Parasympathetic control of gastrointestinal motility and cross-branch actions of parasympathetic neuromodulation.

Abstract

The gastrointestinal (GI) tract is a unique organ that has its own nervous system called enteric nervous system (ENS) and also termed “little brain.” The ENS has 200 to 600 million neurons and can function independently without inputs from the brain. It communicates with the brain via the autonomic nervous system that is composed of sympathetic and parasympathetic nervous systems. The parasympathetic system consists of the vagus nerve and the sacral nerve. In addition to the endogenous parasympathetic controls, GI motility can also be controlled or altered exogenously via vagal nerve stimulation (VNS) or sacral nerve stimulation (SNS), which is the main topic of this manuscript (Full version in supplementary file, https://links.lww.com/CM9/B460). Vagal nerve stimulation for GI motility: VNS can be implemented permanently or chronically via stimulation electrodes placed at the vagus nerve and a pulse generator implanted in a subcutaneous pouch in the chest or abdomen. VNS using implantable devices has received Food and Drug Administration (FDA) approval for treating epilepsy, major depression disorders, heart failure, and obesity. However, none of the surgically implanted devices has received regulatory approval for treating any of GI diseases. Alternatively, VNS can be implemented non-invasively via transcutaneous stimulation of the vagus nerve, such as transcutaneous auricular vagal nerve stimulation (taVNS) and transcutaneous cervical vagal nerve stimulation (tcVNS). Both of these methods have been under investigation for treating GI diseases. Transcutaneous auricular VNS: taVNS is accomplished by placing a pair of stimulation electrodes in the ear, usually in the symba concha as this area is 100% innervated with vagal afferent nerve. Both unilateral (both stimulation electrodes in one ear) and bilateral (one stimulation electrode in each ear) taVNS have been reported; however, there is no published studies comparing difference between unilateral and bilateral stimulation. Transcutaneous auricular VNS for functional dyspepsia (FD): In a recent study, taVNS was performed in 36 patients with FD. A clipper-like carbon electrode was placed in the symba concha of each ear.[1] Electrical stimulation was performed by a watch-size portable device using a special parameter set (2 s on, 3 s off, 25 Hz, 0.5 ms, and maximal tolerable current output) that was known to improve GI motility in other methods of neuromodulation. taVNS was delivered at home 1 h, twice daily for 2 weeks. A significant improvement in symptoms of FD and anxiety/depression was observed with the taVNS, which was not noted with the sham stimulation (same electrical stimulation delivered at the elbow). Physiologically, a significant improvement was reported in gastric accommodation (assessed by a nutrient drink test) and gastric pace-making activity (assessed by non-invasive electrogastrogram). Impaired gastric accommodation and gastric pace-making activity have been frequently reported in patients with FD. The improvement in these measurements suggested restoration of these gastric physiological functions with the taVNS treatment. Mechanistically, the 2-week taVNS increased vagal efferent activity assessed by the spectral analysis of analysis of heart rate variability derived from the electrocardiogram. It was postulated that taVNS ameliorated FD symptoms by restoring gastric motility functions mediated via the vago-vagal pathway. Transcutaneous auricular VNS for irritable bowel syndrome (IBS) in adults: In another study, similar taVNS was performed in 42 patients with constipation-dominant IBS. The patients were randomized to receive taVNS via silicon electrodes placed at bilateral symba concha or sham electrical stimulation (via the elbow). The stimulation was performed at home, 30 min twice daily for 4 weeks. It was reported that in comparison with sham stimulation, taVNS significantly and substantially increased the weekly number of complete spontaneous bowel movements, decreased abdominal pain, and improved overall symptoms of IBS and quality of life. Symptoms of anxiety and depression were also improved with taVNS, compared with both baseline and sham stimulation. Physiologically, taVNS improved recto-anal inhibitory reflex (a rectal distention-induced relaxation of internal anal sphincter) and improved rectal sensation to rectal distention. Mechanically, taVNS-enhanced vagal efferent activity assessed by the spectral analysis of heart rate variability and reduced proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and serotonin. Furthermore, the weekly number of complete spontaneous bowel movements was significantly correlated with the vagal efferent activity, suggesting a parasympathetic pathway involved in the enhanced colon motility. Most interesting and intriguing findings of this study were the improvement in rectal sensation and rectal distention-induced relaxation of the internal anal sphincter, suggesting a vagal afferent and sacral efferent pathway. This is because the rectum and anal sphincter are not innervated with the vagus nerve but the sacral nerve. We postulate that these effects were mediated via the vagal-sacral pathway as follows: taVNS activated the nucleus tractus solitarius (NTS) that projected to other parts of the brain to yield an enhanced sacral efferent activity, acting on the rectum and anal sphincter. In a rodent model of opioid-induced constipation, auricular vagal nerve stimulation (aVNS) with similar stimulation parameters was reported to accelerate transit of the distal colon (not innervated with the vagus nerve) with a concurrent increase in activated neurons in the NTS.