Transcutaneous Electrical Acustimulation Improves Constipation Symptoms and Accelerates Colonic Transit in Patients With Slow Transit Constipation Through Autonomic Mechanism.

OBJECTIVES: Nearly half of patients with slow transit constipation (STC) are not completely satisfied with their traditional remedies. We aimed to evaluate the therapeutic value and possible involved mechanism of transcutaneous electrical acustimulation (TEA) at ST36 in patients with STC. MATERIALS AND METHODS: Seventy patients with STC were randomly divided into TEA (n = 35) and sham-TEA (n = 35) to undergo a two-week treatment with TEA at ST36 or sham point. After the two-week treatment, 18 patients from each group randomly underwent a few physiological tests, including the electrocardiogram (ECG), anorectal manometry, colon transit test, and blood drawing. After a two-week washout period, TEA was performed in both groups for two weeks. RESULTS: Spontaneous bowel movements per week were increased, and scores of constipation symptoms were decreased, after a two-week blind TEA but not sham-TEA, which were sustained after a two-week washout period. Improvement in quality of life and psychologic states also was observed with blind TEA treatment. Mechanistically, the two-week blind TEA accelerated colon transit assessed by barium strip excretion rate (the effect was sustained after a two-week washout period), enhanced vagal nerve activity evaluated by the spectral analysis of heart rate variability derived from the ECG, and decreased circulating vasoactive intestinal peptide. CONCLUSIONS: Noninvasive TEA relieves constipation and improves quality of life and psychologic states in patients with STC, and the effects are sustained for ≥two weeks. The therapeutic effects of TEA may be attributed to the acceleration of colon transit and decrease of vasoactive intestinal peptide mediated through the vagal mechanism.

Acceleration of postoperative recovery with brief intraoperative vagal nerve stimulation mediated via the autonomic mechanism.

Introduction: Postoperative recovery is largely dependent on the restoration of gastrointestinal motility. The aim of this study was to investigate the effects and mechanisms of intraoperative vagus nerve stimulation (iVNS) on postoperative recovery from abdominal surgery in rats. Methods: The Nissen fundoplication surgery was performed on two groups of rats: sham-iVNS group and iVNS group (VNS was performed during surgery). Animal's behavior, eating, drinking and feces' conditions were monitored at specific postoperative days. Gastric slow waves (GSWs) and electrocardiogram (ECG) were recorded; blood samples were collected for the assessment of inflammatory cytokines. Results: (1) iVNS shortened initiate times to water and food intake (p = 0.004) and increased the number of fecal pellets (p < 0.05, vs. sham-iVNS) and the percentage of water content in fecal pellets (p < 0.05). (2) iVNS improved gastric pace-making activity at 6 h after surgery reflected as a higher percentage of normal slow waves (p = 0.015, vs. sham-iVNS). (3) iVNS suppressed inflammatory cytokines at 24 h after surgery compared to sham-iVNS (TNF-α: p = 0.001; IL-1ß: p = 0.037; IL-6: p = 0.002). (4) iVNS increased vagal tone compared to sham-iVNS group at 6 h and 24 h after the surgery (p < 0.05). Increased vagal tone was correlated with a faster postoperative recovery to start water and food intake. Conclusion: Brief iVNS accelerates postoperative recovery by ameliorating postoperative animal behaviors, improving gastrointestinal motility and inhibiting inflammatory cytokines mediated via the enhanced vagal tone.

Electroacupuncture Enhances Gastric Accommodation via the Autonomic and Cytokine Mechanisms in Functional Dyspepsia.

