Cardiac vagal tone, a non-invasive measure of parasympathetic tone, is a clinically relevant tool in Type 1 diabetes mellitus.

AIMS: To compare a novel index of parasympathetic tone, cardiac vagal tone, with established autonomic variables and to test the hypotheses that (1) cardiac vagal tone would be associated with established time and frequency domain measures of heart rate and (2) cardiac vagal tone would be lower in people with Type 1 diabetes than in a matched healthy cohort and lower still in people with established neuropathy. METHODS: Cardiac vagal tone is a validated cardiometrically derived index of parasympathetic tone. It is measured using a standard three-lead electrocardiogram which connects, via Bluetooth, to a smartphone application. A 5-min resting recording of cardiac vagal tone was undertaken and observational comparisons were made between 42 people with Type 1 diabetes and peripheral neuropathy and 23 without peripheral neuropathy and 65 healthy people. In those with neuropathy, 24-h heart rate variability values were compared with cardiac vagal tone. Correlations between cardiac vagal tone and clinical variables were also made. RESULTS: Cardiac vagal tone was lower in people with established neuropathy and Type 1 diabetes in comparison with healthy participants [median (interquartile range) linear vagal scale 3.4 (1.6-5.5 vs 7.0 (5.5-9.6); P < 0.0001]. Cardiac vagal tone was positively associated with time (r = 0.8, P < 0.0001) and frequency domain markers of heart rate variability (r = 0.75, P < 0.0001), representing established measures of parasympathetic function. Cardiac vagal tone was negatively associated with age (r=-0.32, P = 0.003), disease duration (r=-0.43, P < 0.0001) and cardiovascular risk score (r=-0.32, P = 0.006). CONCLUSIONS: Cardiac vagal tone represents a convenient, clinically relevant method of assessing parasympathetic nervous system tone, potentially facilitating the earlier identification of people with Type 1 diabetes who should undergo formal autonomic function testing.

Avoiding the use of long-term parenteral support in patients without intestinal failure: A position paper from the European Society of Clinical Nutrition & Metabolism, the European Society of Neurogastroenterology and Motility and the Rome Foundation for Disorders of Gut-Brain Interaction.

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Clinical and psychosocial functioning in adolescents and young adults with anorectal malformations and chronic idiopathic constipation.

BACKGROUND: Faecal incontinence (FI) and constipation occur following corrective surgery for anorectal malformations (ARMs) and in children or adults with chronic constipation without a structural birth anomaly (chronic idiopathic constipation, CIC). Such symptoms may have profound effects on quality of life (QoL). This study systematically determined the burden of FI and constipation in these patients in adolescence and early adulthood, and their effect on QoL and psychosocial functioning in comparison with controls. METHODS: Patients with ARMs or CIC were compared with age- and sex-matched controls who had undergone appendicectomy more than 1 year previously and had no ongoing gastrointestinal symptoms. Constipation and FI were evaluated using validated Knowles-Eccersley-Scott Symptom (KESS) and Vaizey scores respectively. Standardized QoL and psychometric tests were performed in all groups. RESULTS: The study included 49 patients with ARMs (30 male, aged 11-28 years), 45 with CIC (32 male, aged 11-30 years) and 39 controls (21 male, aged 11-30 years). The frequency of severe constipation among patients with ARMs was approximately half that seen in the CIC group (19 of 49 versus 31 of 45); however, frequencies of incontinence were similar (22 of 49 versus 21 of 45) (P < 0·001 versus controls for both symptoms). Physical and mental well-being were significantly reduced in both ARM and CIC groups compared with controls (P = 0·001 and P = 0·015 respectively), with generally worse scores among patients with CIC. Both were predicted by gastrointestinal symptom burden (P < 0·001). There were no statistically significant differences in state or trait psychiatric morbidity between groups. CONCLUSION: FI and constipation are major determinants of poor QoL in adolescents and young adults with ARMs and in those with CIC.

The cortical topography of human swallowing musculature in health and disease.

