Grolaux PJD. Transcutaneous Vagus Nerve Stimulation in Private Healthcare Center: A Small-Scale Neuromedicine Investigation Targeting Anxiety, Irritable Bowel Syndrome and Chronic Pain. J Neurol Neuromed www.jneurology.com (2019) 4(5): 7-22 Journal of Neurology && NeuromedicineNeuromedicine www.jneurology.com Research Article Open Access Transcutaneous Vagus Nerve Stimulation in Private Healthcare Center: A Small-Scale Investigation Targeting Anxiety, Irritable Bowel Syndrome and Chronic Pain Pascal J.D. Grolaux Department of Osteopathy, Kinesis Health Associates, 2d floor, 155 Ochterloney Street, Dartmouth, B2Y1C9, Nova Scotia, Canada. Article Info Abstract Article Notes Background: Generalized anxiety disorder (GAD), chronic pain (CP) and Received: May 28, 2019 irritable bowel syndrome (IBS) are debilitating inflammatory disorders that are Accepted: October 17, 2019 frequently seen in primary care facilities but not sufficiently addressed by classical *Correspondence: medical treatments. Transcutaneous vagus nerve stimulation (tVNS) is a promising Dr. Pascal J.D. Grolaux, Department of Osteopathy, Kinesis therapeutic tool for a wide range of conditions that showed already encouraging Health Associates, 2d floor, 155 Ochterloney Street, clinical results. However, the effects of tVNS, on these disorders, GAD, IBS and CP, Dartmouth, B2Y1C9, Nova Scotia, Canada; Telephone were not yet explored in the context of an investigation conducted in a private No.: +1(902)464-2225; Fax No: +1(902) 464-2244; Email: healthcare center. [email protected]. Objective: In an uncontrolled, open label, small investigation scale study, we © 2019 Grolaux PJD. This article is distributed under the terms investigated the feasibility, safety and the effects of tVNS for patients suffering from of the Creative Commons Attribution 4.0 International License GAD, CP and IBS in a multidisciplinary healthcare center. Methods: The effects of tVNS on GAD, CP and IBS in 10 participants (anxiety, 40%; chronic pain, 30%; IBS, 30%) were investigated during a 4-week period and a Keywords: 2-month follow-up. GAD, CP and IBS were assessed using the Generalized Anxiety Transcutaneous Vagus Nerve Stimulation (Tvns) Disorder GAD-7, the Brief Pain Inventory Short Form questionnaire and the Irritable Anxiety Bowel Syndrome Severity Scoring System. Transcutaneous vagus nerve stimulation Irritable Bowel Syndrome (IBS) was performed using a transcutaneous electrical nerve stimulation device and ear Chronic Pain clip electrodes plugged in the concha area of the ear. All participants, received a Private Healthcare Center bi-weekly 30-minute stimulation for 4 weeks. The tVNS parameters, (GAD: 20Hz- 80µs), (CP: 5Hz-200 µs), (IBS: 3Hz-250µs), were set for each group to target different physiological effects meditated by the vagus nerve. Results: The anxiety and the IBS group showed a non-statistically significant improvement but an improved clinical status (mean score from “severe” to “moderate”) both at the end of the stimulation period (4 weeks) and at 2-month follow-up. The CP group didn’t show any significant clinical improvement (mean score from “moderate” to “moderate”). Furthermore, tVNS was demonstrated to be likely safe and was well tolerated. Conclusions: Due to low sample size, this study failed to demonstrate significant clinical effects of tVNS on GAD, IBS and CP. However, trend analysis may carefully suggest tVNS to be a noteworthy clinical alternative to be used in private healthcare center in the treatment of chronic inflammation disorders like GAD and IBS. Acute tVNS was well-tolerated and is likely safe. Powerful, double-blind controlled studies are needed to support the use of tVNS for these disorders. Clinical Trial Registration: http:/www.clinicaltrials.gov. Unique identifier: NCT03440255. Abbreviations α7nAChR, alpha7 nicotinic acetylcholine receptor; ABVN, auricular branch of the vagus nerve; CAN, central autonomic network; CAP, cholinergic anti-inflammatory pathway; CP, chronic pain; DMVN, dorsal motor nucleus of the vagus; GABA, γ-aminobutyric acid; GAD, general Page 7 of 22 Grolaux PJD. Transcutaneous Vagus Nerve Stimulation in Private Healthcare Center: A Small-Scale Investigation Targeting Anxiety, Irritable Bowel Syndrome and Chronic Pain. J Neurol Neuromed Journal of Neurology & Neuromedicine (2019) 4(5): 7-22 anxiety disorder; HR, heart rate; HPA, hypothalamic pain management, cardiovascular diseases, diabetes, pituitary adrenal; HRV, heart rate variability; IBS, irritable inflammatory10,11 bowel disease and other autoimmune bowel syndrome; IL, Interleukin; fMRI, functional diseases . magnetic resonance imagery; NF-κB, nuclear factor kappa Transcutaneous vagus nerve stimulation (tVNS) is B; NTS, nucleus tractus solitarius; pNN50, percentage