BACKGROUND: Due to complex pathophysiology of functional dyspepsia, medications to treat functional dyspepsia are not effective for all patients. Transcutaneous electrical acustimulation (TEA) is an potentially effective therapy for functional dyspepsia without proofs of definite mechanisms. AIMS: We aimed to investigate the therapeutic impacts of TEA on postprandial distress syndrome (PDS) and explore potential neuroimmune mechanisms. METHODS: We conducted a double-blinded, randomized, controlled trial in 30 PDS patients randomized for 4-week TEA or sham-TEA. Dyspeptic symptoms, gastric accommodation, gastric emptying and heart rate variability (HRV) were assessed. Duodenal mucosal inflammation was also evaluated. RESULTS: The dyspeptic symptoms were improved with TEA compared with sham-TEA (P = 0.03). The initial satiety volume and the maximum tolerable volume (MTV) were both improved after the TEA treatment, compared with the sham-TEA group (P all < 0.05). The gastric emptying time (T1/2) was not altered with TEA or sham-TEA. The TEA treatment increased vagal activity and decreased sympathovagal ratio assessed by HRV (P all < 0.01). The IL-6 expression in bulb mucosa was downregulated by the TEA treatment compared to the baseline (P < 0.05). CONCLUSIONS: Noninvasive TEA improves gastric accommodation and dyspeptic symptoms, possibly by downregulating the IL-6 expression in duodenal bulb mucosa via the vagal efferent pathway.

In vivo assessment of inflammatory bowel disease in rats with ultrahigh-resolution colonoscopic OCT.

A technology capable of high-resolution, label-free imaging of subtle pathology in vivo during colonoscopy is imperative for the early detection of disease and the performance of accurate biopsies. While colonoscopic OCT has been developed to visualize colonic microstructures beyond the mucosal surface, its clinical potential remains limited by sub-optimal resolution (∼6.5 µm in tissue), inadequate imaging contrast, and a lack of high-resolution OCT criteria for lesion detection. In this study, we developed an ultrahigh-resolution (UHR) colonoscopic OCT and evaluated its ability to volumetrically visualize and identify the pathological features of inflammatory bowel disease (IBD) in a rat model. Owing to its improved resolution (∼1.7 µm in tissue) and enhanced contrast, UHR colonoscopic OCT can accurately delineate fine colonic microstructures and identify the pathophysiological characteristics of IBD in vivo. By using a quantitative optical attenuation map, UHR colonoscopic OCT is able to differentiate diseased tissue (such as crypt distortion and microabscess) from normal colonic mucosa over a large field of view in vivo. Our results suggest the clinical potential of UHR colonoscopic OCT for in vivo assessment of IBD pathology.

Transcutaneous Electrical Acustimulation Improved the Quality of Life in Patients With Diarrhea-Irritable Bowel Syndrome.

BACKGROUND AND AIM: Patients with diarrhea-dominant irritable bowel syndrome (IBS-D) experience abdominal pain and reduced quality of life and need effective treatments. This study aimed to evaluate whether transcutaneous electrical acustimulation (TEA) at two acupuncture points, LI4 and ST36, could improve pain and quality of life of patients with IBS-D. MATERIALS AND METHODS: A total of 42 patients with IBS-D who met the Rome IV criteria were randomly divided into two groups: TEA and sham-TEA. TEA was performed through acupoints Hegu (LI4) and Zusanli (ST36) for one hour twice daily for one month, using previously established parameters; sham-TEA was delivered in the same way as TEA but without actual electrical current stimulation. RESULTS: The sham-TEA group showed a significantly higher rate of drop-out than the TEA group (29% vs 0%, p = 0.021). TEA, but not sham-TEA, significantly improved quality of life (before: 78.55 ± 9.62, after: 85.97 ± 9.49, p < 0.0001). Both TEA and sham-TEA reduced abdominal pain; however, TEA was more potent than sham-TEA (p = 0.014). The IBS symptom severity scale score was reduced by both TEA and sham-TEA. Autonomic functions assessed by plasma norepinephrine and pancreatic polypeptide were not altered with TEA, nor was interleukin 10 or interleukin 6. CONCLUSIONS: TEA at LI4 and ST36 improves abdominal pain and quality of life of patients with IBS-D, probably mediated by mechanisms other than autonomic function or inflammatory cytokines.

Electronic Bypass for Diabetes: Optimization of Stimulation Parameters and Mechanisms of Glucagon-Like Peptide-1.

