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Neuroticism is one of the most robust risk factors for addictive behaviors including food addiction (a key contributor to obesity), although the associated mechanisms are not well understood. A transdiagnostic approach was used to identify the neuroticism-related neuropsychological and gut metabolomic patterns associated with food addiction. Predictive modeling of neuroticism was implemented using multimodal features (23 clinical, 13,531 resting-state functional connectivity (rsFC), 336 gut metabolites) in 114 high body mass index (BMI ≥25 kg/m2) (cross-sectional) participants. Gradient boosting machine and logistic regression models were used to evaluate classification performance for food addiction. Neuroticism was significantly associated with food addiction (P

Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

Alterations of the brain-gut-microbiome system (BGM) have been implicated in the pathophysiology of irritable bowel syndrome (IBS), yet bowel habit-specific alterations have not been elucidated. In this cross-sectional study, we apply a systems biology approach to characterize BGM patterns related to predominant bowel habit. Fecal samples and resting state fMRI were obtained from 102 premenopausal women (36 constipation-predominant IBS (IBS-C), 27 diarrhea-predominant IBS (IBS-D), 39 healthy controls (HCs)). Data integration analysis using latent components (DIABLO) was used to integrate data from the phenome, microbiome, metabolome, and resting-state connectome to predict HCs vs IBS-C vs IBS-D. Bloating and visceral sensitivity, distinguishing IBS from HC, were negatively associated with beneficial microbes and connectivity involving the orbitofrontal cortex. This suggests that gut interactions may generate aberrant central autonomic and descending pain pathways in IBS. The connection between IBS symptom duration, key microbes, and caudate connectivity may provide mechanistic insight to the chronicity of pain in IBS. Compared to IBS-C and HCs, IBS-D had higher levels of many key metabolites including tryptophan and phenylalanine, and increased connectivity between the sensorimotor and default mode networks; thus, suggestingan influence on diarrhea, self-related thoughts, and pain perception in IBS-D ('bottom-up' mechanism). IBS-C's microbiome and metabolome resembled HCs, but IBS-C had increased connectivity in the default mode and salience networks compared to IBS-D, which may indicate importance of visceral signals, suggesting a more 'top-down' BGM pathophysiology. These BGM characteristics highlight possible mechanistic differences for variations in the IBS bowel habit phenome. This article is part of the Special Issue on 'Microbiome & the Brain: Mechanisms & Maladies'.

Obesity contributes to physical comorbidities and mental health consequences. We explored whether physical activity could influence more than metabolic regulation and result in psychological benefits through the brain-gut microbiome (BGM) system in a population with high BMI. Fecal samples were obtained for 16 s rRNA profiling and fecal metabolomics, along with psychological and physical activity questionnaires. Whole brain resting-state functional MRI was acquired, and brain connectivity metrics were calculated. Higher physical activity was significantly associated with increased connectivity in inhibitory appetite control brain regions, while lower physical activity was associated with increased emotional regulation network connections. Higher physical activity was also associated with microbiome and metabolite signatures protective towards mental health and metabolic derangements. The greater resilience and coping, and lower levels of food addiction seen with higher physical activity, may be explained by BGM system differences. These novel findings provide an emphasis on the psychological and resilience benefits of physical activity, beyond metabolic regulation and these influences seem to be related to BGM interactions.

Irritable bowel syndrome (IBS) is a common disorder of brain-gut interactions characterized by chronic abdominal pain, altered bowel movements, often accompanied by somatic and psychiatric comorbidities. We aimed to test the hypothesis that a baseline phenotype composed of multi-modal neuroimaging and clinical features predicts clinical improvement on the IBS Symptom Severity Scale (IBS-SSS) at 3 and 12 months without any targeted intervention. Female participants (N = 60) were identified as "improvers" (50-point decrease on IBS-SSS from baseline) or "non-improvers." Data integration analysis using latent components (DIABLO) was applied to a training and test dataset to determine whether a limited number of sets of multiple correlated baseline'omics data types, including brain morphometry, anatomical connectivity, resting-state functional connectivity, and clinical features could accurately predict improver status. The derived predictive models predicted improvement status at 3-months and 12-months with 91% and 83% accuracy, respectively. Across both time points, non-improvers were classified as having greater correlated morphometry, anatomical connectivity and resting-state functional connectivity characteristics within salience and sensorimotor networks associated with greater pain unpleasantness, but lower default mode network integrity and connectivity. This suggests that non-improvers have a greater engagement of attentional systems to perseverate on painful visceral stimuli, predicting IBS exacerbation. The ability of baseline multimodal brain-clinical signatures to predict symptom trajectories may have implications in guiding integrative treatment in the age of precision medicine, such as treatments targeted at changing attentional systems such as mindfulness or cognitive behavioral therapy.

