[Show abstract][Hide abstract] ABSTRACT: Summary Functional abdominal pain syndrome is characterised by frequent or continuous abdominal pain associated with a degree of loss of daily activity. It has a reported population prevalence of between 0.5% and 1.7%, with a female preponderance. The pathophysiology of functional abdominal pain is incompletely understood although it has been postulated that peripheral sensitisation of visceral afferents, central sensitisation of the spinal dorsal horn and aberrancies within descending modulatory systems may have an important role. The management of patients with functional abdominal pain requires a tailored multidisciplinary approach in a supportive and empathetic environment in order to develop an effective therapeutic relationship. Patient education directed towards an explanation of the pathophysiology of functional abdominal pain is in our opinion a prerequisite step and provides the rationale for the introduction of interventions. Interventions can usefully be categorised into general measures, pharmacotherapy, psychological interventions and 'step-up' treatments. Pharmacotherapeutic/step-up options include tricyclic antidepressants, serotonin noradrenergic reuptake inhibitors and the gabapentinoids. Psychological treatments include cognitive behavioural therapy and hypnotherapy. However, the objective evidence base for these interventions is largely derived from other chronic pain syndrome, and further research is warranted in adult patients with functional abdominal pain.
Journal of the Royal Society of Medicine 09/2014; 107(9):347-354. · 1.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic visceral pain affects millions of individuals worldwide and remains poorly understood, with current therapeutic options constrained by gastrointestinal (GI) side effects. Visceral pain is strongly associated with inflammation and distension of the gut. Here we report that the voltage-gated sodium channel subtype NaV1.9 is expressed in half of gut-projecting rodent dorsal root ganglia sensory neurons. We show that NaV1.9 is required for normal mechanosensation, for direct excitation and for sensitisation of mouse colonic afferents by mediators from inflammatory bowel disease tissues, and by noxious inflammatory mediators individually. Excitatory responses to ATP or PGE2 were substantially reduced in NaV1.9-/- mice. Deletion of NaV1.9 substantially attenuates excitation, and subsequent mechanical hypersensitivity, following application of inflammatory soup (bradykinin, ATP, histamine, PGE2 and 5HT) to visceral nociceptors located in the serosa and mesentery. Responses to mechanical stimulation of mesenteric afferents were also reduced by loss of NaV1.9 and there was a rightward shift in stimulus-response function to ramp colonic distension. By contrast, responses to rapid, high-intensity phasic distension of the colon are initially unaffected; however run-down of responses to repeat phasic distension were exacerbated in NaV1.9-/- afferents. Finally colonic afferent activation by supernatants derived from inflamed human tissue was greatly reduced in NaV1.9-/- mice. These results demonstrate that NaV1.9 is required for persistence of responses to intense mechanical stimulation, contributes to inflammatory mechanical hypersensitivity and is essential for activation by noxious inflammatory mediators including those from diseased human bowel. These observations indicate that NaV1.9 represents a high-value target for development of visceral analgesics.
[Show abstract][Hide abstract] ABSTRACT: With more than 100 studies published over the past two decades, functional brain imaging research in gastroenterology has become an established field; one that has enabled improved insight into the supraspinal responses evoked by gastrointestinal stimulation both in health and disease. However, there remains considerable inter-study variation in the published results, largely owing to methodological differences in stimulation and recording techniques, heterogeneous patient selection, lack of control for psychological factors and so on. These issues with reproducibility, although not unique to studies of the gastrointestinal tract, can lead to unjustified inferences. To obtain consistent and more clinically relevant results, there is a need to optimize and standardize brain imaging studies across different centres. In addition, the use of complementary and more novel brain imaging modalities and analyses, which are now being used in other fields of research, might help unravel the factors at play in functional gastrointestinal disorders. This Review highlights the areas in which functional brain imaging has been useful and what it has revealed, the areas that are in need of improvement, and finally suggestions for future directions.
[Show abstract][Hide abstract] ABSTRACT: Nausea is an aversive experience, which negatively impacts on quality of life, adherence to treatment and is a cause for discontinuation of the development of novel compounds. Significant knowledge gaps remain in our understanding of the cortical and psychophysiological mechanisms involved in the genesis and maintenance of nausea. We aimed to develop and validate a readily administered a visually induced motion sickness (VIMS) stimulus to examine the psychophysiological changes induced by the stimulus and characterise the changes in cortical activity using functional magnetic resonance imaging (fMRI).