OBJECTIVES: Intestinal electrical stimulation (IES) has been proposed for treating diabetes; however, its parameters need to be further systematically optimized. This study aimed to optimize the parameters of IES and investigate its possible mechanisms involving glucagon-like peptide-1 (GLP-1) in diabetic rats. MATERIALS AND METHODS: Thirty-six high-fat diet-induced diabetic rats were chronically implanted with a pair of bipolar electrodes at the duodenum for IES. The oral glucose tolerance test (OGTT) was performed in a number of sessions with IES using different parameters and biphasic charge-balanced waveforms to derive the best values for train on-time, pulse frequency, and pulse width. Incretin hormones such as GLP-1 were assessed and the GLP-1 antagonist Exendin 9-39 was used to assess the role of GLP-1 in the ameliorating effect of IES on hyperglycemia. RESULTS: The most effective IES parameters in reducing blood glucose (BG) during the OGTT were derived: 1.2 sec on, 0.3 sec off, 80 Hz, 3 msec. IES with these parameters reduced BG level by at least 29% from 15 min to 180 min (p < 0.05 for all points, N = 10). IES with these stimulation parameters increased plasma GLP-1 level at 30 min, 60 min, 90 min and gastric inhibitory peptide (GIP) level at 30 min (N = 8). Exendin 9-39 blocked the inhibitory effect of IES on BG (p > 0.05, IES + Exendin 9-39 vs sham-IES, N = 8). CONCLUSION: IES with the most effective parameters derived in this study improves hyperglycemia in diabetic rats. The ameliorating effect of IES on hyperglycemia is attributed to the enhanced release of GLP-1. IES has great potential for treating diabetes.

Integrative effects of transcutaneous electrical acustimulation on abdominal pain, gastrointestinal motility, and inflammation in patients with early-stage acute pancreatitis.

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 were 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 ± 1.78 vs. 1.33 ± 1.02, p < 0.05), bloating score (5.19 ± 1.21 vs. 0.76 ± 0.99, p < 0.001), the first defecation time (65.79 ± 19.51 h vs. 51.38 ± 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 ± 2.04 vs. 3.90 ± 1.90, p < 0.05) and serum TNF-α (7.59 ± 4.80 pg/ml vs. 4.68 ± 1.85 pg/ml, p < 0.05), and upregulated plasma ghrelin (0.85 ± 0.96 ng/ml vs. 2.00 ± 1.71 ng/ml, p = 0.001) but not motilin (33.08 ± 22.65 pg/ml vs. 24.12 ± 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.

Auricular vagal nerve stimulation enhances gastrointestinal motility and improves interstitial cells of Cajal in rats treated with loperamide.

BACKGROUND: Gastrointestinal (GI) motility disorders affect a large proportion of the population with limited treatment options. The aims of this study were to investigate the potential of a non-invasive method of auricular vagal nerve stimulation (aVNS) for treating GI dysmotility and to explore possible mechanisms involving slow waves and interstitial cells of Cajal (ICC). METHODS: Normal rats were treated daily with loperamide for 1 week and then treated, while still on daily loperamide, with aVNS/Sham-aVNS for another 1 week. Gastric emptying (GE), small intestine transit (SIT), and GI slow waves were measured. The plasma level of pancreatic polypeptide (PP) and noradrenaline (NE) was assessed by ELISA. ICC in the gastric antrum were detected by immunohistochemistry. KEY RESULTS: (a) aVNS significantly increased the percentage of normal GI slow waves (p < 0.05 for both fasting and postprandial states, vs. Sham-aVNS) and accelerated GE (p < 0.05, vs. Sham-aVNS) and SIT (p < 0.05, vs. Sham-aVNS) impaired by loperamide. (b) aVNS increased plasma PP (p < 0.01) and decreased plasma NE (p < 0.01), compared with Sham-aVNS. (c) Gastric ICC was decreased by loperamide (p < 0.01) but increased after aVNS (p < 0.01, vs. Sham aVNS). CONCLUSIONS & INFERENCES: Loperamide induces upper GI dysmotility. aVNS accelerates upper GI transit and improving pace-making activity mediated via the ICC. Non-invasive aVNS may have a therapeutic potential for upper GI dysmotility.

Transitional changes in gastrointestinal transit and rectal sensitivity from active to recovery of inflammation in a rodent model of colitis.

