Confined placental mosaicism: placental size and function evaluated on magnetic resonance imaging.

OBJECTIVES: Evidence regarding placental function in pregnancies complicated by confined placental mosaicism (CPM) is conflicting. We aimed to compare placental function between CPM and non-CPM pregnancies prenatally and at birth. A secondary objective was to evaluate the relationship between placental function and chromosomal subtype of CPM. METHODS: This was a retrospective study of pregnancies with CPM and control pregnancies delivered at a tertiary hospital in Denmark between 2014 and 2017. Placental volume and placental transverse relaxation time (T2*) were estimated on magnetic resonance imaging (MRI), fetal weight and uterine artery pulsatility index (UtA-PI) were estimated on ultrasound and fetoplacental ratio was assessed on MRI and at birth. These estimates of placental function were adjusted for gestational age and compared between groups using the Wilcoxon rank-sum test. Within the group of CPM pregnancies, measures of placental function were compared between those at high risk (chromosome numbers 2, 3, 7, 13 and 16) and those at low risk (chromosome numbers 5, 18 and 45X). RESULTS: A total of 90 pregnancies were included, of which 12 had CPM and 78 were controls. MRI and ultrasound examinations were performed at a median gestational age of 32.6 weeks (interquartile range, 24.7-35.3 weeks). On MRI assessment, CPM placentae were characterized by a lower placental T2* Z-score (P = 0.004), a lower fetoplacental ratio (P = 0.03) and a higher UtA-PI Z-score (P = 0.03), compared with non-CPM placentae. At birth, the fetoplacental ratio was significantly lower (P = 0.02) and placental weight Z-score was higher (P = 0.01) in CPM pregnancies compared with non-CPM pregnancies. High-risk CPM pregnancies showed a reduced placental T2* Z-score (P = 0.003), lower birth-weight Z-score (P = 0.041), earlier gestational age at delivery (P = 0.019) and higher UtA-PI Z-score (P = 0.028) compared with low-risk CPM pregnancies. Low-risk CPM pregnancies did not differ in any of these parameters from non-CPM pregnancies. CONCLUSIONS: CPM pregnancies are characterized by an enlarged and dysfunctional placenta. Placental function was highly related to the chromosomal type of CPM; placental dysfunction was seen predominantly in high-risk CPM pregnancies in which chromosomes 2, 3, 7, 13 or 16 were involved. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Placental volume, thickness and transverse relaxation time (T2*) estimated by magnetic resonance imaging in relation to small for gestational age at birth.

INTRODUCTION: Placental magnetic resonance imaging (MRI) may be a valuable tool in the prediction of small for gestational age (SGA) at birth. MRI provides reliable estimates of placental volume and thickness. In addition, placental transverse relaxation time (T2*) may be directly related to placental function. This study aimed to explore and compare the predictive performance of three placental MRI parameters - volume, thickness and T2* - in relation to SGA at birth. METHODS: A mixed cohort of 85 pregnancies was retrieved from the placental MRI database at the study hospital. MRI was performed in a 1.5 T system at gestational weeks 15-41. In normal birthweight (BW) pregnancies [BW > -22 % of expected for gestational age (GA)], the correlation between each of the MRI parameters and GA was investigated by linear regression. The prediction of SGA was investigated by logistic regression analysis adjusted for GA at MRI. RESULTS: In normal BW pregnancies, a significant linear correlation was found between GA and each of the MRI parameters. Univariate analysis demonstrated that placental volume [odds ratio (OR) 0.97, p = 0.001] and placental T2* (OR 0.79, p = 0.003), but not placental thickness (OR 0.92, p = 0.862) were significant predictors of SGA. A multi-variate model including all three MRI parameters found that placental T2* was the only independent predictor of SGA (OR 0.81, p = 0.04). CONCLUSION: Among the MRI parameters investigated in this study, placental T2* was the only independent predictor of SGA in a multi-variate model. This finding underlines the strong position of T2*-weighted placental MRI in the prediction of SGA.

Microstructural white matter brain abnormalities in patients with idiopathic fecal incontinence.

