Key Publications
CHECK THIS PAGE FOR UPDATES ON PUBLICATIONS ABOUT PERIPHERAL NEUROMODULATION
To read a review on Peripheral Neuromodulation published by the British Pain Society, click on the links below:
Controlling pain
There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit “Technology targeting molecular mechanisms” took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.
Bioelectron Med 2021 May 24;7(1):7
Objective: Providing sustained and effective treatment via the peripheral nervous system for the management of chronic pain is challenging. Application of noninvasive high-frequency stimulation at or near the painful area may benefit those with chronic pain. This open-label pilot survey examined the impact of this stimulation on pain intensity, activities of daily living, functional capacity, and medication consumption after 2 weeks of treatment.
Methods: Stimulation was administered at home using two high-frequency sinusoidal alternating signals at 3858 and 3980 Hz delivered between two electrodes placed directly over one or two locations of pain. Individuals completed a survey after 2 weeks to assess pain, activities of daily living (ADL), pain medication consumption, quality of life (QoL), mood, sleep, functional outcomes, and satisfaction.
Results: 463 individuals (372 males; 91 females) retuned the completed survey after 2 weeks of treatment. Pain and ADL scores significantly improved at follow-up compared with baseline (pain mean difference: 3.05; 95% confidence interval [CI]: 2.86, 3.24; ADL mean difference: 1.82; 95% CI: 1.60, 2.04). Corresponding improvements in QoL, sleep, mood, functional outcomes, and satisfaction were noted. On average, 8.00 11.11 hours of pain relief were reported with 54% experiencing reductions in pain medication consumption. 98% would use the stimulation in the future.
Conclusion: Two weeks of noninvasive high-frequency peripheral nerve fiber stimulation appeared to confer positive effects in individuals with chronic pain. Future research employing a control group/arm is needed to establish the long-term impact of this bioelectric technique in specific pain cohorts.
Pain Pract. 2021 Jun;21(5):578-587
Background. Abdominal pain and constipation are 2 main symptoms in patients with constipation-predominant irritable bowel syndrome (IBS-C). This study aimed to investigate the effects and possible mechanisms of transcutaneous auricular vagal nerve stimulation (taVNS) in patients with IBS-C.
Methods. Forty-two patients with IBS-C were randomized into a 4-week sham-taVNS or taVNS treatment. The primary outcomes were complete spontaneous bowel movements per week (CSBMs/week) and visual analog scale (VAS) for abdominal pain. High-resolution anorectal manometry (HRAM) was performed to evaluate anorectal motor and sensory function. Cytokines and brain gut peptides were analyzed in blood samples. ECG was recorded for the assessment of autonomic function.
Results. Compared with sham-taVNS, (a) taVNS increased CSBMs/week (P = 0.001) and decreased VAS pain score (P = 0.001); (b) improved quality of life (P = 0.020) and decreased IBS symptom score (P = 0.001); (c) improved rectoanal inhibitory reflex (P = 0.014) and improved rectal sensation (P < 0.04); (d) decreased a number of proinflammatory cytokines and serotonin in circulation; and (e) enhanced vagal activity (P = 0.040). The vagal activity was weakly correlated with the CSBMs/week (r = 0.391; P = 0.010) and the VAS pain score (r = –0.347; P = 0.025).
Conclusion. Noninvasive taVNS improves both constipation and abdominal pain in patients with IBS-C. The improvement in IBS-C symptoms might be attributed to the integrative effects of taVNS on intestinal functions mediated via the autoimmune mechanisms.
Funding. National Natural Science Foundation of China (grant no. 81970538 for FL).
JCI Insight. 2021 Jul 22; 6(14): e150052.
The mammalian nervous system encodes many different forms of pain, from those that arise as a result of short-term low-grade interactions with noxious thermal, chemical, or mechanical sources to more serious forms of pain induced by trauma and disease. In this Review, we highlight recent advances in our understanding of the neural circuits that encode these types of pain. Promising therapeutic strategies based on recent advances are also highlighted.