Patients with ulcerative colitis are typically suspected of an inflammatory flare based on suggestive symptoms of inflammation. The aim of this study was to evaluate the impact of inflammation on colonic motility and rectal sensitivity from active to recovery of inflammation. Male rats were given drinking water with 5% dextran sulfate sodium for 7 days. Inflammation, intestinal motor and sensory functions were investigated weekly for 6 weeks. (1) The disease activity index score, fecal calprotectin and tumor necrosis factor alpha were increased from Day 0 to Day 7 (active inflammation) and then decreased gradually until recovery. (2) Distal colon transit was accelerated on Day 7, and then remained unchanged. Whole gut transit was delayed on Day 7 but accelerated from Day 14 to Day 42. (3) Rectal compliance was unaffected from Day 0 to Day 7, but decreased afterwards. (4) Rectal hypersensitivity was noted on Day 7 and persistent. (5) Plasma acetylcholine was decreased on Day 7 but increased from Day 14 to Day 42. Nerve growth factor was increased from Day 7 to Day 42. DSS-induced inflammation leads to visceral hypersensitivity that is sustained until the resolution of inflammation, probably mediated by NGF. Rectal compliance is reduced one week after the DSS-induced inflammation and the reduction is sustained until the resolution of inflammation. Gastrointestinal transit is also altered during and after active colonic inflammation.

Intestinal Electrical Stimulation Enhances Release of Postprandial Incretin Hormones Via Cholinergic Mechanisms.

INTRODUCTION: Intestinal electrical stimulation (IES) has been reported to reduce body weight and improve glucose tolerance in obese and diabetic rats. Our study aimed to investigate possible IES mechanisms involving incretin hormones using intraduodenal glucose infusion in rats. We hypothesized that the enhanced release of postprandial glucagon-like peptide-1 (GLP-1) at early phase by IES was mediated through neuro/paracrine mechanisms involving the vagal nerve and glucose-dependent insulinotropic peptide (GIP). METHODS: Fifteen normal male Sprague-Dawley rats chronically implanted with duodenal electrodes for IES, and an intra-duodenum catheter for the infusion of glucose were studied in a series of sessions with IES of different parameters with and without atropine and M3 receptor antagonist. Blood samples were collected via the tail vein for the measurement of blood glucose, and plasma GLP-1, and GIP. RESULTS: (1) Compared to sham-IES, IES of 0.3 ms reduced blood glucose by 16.5-28.4% between 30 and 120 min (all time points p < 0.05), and IES of 3-ms reduced blood glucose at 60 (12.6%) and 90 min (11.8%). IES of 0.3 ms showed a greater hypoglycemic effect than 3 ms (p = 0.024) at 30 min. (2) IES elevated plasma GLP-1 with 0.3 ms (p = 0.001) and with 3 ms p = 0.03). (3) IES substantially elevated plasma GIP with 0.3 ms (p = 0.002) and with 3 ms (p < 0.001). (4) Pretreatment of atropine and the M3 receptor antagonist 4-DAMP blocked the effects of IES on GLP-1, GIP, and blood glucose. CONCLUSIONS: IES reduces postprandial blood glucose by enhancing the release of GLP-1 and GIP mediated via the cholinergic mechanism.

Intestinal Electrical Stimulation Alters Hypothalamic Expression of Oxytocin and Orexin and Ameliorates Diet-Induced Obesity in Rats.

BACKGROUND: Intestinal electrical stimulation (IES) has been proposed as a potential treatment for obesity. The aim of this study was to explore the central mechanism underlying the reduction of food intake and body weight by IES by studying the expression of anorexigenic- and orexigenic-peptide-containing neurons in the hypothalamus. MATERIALS AND METHODS: Diet-induced obese (DIO) rats were divided into three groups to receive sham, IES, and pair-feeding for 4 weeks. Food intake was measured automatically and presented as daily and body weight measured weekly. The expressions of oxytocin, an anorexigenic neuropeptide, in the paraventricular nucleus of the hypothalamus (PVN) and the supraoptic nuclei of the hypothalamus (SON) and orexin-A, an orexigenic neuropeptide, in the lateral hypothalamic area (LHA) were studied using immunohistochemistry. RESULTS: Compared with sham, IES reduced daily food intake by 28.3% at week 1, 35.6% at week 2, 15.6% at week 3, and 27.1% at week 4. Consistently, IES reduced body weight by 6.3%, compared with a weight gain of 7.2% in sham, and a slight weight loss of 0.5% in pair-feeding. Compared with sham, IES increased the expression of oxytocin-immunoreactive neurons in PVN and SON. Compared with sham, IES decreased the expression of orexin-immunoreactive neurons in LHA. Rats with pair-feeding also showed a relative decease in weight without any changes in the central hormones. CONCLUSION: IES reduces food intake and body weight and improves glucose tolerance and insulin sensitivity in DIO rats. Its central mechanisms involve enhancement of anorexigenic peptides and suppression of orexigenic peptides in the hypothalamus.

