Fecobionics in proctology: review and perspectives.

Fecobionics is a novel integrated technology for assessment of anorectal function. It is a defecatory test with simultaneous measurements of pressures, orientation, and device angle (a proxy of the anorectal angle). Furthermore, the latest Fecobionics prototypes measure diameters (shape) using impedance planimetry during evacuation of the device. The simultaneous measurement of multiple variables in the integrated test allows new metrics to be developed including more advanced novel defecation indices, enabling mechanistic insight in the defecation process at an unprecedented level in patients with anorectal disorders including patients suffering from obstructed defecation, fecal incontinence, and low anterior resection syndrome. The device has the consistency and shape of a normal stool (type 3-4 on the Bristol Stool Form Scale). Fecobionics has been validated on the bench and in animal studies and used in clinical trials to study defecation phenotypes in normal human subjects and patients with obstructed defecation, fecal incontinence, and low anterior resection syndrome after rectal cancer surgery. Subtypes have been defined, especially of patients with obstructed defecation. Furthermore, Fecobionics has been used to monitor biofeedback therapy in patients with fecal incontinence to predict the outcome of the therapy (responder versus non-responder). Most Fecobionics studies showed a closer correlation to symptoms as compared to current technologies for anorectal assessment. The present article outlines previous and ongoing work, and perspectives for future studies in proctology, including in physiological assessment of function, diagnostics, monitoring of therapy, and as a tool for biofeedback therapy.

New developments in defecatory studies based on biomechatronics.

Introduction: Defecation is a complex process that is difficult to study and analyze directly. In anorectal disease conditions, the defecation process may be disturbed, resulting in symptoms including fecal incontinence and constipation. Current state-of-the-art technology measures various aspects of anorectal function but detailed analysis is impossible because they are stand-alone tests rather than an integrated multi-dimensional test. Objectives: The need for physiologically-relevant and easy-to-use diagnostic tests for identifying underlying mechanisms is substantial. We aimed to advance the field with integrated technology for anorectal function assessment. Methods: We developed a simulated stool named Fecobionics that integrates several tests to assess defecation pressures, dimensions, shape, orientation and bending during evacuation. A novelty is that pressures are measured in axial direction, i.e. in the direction of the trajectory. Using this novel tool, we present new analytical methods to calculate physiologically relevant parameters during expulsion in normal human subjects. Results: Data are reported from 28 human subjects with progressively more advanced versions of Fecobionics. A new concept utilizes the rear-front pressure (preload-afterload) diagram for computation of novel defecation indices. Fecobionics obtained physiological data that cannot be obtained with current state-of-the-art technologies. Conclusion: Fecobionics measures well known parameters such as expulsion time and pressures as well as new metrics including defecation indices. The study suggests that Fecobionics is effective in evaluation of key defecatory parameters and well positioned as an integrated technology for assessment of anorectal function and dysfunction.

Novel bionics developments in gastroenterology: fecobionics assessment of lower GI tract function.

Biomechatronics (bionics) is an applied science that is interdisciplinary between biology and engineering (mechanical, electrical and electronics engineering). Biomechatronics covers a wide area and is probably best known in development of prosthetic limbs, vision aids, robotics and neuroscience. Although the gastrointestinal tract is difficult to study, it is particularly suited for a bionics approach as demonstrated by recent developments. Ingestible capsules that travel the tract and record physiological variables have been used in the clinic. Other examples include sacral nerve stimulators that seek to restore normal anorectal function. Recently, we developed a simulated stool termed fecobionics. It has the shape of normal stool and records a variety of parameters including pressures, bending (anorectal angle) and shape changes during colonic transit and defecation, i.e. it integrates several current tests. Fecobionics has been used to study defecation patterns in large animals as well as in humans (normal subjects and patient groups including patients with symptoms of obstructed defecation and fecal incontinence). Recently, it was applied in a canine colon model where it revealed patterns consistent with shallow waves originating from slow waves generated by the interstitial cells of Cajal. Furthermore, novel analysis such as the rear-front pressure (preload-afterload) diagram and quantification of defecation indices have been developed that enable mechanistic insight. This paper reviews the fecobionics technology and outlines perspectives for future applications.