Science 2016 2016 Nov 4;354(6312):578-584
Background/Aims: Gastrointestinal (GI) dysmotility in acute pancreatitis (AP) aggravates inflammation and results in severe complications. This study aimed to explore effects and possible mechanisms of transcutaneous electrical acustimulation (TEA) on abdominal pain, GI dysmotility, and inflammation in AP patients.
Methods: Forty-two AP patients were blindly randomized to receive TEA (n = 21) at acupoints PC6 and ST36 or Sham-TEA (n = 21) at sham points for 2 days. Symptom scores, gastric slow waves, autonomic functions (assessed by spectral analysis of heart rate variability), circulatory levels of motilin, ghrelin, and TNF-α measured before and after the treatment. Sixteen healthy controls (HCs) were also included without treatment for the assessment of gastric slow waves and biochemistry.
Key Results: Compared with Sham-TEA, TEA decreased abdominal pain score (2.57 Å} 1.78 vs. 1.33 Å} 1.02, p < 0.05), bloating score (5.19 Å} 1.21 vs. 0.76 Å} 0.99, p < 0.001), the first defecation time (65.79 Å} 19.51 h vs. 51.38 Å} 17.19 h, p < 0.05); TEA, but not Sham-TEA, improved the percentage of normal gastric slow waves by 41.6% (p < 0.05), reduced AP severity score (5.52 Å} 2.04 vs. 3.90 Å} 1.90, p < 0.05) and serum TNF-α (7.59 Å} 4.80 pg/ml vs. 4.68 Å} 1.85 pg/ml, p < 0.05), and upregulated plasma ghrelin (0.85 Å} 0.96 ng/ml vs. 2.00 Å} 1.71 ng/ml, p = 0.001) but not motilin (33.08 Å} 22.65 pg/ml vs. 24.12 Å} 13.95 pg/ml, p > 0.05); TEA decreased sympathetic activity by 15.0% and increased vagal activity by 18.3% (both p < 0.05).
Conclusions & Inferences: TEA at PC6 and ST36 administrated at early stage of AP reduces abdominal pain, improves GI motility, and inhibits inflammatory cytokine, TNF-α, probably mediated via the autonomic and ghrelin mechanisms.
Neurogastroenterol Motil 2022 Apr;34(4):e14249
Chronic primary pelvic pain syndrome (CPPPS) is a heterogeneous disease with unknown pathogenesis and a lack of distinct pathological features, which complicates diagnosis and therapy and has a significant impact on patients’ daily life. Because pharmacological management is ineffective and long-term use may result in additional system damage, developing a more effective treatment is critical.
Neuromodulation has advanced rapidly over the last few decades, and various types of neuromodulations have demonstrated efficacy in the treatment of CPPPS. In this article we discuss the evolution of neuromodulation technology in the treatment of chronic pelvic pain, its application to various subtypes of chronic pelvic pain, and the comparison of relevant efficacy and parameter differences, as well as assess the relative advantages and disadvantages of sacral neuromodulation, percutaneous tibial nerve stimulation , transcutaneous electrical nerve stimulation, electroacupuncture, and pudendal neuromodulation. Furthermore, it was noted that chronic pelvic pain should be evaluated in terms of pain, associated symptoms, psychological problems, and quality of life. Although neuromodulation approaches have been shown to be effective in treating chronic pelvic pain, more extensive multicenter trials are required to confirm this.
Pain Ther (2022) 11:789-816
Purpose of review: Peripheral nerve stimulation (PNS) refers to the technique of utilizing electrical stimulation of peripheral nerves to inhibit the transmission of pain signals. PNS is used to treat chronic intractable pain and post-surgical or post-traumatic pain alongside a variety of other pain conditions, including headaches, facial pain, pelvic and urogenital pain, chest wall pain, residual limb or phantom limb pain, and back pain.