Transcutaneous Neuromodulation improved inflammation and sympathovagal ratio in patients with primary biliary ssscholangitis and inadequate response to Ursodeoxycholic acid: a pilot study.

BACKGROUND: At present, ursodeoxycholic acid (UDCA) is internationally recognized as a therapeutic drug in clinic. However, about 40% Primary Biliary Cholangitis (PBC) patients are poor responders to UDCA. It has been demonstrated that Transcutaneous Neuromodulation (TN) can be involved in gut motility, metabolism of bile acids, immune inflammation, and autonomic nerve. Therefore, this study aimed to explore the effect of TN combined with UDCA on PBC and related mechanisms. METHODS: According to inclusion and exclusion criteria, 10 healthy volunteers and 15 PBC patients were recruited to control group and TN group, respectively. PBC patients were alternately but blindly assigned to group A (TN combined with UDCA) and group B (sham-TN combined with UDCA), and a crossover design was used. The TN treatment was performed via the posterior tibial nerve and acupoint ST36 (Zusanli) 1 h twice/day for 2 weeks. T test and nonparametric test were used to analyze the data. RESULTS: 1. TN combined with UDCA improved the liver function of PBC patients shown by a significant decrease of alkaline phosphatase and gamma-glutamyltransferase (γ-GT) (P < 0.05). 2. The treatment also decreased serum IL-6 levels (P < 0.05), but not the level of Tumor Necrosis Factor-α, IL-1ß or IL-10. 3. TN combined with UDCA regulated autonomic function, enhanced vagal activity, and decreased the sympathovagal ratio assessed by the spectral analysis of heart rate variability (P < 0.05). 4. There was no change in 13 bile acids in serum or stool after TN or sham-TN. CONCLUSIONS: TN cssombined with UDCA can significantly improve the liver function of PBC patients. It is possibly via the cholinergic anti-inflammatory pathway. TN might be a new non-drug therapy for PBC. Further studies are required. TRIAL REGISTRATION: The study protocol was registered in Chinese Clinical Trial Registry (number ChiCTR1800014633 ) on 25 January 2018.

Effects of electroacupuncture on stress-induced gastric dysrhythmia and mechanisms involving autonomic and central nervous systems in functional dyspepsia.

Electroacupuncture (EA) is widely used as an effective method to treat stress-related disorders. However, its mechanisms remain largely unknown. The aim of this study was to investigate the effects and mechanisms of EA on gastric slow wave (GSW) dysrhythmia and c-Fos expression in the nucleus of the solitary tract (NTS) induced by stress in a rodent model of functional dyspepsia (FD). Rats in the neonatal stage were treated using intragastric iodoacetamide. Eight weeks later, the rats were implanted with electrodes in the stomach for the measurement of GSW and electrodes into accupoints ST36 for EA. Autonomic functions were assessed by spectral analysis of heart rate variability. Rats were placed for 30 min in a cylindrical plastic tube for acute restraint stress. The involvement of a central afferent pathway was assessed by measuring c-Fos-immunoreactive cells in the NTS. 1) EA normalized restraint stress-induced impairment of GSW in FD rats. 2) EA significantly increased vagal activity (P = 0.002) and improved sympathovagal balance (P = 0.004) under stress in FD rats. 3) In FD rats under restraint stress, plasma norepinephrine concentration was increased substantially (P < 0.01), which was suppressed with EA. 4) The EA group showed increased c-Fos-positive cell counts in the NTS compared with the sham EA group (P < 0.05) in FD rats. Acute restraint stress induces gastric dysrhythmia in a rodent model of FD. EA at ST36 improves GSW under stress in FD rats mediated via the central and autonomic pathways, involving the NTS and vagal efferent pathway.

