The emergence of bioelectronic medicine in vagus nerve neuromodulation and chiropractic care
The complexity of the autonomic nervous system is especially apparent when it fails to function. Such is the case in diabetes mellitus. Critical systems like the cardiovascular, musculoskeletal and others will be maintained in a state of compromised and maladaptive autonomic neuroplasticity with progressive dire clinical outcomes.
This review briefly addresses autonomic physiology, heart rate variability (HRV) as a metric for sympathetic and parasympathetic function, pathophysiology of autonomic sympatho-vagal imbalance, vagus nerve neuromodulation, and examples of brain responses mapped by functional brain imaging (fMRI). Emphasis is directed to the vagus nerve, known to anatomically “wander” with innervation in the head, neck, thorax and abdomen. Although clinical trials are yielding a broad range of human clinical benefits from vagus nerve neuromodulation, there is still a long road before all of the secrets of the “wandering” nerve are elucidated and harnessed for therapy.
Autonomic nervous system and homeostasis, allostasis
Virtually all physiological activity in our body is regulated, modulated and integrated by the central and peripheral pathways of the autonomic nervous system (ANS). The ANS optimizes the parameters of physiological responses of cells, tissues, organs and systems to external varying environmental challenges. Neural, immune, endocrine, gastrointestinal, cardiorespiratory and somatomotor homeostatic responses, vital to survival, depend upon the function of the ANS.
The notion of allostasis, maintaining physiological stability through change, extended the concept of homeostasis. Allostasis means adaptation in the face of potentially stressful challenges. Stress will activate neural, endocrine and immune mechanisms. Allostasis is an essential component for maintaining homeostasis. If, however, these adaptive systems are activated and inhibited efficiently, and not excessively, we can cope with challenges that might not otherwise sustain our survival. However, there are a number of processes in which allostatic systems may either be overstimulated or inadequate in their response, and this condition has been termed “allostatic load.” It is the cost of adaptation and may trigger pathophysiology.1,2
The central autonomic network (CAN)3,4,5 connects multiple brain regions with the ANS via three pathways:
- Spinal cord reflexes utilize the sympathetic and parasympathetic divisions. The principal visceral afferent source is the main nerve of the parasympathetic division, the vagus nerve, a mixed nerve, 80% afferent and 20% motor. The vagus integrates interoceptive information.6 It is associated with the nucleus of the solitary tract (NTS) in the caudal brainstem, which is somato-topically organized. The ANS may confer potent systemic anti-inflammatory effects7 through the vagus nerve activation by neuromodulation with benefit provided by both afferent and efferent activation. The vagus on the afferent side provides anti-inflammatory control by the activation of the hypothalamic-pituitary-adrenal (HPA) axis and release of glucocorticoid hormones, often with immunosuppressive action.8 On the efferent side, the vagal cholinergic anti-inflammatory response produces anti-TNFα effects.9, 10 The efferent output of the vagus is the dorsal motor nucleus complex nearby the NTS in the medulla oblongata. In addition to the spinal cord:
- The brainstem plays a central role in connecting the cerebrum, the cerebellum and the spinal cord, via its relay nuclei for afferent and efferent signaling, and multiple nuclei driving the neuro-modulatory functions of the central nervous system. The brainstem, and specifically the NTS, parabrachial nucleus and ventrolateral medulla, modulate the function of major systems like the respiratory and gastrointestinal. In addition, the periaqueductal grey nucleus in the midbrain integrates nociceptive and autonomic signals that relay to the cortical regions of the CAN, enabling the activation of the descending nociceptive pathway, the bidirectional (increase/decrease pain) endogenous (opioid) pain modulating system of the CNS. Along with pain management, other vital functions including cardiovascular, sleep and emotional responses are governed by the CAN including:
- HPA and forebrain neocortical regions of the insula, anterior cingulate and amygdala. The neocortex, limbic system and HPA exert powerful dynamic controls over the ANS. This highly complex neuroanatomical pathway also allows for autonomic influence by cognitive and emotional processing, capable of generating psychophysiological, psychosomatic interactions resulting in psychological and psychiatric disturbances.