BACKGROUND: Abnormal central nervous system processing of visceral sensation may be a part of the pathogenesis behind idiopathic fecal incontinence (IFI). Our aim was to characterize brain differences in patients with IFI and healthy controls by means of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). METHODS: In 21 female patients with IFI and 15 female healthy controls, whole-brain structural differences in gray matter volume (GMV), cortical thickness, and white matter tracts fractional anisotropy (FA) were quantified. For this purpose, we used voxel-based morphometry, surface based morphometry and tract-based spatial statistic, respectively. Furthermore, associations between structural brain characteristics and latencies of rectal sensory evoked electroencephalography potentials were determined. KEY RESULTS: Compared to healthy controls, IFI patients had significantly reduced FA values, reflecting reduced white matter tract integrity, in the left hemisphere superior longitudinal fasciculus (SLF), posterior thalamic radiation, and middle frontal gyrus (MFG), all P<.05. No differences were observed in GMV or in cortical thickness. The reduced FA values in the SLF and MFG were correlated with prolonged latencies of cortical potentials evoked by rectal stimuli (all P<.05). CONCLUSIONS & INFERENCES: This explorative study suggests that IFI patients have no macrostructural brain changes, but exhibit microstructural changes in white matter tracts relevant for sensory processing. The clinical relevance of this finding is supported by its correlations with prolonged latencies of cortical potentials evoked by rectal stimulation. This supports the theories of central nervous system changes as part of the pathogenesis in IFI patients.

Assessment of colorectal length using the electromagnetic capsule tracking system: a comparative validation study in healthy subjects.

AIM: We aimed to determine colorectal length with the 3D-Transit system by describing a 'centreline' of capsule movement and comparing it with known anatomy, as determined by magnetic resonance imaging (MRI). Further, we aimed to test the day-to-day variation of colorectal length assessed with the system. METHOD: The 3D-Transit system consists of electromagnetic capsules that can be tracked as they traverse the gastrointestinal tract. Twenty-five healthy subjects were examined with both 3D-Transit and MRI. Another 21 healthy subjects were examined with 3D-Transit on two consecutive days. RESULTS: Computation of colorectal length from capsule passage was possible for 60 of the 67 3D-Transit recordings. The length of the colorectum measured with MRI and 3D-Transit was 95 (75-153) cm and 99 (77-147) cm, respectively (P = 0.15). The coefficient of variation (CV) between MRI and 3D-Transit was 7.8%. Apart from the caecum/ascending colon being 26% (P = 0.002) shorter on MRI, there were no other differences in total or segmental colorectal lengths between methods (all P > 0.05). The length of the colorectum measured with 3D-Transit on two consecutive days was 102 (73-119) cm and 103 (75-123) cm (P = 0.67). The CV between days was 7.3%. CONCLUSION: The 3D-Transit system allows accurate and reliable determination of colorectal length compared with MRI-derived colorectal length and between days. Antegrade or retrograde capsule movement relative to this centreline, as well as the length and speed of movements, may be determined by future studies to allow better classification and treatment in patients with dysmotility.

Established and emerging methods for assessment of small and large intestinal motility.

BACKGROUND: Gastrointestinal symptoms are common in the general population and may originate from disturbances in gut motility. However, fundamental mechanistic understanding of motility remains inadequate, especially of the less accessible regions of the small bowel and colon. Hence, refinement and validation of objective methods to evaluate motility of the whole gut is important. Such techniques may be applied in clinical settings as diagnostic tools, in research to elucidate underlying mechanisms of diseases, and to evaluate how the gut responds to various drugs. A wide array of such methods exists; however, a limited number are used universally due to drawbacks like radiation exposure, lack of standardization, and difficulties interpreting data. In recent years, several new methods such as the 3D-Transit system and magnetic resonance imaging assessments on small bowel and colonic motility have emerged, with the advantages that they are less invasive, use no radiation, and provide much more detailed information. PURPOSE: This review outlines well-established and emerging methods to evaluate small bowel and colonic motility in clinical settings and in research. The latter include the 3D-Transit system, magnetic resonance imaging assessments, and high-resolution manometry. Procedures, indications, and the relative strengths and weaknesses of each method are summarized.

Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity.

