Inhibited postprandial retrograde cyclic motor pattern in the distal colon of patients with diarrhea-predominant irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) have recurrent lower abdominal pain, associated with altered bowel habit (diarrhea and/or constipation). As bowel habit is altered, abnormalities in colonic motility are likely to contribute; however, characterization of colonic motor patterns in patients with IBS remains poor. Utilizing fiber-optic manometry, we aimed to characterize distal colonic postprandial colon motility in diarrhea-predominant IBS. After an overnight fast, a 72-sensor (spaced at 1-cm intervals) manometry catheter was colonoscopically placed to the proximal colon, in 13 patients with IBS-D and 12 healthy adults. Recordings were taken for 2 h pre and post a 700 kcal meal. Data were analyzed with our two developed automated techniques. In both healthy adults and patients with IBS-D, the dominant frequencies of pressure waves throughout the colon are between 2 and 4 cycles per minute (cpm) and the power of these frequencies increased significantly after a meal. Although these pressure waves formed propagating contractions in both groups, the postprandial propagating contraction increase was significantly smaller in patients compared with healthy adults. In healthy adults during the meal period, retrograde propagation between 2 and 8 cpm was significantly greater than antegrade propagation at the same frequencies. This difference was not observed in IBS-D. Patients with IBS-D show reduced prevalence of the retrograde cyclic motor pattern postprandially compared with the marked prevalence in healthy adults. We hypothesize that this reduction may allow premature rectal filling, leading to postprandial urgency and diarrhea.NEW & NOTEWORTHY Compared with healthy adults this study has shown a significant reduction in the prevalence of the postprandial retrograde cyclic motor pattern in the distal colon of patients with diarrhea-predominant irritable bowel syndrome. We hypothesize that this altered motility may allow for premature rectal filling which contributes to the postprandial urgency and diarrhea experienced by these patients.

Mechanisms underlying initiation of propulsion in guinea pig distal colon.

Colonic motor complexes (CMCs) are a major neurogenic activity in guineapig distal colon. The identity of the enteric neurons that initiate this activity is not established. Specialized intrinsic primary afferent neurons (IPANs) are a major candidate. We aimed to test this hypothesis. To do this, segments of guineapig distal colon were suspended vertically in heated organ baths and propulsive forces acting on a pellet inside the lumen were recorded by isometric force transducer while pharmacological agents were applied to affect IPAN function. In the absence of drugs, CMCs acted periodically on the pellet, generating peak propulsive forces of 12.7 ± 5 g at 0.56 ± 0.22 cpm, lasting 49 ± 17 s (215 preparations; n = 60). Most but not all CMCs were abolished by nicotinic receptor blockade to inhibit fast excitatory synaptic transmission (50/62 preparations; n = 25). Remarkably, CMCs inhibited by hexamethonium were restored by a pharmacological strategy that aimed to enhance IPAN excitability. Thus, CMCs were restored by increased smooth muscle tension (using BAY K8644, bethanechol or carbachol) and by IPAN excitation using phorbol dibutyrate; NK3 receptor agonist, senktide; and partially by αCGRP. The IPAN inhibitor, 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazole-2-one (DCEBIO), decreased CMC frequency. CGRP, but not NK3-receptor antagonists, decreased CMC frequency in naive preparations. Finally, CMCs were blocked by tetrodotoxin, and this was not reversed by any drugs listed above. These results support a major role for IPANs that does not require fast synaptic transmission, in the periodic initiation of neurogenic propulsive contractions. Endogenous CGRP plays a role in determining CMC frequency, whereas further unidentified signaling pathways may determine their amplitude and duration.NEW & NOTEWORTHY The colonic motor complex (CMC) initiates propulsion in guinea pig colon. Here, CMCs evoked by an intraluminal pellet were restored during nicotinic receptor blockade by pharmacological agents that directly or indirectly enhance intrinsic primary afferent neuron (IPAN) excitability. IPANs are the only enteric neuron in colon that contain CGRP. Blocking CGRP receptors decreased CMC frequency, implicating their role in CMC initiation. The results support a role for IPANs in the initiation of CMCs.

