Machine learning model to predict obesity using gut metabolite and brain microstructure data.

A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions may contribute to obesity pathogenesis. In this study, we use a machine learning approach to leverage the enormous amount of microstructural neuroimaging and fecal metabolomic data to better understand key drivers of the obese compared to overweight phenotype. Our findings reveal that although gut-derived factors play a role in this distinction, it is primarily brain-directed changes that differentiate obese from overweight individuals. Of the key gut metabolites that emerged from our model, many are likely at least in part derived or influenced by the gut-microbiota, including some amino-acid derivatives. Remarkably, key regions outside of the central nervous system extended reward network emerged as important differentiators, suggesting a role for previously unexplored neural pathways in the pathogenesis of obesity.

Obesity is associated with a distinct brain-gut microbiome signature that connects Prevotella and Bacteroides to the brain's reward center.

The prevalence of obesity has risen to its highest values over the last two decades. While many studies have either shown brain or microbiome connections to obesity, few have attempted to analyze the brain-gut-microbiome relationship in a large cohort adjusting for cofounders. Therefore, we aim to explore the connection of the brain-gut-microbiome axis to obesity controlling for such cofounders as sex, race, and diet. Whole brain resting state functional MRI was acquired, and connectivity and brain network properties were calculated. Fecal samples were obtained from 287 obese and non-obese participants (males n = 99, females n = 198) for 16s rRNA profiling and fecal metabolites, along with a validated dietary questionnaire. Obesity was associated with alterations in the brain's reward network (nucleus accumbens, brainstem). Microbial diversity (p = .03) and composition (p = .03) differed by obesity independent of sex, race, or diet. Obesity was associated with an increase in Prevotella/Bacteroides (P/B) ratio and a decrease in fecal tryptophan (p = .02). P/B ratio was positively correlated to nucleus accumbens centrality (p = .03) and negatively correlated to fecal tryptophan (p = .004). Being Hispanic, eating a standard American diet, having a high Prevotella/Bacteroides ratio, and a high nucleus accumbens centrality were all independent risk factors for obesity. There are obesity-related signatures in the BGM-axis independent of sex, race, and diet. Race, diet, P/B ratio and increased nucleus accumbens centrality were independent risk factors for obesity. P/B ratio was inversely related to fecal tryptophan, a metabolite related to serotonin biosynthesis, and positively related to nucleus accumbens centrality, a region central to the brain's reward center. These findings may expand the field of therapies for obesity through novel pathways directed at the BGM axis.

Reduced concentrations of vaginal metabolites involved in steroid hormone biosynthesis are associated with increased vulvar vestibular pain and vaginal muscle tenderness in provoked vestibulodynia: An exploratory metabolomics study.

Provoked vestibulodynia (PVD) is a chronic vulvar pain disorder characterized by hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Knowledge regarding pathophysiological mechanisms contributing to the etiology and production of symptoms in PVD remains incomplete but is considered multifactorial. Using a cross-sectional observational study design, data from untargeted metabolomic profiling of vaginal fluid and plasma in women with PVD and healthy women was combined with pain testing and brain imaging in women with PVD to test the hypotheses that women with PVD compared to healthy women show differences in vaginal and plasma metabolites involved in steroid hormone biosynthesis. Steroid hormone metabolites showing group differences were correlated with vulvar vestibular pain and vaginal muscle tenderness and functional connectivity of brain regions involved in pain processing in women with PVD to provide insight into the functional mechanisms linked to the identified alterations. Sensitivity analyses were also performed to determine the impact of hormonal contraceptive use on the study findings. Women with PVD compared to healthy controls had significant reductions primarily in vaginal fluid concentrations of androgenic, pregnenolone and progestin metabolites involved in steroidogenesis, suggesting localized rather than systemic effects in vagina and vulvar vestibule. The observed reductions in androgenic metabolite levels showed large effect size associations with increased vulvar vestibular pain and vulvar muscle tenderness and decreases in androgenic and progestin metabolites were associated with decreased connectivity strength in primary sensorimotor cortices. Women with PVD showed symptom-associated reductions in vaginal fluid concentrations of metabolites involved in the biosynthesis of steroid hormones previously shown to affect the integrity of vulvar and vaginal tissue and nociceptive processing. Deficiency of certain steroids may be an important mechanism contributing to the pathophysiology of symptoms in PVD may provide potential diagnostic markers that could lead to new targets for therapeutic intervention.