Translating Fecobionics Into a Technique That Addresses Clinical Needs for Objective Perineal Descent Measurements.

INTRODUCTION: Perineal descent is a phenomenon associated with anorectal dysfunction. It is diagnosed by defecography but subjected to manual measurements on the images/videos and interobserver bias. Fecobionics is a simulated feces for assessing important physiological parameters during defecation. Here, we translate Fecobionics into a new method for estimation of perineal descent based on electronic signals from the embedded inertial measurement units (IMUs). METHODS: A displacement measurement method by a combined zero-velocity update and gravity compensation algorithm from IMUs was developed. The method was verified in a robot model, which mimicked perineal descent motion. RESULTS: The method correlated well with the reference (R = 0.9789) and had a deviation from the peak displacement (range 0.25-2.5 cm) of -0.04 ± 0.498 cm. The method was further validated in 5 human experiments with comparison to the benchmark defecography technology (R = 0.79). DISCUSSION: The proposed technology is objective, i.e., electronic measurements rather than by fluoroscopy or MRI. The development may impact clinical practice by providing a resource-saving and objective technology for diagnosing perineal descent in the many patients suffering from anorectal disorders. The technology may also be used in colon experiments with Fecobionics and for other gastrointestinal devices containing IMUs such as ingestible capsules like the Smartpill.

Fecobionics assessment of the effect of position on defecatory efficacy in normal subjects.

BACKGROUND: Defecation is a complex process and up to 25% of the population suffer from symptoms of defecatory dysfunction. For functional testing, diagnostics, and therapy of anorectal disorders, it is important to know the optimal defecation position. is The aim of this study was to evaluate defecation pressure patterns in side lying, seated and squatting defecation positions in normal subjects using a simulated stool device called Fecobionics. METHODS: The Fecobionics expulsion parameters were assessed in an interventional study design conducted from May 29 to December 9 2019. Subjects were invited to participate in the study through advertisement at The Chinese University of Hong Kong. The Fecobionics device consisted of a core containing pressure sensors at the front (caudal end) and rear (cranial end) and a polyester-urethane bag spanning most of the core length which also contained sensors. The Fecobionics bag was distended to 50 ml in the rectum of normal subjects (no present and past symptoms of defecatory disorders, no prior abdominal surgery, medication or chronic diseases). Studies were done in side lying (left lateral recumbent position), seated (hip flexed 90°) and squatting position (hip flexed 25°). Pressure endpoints including the rear-front pressure diagram and defecation indices were compared between positions. RESULTS: Twelve subjects (6 females/6 males, mean age 26.3 ± 2.6 [19.0-48.0] years) were included and underwent the planned procedures. The resting anal pressure for side lying and seated positions were 33.1 ± 4.1 cmH2O and 37.1 ± 4.0 cmH2O (p > 0.3). The anal squeeze pressure for side lying and seated positions were 98.4 ± 6.9 cmH2O and 142.3 ± 16.4 cmH2O (p < 0.05). The expulsion duration for the side lying, seated and squatting positions were 108.9 ± 8.3 s, 15.0 ± 2.1 s and 16.1 ± 2.9 s, respectively (p < 0.01 between lying and the two other positions). The maximum evacuation pressure for seated and squatting were 130.1 ± 12.4 cmH2O and 134.0 ± 11.1 cmH2O (p > 0.5). Rear-front pressure diagrams and distensibility indices demonstrated distinct differences in pressure patterns between the side lying position group and the other positions. CONCLUSIONS: The delay in expelling the Fecobionics device in the lying position was associated with dyssynergic pressure patterns on the device. Quantitative differences were not found between the seated and squatting position. Trial Registration http://www.clinicaltrials.gov Identifier: NCT03317938.

Theoretical Tools to Analyze Anorectal Mechanophysiological Data Generated by the Fecobionics Device.

