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The brain-gut-microbiome (BGM) system plays an influential role on mental health. We characterized BGM patterns related to resilience using fecal samples and multimodal MRI. Data integration analysis using latent components showed the high resilience phenotype was associated with lower depression and anxiety symptoms, higher frequency of bacterial transcriptomes (related to environmental adaptation, genetic propagation, energy metabolism, anti-inflammation), increased metabolites (N-acetylglutamate; dimethylglycine), and cortical signatures (increased resting state functional connectivity between reward circuits and sensorimotor networks; decreased grey matter volume and white matter tracts within the emotion regulation network). Our findings support a multi-omic signature involving the BGM system suggesting that resilience impacts psychological symptoms, emotion regulation and cognitive function as reflected by unique neural correlates and microbiome function supporting eubiosis and gut barrier integrity. Bacterial transcriptomes provided the highest classification accuracy suggesting that the microbiome is critical in shaping resilience and highlights that microbiome modifications can optimize mental health., Competing Interests: Competing Interests Statement: AG is scientific advisor to Yamaha. All other authors have nothing to disclose.

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.

Background: Chronic pain affects nearly 20% of the U.S., Population: It is a leading cause of disability globally and is associated with a heightened risk for suicide. The role of the central nervous system in the perception and maintenance of chronic pain has recently been accepted, but specific brain circuitries involved have yet to be mapped across pain types in a large-scale study., Methods: We used data from the UK Biobank (N = 21,968) to investigate brain structural alterations in individuals reporting chronic pain compared with pain-free control participants and their mediating effect on history of suicide attempt., Results: Chronic pain and, more notably, chronic multisite pain was associated with, on average, lower surface area throughout the cortex after adjusting for demographic, clinical, and neuropsychiatric confounds. Only participants with abdominal pain showed lower subcortical volumes, including the amygdala and brainstem, and lower cerebellum volumes. Participants with chronic headaches showed a widespread thicker cortex compared with control participants. Mediation analyses revealed that precuneus thickness mediated the relationship of chronic multisite pain and history of suicide attempt. Mediating effects were also identified specific to localized pain, with the strongest effect being amygdala volume in individuals with chronic abdominal pain., Conclusions: Results support a widespread effect of chronic pain on brain structure and distinct brain structures underlying chronic musculoskeletal pain, visceral pain, and headaches. Mediation effects of regions in the extended ventromedial prefrontal cortex subsystem suggest that exacerbated negative internal states, negative self-referencing, and impairments in future planning may underlie suicidal behaviors in individuals with chronic pain., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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/m 2 ) (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 < 0.001). Neuroticism-related features predicted food addiction with high performance (89% accuracy). Multimodal models performed better than single-modal models in predicting food addiction. Transdiagnostic alterations corresponded to rsFC involved in the emotion regulation, reward, and cognitive control and self-monitoring networks, and the metabolite 3-(4-hydroxyphenyl) propionate, as well as anxiety symptoms. Neuroticism moderated the relationship between BMI and food addiction. Neuroticism drives neuropsychological and gut microbial signatures implicated in dopamine synthesis and inflammation, anxiety, and food addiction. Such transdiagnostic models are essential in identifying mechanisms underlying food addiction in obesity, as it can help develop multiprong interventions to improve symptoms., Competing Interests: Declaration of Competing Interest AG is a scientific consultant to Yamaha. All other authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In brain imaging research, it is becoming standard practice to remove the face from the individual's 3D structural MRI scan to ensure data privacy standards are met. Face removal - or 'defacing' - is being advocated for large, multi-site studies where data is transferred across geographically diverse sites. Several methods have been developed to limit the loss of important brain data by accurately and precisely removing non-brain facial tissue. At the same time, deep learning methods such as convolutional neural networks (CNNs) are increasingly being used in medical imaging research for diagnostic classification and prognosis in neurological diseases. These neural networks train predictive models based on patterns in large numbers of images. Because of this, defacing scans could remove informative data. Here, we evaluated 4 popular defacing methods to identify the effects of defacing on 'brain age' prediction - a common benchmarking task of predicting a subject's chronological age from their 3D T1-weighted brain MRI. We compared brain-age calculations using defaced MRIs to those that were directly brain extracted, and those with both brain and face. Significant differences were present when comparing average per-subject error rates between algorithms in both the defaced brain data and the extracted facial tissue. Results also indicated brain age accuracy depends on defacing and the choice of algorithm. In a secondary analysis, we also examined how well comparable CNNs could predict chronological age from the facial region only (the extracted portion of the defaced image), as well as visualize areas of importance in facial tissue for predictive tasks using CNNs. We obtained better performance in age prediction when using the extracted face portion alone than images of the brain, suggesting the need for caution when defacing methods are used in medical image analysis.