Abnormal ANS function may be reflected in reduced HRV, a metric obtained from the fluctuations in the cardiac interbeat interval, which can be quantified using the standard deviation of RR intervals (SDRR) obtained from an ECG.11 It offers the display of cardiovagal balance and measures of the control of the CAN over the ANS. Higher HRV typically indicates a responsive state to environmental changes and demands, consistent with resilience.
When the RR fluctuations are examined in the frequency domain, the autonomic states are defined by frequency bands that include high frequency (HF) (0.15-0.40 Hz), predominantly reflecting parasympathetic, and low frequency (LF) (0.04-0.15 Hz), produced by both sympathetic and parasympathetic activity. The LF/HF ratio reflects the influence of sympathetic and parasympathetic activity. A low ratio suggests parasympathetic dominance. In addition, the use of HRV in a biofeedback mode has shown promising results in fibromyalgia and depression.12
The ANS may be conceptualized as the intermediary between our internal and external environments (vagus n. afference) and the brain optimizing adaptation to internal and external stressors (vagus n. efference). Recently, modulation of the ANS has been highlighted as a mechanism underlying the interventions in complementary and integrative techniques such as acupuncture, yoga and manual therapy.13,14,15,16
Similar to transcutaneous electrical nerve stimulation, the use of vagus neuromodulation has opened a range of disorders to non-pharmacological intervention by this powerful bioelectronic or electroceutical method.17
There are a growing number of disorders in which a focal point of pathophysiology is characterized by autonomic disruption and sympatho-vagal imbalance. The chronic imbalance is often dominated by elevated sympathetic tone and parasympathetic withdrawal. A few examples will be cited.
In hypertension and even in the prehypertensive state, elevated sympathetic tone is a dominant etiological variable.18 The gastrointestinal system offers multiple examples of the role of sympatho-vagal imbalance in its clinical disorders. Gastroesophageal reflux disease (GERD) is characterized by a vagally mediated patulous and relaxed lower esophageal sphincter at the esophageal gastric junction. Refluxing gastric contents, typically low pH, may then trigger inflammatory ulceration of the esophageal mucosa. GERD is often associated with obesity and both disorders display reduced parasympathetic (vagal) tone. Diminished parasympathetic activity may be reversed in treated obesity.19
Evidence for sympatho-vagal imbalance in inflammatory bowel disease, with reduced HPA axis and elevated inflammatory change, is observed in the intestinal mucosa.20 Diabetic neuropathy, both peripheral sensorimotor and autonomic, may be related to glycemic variability leading to sympatho-vagal imbalance by damaging radical oxygen species and inflammatory cytokines.21
Peripheral nerve stimulation
Electrical neural stimulation or inhibition of action potentials (neuromodulation) has a long history of clinical application. The earliest application of electrical sources for pain management dates to the ancient Egyptians, who used the shocks of electric fish to treat pain.22
During the 18th and 19th centuries, primitive electrical gadgets were designed to generate static electricity and shocks were delivered to the patient’s skin. Electrotherapy flourished in the 1800s, with wide clinical indications ranging from neurological to psychiatric and gynecological disorders. Interest in electrotherapy suddenly diminished in the early 20th century with the development of analgesic pharmaceuticals.
However, by the 1960s neurophysiological, preclinical and clinical models had begun offering rational analgesic mechanisms, such as the Gate Control Theory of Melzack and Wall. This model identified A-beta fiber electrically generated paresthesia that depolarized inhibitory interneurons blocking nociceptive C fibers and inducing analgesia.23 The elucidation of the gate or spinal segmental inhibition of pain and the description of the descending inhibitory pathway reignited interest in noninvasive electrical stimulation for pain, and for peripheral nerve pathology, a frequent antecedent to chronic pain.