of an emerging, promising alternative therapeutic tool that successive R-R intervals that differ by more than 50ms allows for the stimulation of the VN without the need of from the preceding one; PW, pulse width; RMSSD, root surgery. Transcutaneous auricular vagus nerve stimulation mean square of successive R-R interval differences; RR, sends electrical impulses along the auricular branch of respiratory rate; RSA, respiratory sinus arrhythmia; SD1, the VN (ABVN) that will trigger the same physiological standard deviation of the distance of each point from the y effects as the invasive12-14 stimulation but without the side = x axis in a Poincaré plot; TENS, transcutaneous electrical effects of surgery . Indeed, in humans, high density nerve stimulation; TNF, tumor necrosis factor; VN, vagus of afferent fibers of the ABVN are found in the meatus nerve; nVNS, non-invasive vagus nerve stimulation; tVNS, acusticus externus cartilaginous and innervate 100% of transcutaneousIntroduction vagus nerve stimulation. the 15,16cymba conchae and 45% of the cavum of the outer ear . The somatic sensory vagal afferents or Arnold’s The vagus nerve (VN), the tenth cranial nerve, is the nerve represent a small fraction of the vagus, they transmit major component of the parasympathetic nervous system sensation from the concha to its termination2 center located and plays a key role in the regulation of neuroendocrine- in the nucleus tractus solitarius (NTS) . The purpose of the immune physiological and allostatic processes to maintain tVNS to reach clinical efficacy is to selectively excite, by homeostasis through a complex integrated central and low-intensity current (0,1 to 1.8 mA), the thick myelinated peripheral autonomic network, i.e., the activation of the sensory Aβ-fiber in the ABVN, but 17-19not the Aδ thin hypothalamic pituitary adrenal (HPA) axis by its afferents myelinated and C-fibers conveying pain . Indeed, it was (sensory), and the ‘cholinergic anti-inflammatory pathway’ demonstratedet al. that the vagal afferent C-fibers destructed20 (CAP) through its efferents (motor). This mixed nerve, by capsaicin do not alter the antiepileptic effect of VNS . described as the single most important nerve in the body, Safi estimated that the ratio of Aβ-fiber in the ABVN contains 80% afferent and 20% efferent fibers (80.000 to compared to the cervical VN stimulated in invasive therapy 100.000 fibers, non-myelinated and myelinated), although was ∼1:5 and ∼1:6 on the left and right side, respectively. the 1 right cervical portion of the VN is thicker than the They concluded that Transcutaneous auricular vagus nerve left . The sensory vagal pathways terminating in the stimulation might19 be a promising alternative to invasive nucleus of the solitary tract convey visceral, somatic and VNS stimulation . Several animals and functional magnetic taste sensations to the brain; including cardiorespiratory,2,3 resonance imagery (fMRI) human studies confirmed that gastrointestinal and immunological signals . The motor the 13,18,21,22auricular fibers of the vagus nerveVN activated the efferent fibers, emerging from the nucleus ambiguus NTS . These fibers projecting to the NTS will activate and the dorsal motor nucleus of the vagus (DMNV) in and modulate several simple and complex loops and the medulla, project to several organs of the neck, the circuitry (i.e., autonomic brainstem and forebrain loops), thorax and the abdomen including the organs of the4 centrally in a bottom-up mode, and trough up-down reticuloendothelial system such as the liver and the spleen reactions, the23-25 HPA axis and, in the periphery, immune tracts rich in macrophages activated by the inflammatory reflex . as the CAP . Traditionally and otherwise indicated only Furthermore, the VN, through enteric neurons, he connects the left branch of the ABVN is stimulated so that there is to the autonomic enteric nervous5 system, making the bi- less influence on the heart rate, since the left VN innervates directional gut-brain connection . the atrioventricular node and the right VN innervates the sinoatrial26 node controlling the pace-making function of the Less than two decades ago, vagus nerve stimulation heart . (VNS) had been approved in Canada, in the U.S. and in Europe for the treatment of multiple difficult-to- Recently, the booming of pre-clinical and clinical studies treat conditions6-8 including drug- resistant epilepsy and in bioelectronic medicine showed very encouraging results of depression . Implantable VNS device received CE Mark tVNS in the field of psychiatry as well as27-36 in gastroenterology approval in 2001 for the treatment of mood disorders. andAnxiety in the management of chronic pain . Since the earliest report of VNS implantation in 1988,