Despite recent advances, there is still a major need to better understand the interactions between brain function and chronic gut inflammation and its clinical implications. Alterations in executive function have previously been identified in several chronic inflammatory conditions, including inflammatory bowel diseases. Inflammation-associated brain alterations can be captured by connectome analysis. Here, we used the resting-state fMRI data from 222 participants comprising three groups (ulcerative colitis (UC), irritable bowel syndrome (IBS), and healthy controls (HC), N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in UC compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, UC participants showed increased functional connectivity and decreased modularity compared to IBS and HC groups. Regionally, UC showed decreased eigenvector centrality in the executive control network (UC  IBS > HC). UC also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish UC participants from HCs and IBS with high accuracy. Dynamic functional connectome analysis revealed that UC showed enhanced cortical stability in the medial prefrontal cortex (mPFC), which correlated with severe depression and anxiety-related measures. None of the observed brain changes were correlated with disease duration. Together, these findings are consistent with compromised functioning of networks involved in executive function and sensory integration in UC.

BackgroundThere is growing recognition that bidirectional signaling between the digestive tract and the brain contributes to irritable bowel syndrome (IBS). We recently showed in a large randomized controlled trial that cognitive behavioral therapy (CBT) reduces IBS symptom severity. This study investigated whether baseline brain and gut microbiome parameters predict CBT response and whether response is associated with changes in the brain-gut-microbiome (BGM) axis.MethodsEighty-four Rome III-diagnosed IBS patients receiving CBT were drawn from the Irritable Bowel Syndrome Outcome Study (IBSOS; ClinicalTrials.gov NCT00738920) for multimodal brain imaging and psychological assessments at baseline and after study completion. Fecal samples were collected at baseline and post-treatment from 34 CBT recipients for 16S rRNA gene sequencing, untargeted metabolomics, and measurement of short-chain fatty acids. Clinical measures, brain functional connectivity and microstructure, and microbiome features associated with CBT response were identified by multivariate linear and negative binomial models.ResultsAt baseline, CBT responders had increased fecal serotonin levels, and increased Clostridiales and decreased Bacteroides compared to non-responders. A random forests classifier containing 11 microbial genera predicted CBT response with high accuracy (AUROC 0.96). Following treatment, CBT responders demonstrated reduced functional connectivity in regions of the sensorimotor, brainstem, salience, and default mode networks and changes in white matter in the basal ganglia and other structures. Brain changes correlated with microbiome shifts including Bacteroides expansion in responders.ConclusionsPre-treatment intestinal microbiota and serotonin levels were associated with CBT response, suggesting that peripheral signals from the microbiota can modulate central processes affected by CBT that generate abdominal symptoms in IBS. CBT response is characterized by co-correlated shifts in brain networks and gut microbiome that may reflect top-down effects of the brain on the microbiome during CBT. Video abstract.

ObjectiveWe aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis (UC) participants who had a history of chronic gut inflammation, healthy controls (HCs) and a disease control group without gut inflammation (irritable bowel syndrome; IBS).DesignDiffusion weighted imaging was conducted in age and sex-matched participants with UC, IBS, and HCs (N = 74 each), together with measures of gastrointestinal and psychological symptom severity. Using streamline connectivity matrices and graph theory, we aimed to quantify group differences in brain network connectivity. Regions showing group connectivity differences were correlated with measures showing group behavioral and clinical differences.ResultsUC participants exhibited greater centrality in regions of the somatosensory network and default mode network, but lower centrality in the posterior insula and globus pallidus compared to HCs (q

BackgroundBariatric 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.MethodsPatient 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.ResultsLSG 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.ConclusionBariatric surgery modulates brain networks that affect eating behavior, potentially through effects on the gut microbiota and its metabolites.

