Circadian variation of rectal sensitivity and gastrointestinal peptides in healthy volunteers

Abstract  The aim of our study was to identify diurnal variation of perception of rectal distension and the release of gastroenteropancreatic hormones. In 12 healthy male volunteers (25 years, range 22–32), a rectal balloon distension was performed. Rectal perception thresholds (minimal, urge and pain) and rectal compliance were double-measured with a computer-controlled barostat at seven standardized time points during the day (from 16.00 to 14.00 hours the following day). Blood samples were taken 30 min before and after each rectal distension procedure to determine plasma levels of cholecystokinin (CCK), pancreatic polypeptide (PP) and motilin. Sensory thresholds for urge and pain varied significantly with the time of day, with higher threshold levels in the evening than in the morning hours. Bowel wall compliance showed as well-significant variance at pain threshold and was higher during daytime than in the evening or at night. In contrast to motilin, release of CCK and PP also showed a significant variation depending on daytime. Perception of rectal distension stimuli as well as compliance was independent of intake of food and peptide hormone levels, but CCK and PP levels increased with food, and PP levels decreased with rectal distension. Significant differences in the perception of rectal distension stimuli for urge and pain depending on daytime were found, but the release of gastrointestinal peptides seemed not to be involved. This circadian variation needs to be taken into account in patients and volunteer studies.     

The external anal sphincter and the role of surface electromyography

Abstract  Assessment of the neuronal control of the external anal sphincter (EAS) has long been restricted to investigating patients with defecation disorders by invasive tools such as needle electromyography (EMG), while less invasive techniques have been regarded as non-suitable for diagnostic purposes. Multichannel surface EMG by means of electrode arrays applied to anal sphincter muscle records and identifies individual motor unit action potentials, their place of origin along the circumference, their repetitive firing frequency, and their progression along the muscle fibres at different levels within the anal canal. These data shed doubts on conventional knowledge about the anatomy of the EAS muscle, and confirms new concepts of anatomical differences between gender. This may eventually be transferred to a new understanding of the role of symmetry and asymmetry of pelvic floor innervation and its role in the pathogenesis of fecal incontinence.     

The puborectalis muscle

Abstract  The role of the levator ani and puborectalis muscle in preserving continence has been underestimated in the past, due predominantly to technical difficulties to investigate its proper function in healthy subjects, and its dysfunction as in patients with incontinence problems. This has recently been overcome by applying new investigational procedures such as a perineal dynamometer which measures the traction exerted by the levator ani on an intrarectal balloon catheter, or by multi-electrode arrays recording the generation of motor unit action potentials from various parts of the puborectalis muscle sling via intrarectal surface electrodes. Both techniques have the potential to provide new insights into the physiology of defecation and the pathophysiology of incontinence and constipation.     

The placebo response in functional dyspepsia – reanalysis of trial data

Abstract  Clinical trial data rarely identify factors contributing to the placebo response. We reanalysed the data from the placebo arm ( n  = 157) of a functional dyspepsia (FD) trial to determine predictors of placebo response including total GIS score, change in GIS score during run-in, type of FD symptoms, duration of illness, age, gender, body mass index (BMI), family occurrence of FD-like symptoms, smoking and alcohol consumption. The same response criteria were applied to the drug arm ( n  = 158) of the study. Based on the initial 40% response criterion of the study, 35 (22.2%) were classified as placebo responders (PR), whilst 122 (78.8%) were placebo non-responders (PnR). Response rates for the drug arm were 41.1 and 56.9% respectively. PR had significantly lower GIS scores compared to PnR at visit 1 (10.6 ± 0.6 and 12.3 ± 0.4, respectively, P  = 0.035), but not at visit 2 with study medication dispensing (10.9 ± 0.5 and 11.3 ± 0.4). Hence, PR symptoms increased during run-in by 4.2% whilst PnR symptoms decreased by 6.3% ( P  < 0.005). Gender, age and duration and type of FD symptoms were not different between PR and PnR. Smoking was less prevalent in PR (3%) compared to PnR (21%) ( P  < 0.025). Increasing the criteria for the placebo response resulted in higher BMI for PR than for PnR ( P  = 0.035). None of the predictors for placebo response were able to distinguish responders from non-responders to the drug. Variables predicting the PR point towards behavioural and biological mechanism of the PR, operating simultaneously and independently.     