Gut 06/2014; 63(Suppl 1):A31-A32. · 10.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Eysenck proposed 'trait theory' of personality, where the dimensions extraversion (degree of optimism and sociability) and neuroticism (degree of anxiety and fear) encompass numerous individual qualities. Whilst the influence of neuroticism on the brain processing of pain is well studied, the role of extraversion in pain processing remains to be investigated and thus this was the aim of our study using functional magnetic resonance imaging (fMRI).
Gut 06/2014; 63(Suppl 1):A32-A33. · 10.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder with a prevalence of 20%. It is characterised by joint hypermobility,chronic pain, fibromyalgia (FM) and dysautonomia. Gastrointestinal (GI) symptoms e.g., dyspepsia, reflux, bloating and constipation are present in up to 80% of affected individuals. Small studies suggest that FGID are common in these patients yet no controlled studies have systematically investigated if JHS is associated with particular GI diagnoses nor explored the effect of JHS on non-GI symptom presentation and quality of life (QOL).
Gut 06/2014; 63(Suppl 1):A194-A195. · 10.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Symptoms of chronic constipation are common, with a prevalence of ~14% in adults worldwide. Although increasing fibre intake is universally accepted as a first-line treatment, patient dissatisfaction is common. A systematic review is thus required in order to evaluate the quality of scientific evidence behind this management approach. The aim was to assess the effect of fibre on chronic constipation and IBS-C in adults via a systematic review of randomised controlled trials (RCTs).
Gut 06/2014; 63(Suppl 1):A206-A207. · 10.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autonomic nervous system dysfunction has been implicated in visceral hypersensitivity. However, the specific contribution of the parasympathetic nervous system (PNS) is unclear. We aimed to determine whether physiological and pharmacological manipulation of parasympathetic tone influences the development of hypersensitivity in a validated model of acid-induced oesophageal pain.
[Show abstract][Hide abstract] ABSTRACT: Heightened perception of gastrointestinal sensation is termed visceral hypersensitivity (VH) and is commonly observed in patients with gastrointestinal disorders. VH is thought to be a major contributory factor in oesophageal disease, particularly gastro-oesophageal reflux disease that does not respond to standard (proton pump inhibitor) treatment, and in functional heartburn. Clinical tools that can help phenotype according to the mechanism of chronic pain and thus allow targeted drug treatment (e.g. with pain modulator therapy) would be very desirable. A technique that produces repeatable and controllable thermal stimuli within the oesophagus could meet this need. The aims of this study were to develop a method for linear control of the heat stimulation in the oesophagus, to assess the reproducibility of this method, and obtain normal thermal sensitivity values in the distal and proximal oesophagus. The 7 mm diameter Peltier-based thermal device was investigated on 27 healthy subjects using a heating ramp of 0.2 °C s−1. The pain detection threshold (PDT) temperature was recorded. To assess the reproducibility of the device, each subject underwent the procedure twice, with a minimum of two weeks between each procedure. The mean PDT temperature measured in the distal oesophagus, was 53.8 ± 2.9 °C and 53.6 ± 2.6 °C, for visits 1 and 2 respectively. The mean PDT temperature measured in the proximal oesophagus was 54.1 ± 2.4 °C and 54.0 ± 2.8 °C, for visits 1 and 2 respectively. The reproducibility of the PDT temperature in the distal and proximal oesophagus, was good (intra-class correlation >0.6). Future studies should be aimed to determine whether oesophageal thermal sensitivity can act as a biomarker of transient receptor potential vallanoid 1 upregulation.