PurposeWe exposed premature infants to womb-like sounds to evaluate such exposure on breathing and cardiovascular patterns. We hypothesized that these sounds would reduce apnea and intermittent hypoxemia, enhance parasympathetic outflow, and improve cardiovascular patterns.MethodsA total of 20 cases and 5 control infants at ≤32-36 weeks corrected gestational age participated in a prospective observational cohort study. Twenty-four hours of continuous ECG, respiratory and oxygen saturation data were collected in all infants. Womb-like sounds were played intermittently in 6-hour blocks. Salivary samples were collected at study beginning and end for cortisol. Apnea, intermittent hypoxemia, and bradycardia were evaluated, and heart rate variability was assessed by time domain and spectral techniques.ResultsIntermittent hypoxemia and bradycardia significantly declined after sound exposure. No significant differences in apnea, cortisol levels, or heart rate variability were evident among the study infants.ConclusionsExposing premature infants to womb-like sounds has the potential to reduce hypoxemic and bradycardic events, and be used as an intervention to stabilize breathing and cardiac control in preterm infants.

OBJECTIVE:This study aimed to characterize obesity-related sex differences in the intrinsic activity and connectivity of the brain's reward networks. METHODS:Eighty-six women (n = 43) and men (n = 43) completed a 10-minute resting functional magnetic resonance imaging scan. Sex differences and commonalities in BMI-related frequency power distribution and reward seed-based connectivity were investigated by using partial least squares analysis. RESULTS:For whole-brain activity in both men and women, increased BMI was associated with increased slow-5 activity in the left globus pallidus (GP) and substantia nigra. In women only, increased BMI was associated with increased slow-4 activity in the right GP and bilateral putamen. For seed-based connectivity in women, increased BMI was associated with reduced slow-5 connectivity between the left GP and putamen and the emotion and cortical regulation regions, but in men, increased BMI was associated with increased connectivity with the medial frontal cortex. In both men and women, increased BMI was associated with increased slow-4 connectivity between the right GP and bilateral putamen and the emotion regulation and sensorimotor-related regions. CONCLUSIONS:The stronger relationship between increased BMI and decreased connectivity of core reward network components with cortical and emotion regulation regions in women may be related to the greater prevalence of emotional eating. The present findings suggest the importance of personalized treatments for obesity that consider the sex of the affected individual.

Automatic neuroimaging processing tools provide convenient and systematic methods for extracting features from brain magnetic resonance imaging scans. One tool, FreeSurfer, provides an easy‐to‐use pipeline to extract cortical and subcortical morphometric measures. There have been over 25 stable releases of FreeSurfer, with different versions used across published works. The reliability and compatibility of regional morphometric metrics derived from the most recent version releases have yet to be empirically assessed. Here, we used test–retest data from three public data sets to determine within‐version reliability and between‐version compatibility across 42 regional outputs from FreeSurfer versions 7.1, 6.0, and 5.3. Cortical thickness from v7.1 was less compatible with that of older versions, particularly along the cingulate gyrus, where the lowest version compatibility was observed (intraclass correlation coefficient 0.37–0.61). Surface area of the temporal pole, frontal pole, and medial orbitofrontal cortex, also showed low to moderate version compatibility. We confirm low compatibility between v6.0 and v5.3 of pallidum and putamen volumes, while those from v7.1 were compatible with v6.0. Replication in an independent sample showed largely similar results for measures of surface area and subcortical volumes, but had lower overall regional thickness reliability and compatibility. Batch effect correction may adjust for some inter‐version effects when most sites are run with one version, but results vary when more sites are run with different versions. Age associations in a quality controlled independent sample (N = 106) revealed version differences in results of downstream statistical analysis. We provide a reference to highlight the regional metrics that may yield recent version‐related inconsistencies in published findings. An interactive viewer is provided at http://data.brainescience.org/Freesurfer_Reliability/. [ABSTRACT FROM AUTHOR]

Pain is a highly complex and individualized experience with biopsychosocial components. Neuroimaging research has shown evidence of the involvement of the central nervous system in the development and maintenance of chronic pain conditions, including urological chronic pelvic pain syndrome (UCPPS). Furthermore, a history of early adverse life events (EALs) has been shown to adversely impact symptoms throughout childhood and into adulthood. However, to date, the role of EAL’s in the central processes of chronic pain have not been adequately investigated. We studied 85 patients (56 females) with UCPPS along with 86 healthy controls (HCs) who had resting-state magnetic resonance imaging scans (59 females), and data on EALs as a part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Study. We used graph theory methods in order to investigate the impact of EALs on measures of centrality, which characterize information flow, communication, influence, and integration in a priori selected regions of interest. Patients with UCPPS exhibited lower centrality in the right anterior insula compared to HCs, a key node in the salience network. Males with UCPPS exhibited lower centrality in the right anterior insula compared the HC males. Females with UCPPS exhibited greater centrality in the right caudate nucleus and left angular gyrus compared to HC females. Males with UCPPS exhibited lower centrality in the left posterior cingulate, angular gyrus, middle temporal gyrus, and superior temporal sulcus, but greater centrality in the precuneus and anterior mid-cingulate cortex (aMCC) compared to females with UCPPS. Higher reports of EALs was associated with greater centrality in the left precuneus and left aMCC in females with UCPPS. This study provides evidence for disease and sex-related alterations in the default mode, salience, and basal ganglia networks in patients with UCPPS, which are moderated by EALs, and associated with clinical symptoms and quality of life (QoL). [ABSTRACT FROM AUTHOR]

