missouri.

“RAVANS is a non-invasive, safe peripheral nerve stimulation intervention and while our results are encouraging, further research is needed to estimate the optimal dose and timings of this intervention.”

Sclocco and colleagues tested RAVANS in 12 volunteers with functional dyspepsia.

All volunteers participated in two research sessions in which they wore the RAVANS device or control, ate a meal and underwent magnetic resonance imaging (MRI) scans 15, 65 and 80 minutes after eating.

MRI scans revealed the ratio of stomach volume to the volume of ingested food was higher during RAVANS, indicating that taVNS helped participants’ stomachs expand to accommodate the meal. In addition, the stomach emptied more quickly during the 80 minutes following the meal during RAVANS.

The findings suggest that modulating the activity of the vagus nerve with taVNS could help reduce symptoms of indigestion, though Sclocco cautioned that patients should ask a doctor before trying it.

Stimulating the vagus nerve can potentially affect many organs, including the heart. In addition, different taVNS technologies work in different ways, and more research is needed to identify the best approach for functional dyspepsia.

“While taVNS is relatively safe and without major side effects, systems currently available on the market are all different and not optimized for gastric applications,” said Sclocco.

“Patients with certain medical conditions may not be good candidates for this therapy and discussing the taVNS option with a medical doctor in the context of a patient’s overall clinical picture is always advisable.”

Sclocco noted that some people find relief from indigestion with non-technological and non-medical approaches, such as taking slow, deep breaths after eating. The researchers plan to test RAVANS in more volunteers to determine which patients are likely to benefit the most. The team is also working with industry partners to further develop this non-invasive stimulation approach.


The autonomic nervous system (ANS) via its sympathetic and parasympathetic divisions influences the function of numerous organs, glands and involuntary muscles throughout the body.

A major component of the parasympathetic nervous system is the vagus nerve, the 10th and longest of the cranial nerves, which serves an important bidirectional conduit between the body and brain, largely serving to maintain homeostasis.

Derived from the Latin word meaning ‘wandering’, the vagus nerve courses from the brainstem to the proximal two‐thirds of the colon, innervating multiple thoracic and abdominal viscera en route. It is a mixed nerve composed of 20% efferent fibres and 80% afferent fibres (Bonaz et al. 2018).

Imbalances in the activity of the constituent parts of the ANS have been linked with several clinical disorders (Farmer et al. 2016): heart failure (De Ferrari et al. 2011), inflammatory bowel disease (Ghia et al. 2006) and chronic pain syndromes (Farmer et al. 2014).

In general, the reported imbalance involves relatively higher sympathetic activity associated with a paucity of parasympathetic activity (Farmer et al. 2016). In conjunction with deep slow‐paced breathing, tVNS has been proposed as novel non‐pharmacological analgesic intervention for pain management (Botha et al. 2014; Farmer & Aziz, 2015).

In healthy subjects, we have previously demonstrated that central sensitisation can be prevented by physiological stimulation of the vagus nerve, using deep slow‐paced breathing, in a validated model of oesophageal pain hypersensitivity (Botha et al. 2015).

Therefore, efforts to therapeutically rebalance this equilibrium with techniques such as vagus nerve stimulation (VNS), which putatively increases the activity of the vagus nerve, are of interest across a range of clinical disciplines.

Both invasive (surgically implanted) and non‐invasive (transcutaneous) techniques of VNS exist. Invasive VNS (iVNS) involves the surgical implantation of a programmable pulse generator device in the chest wall and the placement of electrodes around the left (typically) cervical vagus nerve.

As it currently stands, iVNS has several potential risks. There are reports of bradycardia and asystole occurring during intraoperative lead testing, as a result of unintentional direct stimulation of the cardiac branches of the vagus nerve, occurring in approximately 1 in 1000 implantations (Asconape et al. 1999).

In the direct postoperative period, implantation can result in a peri‐incisional haematoma, dyspnoea and localised infection around the wound site (Fahy, 2010). Up to two‐thirds of patients suffer from transient dysphonia and some patients can experience paraesthesia and pain (Watkins et al. 1995; Malow et al. 2000; Santos, 2003).

Further information on iVNS, which is outside the scope of this article, is available elsewhere (Farmer et al. 2016).

Novel non‐invasive (or transcutaneous) VNS delivery systems rely on the cutaneous distribution of vagal fibres, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation and facilitating further investigations across a wide range of uses (Ben‐Menachem et al. 2015).