Dysregulation in Sphingolipid Signaling Pathways is Associated With Symptoms and Functional Connectivity of Pain Processing Brain Regions in Provoked Vestibulodynia.

Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention. PERSPECTIVE: This manuscript presents the results of a robust, unbiased molecular assessment of plasma and vaginal fluid samples in women with provoked vestibulodynia compared to healthy controls. The findings suggest that alterations in sphingolipid signaling pathways are associated with symptoms and brain biomarkers and may be an important molecular marker that could provide new targets for therapeutic intervention.

Alterations in reward network functional connectivity are associated with increased food addiction in obese individuals.

Functional neuroimaging studies in obesity have identified alterations in the connectivity within the reward network leading to decreased homeostatic control of ingestive behavior. However, the neural mechanisms underlying sex differences in the prevalence of food addiction in obesity is unknown. The aim of the study was to identify functional connectivity alterations associated with: (1) Food addiction, (2) Sex- differences in food addiction, (3) Ingestive behaviors. 150 participants (females: N = 103, males: N = 47; food addiction: N = 40, no food addiction: N = 110) with high BMI ≥ 25 kg/m2 underwent functional resting state MRIs. Participants were administered the Yale Food Addiction Scale (YFAS), to determine diagnostic criteria for food addiction (YFAS Symptom Count ≥ 3 with clinically significant impairment or distress), and completed ingestive behavior questionnaires. Connectivity differences were analyzed using a general linear model in the CONN Toolbox and images were segmented using the Schaefer 400, Harvard-Oxford Subcortical, and Ascending Arousal Network atlases. Significant connectivities and clinical variables were correlated. Statistical significance was corrected for multiple comparisons at q < .05. (1) Individuals with food addiction had greater connectivity between brainstem regions and the orbital frontal gyrus compared to individuals with no food addiction. (2) Females with food addiction had greater connectivity in the salience and emotional regulation networks and lowered connectivity between the default mode network and central executive network compared to males with food addiction. (3) Increased connectivity between regions of the reward network was positively associated with scores on the General Food Cravings Questionnaire-Trait, indicative of greater food cravings in individuals with food addiction. Individuals with food addiction showed greater connectivity between regions of the reward network suggesting dysregulation of the dopaminergic pathway. Additionally, greater connectivity in the locus coeruleus could indicate that the maladaptive food behaviors displayed by individuals with food addiction serve as a coping mechanism in response to pathological anxiety and stress. Sex differences in functional connectivity suggest that females with food addiction engage more in emotional overeating and less cognitive control and homeostatic processing compared to males. These mechanistic pathways may have clinical implications for understanding the sex-dependent variability in response to diet interventions.

Understanding the Heterogeneity of Obesity and the Relationship to the Brain-Gut Axis.

Obesity is best understood as a multifactorial metabolic imbalances disorder. In a cross-sectional study, we aimed to explore sociodemographic and dietary determinants of obesity in relation to brain-gut homeostasis among overweight and obese individuals. Multivariate logistic regression models were used to examine obesity and its association with sociodemographic and dietary factors. Biological variables examined included the gut microbiome, fecal amino acid metabolites and brain structural volumes. Among 130 participants, there were higher odds of obesity if individuals were Hispanic (adjusted odds ratio (aOR) 1.56, p = 0.014). Compared to non-Hispanics, Hispanics differed in gut microbial composition (p = 0.046) with lower microbial species richness (Chao1) (p = 0.032) and evenness (Shannon) (p = 0.0029). Fourteen of the twenty fecal amino acids including branch-chain- and aromatic- amino acids were increased among Hispanics (q < 0.05). Brain structural volumes in reward regions were decreased in Hispanics (pallidum, q = 0.036; brainstem, q = 0.011). Correlation patterns suggest complex brain-gut interactions differ by Hispanic ethnicity. In conclusion, Hispanics expressed a unique brain-gut microbial signature, which was associated with obesity despite sociodemographic and dietary differences. Addressing ethnic disparities guided by biologic phenotypes may unlock novel understanding of obesity heterogeneity and treatment strategies.

A Distinct Brain-Gut-Microbiome Profile Exists for Females with Obesity and Food Addiction.