A mechanical approach is needed for understanding anorectal function and defecation. Fecal continence is achieved by several interacting mechanisms including anatomical factors, anorectal sensation, rectal compliance, stool consistency, anal muscle strength, motility, and psychological factors. The balance is easily disturbed, resulting in symptoms such as fecal incontinence and constipation. Novel technologies have been developed in recent years for studying anorectal function. Especially, the Fecobionics device, a simulated feces, has gained attention recently. This facilitates new analysis of anorectal mechanical function. In this study, a theoretical model is developed to analyze anorectal mechanophysiological data generated by the Fecobionics device. Theoretical approaches can enhance future interdisciplinary research for unraveling defecatory function, sensory-motor disorders, and symptoms. This is a step in the direction of personalized treatment for gastrointestinal disorders based on optimized subtyping of anorectal disorders.

Blood Flow Regulates Zebrafish Caudal Vein Plexus Angiogenesis by ERK5-klf2a-nos2b Signaling.

BACKGROUND: Vascular network formation induced by angiogenesis plays an important role in many physiological and pathological processes. However, the role of blood flow and underlying mechanisms in vascular network formation, for example for the development of the caudal vein plexus (CVP), is poorly understood. OBJECTIVE: The aim of this study was to explore the role of ERK5-klf2a-nos2b signaling in the CVP angiogenesis. METHOD AND RESULTS: In this study on tnnt2a-MO injection and chemical blood flow modulator treatment in zebrafish embryos, we demonstrated that decreased blood flow disrupted CVP formation. The hemodynamic force was quantitatively analyzed. Furthermore, CVP angiogenesis in zebrafish embryos was inhibited by disruption of the blood flow downstream effectors ERK5, klf2a, and nos2b in response to treatment with the ERK5 specific inhibitor and to injection of klf2a-MO, nos2b-MO. Overexpression of klf2a mRNA or nos2b mRNA restored vascular defects in tnnt2a or klf2a morphants. The data suggest that flow-induced ERK5-klf2a-nos2b signaling is involved in CVP angiogenesis in zebrafish embryos. CONCLUSION: We have demonstrated that blood flow is essential for vascular network formation, specifically for CVP angiogenesis in zebrafish. A novel genetic and mechanical mechanism was discovered in which ERK5 facilitates the integration of blood flow with the downstream klf2a-nos2b signaling for CVP angiogenesis.

No beneficial effect of Polidocanol treatment in Achilles tendinopathy: a randomised controlled trial.

PURPOSE: Polidocanol injections have been used to treat chronic Achilles tendinopathy in clinical settings, but the few studies published show inconsistent results. The aim of this study was to evaluate the mid-term effect of Polidocanol in patients with chronic Achilles tendinopathy. It was hypothesised that patients treated with Polidocanol would have significant improvements in the outcome measures investigated compared to patients treated with a placebo treatment at mid-term follow-up. METHODS: This randomised controlled trial included forty-eight patients aged 32-77 years with a history of Achilles tendinopathy for at least 3 months and with neovascularisation demonstrated by ultrasonography was included. A minimum of 3 months of eccentric exercise treatment was required before participating. The patients were allocated to a maximum of two injection of either Polidocanol or Lidocaine (placebo). The primary outcome measure was pain during walking reported on a visual analogue scale. Secondary outcome measures were Foot and Ankle Outcome Score (FAOS), patient satisfaction with treatment and, shortly after inclusion, the Victorian Institute of Sports Assessment-Achilles questionnaire (VISA-A) was also included. Follow-up examinations were performed after 3 and 6 months. RESULTS: Pain during walking decreased during the 6-month follow-up period, but no significant differences were seen between the two groups. The same tendency was seen for FAOS and VISA-A in which both groups showed an improvement at 3- and 6-month follow-up, but no mid-term differences between the groups were seen. An equal number of patients in the two groups were satisfied with the treatment at follow-up. CONCLUSIONS: The results indicate that Polidocanol is a safe treatment, but the mid-term effects are the same as a placebo treatment. This further questions the use of Polidocanol in the treatment of chronic Achilles tendinopathy. LEVEL OF EVIDENCE: I.

Esophagogastric junction in systemic sclerosis: A study with the functional lumen imaging probe.