Because no detailed information exists regarding the topographic representation of swallowing musculature on the human cerebral cortex in health or disease, we used transcranial magnetic stimulation to study the cortical topography of human oral, pharyngeal and esophageal musculature in 20 healthy individuals and the topography of pharyngeal musculature in two stroke patients, one with and one without dysphagia. Our results demonstrate that swallowing musculature is discretely and somatotopically represented on the motor and premotor cortex of both hemispheres but displays interhemispheric asymmetry, independent of handedness. Following stroke, dysphagia appeared to be associated with smaller pharyngeal representation on the intact hemisphere, which increases in size with recovery of swallowing.

Visceral pain hypersensitivity in functional gastrointestinal disorders.

INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are a highly prevalent group of heterogeneous disorders whose diagnostic criteria are symptom based in the absence of a demonstrable structural or biochemical abnormality. Chronic abdominal pain or discomfort is a defining characteristic of these disorders and a proportion of patients may display heightened pain sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity (VPH). SOURCES OF DATA: We examined the most recent literature in order to concisely review the evidence for some of the most important recent advances in the putative mechanisms concerned in the pathophysiology of VPH. AREAS OF AGREEMENT: VPH may occur due to anomalies at any level of the visceral nociceptive neuraxis. Important peripheral and central mechanisms of sensitization that have been postulated include a wide range of ion channels, neurotransmitter receptors and trophic factors. Data from functional brain imaging studies have also provided evidence for aberrant central pain processing in cortical and subcortical regions. In addition, descending modulation of visceral nociceptive pathways by the autonomic nervous system, hypothalamo-pituitary-adrenal axis and psychological factors have all been implicated in the generation of VPH. AREAS OF CONTROVERSY: Particular areas of controversy have included the development of efficacious treatment of VPH. Therapies have been slow to emerge, mainly due to concerns regarding safety. GROWING POINTS: The burgeoning field of genome wide association studies may provide further evidence for the pleiotropic genetic basis of VPH development. AREAS TIMELY FOR DEVELOPING RESEARCH: Tangible progress will only be made in the treatment of VPH when we begin to individually characterize patients with FGIDs based on their clinical phenotype, genetics and visceral nociceptive physiology.

Effective electromagnetic noise cancellation with beamformers and synthetic gradiometry in shielded and partly shielded environments.

The major challenge of MEG, the inverse problem, is to estimate the very weak primary neuronal currents from the measurements of extracranial magnetic fields. The non-uniqueness of this inverse solution is compounded by the fact that MEG signals contain large environmental and physiological noise that further complicates the problem. In this paper, we evaluate the effectiveness of magnetic noise cancellation by synthetic gradiometers and the beamformer analysis method of synthetic aperture magnetometry (SAM) for source localisation in the presence of large stimulus-generated noise. We demonstrate that activation of primary somatosensory cortex can be accurately identified using SAM despite the presence of significant stimulus-related magnetic interference. This interference was generated by a contact heat evoked potential stimulator (CHEPS), recently developed for thermal pain research, but which to date has not been used in a MEG environment. We also show that in a reduced shielding environment the use of higher order synthetic gradiometry is sufficient to obtain signal-to-noise ratios (SNRs) that allow for accurate localisation of cortical sensory function.

Pharmacology of visceral pain: central factors.

Clinically, pain can be sub-classified into superficial, neuropathic and deep pain. Deep pain as a result of stimulation to structures such as the viscera is the most poorly understood and notoriously difficult to treat. The dorsal horn of the spinal cord is the gateway to conscious nociception and it is at this point in the pain processing pathway that the peripheral afferent input can be enhanced or inhibited by several mechanisms, the most important being central sensitisation. Long-term potentiation, another mechanism, can also be elicited in the spinal cord. Here nociceptor activity and/or peripheral tissue inflammation produces long-term changes in synaptic efficacy in the dorsal horns. This plays a major role in the generation of acute post-operative and post-traumatic pain, migraine and neuropathic pain. Behavioural consequences of central sensitisation can even be readily detected in human psychophysical experiments. Another important mechanism is 'wind-up', a form of homosynaptic activity-dependent plasticity characterised by a progressive increase in action potential output from dorsal horn neurones. There is an extensive body of literature which has highlighted the importance of central sensitisation. This review examines some of the most significant recent findings with regards to future pharmacology. As we are beginning to understand some of the mechanisms of central sensitisation and its importance in visceral pain, novel receptor sites have been identified, offering exciting possibilities with regards to future pharmacological development not only to visceral pain, but for pain management as a whole.