Background: Vaso-occlusive pain crises (VOCs) are the "hallmark" of sickle-cell disease (SCD) and can lead to sympathetic nervous system dysfunction. Increased sympathetic nervous system activation during VOCs and/or pain can result in vasoconstriction, which may increase the risk for subsequent VOCs and pain. Hypnosis is a neuromodulatory intervention that may attenuate vascular and pain responsiveness. Due to the lack of laboratory-controlled pain studies in patients with SCD and healthy controls, the specific effects of hypnosis on acute pain-associated vascular responses are unknown. The current study assessed the effects of hypnosis on peripheral blood flow, pain threshold, tolerance, and intensity in adults with and without SCD. Subjects and methods: Fourteen patients with SCD and 14 healthy controls were included. Participants underwent three laboratory pain tasks before and during a 30-minute hypnosis session. Peripheral blood flow, pain threshold, tolerance, and intensity before and during hypnosis were examined. Results: A single 30-minute hypnosis session decreased pain intensity by a moderate amount in patients with SCD. Pain threshold and tolerance increased following hypnosis in the control group, but not in patients with SCD. Patients with SCD exhibited lower baseline peripheral blood flow and a greater increase in blood flow following hypnosis than controls. Conclusion: Given that peripheral vasoconstriction plays a role in the development of VOC, current findings provide support for further laboratory and clinical investigations of the effects of cognitive--behavioral neuromodulatory interventions on pain responses and peripheral vascular flow in patients with SCD. Current results suggest that hypnosis may increase peripheral vasodilation during both the anticipation and experience of pain in patients with SCD. These findings indicate a need for further examination of the effects of hypnosis on pain and vascular responses utilizing a randomized controlled trial design. Further evidence may help determine unique effects of hypnosis and potential benefits of integrating cognitive--behavioral neuromodulatory interventions into SCD treatment. [ABSTRACT FROM AUTHOR]

This Letter to the Editor reports findings from a randomized controlled cross-over trial, extending a previous study on the effects of music listening to reduce sensitivity to cold pain stimulation. Within this small replication, participants listened to music or white noise (compared to a silence condition) before nociceptive stimulation by the cold pressor task. Results show that in line with previous research pleasant music may increase pain threshold and tolerance compared to silence. Most interestingly we were able to show that annoying white noise may reduce pain threshold and tolerance. However, due to the small sample size these differences were not statistically significant. Clinical implications of these preliminary results linking pain sensitivity to environmental noise are discussed. [ABSTRACT FROM AUTHOR]

The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses, performing associative/executive functions, and representing information in multiple dimensions. Understanding which genetic variants underpin corpus callosum morphometry, and their shared influence on cortical structure and susceptibility to neuropsychiatric disorders, can provide molecular insights into the CC's role in mediating cortical development and its contribution to neuropsychiatric disease. To characterize the morphometry of the midsagittal corpus callosum, we developed a publicly available artificial intelligence based tool to extract, parcellate, and calculate its total and regional area and thickness. Using the UK Biobank (UKB) and the Adolescent Brain Cognitive Development study (ABCD), we extracted measures of midsagittal corpus callosum morphometry and performed a genome-wide association study (GWAS) meta-analysis of European participants (combined N = 46,685). We then examined evidence for generalization to the non-European participants of the UKB and ABCD cohorts (combined N = 7,040). Post-GWAS analyses implicate prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin, suggesting transcriptional activity regulation in early development. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Global and local genetic overlap, along with causal genetic liability, between the corpus callosum, cerebral cortex, and neuropsychiatric disorders such as attention-deficit/hyperactivity and bipolar disorders were identified. These results provide insight into variability of corpus callosum development, its genetic influence on the cerebral cortex, and biological mechanisms related to neuropsychiatric dysfunction., Competing Interests: Ethics Declarations Competing Interests No authors have any other conflicts of interest to disclose.