[2] These findings suggest that aVNS may alter colorectum motility and sensation via both vago-vagal pathway and vago-sacral pathway. Percutaneous aVNS for IBS in adolescents: Rather than with the use of surface electrodes, 2-mm needles were used for stimulation in an aVNS study in adolescents with IBS.[3] The authors called it percutaneous electrical nerve field stimulation (PENFS). The stimulation was performed via 2-mm needles placed at different areas of one ear via a small pulse generator attached to the back of the ear. Instead of delivering constant current, the device delivered 3.2 V 1 ms pulses alternating at 1 Hz and 10 Hz frequencies every 2 s, with 2 h on and 2 h off. The treatment was administered 5 days/week for 4 weeks. The study outcome was the % of responders with the PENFS (N = 27) compared with sham treatment (a mock device with no stimulation output [N = 23]). The responder was defined as a decrease of 30% or more in the worst abdominal pain score from baseline to 3 weeks of the therapy. It was found that the % of responders were significantly higher with the PENFS than the sham treatment (59% vs. 26%, P = 0.024). No physiological or mechanistic outcomes were assessed. The same therapy was applied for treating abdominal pain in adolescent patients with functional GI diseases (IBS, FD, abdominal migraine, functional abdominal pain, or functional abdominal pain syndrome). A significant reduction in worst abdominal pain score was reported after a 3-week treatment (N = 60), compared with the sham treatment (no stimulation). Transcutaneous cervical VNS for gastroparesis: tcVNS is performed by placing electrical stimulation transcutaneously over the cervical vagus nerve. tcVNS using a hand-held device (gammaCore) has been approved for treating cluster headache and migraine and is being explored for treating complications of Coronavirus disease 19 (COVID-19) infections. A recent open-label clinical trial explored its application for treating gastroparesis. In this study, tcVNS was performed a few minutes daily via a hand-held device for a period of 4 weeks in 15 patients with idiopathic gastroparesis. A moderate but significant decrease (about 35%) was noted at the end of the treatment in the total gastroparesis symptom score. Concurrently, tcVNS also improved gastric emptying assessed by the breath test. While this single-center uncontrolled study with a very small number of patients suggested a therapeutic potential of tcVNS for gastroparesis, more follow-up research is needed to demonstrate its clinical efficacy and possible mechanisms. Sacral Nerve Stimulation for GI Motility: Due to its anatomical innervation, electrical stimulation of the sacral nerve is developed for treating diseases of pelvic organs. SNS has been approved by FDA for treating overactive bladder and urinary incontinence as well as fecal incontinence (FC). It has also been explored for treating constipation, ulcerative colitis, and IBS. Interestingly, recent preclinical studies have revealed its potential for treating disorders of GI organs not innervated by the sacral nerve, suggesting a sacral afferent and vagal efferent pathway. Methodologically, SNS has to be performed using surgically implanted electrodes and transcutaneous stimulation over the sacral nerve is less feasible due to the depth of the nerve underneath the skin. Sacral nerve stimulation for FC: SNS has been approved in most of countries in the world for treating FC that affects about 7% to 15% of general population. In this method, electrical stimulation is delivered via chronically implanted electrodes at S3 and an implantable pulse generator placed at a subcutaneous pouch in the buttocks. The stimulation is performed continuously with a frequency of 14 Hz, pulse width of 210 μs and voltage of 1 to 10 V based on patient's perception. Clinically, SNS is used for treating chronic FD in patients who have failed or are not candidates for medical or physical therapy. The success rate was reported in large clinical trials to be around 80%, defined as a reduction in >50% of FC episodes. The SNS mechanisms for FC are largely unknown, but some studies have demonstrated an increase in anal sphincter pressure and rectal sensation. Sacral nerve stimulation for chronic constipation: Chronic constipation affects about 16% of adults worldwide and classified as slow transit constipation, defecatory disorder, and normal transit