BACKGROUND: Fibrosis and atrophy of esophageal smooth muscle cells cause gastro-esophageal reflux and dysphagia in most patients with systemic sclerosis (SSc). Recent studies indicate that distensibility of the esophagogastric junction (EGJ), assessed with the Functional Lumen Imaging Probe (FLIP) may be a more sensitive and accurate measure of sphincter function than manometry. We aim to describe and compare distension parameters of the EGJ in a well-characterized group of patients with SSc. METHOD: Twelve patients with SSc reporting reflux or dysphagia (11 women, median age 53 [range 35-72], duration of disease: 1-20 years) were investigated using distensibility testing of the EGJ. Patients were compared with 11 healthy volunteers (HV) (10 women, median age 53 [range 40-68]). The pressure and minimum diameter along the EGJ during ramp distension were used for distensibility analysis. KEY RESULTS: Patients with SSc had significantly lower EGJ yield pressure (median: 4.0 mm Hg [Inter Quartile Range (IQR): 2.8-7.7]) than HV (median: 6.2 mm Hg [IQR: 9.4-26]) (P=.007). Likewise, the pressure-strain elastic modulus was lower in SSc patients (median 1.73 kPa [IQR: 1.16-2.15]) than in HV (median 2.41 kPa [IQR: 1.85-2.67]) (P=.03), indicating the reduced resistance to distension in SSc patient. CONCLUSION & INFERENCES: Patients with SSc and symptoms of reflux and dysphagia have significantly reduced resistance to distension of the EGJ.

Increased yield pressure in the anal canal during sacral nerve stimulation: a pilot study with the functional lumen imaging probe.

BACKGROUND: Sacral nerve stimulation (SNS) is a well-established treatment for fecal incontinence but its mode of action remains obscure. Anal sphincter function is usually evaluated with manometry but resistance to distension may be a more appropriate parameter than luminal pressure. The functional lumen imaging probe allows detailed description of distension properties of the anal canal. Our objective in this study was to characterize the impact of SNS on distension properties of the anal canal in patients with idiopathic fecal incontinence. METHODS: We studied 10 women (median age 64 [44-79] years) with idiopathic fecal incontinence at baseline and during SNS. The luminal geometry of the anal canal was examined with the FLIP at rest and during squeeze and the distensibility of the anal canal was investigated during filling of the bag. KEY RESULTS: All patients were successfully treated with SNS and the mean Wexner Incontinence Score was reduced from 14.9 ± 4 to 7.1 ± 4.8 (P<.001). The pressure required to open the narrowest point of the anal canal during distension (yield pressure) increased from 14.5 ± 12.2 mmHg at baseline to 20.5 ± 13.3 mmHg during SNS (P<.01). The pressure-strain elastic modulus increased non-significantly from 2.2 ± 0.5 to 2.9 ± 1.6 kPa, indicating increased stiffness of the anal canal. CONCLUSION AND INFERENCES: The yield pressure and the resistance to distension increased in response to SNS for idiopathic fecal incontinence. This will inevitably increase the resistance to flow through the anal canal, which may contribute to the benefits of sacral nerve stimulation.

P2X3 receptor-mediated visceral hyperalgesia and neuronal sensitization following exposure to PTSD-like stress in the dorsal root ganglia of rats.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) often share co-morbidity with chronic pain conditions. Recent studies suggest a role of P2X3 receptors and ATP signaling in pain conditions. However, the underlying mechanisms of visceral hyperalgesia following exposure to PTSD-like stress conditions remain unclarified. METHODS: The behavior and hormones relevant for PTSD were studied. Visceromotor responses (VMR) and the abdominal withdrawal reflexes (AWR) to colorectal distention (CRD) were recorded to determine P2X3-receptor-mediated alteration of hyperalgesia following single-prolonged stress (SPS) exposure. Immunofluorescence, Western blotting, and patch-clamp were used. KEY RESULTS: The escape latency, adrenocorticotropic hormone and cortisol were increased on days 7-14. Visceromotor responses and AWR was reduced at day 1 in SPS rats but increased to higher levels than in controls after exposure to day 7. Intrathecal administration of the P2X3-receptor antagonist TNP-ATP abolished the CRD response. Based on immunofluorescence and Western blotting analysis, SPS-treated rats exhibited reduced P2X3 expression in dorsal root ganglia (DRG) after day 1 compared with controls. P2X3 expression in DRG was enhanced on day 7 after SPS and the increase of the P2X3 expression was maintained on day 14 and 21 compared with controls. The P2X3-receptor agonist α,ß-me ATP (10 µM) induced a fast desensitizing inward current in DRG neurons of both control and SPS-treated rats. The average peak current densities in SPS-treated group were increased 3.6-fold. TNP-ATP (100 nM) markedly blocked all fast α,ß-me ATP-induced inward currents in the DRG neurons both in control and SPS-treated rats. CONCLUSIONS & INFERENCES: The data indicate an important role of P2X3 signaling in visceral hyperalgesia following PTSD-like stress.