Abnormal Perception of Urge to Defecate: An Important Pathophysiological Mechanism in Women With Chronic Constipation.

INTRODUCTION: Although the association of absent or attenuated "call to stool" with constipation is well-recognized, no studies have systematically evaluated the perception of urge to defecate in a well-defined cohort of patients with chronic constipation (CC). METHODS: A prospective study of 43 healthy adult women and 140 consecutive adult women attending a tertiary center for investigation of CC. All participants completed a 5-day viscerosensory questionnaire, and all women with CC also underwent anorectal physiologic investigations. Normal urge perception and abnormal urge perception were defined using a Naive Bayes model trained in healthy women (95% having normal urge). RESULTS: In total, 181 toilet visits in healthy women and 595 in women with CC were analyzed. Abnormal urge perception occurred in 70 (50.0%) women with CC. In this group, the urge to defecate was more often experienced as abdominal sensation (69.3% vs 41.4%; P < 0.0001), and the viscerosensory referral area was 81% larger (median pixels anterior: 1,849 vs 1,022; P < 0.0001) compared to women with CC and normal urge perception. Abnormal (vs normal) urge in women with CC was associated with more severe constipation (Cleveland Clinic constipation score: 19 vs 15 P < 0.0001), irritable bowel syndrome (45.7% vs 22.9% P < 0.0001), and a functional evacuation disorder on defecography (31.3% vs 14.3% P = 0.023). A distinct pattern of abnormal urge was found in women with CC and rectal hyposensitivity. DISCUSSION: Abnormal urge perception was observed in 50% of women with CC and was frequently described as abdominal sensation, supporting the concept that sensory dysfunction makes an important contribution to the pathophysiology of constipation.

Faecal incontinence is associated with an impaired rectosigmoid brake and improved by sacral neuromodulation.

BACKGROUND: The rectosigmoid brake, characterised by retrograde cyclic motor patterns on high-resolution colonic manometry, has been postulated as a contributor to the maintenance of bowel continence. Sacral neuromodulation (SNM) is an effective therapy for faecal incontinence, but its mechanism of action is unclear. This study aims to investigate the colonic motility patterns in the distal colon of patients with faecal incontinence, and how these are modulated by SNM. METHODS: A high-resolution fibreoptic colonic manometry catheter, containing 36 sensors spaced at 1-cm intervals, was positioned in patients with faecal incontinence undergoing stage 1 SNM. One hour of pre- and post meal recordings were obtained followed by pre- and post meal recordings with suprasensory SNM. A 700-kcal meal was given. Data were analysed to identify propagating contractions. RESULTS: Fifteen patients with faecal incontinence were analysed. Patients had an abnormal meal response (fewer retrograde propagating contractions compared to controls; p = 0.027) and failed to show a post meal increase in propagating contractions (mean 17 ± 6/h premeal vs. 22 ± 9/h post meal, p = 0.438). Compared to baseline, SNM significantly increased the number of retrograde propagating contractions in the distal colon (8 ± 3/h premeal vs. 14 ± 3/h premeal with SNM, p = 0.028). Consuming a meal did not further increase the number of propagating contractions beyond the baseline upregulating effect of SNM. CONCLUSION: The rectosigmoid brake was suppressed in this cohort of patients with faecal incontinence. SNM may exert a therapeutic effect by modulating this rectosigmoid brake.

Colonic Response to Physiological, Chemical, Electrical and Mechanical Stimuli; What Can Be Used to Define Normal Motility?

The colon plays an important functional role in the bacterial fermentation of carbohydrates, transmural exchange of fluid and short-chain fatty acids, and the formation, storage and evacuation of faeces and gaseous contents. Coordinated colonic motor patterns are essential for these functions to occur. Our understanding of human colonic motor patterns has largely come through the use of various forms of colonic manometry catheters, combined with a range of stimuli, both physiological and artificial. These stimuli are used in patients with colonic disorders such as constipation, irritable bowel syndrome and faecal incontinence to understand the pathophysiology mechanisms that may cause the disorder and/or the associated symptoms. However, our understanding of a "normal" colonic response remains poor. This review will assess our understanding of the normal colonic response to commonly used stimuli in short duration studies (<8 hrs) and the mechanisms that control the response.