Volunteer studies in pain research--opportunities and challenges to replace animal experiments: the report and recommendations of a Focus on Alternatives workshop.

Despite considerable research, effective and safe treatments for human pain disorders remain elusive. Understanding the biology of different human pain conditions and researching effective treatments continue to be dominated by animal models, some of which are of limited value. British and European legislation demands that non-animal approaches should be considered before embarking on research using experimental animals. Recent scientific and technical developments, particularly in human neuroimaging, offer the potential to replace some animal procedures in the study of human pain. A group of pain research experts from academia and industry met with the aim of exploring creatively the tools, strategies and challenges of replacing some animal experiments in pain research with ethically conducted studies of human patients and healthy volunteers, in combination with in vitro methods. This report considers how a range of neuroimaging techniques including functional magnetic resonance imaging, magnetoencephalography and positron emission tomography, singly and combined, can address human pain conditions. In addition, microdialysis in human subjects; genome-wide association research, twin studies and other epidemiological approaches; and in vitro cell and tissue research, are examined for their replacement potential in combination with neuroimaging. Recommendations highlight further opportunities to advance the replacement of animal studies with robust methods of relevance to understanding and treating human pain.

Long-term reorganization of human motor cortex driven by short-term sensory stimulation.

Removal of sensory input can induce changes in cortical motor representation that reverse when sensation is restored. Here we ask whether manipulation of sensory input can induce long-term reorganization in human motor cortex that outlasts the initial conditioning. We report that for at least 30 minutes after pharyngeal stimulation, motor cortex excitability and area of representation for the pharynx increased, while esophagus representation decreased, without parallel changes in the excitability of brainstem-mediated reflexes. Therefore increased sensory input can drive long-term cross-system changes in motor areas of the cerebral cortex, which suggests that sensory stimulation might rehabilitate dysphagia, a frequent consequence of cerebral injury.

Guidelines on the irritable bowel syndrome: mechanisms and practical management.

BACKGROUND: IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. AIM: To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. METHODS: Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. RESULTS: Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. CONCLUSIONS: Better ways of identifying which patients will respond to specific treatments are urgently needed.

Delineation between different components of chronic pain using dimension reduction - an ASL fMRI study in hand osteoarthritis.

BACKGROUND: Traditional psychometric measures aimed at characterizing the pain experience often show considerable overlap, due to interlinked affective and modulatory processes under central nervous system control. Neuroimaging studies have been employed to investigate this complexity of pain processing, in an attempt to provide a quantifiable, adjunctive description of pain perception. In this exploratory study, we examine psychometric and neuroimaging data from 38 patients with painful osteoarthritis of the carpometacarpal joint. We had two aims: first, to utilize principal component analysis (PCA) as a dimension reduction strategy across multiple self-reported endpoints of pain, cognitive and affective functioning; second, to investigate the relationship between identified dimensions and regional cerebral blood flow (rCBF) as an indirect measure of brain activity underpinning their ongoing pain experiences. METHODS: Psychometric data were collected using validated questionnaires. Quantitative estimates of rCBF were acquired using pseudo-continuous arterial spin-labelled functional magnetic resonance imaging. RESULTS: Two principal components were identified that accounted for 73% of data variance; one related to pain scores and a second to psychological traits. Voxel-wise multiple regression analysis revealed a significant negative association between the 'pain score' component and rCBF to a right temporal lobe cluster, including the amygdala and the parahippocampal cortex. CONCLUSION: We suggest this association may represent a coping mechanism that aims to reduce fear-related pain-anxiety. Further investigation of central brain processing mechanisms in osteoarthritis-related pain may offer insights into more effective therapeutic strategies. SIGNIFICANCE: This study demonstrates that dimension reduction using PCA allows insight into pain perception and its affective components in relation to brain activation patterns in patients with painful hand osteoarthritis.