Patients with Barrett's esophagus are hypersensitive to acid but hyposensitive to other stimuli compared with healthy controls.

BACKGROUND: Esophageal hyposensitivity has been observed in Barrett's esophagus and may contribute to its pathophysiology. However, studies are few, in particular those assessing different sensory modalities. We aimed to compare esophageal sensitivity to multimodal stimulation in patients with Barrett's esophagus and in healthy controls. METHODS: Twenty-three patients with Barrett's esophagus and 12 healthy controls were examined. A multimodal probe was placed in the lower esophagus. Mechanical, thermal, and electrical stimulation was applied followed by an acid perfusion test with 0.1 N hydrochloric acid. KEY RESULTS: Compared with controls, patients were hyposensitive to mechanical distension, heat, and electrical stimulation (all P<.05), but hypersensitive to acid (mean tolerated acid volume 57% lower, P=.001). A linear correlation between acid hypersensitivity and lower baseline impedance was found (P<.001). Patients had longer esophageal acid exposure time than controls (median acid exposure time 18 vs 5%, P=.03). Asymptomatic patients (no reflux symptoms at baseline) were hyposensitive to mechanical distension, electrical stimulation, and acid perfusion (all P<.05) compared with symptomatic patients. CONCLUSIONS & INFERENCES: Patients with Barrett's esophagus exhibited acid hypersensitivity but hyposensitivity to other stimuli. Lower mucosal baseline impedance, a likely surrogate marker for impaired mucosal integrity, may explain the selective hypersensitivity to acid. On the other hand, the concurrent hyposensitivity may theoretically be explained by changes in central pain modulation. Patients with Barrett's esophagus seem to compose symptomatic and asymptomatic subgroups, showing different esophageal sensory profiles.

Low-residue diet fed to rabbits induces histomorphological and biomechanical remodeling of small intestine.

BACKGROUND: The composition of ingested food is important for the gut microbiome and intestinal homeostasis. We have previously demonstrated that the structure and mechanical properties in the small intestine remodel significantly during fasting. However, it is not clear to what extent the intestinal mechanical properties changes when the composition of food is changed. This study aimed to investigate the passive biomechanical properties and intestinal tissue remodeling in rabbits fed a low-residue diet. METHODS: New Zealand rabbits (control group n=6, intervention group n=7) were studied. Segments from duodenum, jejunum and ileum were excised. The intestinal diameter and length were obtained from digitized images of the segments at preselected luminal pressure levels and at no-load and zero-stress states. Circumferential and longitudinal stresses (force per area) and strains (deformation) were computed from the length, diameter and pressure data referenced to the zero-stress state geometry. Histomorphometric data were also obtained. KEY RESULTS: The wet weight-per-unit length, wall thickness and wall area decreased in the intervention group (P<.05, P<.01). Histological measurement confirmed that the wall thickness decreased in all three segments, which was primarily due to mucosal thinning (P<.05). The opening angle tended to increase in all segments in the intervention group. Significant difference between the two groups was found for the jejunum (P<.05). Feeding the low-residue diet shifted the circumferential stress-strain curves in the intervention group to the right, indicating intestinal wall softening. CONCLUSIONS & INFERENCES: Low-residue diet in rabbits for 1 month induces location-dependent histomorphometric and biomechanical remodeling of the intestine.

Esophageal morphometric and biomechanical changes during aging in rats.