Luminal Chemoreceptors and Intrinsic Nerves: Key Modulators of Digestive Motor Function.

This chapter reviews data on the pathways by which luminal, mainly duodenal, chemoreceptors modulate gastro-pyloro-duodenal motor function to control emptying of nutrients into the small intestine. The vagus mediates proximal gastric relaxation caused by nutrient stimulation of duodenal/jejunal mucosal chemoreceptors. Modulation of the spatial patterning and inhibition of antral contractions during duodenal chemoreceptor activation are somewhat conflicting: both vagal control and ascending intramural nerves appear to play a role. Intraduodenal nutrients stimulate the localized pyloric contractions that prevent transpyloric flow via ascending duodenal intramural nerve pathways. Though not yet formally investigated, patterns of activation of the duodenal brake motor mechanism suggest that duodenal loop mucosal chemoreceptors signal to a brake mechanism at the most aborad region of the duodenum via descending intramural duodenal nerves.Intrinsic intramural pathways are important in the control of the first stages of digestion.

Analysis of Intestinal Movements with Spatiotemporal Maps: Beyond Anatomy and Physiology.

Over 150 years ago, methods for quantitative analysis of gastrointestinal motor patterns first appeared. Graphic representations of physiological variables were recorded with the kymograph after the mid-1800s. Changes in force or length of intestinal muscles could be quantified, however most recordings were limited to a single point along the digestive tract.In parallel, photography and cinematography with X-Rays visualised changes in intestinal shape, but were hard to quantify. More recently, the ability to record physiological events at many sites along the gut in combination with computer processing allowed construction of spatiotemporal maps. These included diameter maps (DMaps), constructed from video recordings of intestinal movements and pressure maps (PMaps), constructed using data from high-resolution manometry catheters. Combining different kinds of spatiotemporal maps revealed additional details about gut wall status, including compliance, which relates forces to changes in length. Plotting compliance values along the intestine enabled combined DPMaps to be constructed, which can distinguish active contractions and relaxations from passive changes. From combinations of spatiotemporal maps, it is possible to deduce the role of enteric circuits and pacemaker cells in the generation of complex motor patterns. Development and application of spatiotemporal methods to normal and abnormal motor patterns in animals and humans is ongoing, with further technical improvements arising from their combination with impedance manometry, magnetic resonance imaging, electrophysiology, and ultrasonography.

Identifying Types of Neurons in the Human Colonic Enteric Nervous System.

Distinguishing and characterising the different classes of neurons that make up a neural circuit has been a long-term goal for many neuroscientists. The enteric nervous system is a large but moderately simple part of the nervous system. Enteric neurons in laboratory animals have been extensively characterised morphologically, electrophysiologically, by projections and immunohistochemically. However, studies of human enteric nervous system are less advanced despite the potential availability of tissue from elective surgery (with appropriate ethics permits). Recent studies using single cell sequencing have confirmed and extended the classification of enteric neurons in mice and human, but it is not clear whether an encompassing classification has been achieved. We present preliminary data on a means to distinguish classes of myenteric neurons in specimens of human colon combining immunohistochemical, morphological, projection and size data on single cells. A method to apply multiple layers of antisera to specimens was developed, allowing up to 12 markers to be characterised in individual neurons. Applied to multi-axonal Dogiel type II neurons, this approach demonstrated that they constitute fewer than 5% of myenteric neurons, are nearly all immunoreactive for choline acetyltransferase and tachykinins. Many express the calcium-binding proteins calbindin and calretinin and they are larger than average myenteric cells. This methodology provides a complementary approach to single-cell mRNA profiling to provide a comprehensive account of the types of myenteric neurons in the human colon.

Novel intrinsic neurogenic and myogenic mechanisms underlying the formation of faecal pellets along the large intestine of guinea-pigs.

