Recent advances in clinical practice Role of brain imaging in disorders of brain–gut interaction: a Rome Working Team Report Gut: first published as 10.1136/gutjnl-2019-318308 on 7 June 2019. Downloaded from Emeran A. Mayer, 1 Jennifer Labus,1 Qasim Aziz,2 Irene Tracey,3 Lisa Kilpatrick,1 Sigrid Elsenbruch,4 Petra Schweinhardt,5 Lukas van Oudenhove,6 David Borsook7 1G. Oppenheimer Center for ABStract The current diagnostic criteria for DBGIs, as Neurobiology of Stress and Imaging of the living human brain is a powerful tool well as illness severity, frequency, duration and Resilience, Vatche and Tamar to probe the interactions between brain, gut and treatment efficacy all rely exclusively on subjective Manoukian Division of Digestive 3 6 Diseases David Geffen School of microbiome in health and in disorders of brain–gut patient reports and not on objective biomarkers. Medicine at UCLA, Los Angeles, interactions, in particular IBS. While altered signals from Regardless of the primary aetiology, these subjective California, USA symptom reports are generated in part by the brain 2 the viscera contribute to clinical symptoms, the brain Neurogastroenterology Group, integrates these interoceptive signals with emotional, from interoceptive signals originating in the GI Queen Mary University of London, London, UK cognitive and memory related inputs in a non-linear tract, from memories of such signals, and are exten- 3Departments of Anaesthetics fashion to produce symptoms. Tremendous progress has sively modulated by emotional (anxiety and depres- and Clinical Neurology, occurred in the development of new imaging techniques sion), cognitive (attention and expectation) and Pembroke College, Oxford, UK 4 that look at structural, functional and metabolic motivational factors. As pointed out for all other Institute of Medical Psychology chronic pain disorders, this translation of objec- & Behavioral Immunobiology, properties of brain regions and networks. Standardisation University Hospital Essen, in image acquisition and advances in computational tive gut signals into subjective symptoms is highly University of Duisburg, approaches has made it possible to study large data non-linear.9 10 Therefore, multimodal assessment Duisburg, Germany of the brain’s structure, function and biochemical 5 sets of imaging studies, identify network properties and Division of Biomedical Sciences, integrate them with non-imaging data. These approaches and receptor properties has the potential to provide McGill University, Canada 6Translational Research in are beginning to generate brain signatures in IBS that more objective information about pathophysiology, GastroIntestinal Disorders, KU share some features with those obtained in other often treatment efficacy and biologically based patient Leuven Department of Clinical overlapping chronic pain disorders such as urological subgroups in these conditions by elucidating the and Experimental Medicine, pelvic pain syndromes and vulvodynia, suggesting shared contribution of multiple brain networks to the University of Leuven, Leuven, subjective symptom reports. Indeed, numerous Belgium mechanisms. Despite this progress, the identification of 7Center for Pain and the preclinical vulnerability factors and outcome predictors studies examining brain processing of visceral Brain, Boston Children’s, has been slow. To overcome current obstacles, the sensations have been published in an attempt to Massachusetts General and creation of consortia and the generation of standardised identify biomarkers of these disorders (see details http://gut.bmj.com/ McLean Hospitals, Harvard multisite repositories for brain imaging and metadata in refs 7 11 12) (reviewed in refs 2 9 13). A compre- Medical School, Boston, Massachusetts, USA from multisite studies are required. hensive model of brain–gut interactions incorpo- rating reported alterations in brain networks (‘brain Correspondence to connectome’) and networks of interacting systems Dr. Emeran A. Mayer; in the gut (‘gut connectome’)14 is shown in figure 1. emayer@ ucla. edu INTRODUCTION In the last two decades, and in particular since Functional brain imaging research in gastroen- the last Rome Working Team report on this topic on September 27, 2021 by guest. Protected copyright. Received 5 February 2019 terology has allowed for improved insight into 7 Revised 18 March 2019 in 2009, multimodal brain imaging