BACKGROUND: Human studies have demonstrated aging-related changes in esophagus which may contribute to the increased rate of gastro-esophageal reflux in elderly. The aim of this study was to investigate esophageal morphometric and biomechanical remodeling in aging rats to obtain detailed information about aging-related changes. METHODS: Twenty-four male Wistar rats, aged from 6 to 22 months, were studied. Morphometric data were obtained by measuring the wall thickness and cross-sectional area. The esophageal diameter and length were obtained from digitized images of the segments at preselected luminal pressure levels and at no-load and zero-stress states. Circumferential and longitudinal stresses (force per area) and strains (deformation) were computed from the length, diameter and pressure data, and from the zero-stress state geometry. KEY RESULTS: The esophageal parameters such as the weight per unit length, the wall thickness and the wall cross-sectional area increased slightly from 6 to 22 months (p < 0.05 to p < 0.001). The opening angle gradually decreased during aging (p < 0.05). The interface between the mucosa-submucosa and muscle layers slightly moved outwards and the neutral axis moved inwards during aging. The stress-strain data showed that the esophageal wall became stiffer circumferentially and longitudinally during aging (p < 0.05, p < 0.01). However, the circumferential wall stiffness showed no further change after 12 months. CONCLUSIONS & INFERENCES: A pronounced morphometric and biomechanical remodeling occurred in the rat esophagus during aging.

Salvage bortezomib-dexamethasone and high-dose melphalan (HDM) and autologous stem cell support (ASCT) in myeloma patients at first relapse after HDM with ASCT. A phase-2 trial.

Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.

Sacral nerve stimulation changes rectal sensitivity and biomechanical properties in patients with irritable bowel syndrome.

BACKGROUND: Sacral nerve stimulation (SNS) has been demonstrated to alleviate symptoms and improve quality of life in selected patients with irritable bowel syndrome (IBS). The mechanisms of action, however, remain unknown. The aim of the study was to evaluate the effects of SNS on rectal sensitivity and biomechanical properties in patients with IBS. METHODS: Twenty patients with diarrhea-predominant (n = 11) or mixed (n = 9) IBS were treated with SNS in a controlled, randomized crossover trial. They were randomized to either 1 month of SNS (ON) or placebo (OFF) with the opposite setting for the next month. Sensory and biomechanical parameters were assessed by multimodal rectal stimulation at the end of each period. IBS-specific symptoms were evaluated at baseline and at the end of each treatment period. KEY RESULTS: Cold stimuli were better tolerated in the ON period (19.9 °C[± 0.6]) compared to the OFF period (21.8 °C[± 0.6]; p = 0.03). Significantly lower cross-sectional areas were needed to elicit sensory responses in the ON period (1545 mm(2) [± 95]) compared to the OFF period (1869 mm(2) [± 92]; p = 0.015). The association between reduced sensory threshold and improvement of constipation was of borderline significance (p = 0.05). Wall stiffness was significantly lower in the ON period (192 mmHg[± 10]) compared to the OFF period (234 mmHg[± 10]; p = 0.004). Reduced wall stiffness was significantly associated with improved overall GSRS-IBS symptom score (p = 0.01). Reduced sensory threshold to stretch (p = 0.02) and reduced wall stiffness (p < 0.001) were predictors of the GSRS-IBS symptom score. CONCLUSIONS & INFERENCES: SNS for diarrhea-predominant and mixed IBS relaxes the rectal wall, while making it more sensitive to stretch and less sensitive to cold. Reduced wall stiffness and increased sensitivity to stretch are associated with improved GSRS-IBS symptom score.

Morphine modifies the cingulate-operculum network underlying painful rectal evoked potentials.