BACKGROUND: Alterations in brain-gut-microbiome interactions have been implicated as an important factor in obesity. This study aimed to explore the relationship between food addiction (FA) and the brain-gut-microbiome axis, using a multi-omics approach involving microbiome data, metabolomics, and brain imaging. METHODS: Brain magnetic resonance imaging was obtained in 105 females. FA was defined by using the Yale Food Addiction Scale. Fecal samples were collected for sequencing and metabolomics. Statistical analysis was done by using multivariate analyses and machine learning algorithms. RESULTS: Of the females with obesity, 33.3% exhibited FA as compared with 5.3% and 0.0% of females with overweight and normal BMI, respectively (P = 0.0001). Based on a multilevel sparse partial least square discriminant analysis, there was a difference in the gut microbiome of females with FA versus those without. Differential abundance testing showed Bacteroides, Megamonas, Eubacterium, and Akkermansia were statistically associated with FA (q < 0.05). Metabolomics showed that indolepropionic acid was inversely correlated with FA. FA was also correlated with increased connectivity within the brain's reward network, specifically between the intraparietal sulcus, brain stem, and putamen. CONCLUSIONS: This is the first study to examine FA along the brain-gut-microbiome axis and it supports the idea of targeting the brain-gut-microbiome axis for the treatment of FA and obesity.

Improvement in Uncontrolled Eating Behavior after Laparoscopic Sleeve Gastrectomy Is Associated with Alterations in the Brain-Gut-Microbiome Axis in Obese Women.

BACKGROUND: Bariatric surgery is proven to change eating behavior and cause sustained weight loss, yet the exact mechanisms underlying these changes are not clearly understood. We explore this in a novel way by examining how bariatric surgery affects the brain-gut-microbiome (BGM) axis. METHODS: Patient demographics, serum, stool, eating behavior questionnaires, and brain magnetic resonance imaging (MRI) were collected before and 6 months after laparoscopic sleeve gastrectomy (LSG). Differences in eating behavior and brain morphology and resting-state functional connectivity in core reward regions were correlated with serum metabolite and 16S microbiome data. RESULTS: LSG resulted in significant weight loss and improvement in maladaptive eating behaviors as measured by the Yale Food Addiction Scale (YFAS). Brain imaging showed a significant increase in brain volume of the putamen (p.adj < 0.05) and amygdala (p.adj < 0.05) after surgery. Resting-state connectivity between the precuneus and the putamen was significantly reduced after LSG (p.adj = 0.046). This change was associated with YFAS symptom count. Bacteroides, Ruminococcus, and Holdemanella were associated with reduced connectivity between these areas. Metabolomic profiles showed a positive correlation between this brain connection and a phosphatidylcholine metabolite. CONCLUSION: Bariatric surgery modulates brain networks that affect eating behavior, potentially through effects on the gut microbiota and its metabolites.

Mindfulness-based stress reduction improves irritable bowel syndrome (IBS) symptoms via specific aspects of mindfulness.

BACKGROUND: Irritable bowel syndrome (IBS) is a common and often debilitating chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Pharmacological treatments are often ineffective, leading to the development of a variety of behavioral interventions. Mindfulness-based stress reduction (MBSR) is one such program that has shown efficacy in reducing gastrointestinal (GI) symptoms and improving quality of life (QOL). This single-arm intervention study examines the association of clinical outcomes with changes in specific aspects of mindfulness. METHODS: Adults with IBS (53 women, 15 men) participated in an 8-week MBSR class. Primary outcomes of GI symptom severity, quality of life, and GI-specific anxiety, as well as specific aspects of mindfulness using the Five Factor Mindfulness Questionnaire (FFMQ), were assessed at baseline, post-treatment, and 6-month follow-up. KEY RESULTS: Gastrointestinal symptom responder rate was 71%, and there was a significant pre-post treatment change for three of the five FFMQ scales. Regression analysis indicated that change in the Act with Awareness (P = .02) facet of mindfulness was the strongest predictor of GI symptom and QOL improvement. CONCLUSIONS & INFERENCES: Mindfulness-based stress reduction training was associated with robust improvements in GI symptoms and associated problems in participants with IBS. Although significant increases in 3 of the 5 measured facets of mindfulness were found, regression analyses suggest that increases in the ability to retain present moment focus and act with awareness may be particularly important for improving outcomes in individuals with IBS. These results may inform the refinement of mindfulness-based protocols specifically for treatment of IBS.

Altered gray matter volume in sensorimotor and thalamic regions associated with pain in localized provoked vulvodynia: a voxel-based morphometry study.

