Nathalie Weltens

Where is the comfort in comfort foods? Mechanisms linking fat signaling, reward, and emotion.

Food in general, and fatty foods in particular, have obtained intrinsic reward value throughout evolution. This reward value results from an interaction between exteroceptive signals from different sensory modalities, interoceptive hunger/satiety signals from the gastrointestinal tract to the brain, as well as ongoing affective and cognitive processes. Further evidence linking food to emotions stems from folk psychology (‘comfort foods’) and epidemiological studies demonstrating high comorbidity rates between disorders of food intake, including obesity, and mood disorders such as depression.

Imaging neuron-glia interactions in the enteric nervous system

The enteric nervous system (ENS) is a network of neurons and glia within the wall of the gastrointestinal tract that is able to control many aspects of digestive function independently from the central nervous system. Enteric glial cells share several features with astrocytes and are closely associated with enteric neurons and their processes both within enteric ganglia, and along interconnecting fiber bundles. Similar to other parts of the nervous system, there is communication between enteric neurons and glia; enteric glial cells can detect neuronal activity and have the machinery to intermediate neurotransmission. However, due to the close contact between these two cell types and the particular characteristics of the gut wall, the recording of enteric glial cell activity in live imaging experiments, especially in the context of their interaction with neurons, is not straightforward. Most studies have used calcium imaging approaches to examine enteric glial cell activity but in many cases, it is difficult to distinguish whether observed transients arise from glial cells, or neuronal processes or varicosities in their vicinity. In this technical report, we describe a number of approaches to unravel the complex neuron-glia crosstalk in the ENS, focusing on the challenges and possibilities of live microscopic imaging in both animal models and human tissue samples.

Increased Cerebral Cannabinoid-1 Receptor Availability Is a Stable Feature of Functional Dyspepsia: A [18F]MK-9470 PET Study

Background: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). Methods: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [18F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months). Results: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months. Conclusions: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs.

Influence of Interoceptive Fear Learning on Visceral Perception.

Objectives Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. Methods In a novel fear learning–generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. Results Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p < .001). The thresholds for first sensation habituated in the control group, whereas it remained constant in the conditioning group (F(1,43) = 9.77, p = .003). Conclusions These data show that fear learning using visceral stimuli induces fear generalization and influences visceral perception. These findings support the idea that in functional gastrointestinal disorder, fear learning and generalization can foster gastrointestinal-specific anxiety and contribute to visceral hypersensitivity.

Prevalence and impact of childhood adversities and post‐traumatic stress disorder in women with fibromyalgia and chronic widespread pain

This study investigates the prevalence of different types of childhood adversities (CA) and posttraumatic stress disorder (PTSD) in female patients with Fibromyalgia or Chronic Widespread Pain (FM/CWP) compared to patients with Functional Dyspepsia (FD) and achalasia. In FM/CWP, we also investigated the association between CA and PTSD on the one hand and pain severity on the other.

Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study.

Although of great public health relevance, the mechanisms underlying disordered eating behavior and body weight regulation remain insufficiently understood. Compelling preclinical evidence corroborates a critical role of the endocannabinoid system (ECS) in the central regulation of appetite and food intake. However, in vivo human evidence on ECS functioning in brain circuits involved in food intake regulation as well as its relationship with body weight is lacking, both in health and disease. Here, we measured cannabinoid 1 receptor (CB1R) availability using positron emission tomography (PET) with [18F]MK-9470 in 54 patients with food intake disorders (FID) covering a wide body mass index (BMI) range (anorexia nervosa, bulimia nervosa, functional dyspepsia with weight loss and obesity; BMI range=12.5–40.6 kg/m2) and 26 age-, gender- and average BMI-matched healthy subjects (BMI range=18.5–26.6 kg/m2). The association between regional CB1R availability and BMI was assessed within predefined homeostatic and reward-related regions of interest using voxel-based linear regression analyses. CB1R availability was inversely associated with BMI in homeostatic brain regions such as the hypothalamus and brainstem areas in both patients with FID and healthy subjects. However, in FID patients, CB1R availability was also negatively correlated with BMI throughout the mesolimbic reward system (midbrain, striatum, insula, amygdala and orbitofrontal cortex), which constitutes the key circuit implicated in processing appetitive motivation and hedonic value of perceived food rewards. Our results indicate that the cerebral homeostatic CB1R system is inextricably linked to BMI, with additional involvement of reward areas under conditions of disordered body weight.

The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study

The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.