Structural alterations of the midsagittal corpus callosum (midCC) have been associated with a wide range of brain disorders. The midCC is visible on most MRI contrasts and in many acquisitions with a limited field-of-view. Here, we present an automated tool for segmenting and assessing the shape of the midCC from T1w, T2w, and FLAIR images. We train a UNet on images from multiple public datasets to obtain midCC segmentations. A quality control algorithm is also built-in, trained on the midCC shape features. We calculate intraclass correlations (ICC) and average Dice scores in a test-retest dataset to assess segmentation reliability. We test our segmentation on poor quality and partial brain scans. We highlight the biological significance of our extracted features using data from over 40,000 individuals from the UK Biobank; we classify clinically defined shape abnormalities and perform genetic analyses.

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., (© 2023. The Author(s).)

Structural alterations of the midsagittal corpus callosum (midCC) have been associated with a wide range of brain disorders. The midCC is visible on most MRI contrasts and in many acquisitions with a limited field-of-view. Here, we present an automated tool for segmenting and assessing the shape of the midCC from T1w, T2w, and FLAIR images. We train a UNet on images from multiple public datasets to obtain midCC segmentations. A quality control algorithm is also built-in, trained on the midCC shape features. We calculate intraclass correlations (ICC) and average Dice scores in a test-retest dataset to assess segmentation reliability. We test our segmentation on poor quality and partial brain scans. We highlight the biological significance of our extracted features using data from over 40,000 individuals from the UK Biobank; we classify clinically defined shape abnormalities and perform genetic analyses.

In brain imaging research, it is becoming standard practice to remove the face from the individual's 3D structural MRI scan to ensure data privacy standards are met. Face removal - or 'defacing' - is being advocated for large, multi-site studies where data is transferred across geographically diverse sites. Several methods have been developed to limit the loss of important brain data by accurately and precisely removing non-brain facial tissue. At the same time, deep learning methods such as convolutional neural networks (CNNs) are increasingly being used in medical imaging research for diagnostic classification and prognosis in neurological diseases. These neural networks train predictive models based on patterns in large numbers of images. Because of this, defacing scans could remove informative data. Here, we evaluated 4 popular defacing methods to identify the effects of defacing on 'brain age' prediction - a common benchmarking task of predicting a subject's chronological age from their 3D T1-weighted brain MRI. We compared brain-age calculations using defaced MRIs to those that were directly brain extracted, and those with both brain and face. Significant differences were present when comparing average per-subject error rates between algorithms in both the defaced brain data and the extracted facial tissue. Results also indicated brain age accuracy depends on defacing and the choice of algorithm. In a secondary analysis, we also examined how well comparable CNNs could predict chronological age from the facial region only (the extracted portion of the defaced image), as well as visualize areas of importance in facial tissue for predictive tasks using CNNs. We obtained better performance in age prediction when using the extracted face portion alone than images of the brain, suggesting the need for caution when defacing methods are used in medical image analysis.

Investigating sex as a biological variable is key to determine obesity manifestation and treatment response. Individual neuroimaging modalities have uncovered mechanisms related to obesity and altered ingestive behaviours. However, few, if any, studies have integrated data from multi-modal brain imaging to predict sex-specific brain signatures related to obesity. We used a data-driven approach to investigate how multi-modal MRI and clinical features predict a sex-specific signature of participants with high body mass index (overweight/obese) compared to non-obese body mass index in a sex-specific manner. A total of 78 high body mass index (55 female) and 105 non-obese body mass index (63 female) participants were enrolled in a cross-sectional study. All participants classified as high body mass index had a body mass index greater than 25 kg/m 2 and non-obese body mass index had a body mass index between 19 and 20 kg/m 2 . Multi-modal neuroimaging (morphometry, functional resting-state MRI and diffusion-weighted scan), along with a battery of behavioural and clinical questionnaires were acquired, including measures of mood, early life adversity and altered ingestive behaviours. A Data Integration Analysis for Biomarker discovery using Latent Components was conducted to determine whether clinical features, brain morphometry, functional connectivity and anatomical connectivity could accurately differentiate participants stratified by obesity and sex. The derived models differentiated high body mass index against non-obese body mass index participants, and males with high body mass index against females with high body mass index obtaining balanced accuracies of 77 and 75%, respectively. Sex-specific differences within the cortico-basal-ganglia-thalamic-cortico loop, the choroid plexus-CSF system, salience, sensorimotor and default-mode networks were identified, and were associated with early life adversity, mental health quality and greater somatosensation. Results showed multi-modal brain signatures suggesting sex-specific cortical mechanisms underlying obesity, which fosters clinical implications for tailored obesity interventions based on sex., Competing Interests: A.G. is scientific advisor to Yamaha. Other authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2023. The Author(s).)