BACKGROUND: The parasympathetic nervous system, whose main neural substrate is the vagus nerve, exerts a fundamental antinociceptive role and influences gastrointestinal sensori-motor function. Our research question was to whether combined electrical and physiological modulation of vagal tone, using transcutaneous electrical vagal nerve stimulation (t-VNS) and deep slow breathing (DSB) respectively, could increase musculoskeletal pain thresholds and enhance gastroduodenal motility in healthy subjects. METHODS: Eighteen healthy subjects were randomized to a subject-blinded, sham-controlled, cross-over study with an active protocol including stimulation of auricular branch of the vagus nerve, and breathing at full inspiratory capacity and forced full expiration. Recording of cardiac derived parameters including cardiac vagal tone, moderate pain thresholds to muscle, and bone pressure algometry, conditioned pain modulation using a cold pressor test and a liquid meal ultrasonographic gastroduodenal motility test were performed. KEY RESULTS: Cardiac vagal tone increased during active treatment with t-VNS and DSB compared to sham (p = 0.009). In comparison to sham, thresholds to bone pain increased (p = 0.001), frequency of antral contractions increased (p = 0.004) and gastroduodenal motility index increased (p = 0.016) with active treatment. However, no effect on muscle pain thresholds and conditioned pain modulation was seen. CONCLUSIONS & INFERENCES: This experimental study suggests that this noninvasive approach with combined electrical and physiological modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. These findings warrant further investigation in patients with disorders characterized with chronic pain and gastrointestinal dysmotility such as functional dyspepsia and irritable bowel syndrome.

Placental magnetic resonance imaging T2* measurements in normal pregnancies and in those complicated by fetal growth restriction.

OBJECTIVES: The magnetic resonance imaging (MRI) variable transverse relaxation time (T2*) depends on multiple factors, one important one being the presence of deoxyhemoglobin. We aimed to describe placental T2* measurements in normal pregnancies and in those with fetal growth restriction (FGR). METHODS: We included 24 normal pregnancies at 24-40 weeks' gestation and four FGR cases with an estimated fetal weight below the 1(st) centile. Prior to MRI, an ultrasound examination, including Doppler flow measurements, was performed. The T2* value was calculated using a gradient echo MRI sequence with readout at 16 different echo times. In normal pregnancies, repeat T2* measurements were performed and interobserver reproducibility was assessed in order to estimate the reproducibility of the method. Placental histological examination was performed in the FGR cases. RESULTS: The method was robust regarding the technical and interobserver reproducibility. However, some slice-to-slice variation existed owing to the heterogeneous nature of the normal placenta. We therefore based T2* estimations on the average of two slices from each placenta. In normal pregnancies, the placental T2* value decreased significantly with increasing gestational age, with mean ± SD values of 120 ± 17 ms at 24 weeks' gestation, 84 ± 16 ms at 32 weeks and 47 ± 17 ms at 40 weeks. Three FGR cases had abnormal Doppler flow, histological signs of maternal hypoperfusion and a reduced T2* value (Z-score < -3.5). In the fourth FGR case, Doppler flow, placental histology and T2* value (Z-score, -0.34) were normal. CONCLUSIONS: The established reference values for placental T2* may be clinically useful, as T2* values were significantly lower in FGR cases with histological signs of maternal hypoperfusion. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Quantification and variability in colonic volume with a novel magnetic resonance imaging method.

BACKGROUND: Segmental distribution of colorectal volume is relevant in a number of diseases, but clinical and experimental use demands robust reliability and validity. Using a novel semi-automatic magnetic resonance imaging-based technique, the aims of this study were to describe: (i) inter-individual and intra-individual variability of segmental colorectal volumes between two observations in healthy subjects and (ii) the change in segmental colorectal volume distribution before and after defecation. METHODS: The inter-individual and intra-individual variability of four colorectal volumes (cecum/ascending colon, transverse, descending, and rectosigmoid colon) between two observations (separated by 52 ± 10) days was assessed in 25 healthy males and the effect of defecation on segmental colorectal volumes was studied in another seven healthy males. KEY RESULTS: No significant differences between the two observations were detected for any segments (All p > 0.05). Inter-individual variability varied across segments from low correlation in cecum/ascending colon (intra-class correlation coefficient [ICC] = 0.44) to moderate correlation in the descending colon (ICC = 0.61) and high correlation in the transverse (ICC = 0.78), rectosigmoid (ICC = 0.82), and total volume (ICC = 0.85). Overall intra-individual variability was low (coefficient of variance = 9%). After defecation the volume of the rectosigmoid decreased by 44% (p = 0.003). The change in rectosigmoid volume was associated with the true fecal volume (p = 0.02). CONCLUSIONS & INFERENCES: Imaging of segmental colorectal volume, morphology, and fecal accumulation is advantageous to conventional methods in its low variability, high spatial resolution, and its absence of contrast-enhancing agents and irradiation. Hence, the method is suitable for future clinical and interventional studies and for characterization of defecation physiology.