Soft faecal material is transformed into discrete, pellet-shaped faeces at the colonic flexure. Here, analysis of water content in natural faecal material revealed a decline from cecum to rectum without significant changes at the flexure. Thus, pellet formation is not explained by changes in viscosity alone. We then used video imaging of colonic wall movements with electromyography in isolated preparations containing guinea-pig proximal colon, colonic flexure and distal colon. To investigate the pellet formation process, the colonic segments were infused with artificial contents (Krebs solution and 4-6% methylcellulose) to simulate physiological faecal content flow. Remarkably, pellet formation took place in vitro, without extrinsic neural inputs. Infusion evoked slowly propagating neurogenic contractions, the proximal colon migrating motor complexes (∼0.6 cpm), which initiated pellet formation at the flexure. Lesion of the flexure, but not the proximal colon, disrupted the formation of normal individual pellets. In addition, a distinct myogenic mechanism was identified, whereby slow phasic contractions (∼1.9 cpm) initiated at the flexure and propagated short distances retrogradely into the proximal colon and antegradely into the distal colon. There were no detectable changes in the density or distribution of pacemaker-type interstitial cells of Cajal across the flexure. The findings provide new insights into how solid faecal content is generated, suggesting the major mechanisms underlying faecal pellet formation involve the unique interaction at the colonic flexure between antegrade proximal colon migrating motor complexes, organized by enteric neurons, and retrograde myogenic slow phasic contractions. Additional, as yet unidentified extrinsic and/or humoral influences appear to contribute to processing of faecal content in vivo. KEY POINTS: In herbivores, including guinea-pigs, clearly defined faecal pellets are formed at a distinct location along the large intestine (colonic flexure). The mechanism underlying the formation of these faecal pellets at this region has remained unknown. We reveal a progressive and gradual reduction in water content of faecal content along the bowel. Hence, the distinct transition from amorphous to pellet shaped faecal content could not be explained by a dramatic increase in water reabsorption from a specific site. We discovered patterns of anterograde neurogenic and retrograde myogenic motor activity that facilitate the formation of faecal pellets. The formation of 'pellet-like' boluses at the colonic flexure involves interaction of an antegrade migrating motor complex in the proximal colon and retrograde myogenic slow phasic contractions that emerge from the colonic flexure. The findings uncover intrinsic mechanisms responsible for the formation of discrete faecal scybala in the large intestine of a vertebrate.

Duodenal and proximal jejunal motility inhibition associated with bisacodyl-induced colonic high-amplitude propagating contractions.

Bisacodyl is a stimulant laxative often used in manometric studies of pediatric constipation to determine if it can initiate propulsive high-amplitude propagating contractions (HAPCs). Whereas the effects of bisacodyl infusion on colonic motility are well described, the effects of the drug on other regions of the gut after colonic infusion are not known. The aim of the present study was to characterize the effects of bisacodyl on both colonic and small bowel motility. Twenty-seven children (9.3 ± 1.2 yr) undergoing simultaneous high-resolution antroduodenal and colonic manometry were included. Small bowel and colonic motor patterns were assessed before and after colonic infusion of bisacodyl. Patients were divided into two groups: responders and nonresponders based on the presence of high-amplitude propagating contractions (HAPCs) after bisacodyl infusion. Nineteen patients were responders. A total of 188 postbisacodyl HAPCs was identified with a mean count of 10.4 ± 5.5 (range, 3-22), at a frequency of 0.6 ± 0.2/min and mean amplitude of 119.8 ± 23.6 mmHg. No motor patterns were induced in the small bowel. However, in the 19 responders the onset of HAPCs was associated with a significant decrease in small bowel contractile activity. In the nonresponders, there was no detectable change in small bowel motility after bisacodyl infusion. Bisacodyl-induced HAPCs are associated with a significant reduction in small bowel motility probably mediated by extrinsic sympathetic reflex pathways. This inhibition is potentially related to rectal distension, caused by the HAPC anal propulsion of colonic content.NEW & NOTEWORTHY The present study has shown, for the first time, that the presence of high-amplitude propagating contractions induced by bisacodyl is associated with a significant reduction in small bowel motility. These findings support of possible existence of a reflex pathway that causes inhibition of small bowel motility in response to rectal distension.

Altered colonic motility is associated with low anterior resection syndrome.