Functional magnetic resonance imaging (fMRI) of the brain has demonstrated that tVNS can stimulate brain areas consistent with the contemporaneously accepted understanding of central vagal projections (Frangos et al. 2015).

Several devices can deliver tVNS. For example, the NEMOS® (CerboMed, Erlangen, Germany) stimulates the concha of the outer ear and is CE‐marked (European Conformity) for the European market for the management of epilepsy.

The electrode is connected to a stimulating box, and the stimulation intensity can be adjusted by the patient, caregiver or treating physician (increased at steps of 0.1 mA until the perception threshold of the electrical stimulation is reached; the stimulation frequency is predefined at 25 Hz, the pulse width of 250 µs).

The hand‐held stimulator gammaCore (Electrocore LLC, Basking Ridge, NJ, USA) is used in transcutaneous stimulation of the cervical branch of the vagus nerve and is approved by the Food and Drug Administration for the management of episodic cluster headache (Mwamburi et al. 2017).

The device produces a pulsatile waveform (1‐ms pulses comprising 5‐Hz sine waves repeated at 25 Hz). The recommended duration of stimulation is 2 min and can be administered several times (up to 12 times) a day (Holle‐Lee & Gaul, 2016). Recognised side‐effects of tVNS can include local skin irritation from electrode placement, headache and nasopharyngitis (Redgrave et al. 2018). A common side‐effect of cervical tVNS is painless, mild facial twitching (Holle‐Lee & Gaul, 2016).

Although Eastern medicine has utilised the analgesic effects of auricular acupuncture for thousands of years (Asher et al. 2010; He et al. 2012; Usichenko et al. 2017), the concept of electrically stimulating the auricle is a more recent one (Ventureyra, 2000).

The feasibility of auricular tVNS was first demonstrated using recordings of vagus somato‐sensory evoked potentials from the scalp (Fallgatter et al. 2003) and since then has been proposed as an effective therapeutic strategy in the management of several clinical disorders including epilepsy (Rong et al. 2014), depression (Kong et al. 2018), migraine (Straube et al. 2015) and tinnitus (Hyvarinen et al. 2015).

The basis of auricular tVNS is the cutaneous representation of the auricular branch of the vagus nerve (ABVN), also termed Arnold’s nerve, which provides somatosensory innervation to the external ear.

The latter name of the nerve is an eponym for the German anatomist Friedrich Arnold (1803–1890), who was the first to document that irritation of the posterior wall of the external acoustic meatus could induce a cough reflex in humans (Lekakis, 2003).

The ABVN is sometimes referred to as Alderman’s nerve; a reference to the centuries‐old Aldermen of the City of London and their practice of using rosewater bowls at ceremonial banquets, where attendees were encouraged to place a napkin moistened with rosewater behind their ears in the belief that this would aid digestion (Murray et al. 2016).

Studies have shown that the ear–cough reflex occurs in between 1.7–4.2% of individuals (Bloustine et al. 1976; Gupta et al. 1986; Tekdemir et al. 1998). The ABVN is additionally credited as the afferent pathway to other somewhat unusual somatovisceral reflexes, including (1) the gastro‐auricular phenomenon, (2) the pulmono‐auricular phenomenon, (3) the auriculo‐genital reflex and (4) the auriculo‐uterine reflex (Engel, 1979; Gupta et al. 1986).

The ABVN continues to be an area of pathophysiological interest across a number of clinical disciplines. As research into the use of auricular tVNS is rapidly growing, a review exploring the anatomical basis of this neuromodulatory technique is timely.

To date, there has been no review of the literature investigating the anatomical basis of the ABVN, with reference to its cutaneous, intracranial and central distribution. Our overall aim was to address the aforementioned gap in the literature.

Anatomy of the external ear

The construction of devices for auricular tVNS relies on a precise knowledge of the anatomy and cutaneous innervation of the external ear. Fig. 1 outlines a schematic diagram of the external ear and the current consensus on the cutaneous map of the nerve fibres innervating the lateral auricle, although this dermatome map should be interpreted with caution. Indeed, a precise cutaneous map of the external ear is not practical for several reasons:

(1) the cutaneous distribution of a particular nerve root can vary considerably,

(2) some nerve fibres cross‐communicate with other nerve fibres along their intracranial course and

(3) the boundaries between particular dermatomes are not necessarily distinct and often overlap.