Deformation and pressure propagation in deep somatic tissue during painful cuff algometry.

BACKGROUND: Cuff algometry is used for quantitative pain assessment although it is not clarified which tissues are actually challenged by the stimulation. This study investigated the mechanical stress and strain distribution in superficial and deep tissues during cuff algometry applied on the lower leg at three different intensities (mild pressure, pain threshold and supra pain threshold). METHODS: A computational three-dimensional finite element model of the lower leg with three different layers of soft tissue was developed based on magnetic resonance imaging (MRI) recorded during cuff stimulation. Tissue indentation maps were extracted from the MRI scans and transferred into the model as displacement of boundary condition. In all stimulation conditions, the mean stress of subcutaneous adipose and muscle tissue below the cuff decreased compared with the skin while the mean strain peaked in subcutaneous adipose and decreased in other tissues. RESULTS: At pain threshold stimulation intensity, the mean muscle stress was 2.9% of mean skin stress and the mean muscle strain was 55.1% of mean strain in adipose layer. The mean stress and strain increased by 30.4% and 27.1%, respectively, in muscle tissue from painful to supra pain threshold stimulation. The stress and strain was mainly focused around the bones and superficially under cuff. CONCLUSIONS: This study shows the better capability of cuff algometry for stimulation of deep somatic tissue in terms of generation of mechanical stress and strain in contrast to the more superficial muscle tissue previously demonstrated to be strained by single-point pressure algometry.

Acute respiratory failure during first cyclophosphamide infusion in a patient with systemic lupus erythematosus.

We present a report of what we believe was an extremely rare case of hyperacute respiratory failure caused by first time exposure to cyclophosphamide in a 40-year-old woman with systemic lupus erythematosus. The patient was extensively evaluated for alternative etiologies with negative results. Treatment with methylprednisolone and high doses of human immunoglobulin resulted in gradual improvement of the patient's condition. We review the literature with regard to cyclophosphamide-induced lung toxicity.

Prevalence of venous thromboembolism at diagnosis of upper gastrointestinal cancer.

BACKGROUND: Venous thromboembolism (VTE) in patients with upper gastrointestinal (GI) cancer increases morbidity and mortality. This study aimed to determine the prevalence of VTE at diagnosis of upper GI cancer. METHODS: Patients admitted between February 2008 and February 2011 with upper GI cancer (pancreatic, extrahepatic biliary, lower oesophageal, gastro-oesophageal junction or gastric cancer) were investigated in a cross-sectional cohort study. At cancer diagnosis, all patients were examined for deep vein thrombosis (DVT) by means of bilateral compression ultrasonography. From February 2009 and onwards, computed tomographic pulmonary angiography (CTPA) was also performed for the diagnosis of pulmonary embolism (PE). RESULTS: Some 250 patients had ultrasonography; CTPA was performed in 143 patients on admission. DVT was detected in 13 (5·2 per cent) of the 250 patients, eight (3·2 per cent) of whom were asymptomatic. DVT was correlated with tumour location in the pancreaticobiliary tract (odds ratio (OR) 6·27, 95 per cent confidence interval 1·18 to 33·38; P = 0·031) and tumour stage IV (OR 19·34, 2·33 to 160·70; P = 0·006). PE was detected in 11 (7·7 per cent) of 143 patients, eight (5·6 per cent) of whom were asymptomatic. PE embolism was also significantly more common in patients with pancreaticobiliary tract cancer (OR 7·81, 1·28 to 47·62; P = 0·026) and in those with stage IV disease (OR 17·19, 1·83 to 161·50; P = 0·013). CONCLUSION: The prevalence of VTE at cancer diagnosis was significantly higher in patients with pancreaticobiliary tract cancer than in those with other forms of upper GI cancer, and in patients with advanced cancer stage.