AIM: Patients frequently suffer from low anterior resection syndrome (LARS) after distal colorectal resection. The pathophysiology of LARS has not been clearly elucidated. We hypothesized that rectosigmoid resection could impair motility patterns in the distal colon, such as the rectosigmoid brake, which contribute to control of stool form and frequency. METHOD: High-resolution colonic manometry was performed in patients who had previously undergone distal colorectal resection (mean 6.8 years after resection) and non-operative controls before and after a standardized meal. Symptoms were assessed using the LARS score. Propagating contractions were compared between patients with and without LARS, and controls. RESULTS: Data were analysed from 23 patients (11 no-LARS; 12 LARS) and nine controls. All groups demonstrated a significant meal response. LARS patients had fewer post-prandial antegrade propagating contractions than controls (P = 0.028), and fewer retrograde propagating contractions both pre- (P = 0.005) and post-prandially (P = 0.004). Post-prandially, the LARS group had a significantly lower percentage of propagating contractions that met the criteria for the cyclic motor pattern compared to the control group (26% vs. 58%; P = 0.009). There were significant differences in antegrade and retrograde amplitude (P = 0.049; P = 0.018) and distance of propagation (P = 0.003; P = 0.002) post-prandially between LARS patients and controls. CONCLUSION: Rectosigmoid resection alters the meal response following anterior resection, including impairment of the rectosigmoid brake cyclic motor pattern. These findings help to quantify the impaired functional motility after rectosigmoid resection and offer new insights into the mechanisms of LARS.

Altered anal slow-wave pressure activity in low anterior resection syndrome: short case series in two independent specialist centres provide new mechanistic insights.

AIM: Conventional parameters (anal resting and squeeze pressures) measured with anorectal manometry (ARM) fail to identify anal sphincter dysfunction in many patients with low anterior resection syndrome (LARS). We aimed to assess whether there are differences in anal canal slow-wave pressure activity in LARS patients and healthy individuals. METHOD: High-resolution ARM (HR-ARM) traces of 21 consecutive male LARS patients referred to the Royal London Hospital, UK (n = 12) and Aarhus University Hospital, Denmark (n = 9) were compared with HR-ARM data from 37 healthy men. RESULTS: Qualitatively (by visual inspection of HR-ARM recordings), the frequency of slow-wave pressure activity was strikingly different in 11/21 (52.4%) LARS patients from that observed in all the healthy individuals. Quantitative analysis showed that peaks of the mean spectrum in these 11 LARS patients occurred at approximately 6-7 cycles per minute (cpm), without activity at higher frequencies. An equivalent pattern was found in only 2/37 (5.4%) healthy individuals (P < 0.0001). Peaks of the mean spectrum in healthy individuals were concentrated at 16 cpm and 3-4 cpm. CONCLUSION: Over half of the male LARS patients studied had altered anal slow-wave pressure activity based on analysis of HR-ARM recordings. Further studies could investigate the relative contributions of sex, human baseline variance and neoadjuvant/surgical therapies on anal slow waves, and correlate the presence of abnormal activity with symptom severity.

High-Resolution Colonic Manometry Pressure Profiles Are Similar in Asymptomatic Diverticulosis and Controls.

BACKGROUND: Elevated colonic pressures and increased colonic activity have been thought to contribute to the pathophysiology of diverticulosis. However, evidence for this has been limited to low-resolution manometry, which is of limited accuracy. AIMS: This study aimed to evaluate the contraction pressures, counts, and distance of propagation recorded by high-resolution colonic manometry in diverticulosis vs control patients. METHODS: High-resolution colonic manometry was used to record descending and sigmoid colon activity pre- and post-meal in patients with established, asymptomatic diverticulosis and in healthy controls. Antegrade and retrograde propagating contractions, distance of propagation (mm), and mean contraction pressures (mmHg) in the descending and sigmoid colon were compared between patients and controls for all isolated propagating contractions, the cyclic motor pattern, and high-amplitude propagating contractions independently. RESULTS: Mean manometry pressures were not different between controls and diverticulosis patients (p > 0.05 for all comparisons). In the descending colon, diverticulosis patients had lower post-meal mean distance of propagation for all propagating contractions [10.8 (SE1.5) mm vs 20.0 (2.0) mm, p = 0.003] and the cyclic motor pattern [6.0 (2.5) mm vs 17.1 (2.8) mm, p = 0.01]. In the sigmoid colon, diverticulosis patients showed lower post-meal mean distance of propagation for all propagating contractions [10.8 (1.5) mm vs 20.2 (5.9) mm, p = 0.01] and a lower post-meal increase in retrograde propagating contractions (p = 0.04). CONCLUSIONS: In this first high-resolution colonic manometry study of patients with diverticular disease, we did not find evidence for increased manometric pressures or increased colonic activity in patients with diverticular disease.