[Show abstract][Hide abstract] ABSTRACT: The parasympathetic nervous system (PNS) has been implicated in the development of visually induced motion sickness. The objective of this study was to perform a systematic review and meta-analysis of the effect of visually induced motion sickness on validated parameters of PNS tone. Methods followed PRISMA recommendations. Controlled trials reporting validated measures of PNS tone in visually induced motion sickness in healthy adults were included. One reviewer performed the screening of articles and data extraction, and two reviewers independently performed methodological evaluation. Data were synthesised using standardised mean differences (SMDs) for all relevant outcomes using a random-effects model. Publication bias was assessed via funnel plots and Egger's test. The search strategy identified seven citations comprising 237 healthy individuals. The mean quality score was 4/10 (range 3-7). There was no difference between baseline PNS tone between individuals who developed visually induced motion sickness and those that did not. Visually induced motion sickness (VIMS)-sensitive individuals had a reduction in PNS tone, following exposure to the stimulus (mean weighted SMD = -0.45, 95 % confidence interval -0.64 to -0.27, Z = -4.8, p < 0.0001). There was no evidence of heterogeneity or publication bias. These data suggest that baseline PNS parameters do not provide a useful measure of predicting the probability of developing visually induced motion sickness. However, a fall in PNS tone, as indicated by cardiac activity, is characteristic in sensitive individuals. Further work is needed to characterise these responses in clinical populations, in conjunction with improvements and standardisation in study design.
Experimental Brain Research 05/2014; · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative and qualitative abnormalities in visceral function have been demonstrated in postural orthostatic tachycardia syndrome. Joint hypermobility is frequently associated with both postural orthostatic tachycardia syndrome and gastrointestinal symptoms. Future studies in this area should appropriately and systematically control for the presence of joint hypermobility syndrome.
Clinical Autonomic Research 03/2014; · 1.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nausea is the subjective unpleasant sensation that immediately precedes vomiting. Studies using barostats suggest that gastric fundus and lower esophageal sphincter (LES) relaxation precede vomiting. Unlike barostat, high-resolution manometry (HRM) allows less invasive, detailed measurements of fundus pressure (FP) and axial movement of the gastro-esophageal junction (GEJ). Nausea was induced in 12 healthy volunteers by a motion video and rated on a visual analogue scale. FP was measured as the mean value of the five pressure channels that were clearly positioned below the LES. After intubation, a baseline (BL) recording of 15 min was obtained. This was followed by presentation of the motion video (at least 10 min, max. 20 min) followed by 30min recovery recording. Throughout the experiment we recorded autonomic nervous system (ANS) parameters (blood pressure, heart rate (HR) and cardiac vagal tone (CVT) which reflects efferent vagal activity). 10/12 subjects showed a drop in FP during peak nausea compared to BL (-4.0±0.8mmHg; p=0.005) and8/10 subjects showed a drop in LES pressure (-8.8±2.5mmHg; p=0.04). Peak nausea preceded peak fundus and LES pressure drop.Nausea was associated with configuration changes at the GEJ such as LES shortening and esophageal lengthening. During nausea we observed a significantly increased HR and decreased CVT. In conclusion, nausea is associated with a drop in fundus and LES pressure, configuration changes at the GEJ as well as changes in the ANS activity such as an increased sympathetic tone (increased HR) and decreased parasympathetic tone (decreased CVT).
AJP Gastrointestinal and Liver Physiology 03/2014; · 3.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Common human experience shows that stress and anxiety may modulate gut function. Such observations have been combined with an increasing experimental evidence base have culminated in the concept of the brain-gut axis. Nevertheless, it has not been until recently that the gut and its attendant components, have been considered to influence higher cerebral function and behaviour per se. Moreover, the proposal that the gut and the bacteria contained therein (collectively referred to as the microbiota) can modulate mood and behaviours, has an increasing body of supporting evidence, albeit largely derived from animal studies. The gut microbiota is a dynamic and diverse ecosystem and forms a symbiotic relationship with the host. Herein we describe the components of the gut microbiota and mechanisms by which it can influence neural development, complex behaviours and nociception. Furthermore, we propose the novel concept of a ‘state of gut’ rather than a state of mind, particularly in relation to functional bowel disorders. Finally, we address the exciting possibility that the gut microbiota may offer a novel area of therapeutic intervention across a diverse array of both affective and GI disorders.This article is protected by copyright. All rights reserved
The Journal of Physiology 03/2014; · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Joint Hypermobility Syndrome (JHS) is a common connective tissue disorder characterised by joint hyperflexibility, dysautonomia and chronic pain. Gastrointestinal (GI) symptoms are reported in JHS patients attending rheumatology clinics but the prevalence and symptom pattern of previously undiagnosed JHS in GI clinics is unknown.