The effect of opioids on brain networks underlying rectal evoked potentials (EPs) has never been investigated. This study utilized brain source connectivity to explore whether morphine induced changes in brain networks underlying painful rectal EPs would reflect changes in pain scores due to morphine. Twenty healthy volunteers were included in this placebo-controlled cross-over study. Sensory and pain thresholds to electrically induced rectal stimulation were taken before (baseline) and 70 min after placebo/morphine (30 mg) administration. The stimulation intensity required to evoke moderate pain at baseline was employed for EPs. The pain score of this stimulation intensity was recorded again 70 min after placebo/morphine administration. 62-channel EPs were recorded for both arms. Amplitudes and latencies were analysed and brain source connectivity analysis was done. Changes in any of the parameters describing EPs were correlated to changes in subjective pain ratings. Morphine increased sensory and pain thresholds by 28.8% and 27.5% (P ≤ 0.02). The pain score corresponding to moderate pain at baseline was attenuated in both placebo and morphine arms by 14.5% and 37.5% (P < 0.05). There was a 33.9% reduction in EP amplitudes due to placebo (P < 0.05), whereas EP amplitudes remained stable due to morphine. A dominating cingulate-operculum network to rectal pain was seen. Cingulate source shifted anteriorly in the morphine arm (P < 0.001) and this shift was positively correlated to the change in the pain score (r = 0.6, P < 0.05). These findings indicate that visceral pain relief due to morphine is associated with reorganization within cingulate cortex, which may be used as a biomarker of opioid effects.

Distensibility of the anal canal in patients with idiopathic fecal incontinence: a study with the Functional Lumen Imaging Probe.

BACKGROUND: Anatomical structures and their distensibility vary along the length of the anal canal. The anal sphincter muscles have dynamic properties that are not well-reflected by standard manometry. Abnormal distensibility of the anal canal may be of importance in idiopathic fecal incontinence (IFI). The functional lumen imaging probe (FLIP) allows detailed studies of the distensibility and axial variation of sphincters. We aimed at comparing segmental distensibility of the anal canal in patients with IFI and healthy subjects. METHODS: The FLIP was used for distension of the anal canal in 22 patients with IFI (17 female, age 27-82 years) and 21 healthy volunteers (18 female, age 32-73 years). The distensibility was determined from changes in luminal diameter. Closure of the anal canal during voluntary squeeze was computed as the combined length of closed anal canal and time. Pressure-strain elastic modulus was computed at rest. KEY RESULTS: In all subjects, the proximal anal canal was the most distensible segment. During distension at rest and during squeeze the middle and distal anal canal became significantly larger in IFI than in healthy (F < 22.4, p < 0.05). The closure of the anal canal during voluntary squeeze did not differ between healthy (75.9 ± 92.9 mm s) and IFI patients (90.4 ± 105 mm s; p = 0.6). Compared with healthy, IFI patients had lower pressure-strain elastic modulus of the middle and distal (q > 4.5, p < 0.05) but not the proximal anal canal (q < 0.7, p > 0.05). CONCLUSIONS & INFERENCES: Patients with IFI have increased distensibility of the middle and distal parts of the anal canal.

The brain networks encoding visceral sensation in patients with gastrointestinal symptoms due to diabetic neuropathy.

BACKGROUND: Increasing evidence points to association between long-term diabetes mellitus and abnormal brain processing. The aim of this study was to investigate central changes due to electrical stimulation in esophagus in patients with upper gastrointestinal (GI) symptoms due to diabetic neuropathy. METHODS: Twenty-three diabetes patients with upper GI symptoms and 27 healthy controls were included. A standard ambulatory 24-h electrocardiography was carried out. 122-channel esophageal evoked brain potentials to electrical stimulation were acquired. Brain source/network analysis was performed. Gastroparesis Cardinal Symptom Index was used to evaluate upper GI symptoms and SF-36 questionnaire was utilized to assess patients' quality of life (QOL). KEY RESULTS: Diabetes patients with GI symptoms showed modifications in three brain networks: (i) brainstem/operculum/frontal cortex, (ii) operculum/cingulate, and (iii) mid-cingulate/anterior-cingulate/operculum/deep limbic structures. Operculum brain source in patients was localized deeper and more anterior in all three networks. The shift of operculum source was correlated with the severity of upper GI symptoms, decreased heart beat-to-beat interval, and decreased SD of the intervals. The activation of the first network was delayed in patients. Operculum source had higher activity than cingulate in the second network in patients, and this was correlated with decreased physical QOL. Deep limbic source was localized deeper in patients, which also correlated with decreased physical QOL. CONCLUSIONS & INFERENCES: This study indicates involvement of central nervous system in diabetes. Reorganization within opercular cortex was correlated with GI symptoms suggesting that operculo-cingulate cortex could contribute to development and maintenance of GI symptoms in diabetes patients.