Recent findings: More recently, PNS has been used temporarily for periods of time less than 60 days to treat acute post-surgical pain. Peripheral nerve stimulation is believed to be effective due to its effects on both central and peripheral pathways. Centrally, it is proposed that the electrical pulses of PNS inhibit alpha-delta and C fibers, which decreases pain signaling in the higher centers of the central nervous system. Peripherally, gate theory is applied as it is theorized that PNS downregulates inflammatory mediators, endorphins, and neurotransmitters associated with pain signaling to decrease the transmission of efferent nociception and reduce pain sensations.
Curr Pain Headache Rep. 2023 Oct 27.
Introduction: Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy (RSD), is a difficult to treat condition characterized by debilitating pain and limitations in functional ability. Neuromodulation, in the form of spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS), have been traditionally used as a treatment for CRPS with variable success.
Objective: This chart review describes the use of implantable PNS systems in the treatment of CRPS of the upper and lower extremities spanning nearly three decades.
Materials and methods: A retrospective chart review was performed on 240 patients with PNS implanted between 1990 and 2017 at our institution. Of these, 165 patients were identified who had PNS systems implanted for a diagnosis of CRPS. Patient profile, including baseline characteristics, comorbidities, past/current interventions/medications and targeted nerves, was descriptively summarized through standard summary statistics. Patients' pain scores and opioid consumptions at baseline (preimplant), 1 month, 6 months, and 12 months were collected and compared. Device revisions and explants were summarized, and patient functional outcomes were described.
Results: Pain scores at baseline and at 12-month follow-up were decreased from a mean of 7.4 ± 1.6 to 5.5 ± 2.4 and estimated to be 1.87 (95% CI: [1.29, 2.46], paired t-test p-value <0.001) lower at 12 months. At baseline, 62% of patients were on chronic opioid therapy, compared with 41% at 12 months. Of 126 patients who reported changes in functional status, 64 (51%) reported improvement, 27 (21%) reported worsening, and 35 (28%) did not report any meaningful change. Excluding end-of-life battery replacements, surgical revision occurred in 56 (34%) of patients. Thirteen patients (8%) underwent implantation of a second PNS because of symptomatic expansion outside of the original painful region. Device explant was performed in 32 (19%) of patients. Median length of follow-up was 74 [14, 147] months. Of the 36 patients who continue to follow-up at our institution, 29 (81%) continue to use their PNS.
Conclusions: We can conclude that PNS is a useful modality to improve function and reduce long-term pain in selected patients suffering from CRPS type I and type II.
2021 Aug;24(6):971-982.
Purpose of review: The number of applications for peripheral nerve stimulation (PNS) in the pain management field is ever-growing. With the increasing number of clinical applications for peripheral nerve stimulation, the purpose of this article is to review the mechanism of action surrounding PNS, the recent literature from January 2018 to January 2021, and pertinent clinical outcomes.
Recent findings: The authors searched articles identified from PubMed (January 2018-January 2021), Cochrane Central Register of Controlled Trials databases (January 2018-January 2021), and Scopus (January 2018-January 2021) databases, and manually searched references of identified publications. Broad MeSH terms and Boolean operators were queried in each search, including the following terms and their respective synonyms: peripheral nerve stimulation, mechanism of action, biochemical pathway, and pain pathway. 15 consensus articles were selected for in-depth review and inclusion for qualitative analysis. PNS may activate and modulate higher central nervous system (CNS) centers, including the dorsal lateral prefrontal cortex, somatosensory cortex, anterior cingulate cortex, and parahippocampal areas. Neuromodulatory effects from PNS may also extend into the spinal columns. Also, PNS may lead to changes in endogenous neurotransmitters and affect the plasticity of NMDA pathways.
Curr Pain Headache Rep. 2021 May 11;25(7):47.