Development, content validity, and cross-cultural adaptation of a patient-reported outcome measure for real-time symptom assessment in irritable bowel syndrome.

BACKGROUND: End-of-day questionnaires, which are considered the gold standard for assessing abdominal pain and other gastrointestinal (GI) symptoms in irritable bowel syndrome (IBS), are influenced by recall and ecological bias. The experience sampling method (ESM) is characterized by random and repeated assessments in the natural state and environment of a subject, and herewith overcomes these limitations. This report describes the development of a patient-reported outcome measure (PROM) based on the ESM principle, taking into account content validity and cross-cultural adaptation. METHODS: Focus group interviews with IBS patients and expert meetings with international experts in the fields of neurogastroenterology & motility and pain were performed in order to select the items for the PROM. Forward-and-back translation and cognitive interviews were performed to adapt the instrument for the use in different countries and to assure on patients' understanding with the final items. KEY RESULTS: Focus group interviews revealed 42 items, categorized into five domains: physical status, defecation, mood and psychological factors, context and environment, and nutrition and drug use. Experts reduced the number of items to 32 and cognitive interviewing after translation resulted in a few slight adjustments regarding linguistic issues, but not regarding content of the items. CONCLUSIONS AND INFERENCES: An ESM-based PROM, suitable for momentary assessment of IBS symptom patterns was developed, taking into account content validity and cross-cultural adaptation. This PROM will be implemented in a specifically designed smartphone application and further validation in a multicenter setting will follow.

Neurokinin-1 receptor antagonism in a human model of visceral hypersensitivity.

BACKGROUND: Substance P acting via the neurokinin-1 receptor is involved in the development of hyperalgesia, although studies using neurokinin-1 receptor antagonists (NK-1RA) in human somatic pain have been disappointing. AIM: To evaluate whether Substance P is involved in the development of human visceral pain/hyperalgesia using a selective NK-1RA. METHODS: Using a validated human model of acid-induced oesophageal allodynia, pain thresholds to electrical stimulation (mA) were measured in the proximal oesophagus and the foot (somatic control), pre- and for 4 h postdistal oesophageal acid in 14 healthy subjects, using a double-blind, randomized, two-period, crossover study. Measurements were taken on the third day of dosing with either an oral NK-1RA or matching placebo, with 2 weeks washout between periods. RESULTS: Baseline pain threshold did not differ between treatments (proximal oesophagus 37 +/- 7.4 mA NK-1RA vs. 38 +/- 10.1 placebo P = 0.81, foot 40 +/- 15 mA NK-1RA vs. 38 +/- 14 placebo P = 0.68). NK-1RA did not attenuate the reduction in pain threshold in the proximal oesophagus postacid infusion (AUC-394 +/- 279 NK-1RA vs. -262 +/- 397 placebo P = 0.54). CONCLUSIONS: The lack of effect of NK-1RA on oesophageal pain threshold in our model does not support a role for Substance P in the development of acid-induced oesophageal allodynia.

Peripheral and central mechanisms of visceral sensitization in man.

Visceral hypersensitivity (perception of gastrointestinal sensory events at a lower-than-normal threshold) is considered to be an important pathophysiological mechanism in the development of functional gastrointestinal disorders (FGIDs), such as irritable bowel syndrome, non-cardiac chest pain and functional dyspepsia. These disorders are associated with significant health care and socioeconomic costs due to factors such as repeated visits to consultants, hospitalizations and work absenteeism. Despite the presence of extensive evidence linking visceral hypersensitivity and FGIDs, the mechanism(s) underlying visceral hypersensitivity has not been fully elucidated. Suggested hypotheses include sensitization of afferent neurones, both at the level of the enteric and the (afferent) autonomic nervous system (peripheral sensitization), sensitization of spinal cord dorsal horn neurones (central sensitization) and psychosocial factors/psychiatric comorbidity influencing the processing of afferent signals at the level of the brain. Importantly, these hypotheses may be complementary rather than mutually exclusive. However, the degree to which each of these mechanisms contributes to the overall perception of visceral pain, and therefore the generation of symptoms, still remains unclear. This article discusses the mechanisms that may underlie visceral hypersensitivity, with reference to FGIDs. Understanding these mechanisms is essential in order to improve the diagnosis and treatment of patients with these disorders.