Changes in specific esophageal neuromechanical wall states are associated with conscious awareness of a solid swallowed bolus in healthy subjects.

Esophageal neuromechanical wall states are the physical manifestations of circular muscle inhibition and contraction resulting from neural inputs and leading to bolus propulsion. A novel method infers esophageal neuromechanical wall states through simultaneous determination of pressure and diameter in vivo using impedance manometry. We hypothesized that changes in esophageal neuromechanical wall states relate to conscious awareness of esophageal bolus passage ("bolus perception"). Seven healthy participants were selected for perception of solid bolus passage and were compared with seven healthy participants with no conscious awareness of solid bolus passage. Participants were studied using impedance manometry (MMS Solar, Unisensor, 20 Hz). Subjects swallowed ten 5-ml liquid and ten 2-cm square saline-soaked bread boluses and rated bolus perception using a visual analog scale. Esophageal neuromechanical wall states were calculated and analyzed. Proportions of time spent in states with and without luminal distension were compared using a two-proportions Z-test. Bolus perception was associated with neuromechanical wall states corresponding to luminal distension more frequently than matching states without distension in the proximal esophagus (P < 0.001) and transition zone (P < 0.001), whereas there were no differences for the distal esophagus. In healthy volunteers, perceived swallows relate to changes in esophageal neuromechanical wall states in the proximal esophagus. We postulate that these changes relate to bolus retention and summation of active and passive wall tension activating intramural tension receptors.NEW & NOTEWORTHY This study explores esophageal neuromechanical wall states derived from changes in pressure and impedance-derived distension in relation to conscious awareness of esophageal solid bolus transit in healthy volunteers. There are increases in neuromechanical wall states indicative of esophageal distension in healthy volunteers with conscious awareness of bolus transit as compared with unaware individuals. Bolus-based esophageal distension is postulated as a mechanism for esophageal symptoms such as dysphagia.

Diversity of neurogenic smooth muscle electrical rhythmicity in mouse proximal colon.

The mechanisms underlying electrical rhythmicity in smooth muscle of the proximal colon are incompletely understood. Our aim was to identify patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated whole mouse colon and characterize their mechanisms of origin. Two independent extracellular recording electrodes were used to record the patterns of electrical activity in smooth muscle of the proximal region of whole isolated mouse colon. Cross-correlation analysis was used to quantify spatial coordination of these electrical activities over increasing electrode separation distances. Four distinct neurogenic patterns of electrical rhythmicity were identified in smooth muscle of the proximal colon, three of which have not been identified and consisted of bursts of rhythmic action potentials at 1-2 Hz that were abolished by hexamethonium. These neurogenic patterns of electrical rhythmicity in smooth muscle were spatially and temporally synchronized over large separation distances (≥2 mm rosto-caudal axis). Myogenic slow waves could be recorded from the same preparations, but they showed poor spatial and temporal coordination over even short distances (≤1 mm rostro-caudal axis). It is not commonly thought that electrical rhythmicity in gastrointestinal smooth muscle is dependent upon the enteric nervous system. Here, we identified neurogenic patterns of electrical rhythmicity in smooth muscle of the proximal region of isolated mouse colon, which are dependent on synaptic transmission in the enteric nervous system. If the whole colon is studied in vitro, recordings can preserve novel neurogenic patterns of electrical rhythmicity in smooth muscle.NEW & NOTEWORTHY Previously, it has not often been thought that electrical rhythmicity in smooth muscle of the gastrointestinal tract is dependent upon the enteric nervous system. We identified patterns of electrical rhythmicity in smooth muscle of the mouse proximal colon that were abolished by hexamethonium and involved the temporal synchronization of smooth muscle membrane potential over large spatial fields. We reveal different patterns of electrical rhythmicity in colonic smooth muscle that are dependent on the ENS.