The use of stimulation of peripheral nerves to test or treat various medical disorders has been prevalent for a long time. Over the last few years, there has been growing evidence for the use of peripheral nerve stimulation (PNS) for treating a myriad of chronic pain conditions such as limb mononeuropathies, nerve entrapments, peripheral nerve injuries, phantom limb pain, complex regional pain syndrome, back pain, and even fibromyalgia. The ease of placement of a minimally invasive electrode via percutaneous approach in the close vicinity of the nerve and the ability to target various nerves have led to its widespread use and compliance. While most of the mechanism behind its role in neuromodulation is largely unknown, the gate control theory proposed by Melzack and Wall in the 1960s has been the mainstay for understanding its mechanism of action. In this review article, the authors performed a literature review to discuss the mechanism of action of PNS and discuss its safety and usefulness in treating chronic pain. The authors also discuss current PNS devices available in the market today.
2023 Feb 25;24(5):4540.
Background: Peripheral nerve stimulation (PNS) has been increasingly used to manage acute and chronic pain. However, the level of clinical evidence to support its use is not clear.
Objectives: To assess the clinical evidence of PNS in the treatment of acute or chronic pain.
Study design: A systematic review of the efficacy and safety of PNS in managing acute or chronic pain.
Methods: Data sources were PubMed, Cochrane Library, Scopus, CINAHL Plus, Google Scholar, and reference lists. The literature search was performed up to December 2019. Study selection included randomized trials, observational studies, and case reports of PNS in acute or chronic pain. Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. Data syntheses: 227 studies met inclusion criteria and were included in qualitative synthesis.
Results: Evidence synthesis based on randomized controlled trials (RCTs) and observational studies showed Level I and II evidence of PNS in chronic migraine headache; Level II evidence in cluster headache, postamputation pain, chronic pelvic pain, chronic low back and lower extremity pain; and Level IV evidence in peripheral neuropathic pain, and postsurgical pain. Peripheral field stimulation has Level II evidence in chronic low back pain, and Level IV evidence in cranial pain.
Limitations: Lack of high-quality RCTs. Meta-analysis was not possible due to wide variations in experimental design, research protocol, and heterogeneity of study population.
Conclusions: The findings of this systematic review suggest that PNS may be effective in managing chronic headaches, postamputation pain, chronic pelvic pain, and chronic low back and lower extremity pain, with variable levels of evidence in favor of this technique.
Pain Physician. 2021 Mar;24(2):E131-E152.
Introduction: With the advancement of technology, peripheral nerve stimulation (PNS) has been increasingly used to treat various chronic pain conditions. Its origin is based on the gate control theory postulated by Wall and Melzack in 1965. However, the exact mechanism behind PNS' analgesic effect is largely unknown. In this article, we performed a comprehensive literature review to overview the PNS mechanism of action.
Design: A comprehensive literature review on the mechanism of PNS in chronic pain.
Methods: Comprehensive review of the available literature on the mechanism of PNS in chronic pain. Data were derived from database searches of PubMed, Scopus, and the Cochrane Library and manual searches of bibliographies and known primary or review articles.
Results: Animal, human, and imaging studies have demonstrated the peripheral and central analgesic mechanisms of PNS by modulating the inflammatory pathways, the autonomic nervous system, the endogenous pain inhibition pathways, and involvement of the cortical and subcortical areas.
Conclusions: Peripheral nerve stimulation exhibits its neuromodulatory effect both peripherally and centrally. Further understanding of the mechanism of PNS can help guide stimulation approaches and parameters to optimize the use of PNS.
Pain Med. 2020 Aug 1;21(Suppl 1):S6-S12.
Purpose of review: Peripheral nerve stimulation has seen a recent upsurge in utilization for various chronic pain conditions, specifically from a neuropathic etiology, where a single peripheral nerve can be pinpointed as a culprit for pain.