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'., Competing Interests: Declaration of competing interest AG is scientific advisor to Yamaha. EAM is a scientific advisory board member of Danone, Axial Biotherapeutics, Amare, Mahana Therapeutics, Pendulum, Bloom Biosciences, Seed and APC Microbiome Ireland. All other authors have nothing to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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&#95;Reliability/., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The neurobiological bases of the association between development and psychopathology remain poorly understood. Here, we identify a shared spatial pattern of cortical thickness (CT) in normative development and several psychiatric and neurological disorders. Principal component analysis (PCA) was applied to CT of 68 regions in the Desikan-Killiany atlas derived from three large-scale datasets comprising a total of 41,075 neurotypical participants. PCA produced a spatially broad first principal component (PC1) that was reproducible across datasets. Then PC1 derived from healthy adult participants was compared to the pattern of CT differences associated with psychiatric and neurological disorders comprising a total of 14,886 cases and 20,962 controls from seven ENIGMA disease-related working groups, normative maturation and aging comprising a total of 17,697 scans from the ABCD Study® and the IMAGEN developmental study, and 17,075 participants from the ENIGMA Lifespan working group, as well as gene expression maps from the Allen Human Brain Atlas. Results revealed substantial spatial correspondences between PC1 and widespread lower CT observed in numerous psychiatric disorders. Moreover, the PC1 pattern was also correlated with the spatial pattern of normative maturation and aging. The transcriptional analysis identified a set of genes including KCNA2, KCNS1 and KCNS2 with expression patterns closely related to the spatial pattern of PC1. The gene category enrichment analysis indicated that the transcriptional correlations of PC1 were enriched to multiple gene ontology categories and were specifically over-represented starting at late childhood, coinciding with the onset of significant cortical maturation and emergence of psychopathology during the prepubertal-to-pubertal transition. Collectively, the present study reports a reproducible latent pattern of CT that captures interregional profiles of cortical changes in both normative brain maturation and a spectrum of psychiatric disorders. The pubertal timing of the expression of PC1-related genes implicates disrupted neurodevelopment in the pathogenesis of the spectrum of psychiatric diseases emerging during adolescence., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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) and increased eigenvector centrality in the visual 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., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

Background: Anorexia nervosa (AN) is a disorder characterized by an incapacitating fear of weight gain and by a disturbance in the way the body is experienced, facets that motivate dangerous weight loss behaviors. Multimodal neuroimaging studies highlight atypical neural activity in brain networks involved in interoceptive awareness and reward processing., Methods: The current study used resting-state neuroimaging to model the architecture of large-scale functional brain networks and characterize network properties of individual brain regions to clinical measures. Resting-state neuroimaging was conducted in 62 adolescents, 22 (21 female) with a history of AN and 40 (39 female) healthy controls (HCs). Sensorimotor and basal ganglia regions, as part of a 165-region whole-brain network, were investigated. Subject-specific functional brain networks were computed to index centrality. A contrast analysis within the general linear model covarying for age was performed. Correlations between network properties and behavioral measures were conducted (significance q < .05)., Results: Compared to HCs, AN had lower connectivity from sensorimotor regions, and greater connectivity from the left caudate nucleus to the right postcentral gyrus. AN demonstrated lower sensorimotor centrality, but higher basal ganglia centrality. Sensorimotor connectivity dyads and centrality exhibited negative correlations with body dissatisfaction and drive for thinness, two essential features of AN., Conclusions: These findings suggest that AN is associated with greater communication from the basal ganglia, and lower information propagation in sensorimotor cortices. This is consistent with the clinical presentation of AN, where individuals exhibit patterns of rigid habitual behavior that is not responsive to bodily needs, and seem "disconnected" from their bodies., (© 2022. The Author(s).)