Transcutaneous electrical nerve stimulation (TENS) and percutaneous electrical nerve stimulation (PENS or electro-acupuncture) have since become commonplace in clinical practice. Within the last 20 years, noninvasive therapeutic brain techniques such as transcranial magnetic field and direct current electrical brain stimulation have added powerful resources to the clinical armamentarium for neurological and psychiatric disease.24,25
Vagus nerve neuromodulation
The early-generation vagal stimulation devices were implantable, requiring surgical lead localization on the vagus within the carotid sheath of the cervical spine. The subcutaneous placement of an electrical current generator was also required. This approach was FDA approved for use in epilepsy and depression.
In recent years, electrodes underwent a noninvasive design such as transcutaneous application of the electrodes over the cervical vagus located within the carotid sheath. Most recently, another noninvasive technique, transcutaneous auricular VNS (taVNS) was developed using electrodes in the auricular target of the cymba conchae where the auricular branch of the vagus nerve (ABVN) is cutaneous.26,27 The transcutaneous approaches obviate the need for surgical procedures and potential associated complications and will likely compete with implantable stimulation devices. The use of taVNS appears to be safe and well-tolerated.28,29,30,31,32
Functional neuroimaging of taVNS
Neuroimaging frontiers of central nervous system and autonomic research require access to the mapping of medullary and pontine centers of the brainstem. The progress of fMRI investigations has been hampered by technical barriers related to the complex local environment, e.g. artifacts of CSF pulsations, cardiac motion and density of the brainstem nuclei. The field, however, has seen significant advances in recent years from the use of ultrahigh-field (UHF) 7.0 T MRI scanning.33
The regulatory role of respiration on vagal activity is under increasing investigation. The cardiovagal effects of taVNS using respiratory gating (RAVANS) in the exhalation phase of respiration demonstrated increased cardiovagal tone and reduction of sympathetic tone in hypertensives.34,35
The use of taVNS is known to activate the nucleus tractus solitarii (NTS) in the dorsal medulla by a variety of imaging techniques. The NTS is the primary target of vagal afferent input. The stimulation frequency parameters for taVNS were experimentally optimized by using Respiratory-gated Auricula Vagal Afferent Nerve Stimulation (RAVANS) and fMRI responses of the brainstem medullary centers. The strongest brainstem response under taVNS was associated with a 100-Hz stimulation frequency.36
Another fMRI study of taVNS evaluated the effects of exhalation-gated RAVANS in migraine patients between headache episodes. It revealed NTS increased connectivity with insula and mid-cingulate cortex compared to sham. The increase was correlated with time to the subsequent migraine attack.37
The pathophysiology of migraine headache may involve altered cortical connectivity. Structural and resting state functional MRI monitored the neuroplastic modulation of four weeks of taVNS vagal stimulation. Compared with controls, the symptoms were relieved. Connectivity analysis revealed vagus neuromodulation increased connectivity between motor centers of the thalamus, anterior cingulate and medial prefrontal cortex. Connectivity was decreased between occipital cortex-related thalamus and post-central gyrus and precuneus.38
A new era in non-invasive interventions
The safety and effectiveness of taVNS promises a new era in noninvasive interventions for a spectrum of disorders from chronic pain to hypertension. The operating parameters for clinical application of taVNS continue to be investigated and optimized. The role of this healing resource is likely to have exponential growth and clinical impact into the future.
NORMAN W. KETTNER, DC, works in the Department of Radiology at Logan University in Chesterfield, Mo.