Recent findings: There is conflicting evidence about the efficacy and long-term outcomes of peripheral nerve stimulation for chronic pain, with most studies being small sized. The focus of this article is to review available evidence for the utilization of peripheral nerve stimulation for chronic pain syndromes as well as upcoming evidence in the immediate postoperative realm. The indications for the use of PNS have expanded from neuropathic pain such as occipital neuralgia and post-amputation pain, to more widespread disease processes such as chronic low back pain. Percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain.
Curr Pain Headache Rep. 2023 Sep;27(9):321-327.
Peripheral nerve stimulation (PNS) is rapidly increasing in use. This interventional pain treatment modality involves modulating peripheral nerves for a variety of chronic pain conditions. This review evaluated its use specifically in the context of chronic lower extremity pain. Studies continue to elucidate the utility of PNS and better define indications, contraindications, as well as short- and long-term benefits of the procedure for the lower extremity. While large, prospective evidence is still lacking, the best available evidence suggests that improvements may be seen in pain scores, functionality, and opioid consumption. Overall, evidence synthesis suggests that PNS for the lower extremities may be a viable option for patients with chronic lower extremity pain.
Biomedicines. 2022 Jul 11;10(7):1666
Background: Peripheral nerve stimulation (PNS) is a neuromodulation technique in which electrical current is applied to the peripheral nerves to ameliorate chronic pain through preferential activation of myelinated fibres, inducing long-term depression of synaptic efficacy. External noninvasive peripheral nerve stimulation (EN-PNS) is a novel and simple form of PNS that involves stimulation via an external nerve-mapping probe that is placed on the skin and connected to a power source.
Objectives: We aimed to assess the clinical utility of EN-PNS in patients with refractory neuropathic pains referred to a tertiary pain treatment center.
Methods: We undertook a prospective audit of EN-PNS. Patients with a diagnosis of either complex regional pain syndrome or neuropathic pain after peripheral nerve injury who met inclusion criteria were included. Participants completed three stages of the audit: stage 1, six weekly outpatient treatment sessions; stage 2, six-week equipment home loan; stage 3, six weeks of no EN-PNS treatment. The primary outcome was the average post-treatment instantaneous pain intensity during the last week in stage 2 compared with baseline (11-point numerical rating scale).
Results: EN-PNS provided significant short-term pain relief (n = 20 patients, average reduction of 2.8 numerical rating scale points, 95% CI 1.6-4.0, p < 0.001, intention-to-treat analysis). Eight patients (40%) improved in several outcome parameters ("responders"), including quality of life and function.
Conclusion: In this first prospective report on the use of EN-PNS in neuropathic pain, this technology provided significant clinical benefit for some patients. Controlled studies are required to confirm our results and the place of EN-PNS in future neuromodulation treatment algorithms. Given the refractory nature of these conditions, these results are encouraging.
Neuromodulation. 2015 Jul;18(5):384-91.
Background: External noninvasive peripheral nerve stimulation (EN-PNS) is a neuromodulation technique in which a low-frequency electrical stimulation is applied via a ball-shaped electrode that is placed directly onto the skin.
Objectives: To examine how this modality is being used in the long term, by patients with chronic neuropathic pain who had responded to this treatment in a short-term trial.
Materials and methods: All patients with a diagnosis of neuropathic pain who had obtained a machine for continued long-term use (via special funding requests), following a successful trial between 2009 and 2012 were contacted. A successful trial was considered as >50% pain reduction, duration of any beneficial treatment effect ≥12 hours, and improvements to function/reduced medication use. Data were collected from case notes and a telephone interview.
Results: Thirteen trials were recorded successful, out of 21 conducted. Eleven individual funding applications were made, of which seven were successful. Five patients were contactable. All reported continued stimulator use at follow-up (average = 3.5 years) and ongoing pain relief associated with treatment. Pain intensities (numerical rating scale 0-10) had reduced in all five cases when baseline scores were compared with follow-up scores; average pain 5.6-3.5 and worst pain 8.6-4.8. All patients reported a reduction in frequency of pain flare-ups during device use.
Conclusion: Patients reported EN-PNS to provide ongoing benefit at long-term follow-up. Further prospective investigations are justified.