Background: There 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., Methods: Eighty-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., Results: At 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., Conclusions: Pre-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., (© 2021. The Author(s).)

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/m 2 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.

Objective: We 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)., Design: Diffusion 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., Results: UC 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 < 0.05). Hub analyses revealed compromised hubness of the pallidus in UC and IBS compared to HCs which was replaced by increased hubness of the postcentral sulcus. Surprisingly, few differences in network matrices between UC and IBS were identified. In UC, centrality measures in the secondary somatosensory cortex were associated with depression (q < 0.03), symptom related anxiety (q < 0.04), trait anxiety (q < 0.03), and symptom duration (q < 0.05)., Conclusion: A history of UC is associated with neuroplastic changes in several brain networks, which are associated with symptoms of depression, trait and symptom-related anxiety, as well as symptom duration. When viewed together with the results from IBS subjects, these findings suggest that chronic gut inflammation as well as abdominal pain have a lasting impact on brain network organization, which may play a role in symptoms reported by UC patients, even when gut inflammation has subsided., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic pain is a major public health problem in the United States costing $635 billion annually. Hospitalizations for chronic pain in childhood have increased almost tenfold in the past decade, without breakthroughs in novel treatment strategies. Findings from brain imaging studies using structural and resting-state fMRI could potentially help personalize treatment to address this costly and prevalent health problem by identifying the underlying brain pathways that contribute, facilitate, and maintain chronic pain. The aim of this review is to synthesize structural and resting-state network pathology identified by recent brain imaging studies in pediatric chronic pain populations and discuss the potential impact of chronic pain on cortical development. Sex differences as well as treatment effects on these cortical alterations associated with symptom changes are also summarized. This area of research is still in its infancy with currently limited evidence available from a small number of studies, some of which suffer from limitations such as small sample size and suboptimal methodology. The identification of brain signatures of chronic pain in children may help to develop new pathways for future research as well as treatment strategies.

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.

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.

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)., Competing Interests: The authors have declared that no competing interests exist.

Objective: Imaging studies in adults with irritable bowel syndrome (IBS) have shown both morphological and resting state (RS) functional connectivity (FC) alterations related to cortical modulation of sensory processing. Because analogous differences have not been adequately investigated in children, this study compared gray matter volume (GMV) and RS-FC between girls with IBS and healthy controls (HC) and tested the correlation between brain metrics and laboratory-based pain thresholds (Pth)., Methods: Girls with Rome III criteria IBS (n = 32) and matched HCs (n = 26) were recruited. In a subset of patients, Pth were determined using a thermode to the forearm. Structural and RS scans were acquired. A voxel-based general linear model, adjusting for age, was applied to compare differences between groups. Seeds were selected from regions with group GMV differences for a seed-to-voxel whole brain RS-FC analysis. Significance for analyses was considered at p < .05 after controlling for false discovery rate. Significant group differences were correlated with Pth., Results: Girls with IBS had lower GMV in the thalamus, caudate nucleus, nucleus accumbens, anterior midcingulate (aMCC), and dorsolateral prefrontal cortex. They also exhibited lower RS-FC between the aMCC and the precuneus, but greater connectivity between the caudate nucleus and precentral gyrus. Girls with IBS had higher Pth with a moderate effect size (t(22.81) = 1.63, p = .12, d = 0.64) and lower thalamic GMV bilaterally was correlated with higher Pth (left: r = -.62, p(FDR) = .008; right: r = -.51, p(FDR) = .08)., Conclusions: Girls with IBS had lower GMV in the PFC, basal ganglia, and aMCC, as well as altered FC between multiple brain networks, suggesting that structural changes related to IBS occur early in brain development. Girls with IBS also showed altered relationships between pain sensitivity and brain structure.

Purpose: We 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., Methods: A 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., Results: Intermittent 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., Conclusions: Exposing 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., (© 2017 The Obesity Society.)

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., Competing Interests: Disclosure The abstract of this paper was presented at the 2016 American Society of Hematology meeting as a poster with interim findings. The authors report no conflicts of interest in this work.