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.

Macrostructural brain changes in patients with longstanding type 1 diabetes mellitus - a cortical thickness analysis study.

Longstanding diabetes mellitus (DM) is associated with the risk of complications affecting the central nervous system. The aims were to study brain volume and cortical thickness in regional brain areas in DM patients and to correlate the findings with relevant clinical data.15 patients with longstanding (average 24.6 years) type 1 DM and 20 healthy controls were studied in a 3T magnetic resonance scanner. Using an automated surface based cortical segmentation method, cortical thickness was assessed in anatomical regions including total and lobe-wise grey and white matter volumes. Also morphological changes were evaluated.No differences between patients and controls were found in regard to number of white matter lesions (P=0.50), grey and white matter volumes (P=0.25) and overall cortical thickness (P=0.64). Subanalysis revealed exclusively reduced cortical thickness of the postcentral (P=0.03) and superior parietal gyrus (P=0.008) in patients. The cortical thickness of these regions was not associated with diabetes duration, age at diabetes onset or to HbA1c (all P>0.08). Patients with peripheral neuropathy showed reduced right postcentral gyrus cortical thickness compared to patients without peripheral neuropathy (P=0.02).Patients with longstanding type 1 diabetes showed cortical thinning involving sensory related areas, even though no overall macrostructural brain alterations were detected. This could possibly have underlying functional significance since cortical thinning was associated to presence of peripheral neuropathy. The absence of universal macrostructural changes might illustrate that more pronounced brain pathology is likely to be preceded by more subtle microstructural changes as reported in other studies.

Brain networks encoding rectal sensation in type 1 diabetes.

INTRODUCTION: It has been shown that patients with type 1 diabetes mellitus and gastrointestinal (GI) symptoms have abnormal processing of sensory information following stimulation in the oesophagus. In order to find less invasive stimuli to study visceral afferent processing and to further elaborate the gut-brain network in diabetes, we studied brain networks following rectal electrical stimulations. METHODS: Twelve type 1 diabetes patients with GI symptoms and twelve healthy controls were included. A standard ambulatory 24-h electrocardiography was performed. 122-channel-evoked brain potentials to electrical stimulation in the rectum were recorded. Brain source-connectivity analysis was done. GI symptoms were assessed with the gastroparesis cardinal symptom index and quality of life (QOL) with SF-36. Any changes in brain source connectivity were correlated to duration of the disease, heart beat-to-beat intervals (RRs), clinical symptoms, and QOL of the patients. RESULTS: Diabetic patients with GI symptoms showed changes relative to controls in the operculum-cingulate network with the operculum source localized deeper and more anterior (P≤0.001) and the cingulate source localized more anterior (P=0.03). The shift of operculum source was correlated with the duration of the disease, severity of GI symptoms, and decreased RR (P<0.05). The shift of the cingulate source was correlated with the mental QOL (P=0.04). In healthy controls, the contribution of the cingulate source to the network was higher than the contribution of the operculum source (P≤0.001), whereas in patients the contribution of the two sources was comparable. CONCLUSION: This study gives further evidence for CNS involvement in diabetes. Since network reorganizations were correlated to GI symptoms, irregularities of rectal-evoked potentials can be viewed as a proxy for abnormal bottom-up visceral afferent processing. The network changes might serve as a biomarker for disturbed sensory visceral processing of GI symptoms in diabetes patients.

Peripheral and central nervous contribution to gastrointestinal symptoms in diabetic patients with autonomic neuropathy.