Neuromodulation. 2016 Dec;19(8):893-896.
Improving function & disease
Vagus nerve stimulation is used to treat conditions ranging from inflammation to migraine. Mapping the nerve's complex structure of more than 160,000 fibres could usher in a new era of precision treatments
NewScientist, Grace Wade, 22 August 2023
The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn’s disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.
Front Neurosci 2021 Mar 22:15:650971
Neurostimulation is one manifestation of neuromodulation of the gastrointestinal (GI) tract. This manuscript reviews the history of neurostimulation of the GI tract with emphasis on current methods of stimulation. Upper GI disorders can be modulated with both temporary (placed endoscopically or surgically) or permanent (placed surgically) gastric electrical stimulation (GES) devices. The current gastrointestinal (GI) neurostimulation of stomach (GES) devices have been used in both children and adults and some patients have been followed in excess of 15 years with good long-term results. Similar GES devices have also been used for a variety of lower GI disorders, including constipation and fecal incontinence, for a number of years. Based on these recent developments, the future uses of neurostimulation in the GI tract are discussed with an emphasis on new applications and innovations.
Neuromodulation. 2015 April ; 18(3): 221–227.Background: Overactive bladder (OAB) affects 12 to 30% of the world’s population. The accompanying urinary urgency, frequency and incontinence can have a profound effect on quality of life, leading to depression, social isolation, avoidance of sexual activity and loss of productivity. Conservative measures such as lifestyle modification and pelvic floor physical therapy are the first line of treatment for overactive bladder. Patients who fail these may go on to take medications, undergo neuromodulation or receive injection of botulinum toxin into the bladder wall. While effective, medications have side effects and suffer from poor adherence. Neuromodulation and botulinum toxin injection are also effective but are invasive and not acceptable to some patients.
Methods: We have developed a novel transcutaneous spinal cord neuromodulator (SCONE™ that delivers multifrequency electrical stimulation to the spinal cord without the need for insertion or implantation of stimulating electrodes. Previously, multifrequency transcutaneous stimulation has been demonstrated to penetrate to the spinal cord and lead to motor activation of detrusor and external urethral sphincter muscles. Here, we report on eight patients with idiopathic overactive bladder, who underwent 12 weeks of SCONE™ therapy.
Results: All patients reported statistically significant clinical improvement in multiple symptoms of overactive bladder, such as urinary urgency, frequency and urge incontinence. In addition, patients reported significant symptomatic improvements as captured by validated clinical surveys.
Conclusion: SCONE™ therapy represents the first of its kind therapy to treat symptoms of urgency, frequency andurge urinary incontinence in patients with OAB.
Trial registration: The study was listed on clinicaltrials.gov NCT03 753750
Bioelectron Med. 2022 Mar 23;8(1):5
Background/Aims: Constipation shows both, a high prevalence and a significant impact. However, it is often perceived as minor and treatment choices are limited. The neuromodulation approach is a valuable option to be considered. This study assesses the use of non-invasive sacral nerve stimulation to reduce constipation in children.
Methods: Between February 2013 and May 2015, pediatric patients with chronic constipation were treated with this non-invasive neuromodulation procedure, adapted from classical sacral nerve stimulation. A stimulation device attached to adhesive electrodes on the lower abdomen and back generated an electrical field with a stable frequency of 15Hz via variable stimulation intensity (1–10 V). The effect of therapy was evaluated in routine check-ups and by specialized questionnaires.
Results: The study assessed non-invasive sacral nerve stimulation in 17 patients (9 boys, 8 girls, mean age 6.5 years). They underwent stimulation with 6–9 V for a mean of 11 h per day (range 0.5–24 h) over a mean of 12.7 weeks. Improvement of constipation was achieved in more than half of the patients (12/17) and sustained in almost half of these patients (5/12). Complications were minor (skin irritation, electrode dislocation).