Placebo Response Rates in Electrical Nerve Stimulation Trials for Fecal Incontinence and Constipation: A Systematic Review and Meta-Analysis.

BACKGROUND: Successful treatments following electrical nerve stimulation have been commonly reported in patients with fecal incontinence and constipation. However, many of these nerve stimulation trials have not implemented sham controls, and are, therefore, unable to differentiate overall treatment responses from placebo. This systematic review aimed to quantify placebo effects and responses following sham electrical nerve stimulation in patients with fecal incontinence and constipation. MATERIAL AND METHODS: A literature search of Ovid MEDLINE, PubMed, EMBASE, and Cochrane databases was conducted from inception to April 2017. Randomized sham-controlled trials investigating the effect of lower gastrointestinal electrical nerve stimulation in fecal incontinence and constipation were included. Pediatric and non-sham controlled trials were excluded. RESULTS: Ten randomized sham-controlled trials were included. Sham stimulation resulted in improvements in fecal incontinence episodes by 1.3 episodes per week (95% CI -2.53 to -0.01, p = 0.05), fecal urgency by 1.5 episodes per week (CI -3.32 to 0.25, p = 0.09), and Cleveland Clinic Severity scores by 2.2 points (CI 1.01 to 3.36, p = 0.0003). Sham also improved symptoms of constipation with improved stool frequency (1.3 episodes per week, CI 1.16 to 1.42, p < 0.00001), Wexner Constipation scores (5.0 points, CI -7.45 to -2.54 p < 0.0001), and Gastrointestinal Quality of Life scores (7.9 points, CI -0.46 to 16.18, p = 0.06). CONCLUSIONS: Sham stimulation is associated with clinical and statistically meaningful improvements in symptoms of fecal incontinence and constipation, as well as quality of life scores, highlighting the importance of sham controls in nerve stimulation trials. Noncontrolled studies should be interpreted with caution.

Identification of a Rhythmic Firing Pattern in the Enteric Nervous System That Generates Rhythmic Electrical Activity in Smooth Muscle.

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (∼7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ∼2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs.SIGNIFICANCE STATEMENT How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known that myogenic pacemaker cells exist in the GI tract [called interstitial cells of Cajal (ICCs)] that generate rhythmic myogenic contractions. However, the mechanisms underlying the generation of rhythmic neurogenic contractions of smooth muscle in the GI tract remains unknown. We developed a high-resolution neuronal imaging method with electrophysiology to address this issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI tract.

Roles of three distinct neurogenic motor patterns during pellet propulsion in guinea-pig distal colon.

KEY POINTS: Enteric neural circuits enable isolated preparations of guinea-pig distal colon to propel solid and fluid contents by a self-sustaining neuromechanical loop process. In addition there are at least three neural mechanisms which are not directly involved in propulsion: cyclic motor complexes, transient neural events and distal colon migrating motor complexes. In excised guinea-pig colon we simultaneously recorded high resolution manometry, video-imaging of colonic wall movements and electrophysiological recordings from smooth muscle, which enabled us to identify mechanisms that underlie the propulsion of colonic content. The results show that the intermittent propulsion during emptying of the multiple natural faecal pellets is due to the intermittent activation of cyclic motor complexes and this is facilitated by transient neural events. Loss or dysfunction of these activities is likely to underlie disordered gastrointestinal transit. ABSTRACT: It is well known that there are different patterns of electrical activity in smooth muscle cells along different regions of the gastrointestinal tract. These different patterns can be generated by myogenic and/or neurogenic mechanisms. However, what patterns of electrical activity underlie the propulsion of natural faecal content remains unknown, particularly along the large intestine, where large quantities of water are reabsorbed and semi-solid faeces form. In this study, we developed a novel approach which enables for the first time the simultaneous recording of high resolution intraluminal manometry, electrophysiology from the smooth muscle, and spatio-temporal video imaging of colonic wall movements. Using this approach we were able to reveal the nature of enteric neuromuscular transmission and patterns of motor activity responsible for the movement of content. Three distinct neurogenic patterns of electrical activity were recorded even in the absence of propulsive movement. These were the cyclic motor complexes (CMCs), the transient neural events (TNEs) and the slowly propagating distal colonic migrating motor complexes (DCMMCs). We present evidence that the initiation of pellet propulsion is due to a cyclic motor complex (CMC) occurring oral to the pellet. Furthermore, we discovered that the intermittent propulsion of natural faecal pellets is generated by intermittent activation of CMCs; and this propulsion is facilitated by hexamethonium-sensitive TNEs. However, TNEs were not required for propulsion. The findings reveal the patterns of electrical activity that underlie propulsion of natural colonic content and demonstrate that propulsion is generated by a complex interplay between distinct enteric neural circuits.