Multimodal neuroimaging studies provide support for a role of alterations in sensory processing circuits and endogenous pain modulatory systems in provoked vestibulodynia (PVD). In this study, we tested the hypotheses that PVD compared with healthy controls (HCs) would demonstrate gray matter volume (GMV) alterations in regions associated with sensorimotor, corticothalamic, and basal ganglia circuits. We also tested the replicability of previously reported gray matter increases in basal ganglia and hippocampal volumes in PVD vs HCs. In addition, disease specificity of GMV alterations were examined by comparing PVD with another chronic pain disorder. Finally, we examine whether GMV alterations are correlated with symptom measures. Structural magnetic resonance imaging was obtained in 119 premenopausal women (45 PVD, 45 HCs, and 29 irritable bowel syndrome [IBS]). A voxel-based morphometry analysis was applied to determine group differences in the hypothesized regions of interest. Compared with HCs, PVD women exhibited greater GMV in the basal ganglia, hippocampus, and sensorimotor cortices. Compared to patients with IBS, women with PVD had greater GMV in the hippocampus, and sensorimotor network, but lower GMV in the thalamus and precentral gyrus. Regional GMV alterations were associated with patient reports of pain during intercourse and muscle tenderness. The current findings provide further evidence that GMV is increased in PVD compared with HCs in several regions of the sensorimotor network and the hippocampus in patients with PVD. In addition, GMV distinct alterations in the sensorimotor network were identified between 2 pelvic pain disorders, PVD compared with IBS.

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs. PERSPECTIVE: Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system.

Surgically Induced Changes in Gut Microbiome and Hedonic Eating as Related to Weight Loss: Preliminary Findings in Obese Women Undergoing Bariatric Surgery.

OBJECTIVE: Weight loss surgery results in significant changes in the anatomy, function, and intraluminal environment of the gastrointestinal tract affecting the gut microbiome. Although bariatric surgery results in sustained weight loss, decreased appetite, and hedonic eating, it is unknown whether the surgery-induced alterations in gut microbiota play a role in the observed changes in hedonic eating. We explored the following hypotheses: (1) laparoscopic sleeve gastrectomy (LSG) results in changes in gut microbial composition; (2) alterations in gut microbiota are related to weight loss; (3) alterations in gut microbiome are associated with changes in appetite and hedonic eating. METHODS: Eight obese women underwent LSG. Their body mass index, body fat mass, food intake, hunger, hedonic eating scores, and stool samples were obtained at baseline and 1-month postsurgery. 16S ribosomal RNA gene sequencing was performed on stool samples. DESeq2 changes in microbial abundance. Multilevel-sparse partial least squares discriminant analysis was applied to genus-level abundance for discriminative microbial signatures. RESULTS: LSG resulted in significant reductions in body mass index, food intake, and hedonic eating. A microbial signature composed of five bacterial genera discriminated between pre- and postsurgery status. Several bacterial genera were significantly associated with weight loss (Bilophila, q = 3E-05; Faecalibacterium q = 4E-05), lower appetite (Enterococcus, q = 3E-05), and reduced hedonic eating (Akkermansia, q = .037) after surgery. CONCLUSIONS: In this preliminary analysis, changes in gut microbial abundance discriminated between pre- and postoperative status. Alterations in gut microbiome were significantly associated with weight loss and with reduced hedonic eating after surgery; however, a larger sample is needed to confirm these findings.

Disease-related differences in resting-state networks: a comparison between localized provoked vulvodynia, irritable bowel syndrome, and healthy control subjects.

Localized provoked vulvodynia (LPVD) affects approximately 16% of the female population, but biological mechanisms underlying symptoms remain unknown. Like in other often comorbid chronic pain disorders, altered sensory processing and modulation of pain, including central sensitization, dysregulation of endogenous pain modulatory systems, and attentional enhancement of pain perception, have been implicated. The aim of this study was to test whether regions of interest showing differences in LPVD compared to healthy control subjects (HCs) in structural and evoked-pain neuroimaging studies, also show alterations during rest when compared with HCs and a chronic pain control group (irritable bowel syndrome [IBS]). Functional magnetic resonance imaging was performed during resting state in 87 age-matched premenopausal females (29 LPVD, 29 HCs, and 29 IBS). Group-independent component analysis and general linear models were applied to investigate group differences in the intrinsic connectivity of regions comprising sensorimotor, salience, and default mode resting-state networks. Subjects with LPVD showed substantial alterations in the intrinsic connectivity of these networks compared with HCs and IBS. The intrinsic connectivity of many of the regions showing group differences during rest were moderately associated with clinical symptom reports in LPVD. Findings were robust to controlling for affect and medication usage. The current findings indicate that subjects with LPVD have alterations in the intrinsic connectivity of regions comprising the sensorimotor, salience, and default mode networks. Although shared brain mechanisms between different chronic pain disorders have been postulated, the current findings suggest that some alterations in functional connectivity may show disease specificity.

Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain.

Resting-state functional magnetic resonance imaging has been used to investigate intrinsic brain connectivity in healthy subjects and patients with chronic pain. Sex-related differences in the frequency power distribution within the human insula (INS), a brain region involved in the integration of interoceptive, affective, and cognitive influences, have been reported. Here we aimed to test sex and disease-related alterations in the intrinsic functional connectivity of the dorsal anterior INS. The anterior INS is engaged during goal-directed tasks and modulates the default mode and executive control networks. By comparing functional connectivity of the dorsal anterior INS in age-matched female and male healthy subjects and patients with irritable bowel syndrome (IBS), a common chronic abdominal pain condition, we show evidence for sex and disease-related alterations in the functional connectivity of this region: (1) male patients compared with female patients had increased positive connectivity of the dorsal anterior INS bilaterally with the medial prefrontal cortex (PFC) and dorsal posterior INS; (2) female patients compared with male patients had greater negative connectivity of the left dorsal anterior INS with the left precuneus; (3) disease-related differences in the connectivity between the bilateral dorsal anterior INS and the dorsal medial PFC were observed in female subjects; and (4) clinical characteristics were significantly correlated to the insular connectivity with the dorsal medial PFC in male IBS subjects and with the precuneus in female IBS subjects. These findings are consistent with the INS playing an important role in modulating the intrinsic functional connectivity of major networks in the resting brain and show that this role is influenced by sex and diagnosis.

Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women.

BACKGROUND & AIMS: The study of intrinsic fluctuations in the blood oxygen level-dependent signal of functional magnetic resonance imaging can provide insight into the effect of physiologic states on brain processes. In an effort to better understand the brain-gut communication induced by the absorption and metabolism of nutrients in healthy lean and obese individuals, we investigated whether ingestion of nutritive and non-nutritive sweetened beverages differentially engages the hypothalamus and brainstem vagal pathways in lean and obese women. METHODS: In a 2-day, double-blind crossover study, 11 lean and 11 obese healthy women underwent functional magnetic resonance imaging scans after ingestion of 2 beverages of different sucrose content, but identical sweetness. During scans, subjects rested with eyes closed. RESULTS: Blood oxygen level-dependent fluctuations demonstrated significantly greater power in the highest frequency band (slow-3: 0.073-0.198 Hz) after ingestion of high-sucrose compared with low-sucrose beverages in the nucleus tractus solitarius for both groups. Obese women had greater connectivity between the right lateral hypothalamus and a reward-related brain region and weaker connectivity with homeostasis and gustatory-related brain regions than lean women. CONCLUSIONS: In a functional magnetic resonance imaging study, we observed sucrose-related changes in oscillatory dynamics of blood oxygen level-dependent fluctuations in brainstem and hypothalamus in lean and obese women. The observed frequency changes are consistent with a rapid vagally mediated mechanism due to nutrient absorption, rather than sweet taste receptor activation. These findings provide support for altered interaction between homeostatic and reward networks in obese individuals.

Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain.

Regional cortical thickness alterations have been reported in many chronic inflammatory and painful conditions, including inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), even though the mechanisms underlying such neuroplastic changes remain poorly understood. In order to better understand the mechanisms contributing to grey matter changes, the current study sought to identify the differences in regional alterations in cortical thickness between healthy controls and two chronic visceral pain syndromes, with and without chronic gut inflammation. 41 healthy controls, 11 IBS subjects with diarrhea, and 16 subjects with ulcerative colitis (UC) underwent high-resolution T1-weighted magnetization-prepared rapid acquisition gradient echo scans. Structural image preprocessing and cortical thickness analysis within the region of interests were performed by using the Laboratory of Neuroimaging Pipeline. Group differences were determined using the general linear model and linear contrast analysis. The two disease groups differed significantly in several cortical regions. UC subjects showed greater cortical thickness in anterior cingulate cortical subregions, and in primary somatosensory cortex compared with both IBS and healthy subjects. Compared with healthy subjects, UC subjects showed lower cortical thickness in orbitofrontal cortex and in mid and posterior insula, while IBS subjects showed lower cortical thickness in the anterior insula. Large effects of correlations between symptom duration and thickness in the orbitofrontal cortex and postcentral gyrus were only observed in UC subjects. The findings suggest that the mechanisms underlying the observed gray matter changes in UC subjects represent a consequence of peripheral inflammation, while in IBS subjects central mechanisms may play a primary role.

Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome.

BACKGROUND & AIMS: Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). METHODS: We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. RESULTS: Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. CONCLUSIONS: Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.

Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain.

Abnormal responses of the brain to delivered and expected aversive gut stimuli have been implicated in the pathophysiology of irritable bowel syndrome (IBS), a visceral pain syndrome occurring more commonly in women. Task-free resting-state functional magnetic resonance imaging (fMRI) can provide information about the dynamics of brain activity that may be involved in altered processing and/or modulation of visceral afferent signals. Fractional amplitude of low-frequency fluctuation is a measure of the power spectrum intensity of spontaneous brain oscillations. This approach was used here to identify differences in the resting-state activity of the human brain in IBS subjects compared with healthy controls (HCs) and to identify the role of sex-related differences. We found that both the female HCs and female IBS subjects had a frequency power distribution skewed toward high frequency to a greater extent in the amygdala and hippocampus compared with male subjects. In addition, female IBS subjects had a frequency power distribution skewed toward high frequency in the insula and toward low frequency in the sensorimotor cortex to a greater extent than male IBS subjects. Correlations were observed between resting-state blood oxygen level-dependent signal dynamics and some clinical symptom measures (e.g., abdominal discomfort). These findings provide the first insight into sex-related differences in IBS subjects compared with HCs using resting-state fMRI.

Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects.

Greater responsiveness of emotional arousal circuits in relation to delivered visceral pain has been implicated as underlying central pain amplification in irritable bowel syndrome (IBS), with female subjects showing greater responses than male subjects. Functional magnetic resonance imaging was used to measure neural responses to an emotion recognition paradigm, using faces expressing negative emotions (fear and anger). Sex and disease differences in the connectivity of affective and modulatory cortical circuits were studied in 47 IBS (27 premenopausal female subjects) and 67 healthy control subjects (HCs; 38 premenopausal female subjects). Male subjects (IBS+HC) showed greater overall brain responses to stimuli than female subjects in prefrontal cortex, insula, and amygdala. Effective connectivity analyses identified major sex- and disease-related differences in the functioning of brain networks related to prefrontal regions, cingulate, insula, and amygdala. Male subjects had stronger connectivity between anterior cingulate subregions, amygdala, and insula, whereas female subjects had stronger connectivity to and from the prefrontal modulatory regions (medial/dorsolateral cortex). Male IBS subjects demonstrate greater engagement of cortical and affect-related brain circuitry compared to male control subjects and female subjects, when viewing faces depicting emotions previously shown to elicit greater behavioral and brain responses in male subjects.

Diminished neurokinin-1 receptor availability in patients with two forms of chronic visceral pain.

Central sensitization and dysregulation of peripheral substance P and neurokinin-1 receptor (NK-1R) signaling are associated with chronic abdominal pain in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Although positron emission tomography (PET) has demonstrated that patients with injury-related chronic pain have diminished NK-1R availability in the brain, it is unknown whether these deficits are present in IBD and IBS patients, who have etiologically distinct forms of non-injury-related chronic pain. This study's aim was to determine if patients with IBD or IBS exhibit deficits in brain expression of NK-1Rs relative to healthy controls (HCs), the extent to which expression patterns differ across patient populations, and if these patterns differentially relate to clinical parameters. PET with [(18)F]SPA-RQ was used to measure NK-1R availability by quantifying binding potential (BP) in the 3 groups. Exploratory correlation analyses were performed to detect associations between NK-1R BP and physical symptoms. Compared to HCs, IBD patients had NK-1R BP deficits across a widespread network of cortical and subcortical regions. IBS patients had similar, but less pronounced deficits. BP in a subset of these regions was robustly related to discrete clinical parameters in each patient population. Widespread deficits in NK-1R BP occur in IBD and, to a lesser extent, IBS; however, discrete clinical parameters relate to NK-1R BP in each patient population. This suggests that potential pharmacological interventions that target NK-1R signaling may be most effective for treating distinct symptoms in IBD and IBS.