ROBERTA SCLOCCO, PhD, works at the Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, in Charlestown, Mass.
|1.||McEwen BS, Stellar E:Stress and the individual. Mechanisms leading to disease. Arch Intern Med. 1993 Sep 27;153(18):2093-101.|
|2.||McEwen BS, Gianaros PJ:Stress- and allostasis-induced brain plasticity. Annu Rev Med. 2011;62:431-45.|
|3.||Benarroch EE:The central autonomic network: functional organization, dysfunction, and perspective. Mayo Clin Proc. 1993 Oct;68(10):988-1001.|
|4.||Beissner F, Meissner K, Bär KJ, Napadow V:The autonomic brain: an activation likelihood estimation meta-analysis for central processing of autonomic function. J Neurosci. 2013 Jun 19;33(25):10503-11.|
|5.||Valenza G, Sclocco R, Duggento A, Passamonti L, Napadow V, Barbieri R, Toschi N: The central autonomic network at rest:Uncovering functional MRI correlates of time-varying autonomic outflow. Neuroimage. 2019 Aug 15;197:383-390.|
|6.||Paciorek A, Skora L:Vagus Nerve Stimulation as a Gateway to Interoception. Front Psychol. 2020 Jul 29;11:1659.|
|7.||Bonaz B, Sinniger V, Pellissier S:Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol. 2016 Oct 15;594(20):5781-5790.|
|8.||Spencer RL, Deak T:A users guide to HPA axis research. Physiol Behav. 2017 Sep 1;178:43-65.|
|9.||Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ:Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62.|
|10.||Tracey KJ:The inflammatory reflex. Nature. 2002 Dec 19-26;420(6917):853-9.|
|11.||Shaffer F, Ginsberg JP:An Overview of Heart Rate Variability Metrics and Norms. Front Public Health. 2017 Sep 28;5:258.|
|12.||Lehrer PM, Gevirtz R:Heart rate variability biofeedback: how and why does it work? Front Psychol. 2014 Jul 21;5:756.|
|13.||Boehmer AA, Georgopoulos S, Nagel J, Rostock T, Bauer A, Ehrlich JR:Acupuncture at the auricular branch of the vagus nerve enhances heart rate variability in humans: An exploratory study. Heart Rhythm O2. 2020 Jun 9;1(3):215-221.|
|14.||Ma Q:Somato-Autonomic Reflexes of Acupuncture. Med Acupunct. 2020 Dec 1;32(6):362-366.|
|15.||Streeter CC, Gerbarg PL, Whitfield TH, Owen L, Johnston J, Silveri MM, Gensler M, Faulkner CL, Mann C, Wixted M, Hernon AM, Nyer MB, Brown ERP, Jensen JE:Treatment of Major Depressive Disorder with Iyengar Yoga and Coherent Breathing: A Randomized Controlled Dosing Study. Altern Complement Ther. 2017 Dec 1;23(6):236-243.|
|16.||Fornari M, Carnevali L, Sgoifo A:Single Osteopathic Manipulative Therapy Session Dampens Acute Autonomic and Neuroendocrine Responses to Mental Stress in Healthy Male Participants. J Am Osteopath Assoc. 2017 Sep 1;117(9):559-567.|
|17.||Horn CC, Ardell JL, Fisher LE:Electroceutical Targeting of the Autonomic Nervous System. Physiology (Bethesda). 2019 Mar 1;34(2):150-162.|
|18.||Pal GK, Pal P, Nanda N, Amudharaj D, Adithan C:Cardiovascular dysfunctions and sympathovagal imbalance in hypertension and prehypertension: physiological perspectives. Future Cardiol. 2013 Jan;9(1):53-69.|
|19.||Devendran N, Chauhan N, Armstrong D, Upton AR, Kamath MV:GERD and obesity: is the autonomic nervous system the missing link? Crit Rev Biomed Eng. 2014;42(1):17-24.|
|20.||Mogilevski T, Burgell R, Aziz Q, Gibson PR:Review article: the role of the autonomic nervous system in the pathogenesis and therapy of IBD. Aliment Pharmacol Ther. 2019 Oct;50(7):720-737.|