constipation. SNS has been investigated for treating chronic constipation for >30 years; however, it has not yet received regulatory approval for treating constipation. Although numerous clinical studies have been performed, recent systematic review and meta-analysis revealed ineffectiveness of SNS for constipation. The major issue on the proposed SNS therapy for constipation is the selection of stimulation parameters. Although constipation is a totally different or physiologically opposite disease of FC, the proposed SNS therapy for constipation adopted the same stimulation parameters. More studies are needed to optimize stimulation parameters and SNS modalities for treating constipation. Sacral nerve stimulation for IBS: A few clinical studies have explored therapeutic potential of SNS for IBS that is one of most common forms of functional GI disorders. The major clinical symptom is abdominal pain in conjunction with constipation or diarrhea or both. The method used in the clinical studies adopted the same SNS method as used for treating FC. In a recent randomized clinical trial, SNS was performed using an implanted device in 21 patients with IBS and improved abdominal pain and IBS symptoms during a 2-week SNS period, compared with a 2-week device-off period. Similar to SNS for constipation, more basic and translational research is needed to optimize stimulation parameters and treatment modalities. Since abdominal pain is the hallmark of IBS, SNS should be designed and optimized for treating visceral hypersensitivity that is one of major pathophysiologies of pain in IBS. In a recent animal study, SNS with a different set of stimulation parameters and treatment duration was reported to significantly ameliorate abdominal pain. Sacral nerve stimulation for upper GI disorders: As discussed earlier, the upper GI tract, such as the stomach and small intestine, is innervated with the vagus nerve but not the sacral nerve. Accordingly, there has been absence of clinical studies exploring SNS for upper GI disorders. However, in a few recent animal studies performed in our lab, SNS was found to improve upper GI dysmotility mediated via the sacral afferent and vagal efferent pathway. In one rodent study, acute SNS with parameters known to enhance parasympathetic activity (5 Hz, 0.5 ms, 10 s on and 90 s off) was reported to induce gastric fundic relaxation and increase gastric accommodation mediated via the sacral–vagal reflex.[4] Concurrent mechanistic findings demonstrated SNS-induced activation of neurons in the NTS, enhancement of vagal efferent activity, and release of nitric oxide in the gastric fundus. In another rodent study,[5] acute SNS with the same parameters reported in improved gastric and duodenal slow waves impaired by rectal distention and normalized gastric emptying and small intestinal transit delayed by glucagon injection and rectal distention. Mechanistically, SNS enhanced vagal efferent activity, suggesting the same sacral–vagal pathway. Perspectives of Parasympathetic Neuromodulation for GI Diseases: While parasympathetic activity regulates GI motility endogenously, electrical stimulation of the parasympathetic nerves can also be used to regulate GI motility and treat functional GI diseases exogenously. Most commonly, electrical stimulation location is determined by the neuroanatomy of the parasympathetic nerves, that is, stimulating the nerves that are directly linked to (innervated with) a target organ. However, recent animal and clinical studies seem to suggest that it is possible to apply neuromodulation of one branch of the parasympathetic nerves to alter functions of an organ that is only innervated by another branch of the parasympathetic nerves via the cross-branch pathway (sacral–vagal or vagal–sacral). Neuromodulation of the parasympathetic nerves using implantable device has great potentials in treating chronic and severe functional GI diseases. However, more efforts are needed to optimize stimulation parameters and treatment regimens, such as SNS for constipation and IBS. More basic and translational research is needed to understand mechanisms of action involved in various applications of SNS and VNS. While the sacral nerve has been considered traditionally as a parasympathetic nerve, there was a study suggesting that the sacral autonomic outflow was sympathetic. However, the statement was not substantiated. Non-invasive neuromodulation, such as taVNS and tcVNS, is attractive in functional GI diseases as these are common yet not life-threatening diseases. Scientifically, more mechanistic research is needed to optimize the therapy and thus improve its efficacy. Clinically, multi-center randomized clinical trials are necessary to demonstrate its therapeutic potentials in treating various diseases. Technologically, novel wearable devices should be developed that are easy to use daily and less visible (looks like an entertaining rather than a medical apparatus). Funding This study was supported by grants from American National Institutes of Health (No. UG3NS115108, R01DK107754, and R42DK100212). Conflicts of interest None.