BACKGROUND & AIMS: Long-term diabetes mellitus (DM) has been associated with neuronal changes in the enteric, peripheral and/or central nervous system. Moreover, abnormal visceral sensation and gastrointestinal (GI) symptoms are seen in up to 75% of patients. To explore the role of diabetic autonomic neuropathy (DAN) in patients with long-standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials and dipolar source modelling. METHODS: Fifteen healthy volunteers and 14 type-1 DM patients with DAN were assessed with a symptom score index characterizing upper GI abnormalities. Multichannel (62) electroencephalography was recorded during painful electrical stimulation of the lower oesophagus. Brain activity to painful stimulations was modelled using Brain Electrical Source Analysis (besa). RESULTS: Diabetic patients had higher stimulus intensities to evoke painful sensation (p ≤ 0.001), longer latencies of N2 and P2 components (both p ≤ 0.001), and lower amplitudes of P1-N2 and N2-P2 complexes (p ≤ 0.001; p = 0.02). Inverse modelling of brain sources showed deeper bilateral insular dipolar source localization (p = 0.002). Symptom score index was negatively correlated with the depth of insular activity (p = 0.004) and positively correlated with insular dipole strength (p = 0.03). CONCLUSION: DM patients show peripheral and central neuroplastic changes. Moreover, the role of abnormal insular processing may explain the appearance and persistence of GI symptoms related to DAN. This enhanced understanding of DAN may have future clinical and therapeutical implications.

Esophageal distension parameters as potential biomarkers of impaired gastrointestinal function in diabetes patients.

BACKGROUND: Gastrointestinal (GI) symptoms, such as nausea, vomiting, bloating, postprandial fullness, and abdominal pain, are frequent in patients with diabetes mellitus (DM). The pathogenesis is complex and multi-factorial. To determine easy accessible and valid biomarkers for disordered GI function in DM patients, we aimed to study esophageal mechanical parameters and their relation to symptoms typically arising from the digestive tract. METHODS: Seventeen patients with longstanding DM and GI symptoms and 13 healthy controls were studied using ultrasound monitored esophageal distension. The sensory response was recorded and their symptoms registered. Biomechanical parameters, such as compliance and stiffness were computed from luminal diameters during distension based on the ultrasound images and from pressure data. Biomechanical and sensory parameters were correlated with the clinical data. KEY RESULTS: Diabetes patients had reduced esophageal sensitivity compared with controls (P = 0.046). The esophageal compliance was reduced (P = 0.004) and the esophageal stiffness was increased (P = 0.004) in the diabetes patients. Among patients, both postprandial fullness/early satiety and bloating correlated negatively to the esophageal compliance parameters (all P < 0.05). CONCLUSIONS & INFERENCES: Patients with long-standing DM and GI symptoms had reduced esophageal sensitivity together with reduced compliance and increased stiffness, which were correlated to the patients' GI symptoms. Biomechanical parameters obtained during distension may serve as biomarker for similar pathophysiologic effects of diabetes in the stomach and small bowel. They may contribute to our understanding of the pathophysiology underlying GI dysfunction and symptoms in patients with longstanding DM.

Support vector regression correlates single-sweep evoked brain potentials to gastrointestinal symptoms in diabetes mellitus patients.

Diabetes mellitus (DM) is a multi-factorial and complex disease causing autonomic neuropathy and gastrointestinal symptoms in some patients. The neural mechanisms behind these symptoms are poorly understood, but it is believed that both peripheral and central mechanisms are involved. To gain further knowledge of the central mechanisms, the aim of this study was to identify biomarkers for the altered brain activity in type-1 DM patients compared to healthy volunteers (HV), and to correlate the obtained biomarkers to clinical patient scores. The study included 14 DM patients and 15 HV, with brain activity recorded as multi-channel electroencephalography evoked brain potentials (EPs) elicited by painful electrical stimulations in the esophagus. The single-sweep EPs were decomposed by an optimized discrete wavelet transform (DWT), and averaged for each channel. The DWT features from the DM patients were discriminated from the HV by a support vector machine (SVM) applied in regression mode. For the optimal DWT, the discriminative features were extracted and the SVM regression value representing the overall alteration of the EP was correlated to the clinical scores. A classification performance of 86.2% (P=0.01) was obtained by applying a majority voting scheme to the 5 best performing channels. The biomarker was identified as decreased theta band activity. The regression value was correlated to symptoms reported by the patients (P=0.04). The methodology is an improvement of the present approach to study central mechanisms in diabetes mellitus, and may provide a future application for a clinical tool to optimize treatment in individual patients.

Effects of isolated hyperinsulinaemia on sensory function in healthy adults.