Attentional modulation of visceral and somatic pain.

A better understanding of the cortical processes underlying attentional modulation of visceral and somatic pain in health are essential for interpretation of future imaging studies of hypervigilance towards bodily sensations which is considered to be an aetiologically important factor in the heightened pain reported by patients with irritable bowel syndrome and fibromyalgia. Twelve healthy subjects were recruited for this study. Simultaneous trains of electrical pulses (delivered to either the rectum or lower abdomen) and auditory tones lasting 6 s were delivered to the subjects during a whole-brain functional scan acquisition. Subjects were instructed to attend to the auditory tones (distracter task) or electrical pulses (pain task). Pain intensity ratings were significantly lower during the distraction task compared with the pain task (P < 0.01) in both sensory modalities. The left primary somatosensory cortex increased in activity with increasing pain report, during attention to visceral pain. Bilateral anterior insula (aIns) cortex activity increased with increasing somatic pain report independent of the direction of attention. Conversely, the primary and secondary auditory cortices significantly increased in activation with decreased pain report. These results suggest that pain intensity perception during attentional modulation is reflected in the primary somatosensory cortex (visceral pain) and aIns cortex activity (somatic pain).

Exploring the neurophysiological basis of chest wall allodynia induced by experimental oesophageal acidification - evidence of central sensitization.

In somatic models of central sensitisation (CS) allodynia develops following changes to somatic A-beta fibres, allowing these afferents which normally only process innocuous sensations to encode pain. The aim of this study was to determine whether somatic allodynia induced by visceral sensitisation occurs via N-Methyl-D-Aspartate (NMDA) receptor mediated changes to the neurophysiological characteristics of somatic A-beta fibres. Twelve healthy subjects had oesophageal, chest wall and foot pain thresholds (PT) to electrical stimulation measured, and chest wall evoked potentials (CEP) recorded before and 30 minutes after distal oesophageal acidification on 2 separate visits. Intravenous ketamine (an NMDA receptor antagonist) or saline was given 30 minutes post acid with repeated oesophageal and chest wall PT measurements and CEP recordings. Distal oesophageal acidification reduced PT to electrical stimulation on the anterior chest wall (37 +/- 10 mA v 29 +/- 7 mA p = 0.01) and proximal oesophagus (46 +/- 10 mA v 33 +/- 11 mA p = 0.001) but not the foot (37 +/- 25 mA v 39 +/- 23 mA p = 0.12). The induction of chest wall somatic allodynia was accompanied by a reduction in the latency of the P1 (36 +/- 3 ms to 30 +/- 4 ms p = 0.016) and P2 (87 +/- 7 ms to v 76 +/- 7 ms p = 0.049) components of the CEP. NMDA receptor antagonism reversed both visceral and somatic pain hypersensitivity but did not affect CEP latencies. These data provide objective neurophysiological evidence that CS contributes to the development of somatic allodynia following visceral sensitisation.

Mechanisms underlying reflux symptoms and dysphagia in patients with joint hypermobility syndrome, with and without postural tachycardia syndrome.