Identification of multiple distinct neurogenic motor patterns that can occur simultaneously in the guinea pig distal colon.

In the guinea pig distal colon, nonpropulsive neurally mediated motor patterns have been observed in different experimental conditions. Isolated segments of guinea pig distal colon were used to investigate these neural mechanisms by simultaneously recording wall motion, intraluminal pressure, and smooth muscle electrical activity in different conditions of constant distension and in response to pharmacological agents. Three distinct neurally dependent motor patterns were identified: transient neural events (TNEs), cyclic motor complexes (CMC), and distal colon migrating motor complexes (DCMMC). These could occur simultaneously and were distinguished by their electrophysiological, mechanical, and pharmacological features. TNEs occurred at irregular intervals of ~3s, with bursts of action potentials at 9 Hz. They propagated orally at 12 cm/s via assemblies of ascending cholinergic interneurons that activated final excitatory and inhibitory motor neurons, apparently without involvement of stretch-sensitive intrinsic primary afferent neurons. CMCs occurred during maintained distension and consisted of clusters of closely spaced TNEs, which fused to cause high-frequency action potential firing at 7 Hz lasting ~10 s. They generated periodic pressure peaks mediated by stretch-sensitive intrinsic primary afferent neurons and by cholinergic interneurons. DCMMCs were generated by ongoing activity in excitatory motor neurons without apparent involvement of stretch-sensitive neurons, cholinergic interneurons, or inhibitory motor neurons. In conclusion, we have identified three distinct motor patterns that can occur concurrently in the isolated guinea pig distal colon. The mechanisms underlying the generation of these neural patterns likely involve recruitment of different populations of enteric neurons with distinct temporal activation properties.

The relationship between residual sphincter damage after primary repair, faecal incontinence, and anal sphincter function in primiparous women with an obstetric anal sphincter injury.

BACKGROUND AND AIMS: Anal sphincter injury has been identified as a primary cause of post-partum fecal incontinence in women with obstetric anal sphincter injury. However, women without obstetric anal sphincter injury may also develop fecal incontinence. The aim is to determine the relationship between fecal incontinence severity; and i) residual anal sphincter injury, quantified by the Starck score, and ii) anal sphincter tone. METHODS: Consecutive case series of prospectively collected data set in a Pelvic Floor Unit within a tertiary teaching hospital in Australia. Population 181 primiparous women with Sultan classification Grade 3 and 4 sphincter injuries. MAIN OUTCOME MEASURES: Sultan classification, anal manometry, pudendal nerve terminal motor latency, St Mark's fecal incontinence score, and Starck ultrasound score. RESULTS: 45% of women reported some degree of fecal incontinence. One third of women with normal external sphincter tone were incontinent. Those with higher Starck score had higher St Mark's scores. A higher Sultan classification correlated with more severe incontinence regardless if the repair was complete. Forceps delivery had a twofold risk of incontinence when compared to non-forceps delivery. CONCLUSION: The importance of an effective anal sphincter repair is confirmed. However, overall there is no direct relationship between residual sphincter damage, anal sphincter tone, and fecal incontinence severity. These data indicate that anal sphincter integrity alone is not the sole mechanism for maintaining fecal continence. Rectal and colonic motor function may also play a role and investigation into these components may provide greater insight into the effect of vaginal delivery upon fecal continence mechanisms.