Using validated questionnaires, a prospective cross-sectional study in secondary care GI clinics estimated the prevalence of JHS in new consecutively referred patients, compared GI symptoms in patients with and without JHS, and using multiple regression determined whether the burden of GI symptoms in JHS patients was dependent on chronic pain, autonomic, psychological and medication related factors. A positive control group consisted of JHS patients referred from rheumatology clinics with GI symptoms (JHS-Rh).
From 552 patients recruited, 180 (33%) had JHS (JHS-G) and 372 did not (Non-JHS-G). 44 JHS-Rh patients were included. JHS-G patients were more likely to be younger, female with poorer quality of life (p=0.02) than non-JHS-G patients. Following age and sex matching, heartburn (OR1.66, CI 1.1-2.5 p=0.01), waterbrash (OR: 2.02, CI: 1.3-3.1, p=0.001) and postprandial fullness (OR 1.74, CI 1.2-2.6 p=0.006) were commoner in JHS-G vs. Non-JHS-G. Many upper and lower GI symptoms increased with increasing severity of JHS phenotype. Upper GI symptoms were dependent on autonomic and chronic pain factors.
JHS is common in GI clinics, with increased burden of upper GI and extraintestinal symptoms and poorer quality of life. Recognition of JHS will facilitate multidisciplinary management of GI and extra-GI manifestations.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2014; · 5.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The parasympathetic nervous system has been implicated in the pathogenesis of a number of gastrointestinal disorders including irritable bowel syndrome. Within the field, cardiometric parameters of parasympathetic/vagal tone are most commonly derived from time, or frequency, domain analysis of heart rate variability (HRV), yet it has limited temporal resolution. Cardiac vagal tone (CVT) is a non-invasive beat-to-beat measure of brainstem efferent vagal activity that overcomes many of the temporal limitations of HRV parameters. However, its normal values and reproducibility in healthy subjects are not fully described. The aim of this study was to address these knowledge gaps.
Annals of gastroenterology : quarterly publication of the Hellenic Society of Gastroenterology. 01/2014; 27(4):362-368.
[Show abstract][Hide abstract] ABSTRACT: Background and aims
Chronic visceral pain is common both in patients with identifiable organic disease and also in those without any structural, biochemical or immunological abnormality such as in the functional gastrointestinal disorders (FGIDs). We aim to provide a contemporaneous summary of pathways involved in visceral nociception and how a variety of mechanisms may influence an individual's experience of visceral pain.
In this narrative review, we have brought together evidence through a detailed search of Medline in addition to using our experience and exposure to recent research developments from ourselves and other research groups.
FGIDs are a heterogeneous group of disorders whose aetiology largely remains an enigma. The germane hypothesis for the genesis and maintenance of chronic visceral pain in FGIDs is the concept of visceral hypersensitivity. A number of peripheral and central mechanisms have been proposed to account for this epiphenomenon. In the periphery, inflammatory mediators activate and sensitize nociceptive afferent nerves by reducing their transduction thresholds and by inducing the expression and recruitment of hitherto silent nociceptors culminating in an increase in pain sensitivity at the site of injury known as primary hyperalgesia. Centrally, secondary hyperalgesia, defined as an increase in pain sensitivity in anatomically distinct sites, occurs at the level of the spinal dorsal horn. Moreover, the stress responsive physiological systems, genetic and psychological factors may modulate the experience of visceral pain. We also address some novel aetiological concepts in FGIDs, namely the gastrointestinal microbiota, connective tissue abnormalities and the gastrointestinal neuromuscular disorders. Firstly, the gastrointestinal microbiota is a diverse and dynamic ecosystem, that safeguards the host from external pathogens, aids in the metabolism of polysaccharides and lipids, modulates intestinal motility, in addition to modulating visceral perception. Secondly, connective tissue disorders, which traditionally have been considered to be confined largely to the musculoskeletal system, have an increasing evidence base demonstrating the presence of visceral manifestations. Since the sensorimotor apparatus of the GI tract is embedded within connective tissue it should not be surprising that such disorder may result in visceral pain and abnormal gut motility. Thirdly, gastrointestinal neuromuscular diseases refer to a heterogeneous group of disorders in which symptoms arise from impaired GI motor activity often manifesting as abnormal transit with or without radiological evidence of transient or persistent dilation of the viscera. Although a number of these are readily recognizable, such as achalasia or Hirschsprung's disease, the cause in a number of patients is not. An international working group has recently addressed this “gap”, providing a comprehensive morphologically based diagnostic criteria.