AIMS: Gastrointestinal symptoms such as pain, bloating, nausea and vomiting are more frequent in pre-diabetic states as well as established diabetes, compared to healthy individuals. The mechanisms behind these symptoms are multi-factorial and complex. Furthermore, the effect of isolated hyperinsulinaemia on visceral and peripheral sensory function is poorly understood. Thus, the current study aimed to evaluate effects of acute hyperinsulinaemia on sensory function in healthy adults. METHODS: The sensitivity to electrical oesophageal and median nerve stimulation was assessed in 15 healthy volunteers together with recording of evoked brain potentials. All subjects were studied both fasting and using a euglycaemic hyperinsulinaemic clamp. RESULTS: There was on average a 15% increased sensitivity to oesophageal electrical stimulation during hyperinsulinaemia compared to fasting state (P<0.05), but the sensation after median nerve stimulation remained stable (P=0.58). No significant changes in latencies and amplitudes of evoked brain potentials were observed after oesophageal or median nerve stimulation (all P>0.05). CONCLUSIONS: This study suggests that acute isolated hyperinsulinaemia increases visceral sensitivity, but does not influence the somatic sensory function. The lack of changes in the evoked brain potentials may indicate that hyperinsulinaemia affects the visceral sensory system at a peripheral level. Our result suggests distinct functions of insulin in the various parts of the nervous system, and yields further clues to the significance of insulin as a satiety signal.

Randomised clinical trial: pregabalin attenuates experimental visceral pain through sub-cortical mechanisms in patients with painful chronic pancreatitis.

BACKGROUND: Pregabalin has a broad spectrum of analgesic and antihyperalgesic activity in both basic and clinical studies. However, its mechanisms and sites of action have yet to be determined in humans. AIMS: To assess the antinociceptive effect of pregabalin on experimental gut pain in patients with visceral hyperalgesia due to chronic pancreatitis and to reveal putative changes in corresponding central pain processing as assessed by evoked brain potentials. METHODS: Thirty-one patients were randomly assigned to receive increasing doses of pregabalin or placebo for three consecutive weeks. Perceptual thresholds to electrical stimulation of the sigmoid with recording of corresponding evoked brain potentials were obtained at baseline and study end. The brain source localisations reflecting direct neuronal activity were fitted by a five-dipole model projected to magnetic resonance imaging of the individuals' brains. RESULTS: As compared to placebo, pregabalin significantly increased the pain threshold to electrical gut stimulation from baseline (P=0.02). No differences in evoked brain potential characteristics were seen, neither after pregabalin nor placebo treatment (all P>0.05). In agreement with this, brain source locations remained stable during study treatment (all P>0.05). CONCLUSION: Pregabalin was superior to placebo for attenuation of experimental visceral pain in chronic pancreatitis patients. We suggest its antinociceptive effects to be mediated primarily through sub-cortical mechanisms.

Multimodal sensory testing of the rectum and rectosigmoid: development and reproducibility of a new method.

Evaluation of rectal and rectosigmoid sensation is important in basic, clinical and pharmacological studies. New methods to evoke and assess multimodal (electrical, thermal and mechanical) experimental pain of the upper gut activate distinct pathways and mimics clinical pain. The aims of the current study were to characterize the sensory response and reproducibility to multimodal stimulation of rectum and the rectosigmoid. A multimodal rectal probe was developed. Mucosal electrostimulation was delivered at the recto-sigmoid junction. In Rectum, impedance planimetry was used for measurement of cross-sectional area (CSA) during distension. Circulation of water within the bag at either 4 or 60 degrees C was applied for thermal stimulation. The method was tested in 12 healthy volunteers (six men mean age 32 years) on two subsequent days. Mechanical and sensory responses and referred pain areas were assessed. Stimulation with electrical, thermal and mechanical modalities resulted in different sensory perceptions. The relationship between stimulus intensity and sensory response was linear for all modalities. Sensory response to different modalities did not differ between investigation days (all P-values > 0.1). Approximately 75% of subjects felt referred pain in distinct skin locations. Between-days reproducibility was good for all modalities [intra-class correlation (ICC) > or = 0.6]. At sensory threshold, CSA showed best reproducibility (ICC > or = 0.9). At pain detection threshold stretch ratio, CSA and electrostimulation showed best reproducibility (ICC = 1.0; 0.9; 0.9). The present model was easily implemented, robust and showed good reproducibility. It can be used to study pathophysiology or pharmacological interventions in healthy controls and in patients with diseases involving the distal hindgut.