|21.||Fleischer J:Diabetic autonomic imbalance and glycemic variability. J Diabetes Sci Technol. 2012 Sep 1;6(5):1207-15.|
|22.||Heidland A, Fazeli G, Klassen A, Sebekova K, Hennemann H, Bahner U, Di Iorio B:Neuromuscular electrostimulation techniques: historical aspects and current possibilities in treatment of pain and muscle waisting. Clin Nephrol. 2013 Jan;79 Suppl 1:S12-23.|
|23.||Melzack R, Wall PD:Pain Mechanisms: A New Theory. Science. 1965 Nov 19;150(3699):971-9.|
|24.||Zrenner B, Zrenner C, Gordon PC, Belardinelli P, McDermott EJ, Soekadar SR, Fallgatter AJ, Ziemann U, Müller-Dahlhaus F:Brain oscillation-synchronized stimulation of the left dorsolateral prefrontal cortex in depression using real-time EEG-triggered TMS. Brain Stimul. 2020 Jan-Feb;13(1):197-205.|
|25.||Bikson M, Esmaeilpour Z, Adair D, Kronberg G, Tyler WJ, Antal A, Datta A, Sabel BA, Nitsche MA, Loo C, Edwards D, Ekhtiari H, Knotkova H, Woods AJ, Hampstead BM, Badran BW, Peterchev AV:Transcranial electrical stimulation nomenclature. Brain Stimul. 2019 Nov-Dec;12(6):1349-1366.|
|26.||Peuker ET, Filler TJ:The nerve supply of the human auricle. Clin Anat. 2002 Jan;15(1):35-7.|
|27.||Butt MF, Albusoda A, Farmer AD, Aziz Q:The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat. 2020 Apr;236(4):588-611.|
|28.||Redgrave J, Day D, Leung H, Laud PJ, Ali A, Lindert R, Majid A:Safety and tolerability of Transcutaneous Vagus Nerve stimulation in humans; a systematic review. Brain Stimul. 2018 Nov-Dec;11(6):1225-1238.|
|29.||Ellrich J:Transcutaneous Auricular Vagus Nerve Stimulation. J Clin Neurophysiol. 2019 Nov;36(6):437-442.|
|30.||Yuan H, Silberstein SD:Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I. Headache. 2016 Jan;56(1):71-8.|
|31.||Yuan H, Silberstein SD:Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II. Headache. 2016 Feb;56(2):259-66.|
|32.||Yuan H, Silberstein SD.:Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III. Headache. 2016 Mar;56(3):479-90.|
|33.||Sclocco R, Beissner F, Bianciardi M, Polimeni JR, Napadow V: Challenges and opportunities for brainstem neuroimaging with ultrahigh field MRI. Neuroimage. 2018 Mar;168:412-426.|
|34.||Sclocco R, Garcia RG, Gabriel A, Kettner NW, Napadow V, Barbieri R:Respiratory-gated Auricular Vagal Afferent Nerve Stimulation (RAVANS) effects on autonomic outflow in hypertension. Annu Int Conf IEEE Eng Med Biol Soc. 2017 Jul;2017:3130-3133.|
|35.||Sclocco R, Garcia RG, Kettner NW, Isenburg K, Fisher HP, Hubbard CS, Ay I, Polimeni JR, Goldstein J, Makris N, Toschi N, Barbieri R, Napadow V:The influence of respiration on brainstem and cardiovagal response to auricular vagus nerve stimulation: A multimodal ultrahigh-field (7T) fMRI study. Brain Stimul. 2019 Jul-Aug;12(4):911-921.|
|36.||Sclocco R, Garcia RG, Kettner NW, Fisher HP, Isenburg K, Makarovsky M, Stowell JA, Goldstein J, Barbieri R, Napadow V:Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation. Brain Stimul. 2020 Jul-Aug;13(4):970-978.|
|37.||Garcia RG, Lin RL, Lee J, Kim J, Barbieri R, Sclocco R, Wasan AD, Edwards RR, Rosen BR, Hadjikhani N, Napadow V:Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients. Pain. 2017 Aug;158(8):1461-1472.|
|38.||Zhang Y, Huang Y, Li H, Yan Z, Zhang Y, Liu X, Hou X, Chen W, Tu Y, Hodges S, Chen H, Liu B, Kong J:Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an fMRI study. Reg Anesth Pain Med. 2021 Feb;46(2):145-150.|