Conclusions: Non-invasive sacral nerve stimulation appears to be effective in achieving improvement in pediatric patients with chronic constipation. As an additional external neuromodulation concept, this stimulation may represent a relevant addition to currently available therapeutic options. Further studies are needed to confirm these results.
Frontiers in Pediatrics April 2020; Vol 8; Article 169
The vagus nerve is the tenth and longest of the cranial nerves, whose course runs from the brainstem to the splenic flexure. It is the main neural substrate of the parasympathetic nervous system and has both afferent and efferent pathways, although the former predominate (80%). An increasing body of evidence has demonstrated it has a central role in modulating gastrointestinal pain, inflammation, and motility. Within this issue of the Journal, Gottfried-Blackmore and colleagues report the results from an open-label pilot study examining the role of non-invasive vagus nerve stimulation (VNS) in idiopathic gastroparesis. This mini review provides a contemporaneous summary of the current methods by which non-invasive VNS can be achieved, its potential indications within the field particularly with respect to gastroparesis. In addition, this review also addresses some of the pitfalls and propose the outstanding questions which may inform and guide the future research agenda.
Neurogastroenterology & Motility. 2020;32:e13822.
Background: The vagus nerve has anti-inflammatory properties. We aimed to investigate vagus nerve stimulation (VNS) as a new therapeutic strategy targeting an intrinsic anti-inflammatory pathway in a pilot study in Crohn's disease patients. The main objectives addressed the questions of long-term safety, tolerability, and anti-inflammatory effects of this therapy. This study is the continuation of previous reported findings at 6 months.
Methods: Nine patients with moderate active disease underwent VNS. An electrode wrapped around the left cervical vagus nerve was continuously stimulated over 1 year. Clinical, biological, endoscopic parameters, cytokines (plasma, gut), and mucosal metabolites were followed-up.
Key Results: After 1 year of VNS, five patients were in clinical remission and six in endoscopic remission. C-reactive protein (CRP) and fecal calprotectin decreased in six and five patients, respectively. Seven patients restored their vagal tone and decreased their digestive pain score. The patients' cytokinergic profile evolved toward a more “healthy profile”: Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorβ1 were the most impacted cytokines. Correlations were observed between CRP and tumor necrosis factor α, and some gut mucosa metabolites as taurine, lactate, alanine, and beta-hydroxybutyrate. VNS was well tolerated.
Conclusion & Inferences: Vagus nerve stimulation appears as an innovative and welltolerated treatment in moderate Crohn's disease. After 12 months, VNS has restored a homeostatic vagal tone and reduced the inflammatory state of the patients. VNS has probably a global modulatory effect on the immune system along with gut metabolic regulations. This pilot study needs replication in a larger randomized doubleblinded control study.
Neurogastroenterol Motil. 2020 Oct;32(10):e13911.
Background. Abdominal pain and constipation are 2 main symptoms in patients with constipation-predominant irritable bowel syndrome (IBS-C). This study aimed to investigate the effects and possible mechanisms of transcutaneous auricular vagal nerve stimulation (taVNS) in patients with IBS-C.
Methods. Forty-two patients with IBS-C were randomized into a 4-week sham-taVNS or taVNS treatment. The primary outcomes were complete spontaneous bowel movements per week (CSBMs/week) and visual analog scale (VAS) for abdominal pain. High-resolution anorectal manometry (HRAM) was performed to evaluate anorectal motor and sensory function. Cytokines and brain gut peptides were analyzed in blood samples. ECG was recorded for the assessment of autonomic function.
Results. Compared with sham-taVNS, (a) taVNS increased CSBMs/week (P = 0.001) and decreased VAS pain score (P = 0.001); (b) improved quality of life (P = 0.020) and decreased IBS symptom score (P = 0.001); (c) improved rectoanal inhibitory reflex (P = 0.014) and improved rectal sensation (P < 0.04); (d) decreased a number of proinflammatory cytokines and serotonin in circulation; and (e) enhanced vagal activity (P = 0.040). The vagal activity was weakly correlated with the CSBMs/week (r = 0.391; P = 0.010) and the VAS pain score (r = –0.347; P = 0.025).