The challenges of producing a precise cutaneous map of the auricle and the inter‐study variability in the distribution of ABVN fibres are explored herein.

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Figure 1 : Diagram of the external ear and its hypothesised cutaneous innervation.

Most of the commercially available devices used for auricular tVNS target the concha of the external ear (Bermejo et al. 2017; Redgrave et al. 2018), whose innervation is complicated by multiple neural communications of partly somatogenic and branchiogenic origin: the ABVN, the auriculotemporal nerve – a sensory branch of the posterior division of the mandibular division of the trigeminal nerve (Schmalfuss et al. 2002), the facial nerve, the greater auricular nerve and the lesser occipital nerve. The latter two nerves are superficial branches of the cervical plexus, contributed by fibres from the C2 and C3 spinal nerves (Ginsberg & Eicher, 2000).

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Figure 2 : A schematic diagram of the approximate relationships between the facial, glossopharyngeal and vagus nerves. The ABVN originates from the petrous ganglion of the glossopharyngeal nerve and jugular ganglion of the vagus nerve and ascends through the mastoid canaliculus. In the mastoid, it crosses the fallopian canal 3–4 mm above the stylomastoid foramen and divides into two branches. The first branch of the ABVN has a connection with the chorda tympani and supplies the sensory part of the posterior cranial fossa dura mater, while the second branch supplies the posterior skin of the external auditory meatus and adjacent tympanic membrane. The second branch has an inferior division connecting to the posterior auricular branch of the facial nerve after exiting the stylomastoid foramen. ABVN, auricular branch of the vagus nerve; CT, chorda tympani nerve; FN, facial nerve; TBGN, tympanic branch of the glossopharyngeal nerve.

Acupuncture studies

Eastern medicine has utilised the analgesic effects of auricular acupuncture for thousands of years (Asher et al. 2010; He et al. 2012; Usichenko et al. 2017) and numerous human studies have shown that vagal tone can be elicited by auricular acupuncture (He et al. 2012). Usichenko et al. (2017) extracted data concerning the auricular acupuncture points, used for the treatment of patients with acute and chronic pain in randomised controlled trials, from a previously published meta‐analysis (Asher et al. 2010).

The three most frequently used auricular acupuncture points were: ‘Shenmen’ (TF4) (12/17 studies), located at the apex of the triangular fossa of the auricle, ‘Lung’ (CO14) (7/17 studies), located at the cavum concha, and thalamus (5/17 studies), located close to the antitragus (see Fig. 4).

All 17 RCTs investigating the therapeutic effect of auricular acupuncture targeted the ABVN either exclusively or in a region of shared innervation by the ABVN and greater auricular nerve, as previously reported by Peuker & Filler (2002), and that group therefore concluded that the analgesic effects of auricular acupuncture were mediated by stimulation of the ABVN.

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figure 4 :Auricular acupoints. Permissions: No permissions required.

Moreover, studies have examined the association between auricular acupoint ‘Heart’ (CO15), located in the cavum concha, and cardiovascular regulation (He et al. 2012). In 14 healthy volunteers, a significant decrease in heart rate and increase in heart rate variability has been observed after manual ear acupressure at auricular acupoint CO15, which is located in the cavum concha (Gao et al. 2012).

Moreover, a study by Huang & Liang (1992) of auricular acupuncture at auricular acupoint CO15 in a group of 30 vascular hypertensive patients revealed a marked immediate short‐term and long‐term depressor effect and marked effects on angiotensin II in grade III hypertension.

Interestingly, the same study reported that acupuncture at auricular acupoint ‘Stomach’ (located at the crus helix) produced no depressor effect on vascular hypertension, which fits with the cutaneous map of the ABVN described by Peuker & Filler (2002), in which the crus helix was innervated in 20% of cases by the ABVN (according to the table) and 0% (according to the manuscript).

An acupuncture study (n = 12) reported that a single needle insertion in the left inferior hemi‐concha of the ear resulted in a statistically significant increase in the high frequency component (an indirect measure of parasympathetic outflow) of heart rate variability both during and post‐stimulation compared with pre‐stimulation (Haker et al. 2000) without affecting the heart rate. A more complete analysis of heart rate variability is described later in this review article.


Source:
Experimental Biology

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