Although marked advances have been made in understanding the mechanisms that contribute to the development and maintenance of visceral pain, many interventions have failed to produce tangible improvement in patient outcomes. In the last part of this review we highlight an emerging approach that has allowed the definition and delineation of temporally stable visceral pain clusters, which may improve participant homogeneity in future studies, potentially facilitate stratification of treatment in FGID and lead to improvements in diagnostic criteria and outcomes.
[Show abstract][Hide abstract] ABSTRACT: The interaction between the brain and the gut has been recognized for many centuries. This bidirectional interaction occurs via neural, immunological and hormonal routes, and is important not only in normal gastrointestinal function but also plays a significant role in shaping higher cognitive function such as our feelings and our subconscious decision-making. Therefore, it remains unsurprising that perturbations in normal signalling have been associated with a multitude of disorders, including inflammatory and functional gastrointestinal disorders, and eating disorders.
Advances in experimental medicine and biology 01/2014; 817:135-153. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite chronic pain being a feature of functional chest pain (FCP) its experience is variable. The factors responsible for this variability remain unresolved. We aimed to address these knowledge gaps, hypothesizing that the psychophysiological profiles of FCP patients will be distinct from healthy subjects.
20 Rome III defined FCP patients (nine males, mean age 38.7 years, range 28-59 years) and 20 healthy age-, sex-, and ethnicity-matched controls (nine males, mean 38.2 years, range 24-49) had anxiety, depression, and personality traits measured. Subjects had sympathetic and parasympathetic nervous system parameters measured at baseline and continuously thereafter. Subjects received standardized somatic (nail bed pressure) and visceral (esophageal balloon distension) stimuli to pain tolerance. Venous blood was sampled for cortisol at baseline, post somatic pain and post visceral pain.
Patients had higher neuroticism, state and trait anxiety, and depression scores but lower extroversion scores vs controls (all p < 0.005). Patients tolerated less somatic (p < 0.0001) and visceral stimulus (p = 0.009) and had a higher cortisol at baseline, and following pain (all p < 0.001). At baseline, patients had a higher sympathetic tone (p = 0.04), whereas in response to pain they increased their parasympathetic tone (p ≤ 0.008). The amalgamating the data, we identified two psychophysiologically distinct 'pain clusters'. Patients were overrepresented in the cluster characterized by high neuroticism, trait anxiety, baseline cortisol, pain hypersensitivity, and parasympathetic response to pain (all p < 0.03).
In future, such delineations in FCP populations may facilitate individualization of treatment based on psychophysiological profiling.
Neurogastroenterology and Motility 10/2013; · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Esophageal intubation is a widely utilized technique for a diverse array of physiological studies, activating a complex physiological response mediated, in part, by the autonomic nervous system (ANS). In order to determine the optimal time period after intubation when physiological observations should be recorded, it is important to know the duration of, and factors that influence, this ANS response, in both health and disease.
Fifty healthy subjects (27 males, median age 31.9 years, range 20-53 years) and 20 patients with Rome III defined functional chest pain (nine male, median age of 38.7 years, range 28-59 years) had personality traits and anxiety measured. Subjects had heart rate (HR), blood pressure (BP), sympathetic (cardiac sympathetic index, CSI), and parasympathetic nervous system (cardiac vagal tone, CVT) parameters measured at baseline and in response to per nasum intubation with an esophageal catheter. CSI/CVT recovery was measured following esophageal intubation.
In all subjects, esophageal intubation caused an elevation in HR, BP, CSI, and skin conductance response (SCR; all p < 0.0001) but concomitant CVT and cardiac sensitivity to the baroreflex (CSB) withdrawal (all p < 0.04). Multiple linear regression analysis demonstrated that longer CVT recovery times were independently associated with higher neuroticism (p < 0.001). Patients had prolonged CSI and CVT recovery times in comparison to healthy subjects (112.5 s vs 46.5 s, p = 0.0001 and 549 s vs 223.5 s, p = 0.0001, respectively).
Esophageal intubation activates a flight/flight ANS response. Future studies should allow for at least 10 min of recovery time. Consideration should be given to psychological traits and disease status as these can influence recovery.
Neurogastroenterology and Motility 09/2013; · 2.94 Impact Factor