Sacral nerve stimulation ameliorates colonic barrier functions in a rodent model of colitis.

BACKGROUND: The mucosal barrier damage is recognized as one of the key factors in the pathogenesis of colitis. While sacral nerve stimulation (SNS) was reported to have therapeutic potential for colitis, its mechanisms of actions on colonic permeability remained largely unknown. METHODS: In this study, colitis was induced by intrarectal administration of TNBS in rats. Five days later, they were treated with SNS or sham-SNS for 10 days. The effects of SNS on colonic permeability were assessed by measuring the expression of tight-junction proteins involved in regulating permeability and the FITC-dextran test. The mechanism of actions of SNS was investigated by studying the function of the enteric nervous system (ENS) cells and analyzing the autonomic nervous system. KEY RESULTS: SNS decreased the disease activity index, microscopic and macroscopic scores, myeloperoxidase activity, and pro-inflammatory cytokines (TNF-α, IL-6). SNS increased the expression of Zonula Occludens-1, Occludin, Claudin-1, and Junctional adhesion molecule-A in the colon tissue. The FITC-dextran test showed that the colonic permeability was lower with SCS than sham-SNS. SNS increased ChAT, pancreatic polypeptide, and GDNF and reduced norepinephrine NGF, sub-P, and mast cell overactivation in the colon tissue. Concurrently, SNS increased acetylcholine in colon tissues and elevated vagal efferent activity. CONCLUSIONS & INFERENCES: SNS ameliorates colonic inflammation and enhances colonic barrier function with the proposed mechanisms involving the increase in parasympathetic activity and modulation of the activity of the ENS and immune system, including mast cells.

Transcutaneous Electrical Acustimulation Improves Gastrointestinal Disturbances Induced by Transcatheter Arterial Chemoembolization in Patients With Liver Cancers.

BACKGROUND: Gastrointestinal (GI) disturbances occur in patients who receive chemotherapy via transcatheter arterial chemoembolization (TACE) and could last for an extended period of time in some cases. Antiemetic drugs have a potential risk of developing hepatic failure and are ineffective for delayed nausea and emesis. Transcutaneous electrical acustimulation (TEA) has recently been reported to exert antiemetic and prokinetic effects, but it is unknown whether it has an ameliorating effect on TACE-induced GI disturbances. AIM: This study was designed to evaluate effects and mechanisms of noninvasive TEA on GI symptoms in patients treated with TACE. MATERIALS AND METHODS: Seventy-four patients with liver cancers (eighteen female; age 63.4 ± 1.1 years) scheduled for TACE were randomized to TEA (n = 37) or sham-TEA (n = 37). TEA was performed via acupoints, ST36 and PC6 using parameters previously optimized for GI motility (1 h, bid) from the postoperative day 0 (POD0) to POD2. Sham-TEA was performed using the same parameters via non-acupoints. Symptom questionnaires were completed daily. The electrogastrogram (EGG) and electrocardiogram (ECG) were recorded in the fasting state for 30 mins to assess gastric slow waves and autonomic functions, respectively, before and after the 3-day treatment. RESULTS: 1) In the acute phase (<24 h), TEA showed no effects on any of GI symptoms, compared with sham-TEA. 2) In the delayed phase (>24 h), TEA, compared with sham-TEA, decreased the percentage of patients who experienced nausea on POD3 (0% vs. 13.5%, p = 0.021), the nausea score on POD3 (p = 0.022), the anorexia score on POD2 (p = 0.040) and POD3 (p = 0.004), and the bloating score (POD1-3: p < 0.01). 3) In comparison with sham-TEA, TEA increased the number of spontaneous bowel movements (p = 0.001) and the Bristol score of the first stool (p = 0.014) and decreased the number of patients with the use of laxatives (p = 0.022). 4) Physiologically, the 3-day TEA but not sham-TEA increased the percentage of normal gastric slow waves (p < 0.001) and vagal activity (p = 0.006). The vagal activity was negatively correlated with the anorexia score (r = -0.267, p = 0.026). It was found that the sympathovagal ratio and tumor size>5 cm were independent risk factors predicting the occurrence of nausea in patients after TACE. CONCLUSION: TEA improves major TACE-induced GI disturbances in the delayed phase, including nausea, bloating, impaired gastric pace-making activity, and constipation in patients with liver cancers via the autonomic pathway.