Biofeedback therapy in fecal incontinence and constipation

Abstract  We examine the collected evidence for efficacy of biofeedback therapy (BFT) in incontinence and constipation by means of meta-analysis of randomized controlled trials. PubMed search was performed to identify treatment trials that match quality criteria (adequate control groups, randomization). They were entered into meta-analyses using fixed effect models and computing odds ratio (OR) and 95% confidence interval (CI) of treatment effects. For constipation, eight BFT trials were identified. In four trials, electromyographic (EMG) BFT was compared to non-BFT treatments (laxatives, placebo, sham training and botox injection), while in the remaining four studies EMG BFT was compared to other BFT (balloon pressure, verbal feedback) modes. Meta-analyses revealed superiority of BFT to non-BFT (OR: 3.657; 95% CI: 2.127–6.290, P  < 0.001) but equal efficacy of EMG BFT to other BF applications (OR: 1.436; CI: 0.692–3.089; P  = 0.319). For fecal incontinence, a total of 11 trials were identified, of which six compared BFT to other treatment options (sensory training, pelvic floor exercise and electrical stimulation) and five compared one BFT option to other modalities of BFT. BFT was equal effective than non-BFT therapy (OR: 1.189, CI: 0.689–2.051, P  = 0.535). No difference was found when various modes BFT were compared (OR: 1.278, CI: 0.736–2.220, P  = 0.384). Included trials showed a substantial lack of quality and harmonization, e.g. variable endpoints and missing psychological assessment across studies. BFT for pelvic floor dyssynergia shows substantial specific therapeutic effect while BFT for incontinence is still lacking evidence for efficacy. However, in both conditions the mode of BFT seems to play a minor role.     

The placebo response in functional bowel disorders: perspectives and putative mechanisms

The nature and determinants of the placebo response are widely unknown, as are the underlying psychological and biological mechanisms. High placebo response rates in functional bowel disorders (functional dyspepsia, irritable bowel syndrome) are similar to those in non-intestinal diseases (depression, pain, Parkinson's disease) and not too dissimilar to other organic gastrointestinal diseases (duodenal ulcer, inflammatory bowel diseases). Methodological reasons (regression to the mean, shift in signal detection through manipulation of expectations) and psycho-biological mechanisms (Pavlovian conditioning of biological processes) are proposed to explain a large component of the response variance in clinical trials. Psychobiological mechanisms of the placebo response in functional and organic diseases can also be identified in brain function studies (such as imaging).     

Cortical processing of residual ano-rectal sensation in patients with spinal cord injury: an fMRI study

Abstract  Eleven paraplegic patients with complete traumatic spinal cord injuries (SCI) [according to American Spinal Injury Association (ASIA) criteria] at different levels (Th3–L3) were investigated during non-painful stimulation of the distal rectum and anal canal, using event related functional magnetic resonance imaging. Although a complete lesion was clinically diagnosed in all, four of them experienced reproducible sensations during anal and/or rectal stimulation. In six patients, individual data analysis revealed significant activation in the right secondary somatosensory cortex SII, the posterior cingular gyrus, the prefrontal cortex, and the left posterior cerebellar lobe during either anal or rectal stimulation or both. A Region of interest analysis using a data mask from healthy controls confirmed that SCI patients demonstrate cortical activation in areas similar to those activated in healthy volunteers, but to a less extensive degree. This supports the notion that the diagnosis of complete spinal cord transsection by ASIA criteria alone may be insufficient for assessment of 'completeness' of cord lesions, and that visceral sensitivity testing may be required in addition.     

The story of O – is oxytocin the mediator of the placebo response?

Abstract  While the placebo responses in various medical conditions have been shown to follow a few basic principles such as expectancies, reward learning and Pavlovian conditioning, the underlying neurobiology and the mediating hormonal and/or neuromodulating processing have remained obscure. We here report the collected evidence that oxytocin (OXT), a 389-amino acid polypeptide located on chromosome 3p25 that is released in the brain (hypothalamus) and in peripheral tissue, is the central mediator of the placebo response: we hypothesize that exogenous OXT via an OXT agonist will enhance the placebo response, while exogenous OXT blockade by an antagonist will reduce the placebo response in placebo analgesia and other placebo models. It is furthermore proposed that the placebo response in trials may be predicted by circulating plasma OXT levels, the OXT receptor density in the brain and/or the presence of one or more of the single nucleotide polymorphisms of the OXT promoter gene.