Conclusion. Noninvasive taVNS improves both constipation and abdominal pain in patients with IBS-C. The improvement in IBS-C symptoms might be attributed to the integrative effects of taVNS on intestinal functions mediated via the autoimmune mechanisms.
Funding. National Natural Science Foundation of China (grant no. 81970538 for FL).
JCI Insight. 2021 Jul 22; 6(14): e150052.
Introduction: Gastrointestinal motility disorders are highly prevalent without satisfactory treatment. noninvasive electrical neuromodulation is an emerging therapy for treating various gastrointestinal motility disorders.
Areas covered: In this review, several emerging noninvasive neuromodulation methods are introduced, including transcutaneous auricular vagal nerve stimulation, percutaneous auricular vagal nerve stimulation, transcutaneous cervical vagal nerve stimulation, transcutaneous electrical acustimulation, transabdominal interference stimulation, tibial nerve stimulation, and translumbosacral neuromodulation therapy. Their clinical applications in the most common gastrointestinal motility are discussed, including gastroesophageal reflux disease, functional dyspepsia, gastroparesis, functional constipation, irritable bowel syndrome, and fecal incontinence. PubMed database was searched from 1995 to June 2023 for relevant articles in English.
Expert opinion: Noninvasive neuromodulation is effective and safe in improving both gastrointestinal symptoms and dysmotility; it can be used when pharmacotherapy is ineffective. Future directions include refining the methodology, improving device development and understanding mechanisms of action.
Expert Rev Gastroenterol Hepatol 2023 Dec;17(12):1221-1232.
Background
The inflammatory reflex plays a role in regulating innate and adaptive immunity by modulating cellular and molecular inflammatory pathways. The vagus nerve is a major constituent of the inflammatory reflex and studies have shown that the reflex can be activated by electrical stimulation of the vagus nerve. In this first in-human pilot study, we assessed the safety and efficacy of a novel miniaturised vagus nerve stimulation (VNS) device for the treatment of multidrug-refractory rheumatoid arthritis.
Methods
Participants with moderately to severely active rheumatoid arthritis and prior insufficient response to two or more biological disease-modifying anti-rheumatic drugs or Janus kinase inhibitors with at least two different modes of action were enrolled in a two-stage study done at five clinical research sites in the USA. Stage 1 was open label; participants were implanted with a miniaturised VNS device, which was activated for 1 min once a day. In stage 2, participants were randomly assigned (1:1:1) to receive active stimulation (1 min once a day or 1 min four times a day) or sham stimulation (device implanted but not activated), with the sites and participants masked to treatment assignment. The primary outcome was incidence of treatment-emergent adverse events. Clinical efficacy was assessed as a key secondary outcome. The study was registered with ClinicalTrials.gov, NCT03437473.
Findings
14 patients were enrolled between March 13 and Aug 8, 2018. Three patients received stimulation in stage 1 and, following safety review board approval, the remaining 11 patients were implanted during stage 2 and randomly assigned to receive 1 min of stimulation once daily (n=3), 1 min of stimulation four times daily (n=4), or no stimulation (n=4) for 12 weeks. There were no device-related or treatment-related serious adverse events. Surgery-related adverse events were Horner's syndrome and vocal cord paralysis (in one patient each), which resolved without clinically significant sequelae. No deaths were recorded.
Interpretation
VNS with a miniaturised neurostimulator was safe and well tolerated and reduced signs and symptoms of rheumatoid arthritis in patients with multidrug-refractory disease. These results support further evaluation in a larger randomised sham-controlled study.
Lancet Rheumatol. 2020;2(9):e527–38
Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed "the inflammatory reflex", action potential transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studies in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients.
Proc Natl Acad Sci USA. 2016;113(29):8284– 9