A novel method of sacral nerve stimulation for colonic inflammation.

BACKGROUND: Vagal nerve stimulation has been reported to treat inflammation with promising results. The aims of our study were to optimize sacral nerve stimulation (SNS) methodologies for colonic inflammation in a rodent model of colitis and to investigate autonomic and cytokine mechanisms. METHODS: Three major efforts were made in optimizing SNS: (a) to determine the best stimulation duration: SNS-0.5h daily, SNS-1h daily, and SNS-3h daily with the parameters set at 5 Hz, 10 seconds on, 90 seconds off; (b) to determine the best stimulation position: bilateral, bipolar, and unipolar stimulation; (c) to determine the best stimulation parameters: our 5 Hz intermittent stimulation vs 14 Hz-210 µs continuous stimulation. Inflammatory responses were assessed by the disease activity index (DAI), histological analyses, and the myeloperoxidase (MPO) activity. Levels of inflammatory cytokines, norepinephrine (NE), and pancreatic polypeptide (PP) in both plasma and colon tissues were assessed. KEY RESULTS: Both SNS-1h and SNS-3h significantly ameliorated intestinal inflammation; SNS-1h was superior to SNS-3h. Bipolar but not bilateral or unipolar stimulation improved the inflammation in colitis. SNS with 5 Hz intermittent stimulation but not the 14 Hz continuous SNS was better for treating colitis in rats. SNS with the optimized stimulation parameters increased vagal activity and decreased sympathetic activity. CONCLUSION & INFERENCES: Bipolar stimulation for 1 hour daily using intermittent 5 Hz parameters is most effective in improving colonic inflammation in TNBS-treated rats by inhibiting pro-inflammatory cytokines and increasing anti-inflammatory cytokines via the modulation of the autonomic function.

Artificial Neural Network-Based Automatic Detection of Food Intake for Neuromodulation in Treating Obesity and Diabetes.

PURPOSE: Neuromodulation, such as vagal nerve stimulation and intestinal electrical stimulation, has been introduced for the treatment of obesity and diabetes. Ideally, neuromodulation should be applied automatically after food intake. The purpose of this study was to develop a method of automatic food intake detection through dynamic analysis of heart rate variability (HRV). MATERIALS AND METHODS: Two experiments were conducted: (1) a small sample series with a standard test meal and (2) a large sample series with varying meal size. Electrocardiograms (ECGs) were collected in the fasting and postprandial states. Each ECG was processed to compute the HRV. For each HRV segment, time- and frequency-domain features were derived and used as inputs to train and test an artificial neural network (ANN). The ANN was trained and tested with different cross-validation methods. RESULTS: The highest classification accuracy reached with leave-one-subject-out-leave-one-sample-out cross-validation was 0.93 in experiment 1 and 0.88 in experiment 2. Retraining the ANN on recordings of a subject drastically increased the achieved accuracy for that subject to values of 0.995 and 0.95 in experiments 1 and 2, respectively. CONCLUSIONS: Automatic food intake detection by ANNs, using features from the HRV, is feasible and may have a great potential for neuromodulation-based treatments of meal-related disorders.

Sacral nerve stimulation prompts vagally-mediated amelioration of rodent colitis.