BACKGROUND: The joint hypermobility syndrome (JHS) is a common non-inflammatory connective tissue disorder which frequently co-exists with postural tachycardia syndrome (PoTS), a form of orthostatic intolerance. Gastrointestinal symptoms and dysmotility have been reported in PoTS. Dysphagia and reflux are common symptoms in JHS, yet no studies have examined the physiological mechanism for these, subdivided by PoTS status. METHODS: Thirty patients (28 female, ages: 18-62) with JHS and symptoms of reflux (n=28) ± dysphagia (n=25), underwent high-resolution manometry and 24 hour pH-impedance monitoring after questionnaire-based symptom assessment. Esophageal physiology parameters were examined in JHS, subdivided by PoTS status. RESULTS: Fifty-three percent of JHS patients with reflux symptoms had pathological acid reflux, 21% had reflux hypersensitivity, and 25% had functional heartburn. Acid exposure was more likely to be increased in the recumbent than upright position (64% vs 43%). The prevalence of hypotensive lower esophageal sphincter (33%) and hiatus hernia (33%) was low. Forty percent of patients with dysphagia had minor disorders of motility, 60% had functional dysphagia. Eighteen (60%) patients had coexistent PoTS-they had significantly higher dysphagia (21 vs 11.5, P=.04) and reflux scores (24.5 vs 16.5, P=.05), and double the prevalence of pathological acid reflux (64% vs 36%, P=.1) and esophageal dysmotility (50% vs 25%, P=.2) though this was not significant. CONCLUSIONS AND INFERENCES: A large proportion of JHS patients with esophageal symptoms have true reflux-related symptoms or mild esophageal hypomotility, and this is more likely if they have PoTS.

A magnetic resonance imaging study of gastric motor function in patients with dyspepsia associated with Ehlers-Danlos Syndrome-Hypermobility Type: A feasibility study.

BACKGROUND: The clinical use of Magnetic Resonance Imaging (MRI) for investigating gastric motor function in dyspepsia is limited, largely due to protocol complexity, cost and limited availability. In this study, we explore the feasibility of a sub 60-minute protocol using a water challenge to assess gastric emptying, motility and accommodation in a cohort of Ehlers-Danlos Syndrome-Hypermobility type (EDS-HT) patients presenting with dyspepsia. METHODS: Nine EDS-HT patients (mean age 33, range: 26-50 all female) with a history of dyspepsia were recruited together with nine-matched controls. Subjects fasted for 6 hours prior to MRI. A baseline anatomical and motility scan was performed after which the subjects ingested 300 mL water. The anatomical and motility scans were then repeated every 10 minutes to a total of 60 minutes. Gastric emptying time, motility, and accommodation were calculated based on the observations of two observers for each EDS-HT subject and compared to their matched control using paired statistics. KEY RESULTS: Median motility increase following the water challenge was lower in EDS-HT subjects (11%, range: 0%-22%) compared to controls (22%, range: 13%-56%), P=.03. Median gastric emptying time was non-significantly decreased in EDS-HT subjects (12.5 minutes, range: 6-27) compared to controls (20 minutes, range: 7-30), P=.15. Accommodation was non-significantly reduced in EDS-HT subjects (56% increase, range: 32%-78%) compared to healthy controls (67% increase, range: 52%-78%), P=.19. CONCLUSIONS & INFERENCES: This study demonstrates the feasibility of a water challenge MRI protocol to evaluate gastric physiology in the clinical setting. Motility differences between EDS-HT and controls are worthy of further investigation.

Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: A review for the gastroenterologist.

BACKGROUND: Joint hypermobility syndrome (JHS)/Ehlers-Danlos syndrome hypermobility type (EDS-HT) is the most common hereditary non-inflammatory disorder of connective tissue, characterized by a wide range of symptoms, mainly joint hyperextensibility and musculoskeletal symptoms. A majority of patients also experiences gastrointestinal (GI) symptoms. Furthermore, JHS/EDS-HT has specifically been shown to be highly prevalent in patients with functional GI disorders, such as functional dyspepsia and irritable bowel syndrome. PURPOSE: The aim of this review was to examine the nature of GI symptoms and their underlying pathophysiology in JHS/EDS-HT. In addition, we consider the clinical implications of the diagnosis and treatment of JHS/EDS-HT for practicing clinicians in gastroenterology. Observations summarized in this review may furthermore represent the first step toward the identification of a new pathophysiological basis for a substantial subgroup of patients with functional GI disorders.