Su2098 Positive and Negative Mood Modulate Esophageal Pain Perception in Health

Background: The mechanism(s) mediating the higher prevalence of chronic abdominal pain and IBS in women remain incompletely understood. Although the importance of central mechanisms is increasingly acknowledged, sex differences in associative learning andmemory processes have thus far not been studied in the context of visceral pain. Fear conditioning is an established experimental model to investigate learning and memory processes relevant for the pathophysiology and/or treatment of conditions including anxiety disorders, chronic back pain and fibromyalgia. Fear conditioning appears particularly well-suited also in the context of visceral hyperalgesia and IBS given the well-documented overlap between IBS (and other somatization disorders) with pre-clinical as well as clinical anxiety. We recently implemented the first fear conditioning study with painful rectal distensions as US in healthy subjects (Kattoor et al., PLOS ONE, in press). Herein, we present results from an extension of this study testing sex differences in the behavioral and neural processes mediating aversive visceral learning, extinction and the recovery of fear, i.e., reinstatement. Methods: In BMImatched healthy males and females (N = 15 males, 15 females), visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS-) were presented without US (differential delay conditioning). During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, males and females were compared with respect to conditioned anticipatory neural activation (CS+ . CS-) along with perceived CS-US contingency, CS unpleasantness and salivary cortisol. Results: Pain ratings and distension-induced neural activationwere comparable betweenmales and females. Similarly, no sex differences were observed in perceived CS-US contingency, CS+ valence ratings or cortisol. However, in the late acquisition phase, presentation of the CS+ led to significantly greater anticipatory activation of the insular cortex in women. During extinction, women demonstrated reduced anticipatory activation of the posterior cingulate cortex compared to males. During reinstatement, the CS+ led to significantly greater activation of the hippocampus, thalamus and cerebellum in women. Conclusions: This is the first study to support differences between males and females in the neural processes of aversive visceral learning and memory. Our finding of enhanced neural responses in key brain areas for memory, especially in hippocampus, suggest enhanced reactivation of the old fear memory trace in women. This could play a role in the female preponderance of chronic abdominal pain and irritable bowel syndrome.

The gut-brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation: The gut-brain axis in health neuroscience

Over the past few years, scientific interest in the gut–brain axis (i.e., the bidirectional communication system between the gastrointestinal tract and the brain) has exploded, mostly due to the identification of the gut microbiota as a novel key player in this communication. However, important progress has also been made in other aspects of gut–brain axis research, which has been relatively underemphasized in the review literature. Therefore, in this review, we provide a comprehensive, although not exhaustive, overview of recent research on the functional neuroanatomy of the gut–brain axis and its relevance toward the multidisciplinary field of health neuroscience, excluding studies on the role of the gut microbiota. More specifically, we first focus on irritable bowel syndrome, after which we outline recent findings on the role of the gut–brain axis in appetite and feeding regulation, primarily focusing on the impact of subliminal nutrient‐related gut–brain signals. We conclude by providing future perspectives to facilitate translation of the findings from gut–brain axis neuroscientific research to clinical applications in these domains.

572 Acute Anxiety and Chronic Co-Morbid Anxiety Impair Gastric Accommodation in Functional Dyspepsia

BACKGROUND: While irritable bowel syndrome (IBS) is associated with significant mental and physical comorbidity, little is known about the day to day burden (e.g., quality of life [QOL], physical and mental functioning, distress, IBS symptoms) that comorbidity imposes. METHOD: 175 Rome III-diagnosed IBS patients (M age = 41 yrs, 78% Female, 91% Caucasian) completed psychiatric assessments (MINI International Neuropsychiatric Interview), a physical comorbidity checklist as well as the IBS Symptom Severity Scale, IBSQOL, Brief Symptom Inventory (distress, BSI), abdominal pain intensity scale, and the physical (PCS) and mental (MCS) functioning scales of the SF-12 as part of baseline assessment of an NIH clinical trial. RESULTS. IBS patients in this cohort reported an avg. of 5 diagnosed comorbidities (1 mental, 4 physical). Partial correlations indicated that subjects with more comorbidities reported worse QOL after adjusting for confounding variables. The number of physical comorbidities was more strongly associated with the physical aspects of QOL, while the number of mental comorbidities was more strongly correlated with mental aspects of QOL. The number of comorbidities was unrelated to either the intensity of abdominal pain or global severity of IBS symptoms. Multiple linear regression analyses indicated that comorbidity type was more consistently and strongly associated with illness burden indicators than simple disease counts after confounding variables were held constant. Of 10, 296 possible physicalmental comorbidity pairs, 6 of the 10 most frequent dyads involved a combination of conditions (generalized anxiety disorder, major depression, back pain, agoraphobia, tension headache, insomnia) that were consistently associated with illness (QOL, mental and physical functioning, distress) and symptom (IBS symptom severity, abdominal pain intensity) burden indicators. A comorbidity dyad with consistently large effect sizes was low back pain and major depression. For these patients, scores were expected to decrease by 22 points on the IBS QOL, 10.24 on the PCS, 11.76 on the MCS, and increase by 20.61 points on the BSI in comparison to patients who are not diagnosed with MDD and LBP. For the IBS-SSS, the regression coefficient was 89.67. This means that a patient diagnosed with MDD-LBP had IBS symptom severity scores on the IBS-SSS score that, on average, are 89.67 units higher than a patient undiagnosed with MDD and LBP. CONCLUSIONS. Physical-mental comorbidity in IBS is common, associated with increased distress and QOL impairment and, for patients with specific comorbidity profiles, more severe IBS symptoms. The type of reported comorbidities, rather than their number, may be a more useful way of understanding the full scope of their impact in more severely affected IBS patients. This study was funded by NIH Grant DK77738