Neuromodulation based on the vagal anti-inflammatory reflex has emerged as an exciting therapeutic approach for chronic inflammatory diseases. However, it is unclear whether direct stimulation of the vagus or of pelvic nerves coming from sacral roots, providing the bulk of colonic parasympathetic innervation, is the best approach. We hypothesized that sacral nerve stimulation (SNS) would be an effective treatment for colitis. Age and sex-matched Sprague-Dawley rats were administered 5% dextran sulphate sodium (DSS) in drinking water ad libitum for 7 days. A group of rats was sacrificed after DSS treatment, and the remaining rats were randomized to either sham-SNS or SNS groups, which were performed for 1 hr daily for 10 days. Stimulations were delivered via chronically implanted electrodes using an 8-channel universal pulse generator. Sacral nerve stimulation promoted recovery of colitis demonstrated by decreased disease activity index, myeloperoxidase activity, tissue TNF-alpha, and histological scores as well as an increased colonic M2 macrophage population. Heart rate variability analysis demonstrated a decrease in low frequency and increase in high frequency with SNS, corresponding to increased vagal tone. Additionally, plasma pancreatic peptide was increased and norepinephrine was decreased after SNS in colitis while colon tissue acetylcholine was increased with SNS. This is the first study to the best of our knowledge that demonstrates the benefit of SNS with autonomic mediation. SNS alters the expression of inflammatory cytokines and macrophages as well as modulates neurotransmitters involved in systemic inflammation.

Effects and Mechanisms of Vagal Nerve Stimulation on Body Weight in Diet-Induced Obese Rats.

BACKGROUND: Vagal nerve stimulation (VNS) has recently been indicated as a novel method for treating obesity. However, the optimal stimulation parameters were unknown and mechanisms were poorly understood. The aim of this study was to investigate the effects of VNS on food intake and body weight in diet-induced obesity (DIO) rats and its possible mechanism involving autonomic functions and gut hormones. METHODS: Ten control rats and 16 DIO rats were chronically implanted with one pair of electrodes in the subdiaphragmatic vagal nerve. VNS with different stimulation parameters and sham-VNS were performed in control rats. In a chronic study, 8 DIO rats were applied with VNS and another 8 DIO rats were treated with sham-VNS for 4 weeks. Food intake, body weight, gastric emptying, heart rate variability (HRV), and gut hormones were evaluated. RESULTS: In DIO rats, the food intake (p < 0.001) and body weight (p < 0.001) were significantly decreased in the VNS group, compared with the sham-VNS group. VNS decreased the sympathovagal ratio (p = 0.003) and increased vagal activity (p = 0.032) assessed from the spectral analysis of HRV. It also increased plasma levels of glucagon-like peptide-1 (p = 0.012), polypeptide YY (p = 0.008), and pancreatic polypeptide (p = 0.008) in DIO rats. Physiologically, VNS delayed solid gastric emptying (p < 0.001) and increased gastric volume (p = 0.004). CONCLUSION: VNS with appropriate parameters reduced food intake and body weight by delaying gastric emptying mediated via the enhancement of vagal activity and release of anorexigenic hormones.

Sacral nerve stimulation with appropriate parameters improves constipation in rats by enhancing colon motility mediated via the autonomic-cholinergic mechanisms.

Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, its effects are limited, and mechanisms are largely unknown. We investigated the effects and mechanism of SNS with appropriate parameters on constipation in rats treated with loperamide. First, using rectal compliance as an outcome measure, an experiment was performed to derive effective SNS parameters. Then, a 7-day SNS was performed in rats with constipation induced by loperamide. Autonomic functions were assessed by spectral analysis of heart rate variability (HRV) derived from an electrocardiogram. Serum levels of pancreatic polypeptide (PP), norepinephrine (NE), and acetylcholine (ACh) in colon were assessed. 1) Acute SNS at 5 Hz, 100 µs was found effective in enhancing rectal compliance and accelerating distal colon transit (P < 0.05 vs. sham SNS). 2) The 7-day SNS normalized loperamide-induced constipation, assessed by the number, weight, and water content of fecal pellets, and accelerated the distal colon transit (29.4 ± 3.7 min with sham SNS vs. 16.4 ± 5.3 min with SNS but not gastric emptying or intestinal transit. 3) SNS significantly increased vagal activity (P = 0.035) and decreased sympathetic activity (P = 0.012), assessed by spectral analysis of HRV as well as by the serum PP. 4) SNS increased ACh in the colon tissue; atropine blocked the accelerative effect of SNS on distal colon transit. We concluded that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility, mediated via the autonomic-cholinergic function.NEW & NOTEWORTHY Although sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, effects are limited, and mechanisms are largely unknown. This paper shows that SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility mediated via the autonomic-cholinergic function.