research has Accepted 24 March 2019 spontaneous and evoked brain features and into greatly improved our understanding of the brain– the role of brain–gut interactions in health and gut interactions in DBGIs and identified common- 1 2 disease. Until recently, the focus of brain imaging alities and differences to other functional pain research in gastroenterology has been to gain a syndromes and psychiatric disorders. However, better understanding of the pathophysiology of the ultimate goal of identifying generally agreed on 3 disorders of brain–gut interactions (DBGI), also biomarkers for individual syndromes, patient strati- 1 4 5 known as functional gastrointestinal disorders. fication for treatment trials and assessing treatment DBGIs are defined as a group of disorders classi- efficacy has not been fully realised.13 15 This article fied by the presence of GI symptoms related to any will review the current literature on the use of brain combination of motility disturbance, visceral hyper- imaging in DBGI and will provide recommenda- sensitivity, altered mucosal and immune function, tions for future studies. altered gut microbiota and altered central nervous © Author(s) (or their system (CNS) processing in the absence of detect- employer(s)) 2019. Re-use able organic disease.3 Common DBGIs include IBS, Understanding structural and functional brain permitted under CC BY-NC. No commercial re-use. See rights functional dyspepsia (FD), chest pain of oesoph- alterations and their role in pathophysiology of and permissions. Published ageal origin and functional heartburn. There is DBGIs by BMJ. considerable overlap of the DBGIs with each Although it has long been assumed that specific other, with other visceral and somatic ‘functional’ brain functions, such as pain processing, emotion To cite: Mayer EA., Labus J, Aziz Q, et al. Gut Epub ahead pain syndromes (including urological pelvic pain and cognition are attributable to the isolated oper- of print: [please include Day syndromes (UCPPS), vulvodynia, fibromyalgia and ations of single brain regions, these processes are Month Year]. doi:10.1136/ chronic back pain3 6) and with psychiatric disorders, now viewed as resulting from the dynamic interac- gutjnl-2019-318308 in particular anxiety and depression.7 8 tions of distributed brain areas operating in several Mayer EA., et al. Gut 2019;0:1–15. doi:10.1136/gutjnl-2019-318308 1 Recent advances in clinical practice Gut: first published as 10.1136/gutjnl-2019-318308 on 7 June 2019. Downloaded from Figure 1 Proposed integrative model for disorders of gut–brain Interactions. Replacing the conventional focus on individual brain regions and cell types in the gut, this integrative model posits reciprocal interactions between brain networks (brain connectome) and networks made up of multiple cells in the gut, including the gut microbiota (gut connectome). Gut-to-brain communication is mediated by neural, endocrine and inflammatory pathways, while brain-to-gut communication relies mainly on autonomic nervous system output to the gut. Modified with permission from Enck et al.14 large-scale networks (figure 2; box 1). These networks and their reports, effect sizes are generally small, and causality has not properties have been assessed by using neuroanatomical and been demonstrated for any of these parameters in longitudinal neurophysiological studies in animals,16 as well as different brain studies. Reported associations of clinical, behavioural and biolog- imaging techniques and analyses in humans.17–24 In humans, ical measures with brain parameters are shown in figure 2.43 45–47 http://gut.bmj.com/ several types of networks have been reported: (A) functional Several such associations of specific brain parameters with genes brain networks based on evoked responses7 25 or intrinsic related to the hypothalamic–pituitary–adrenal axis,48 catechol- connectivity of the brain during rest,17 19–21 23 26–30 (B) structural amine46 and 5-hydroxytryptamine (5-HT) signalling49 and with networks based on grey matter parameters31 32 and white matter gene expression profiles in peripheral blood mononuclear cells50 properties and (C) anatomical networks based white matter have been reported. An example of the association of a 5-HT3 connectivities.33 Both evoked and resting state studies performed receptor polymorphism with amygdala activation is shown in 49 in patients with IBS have demonstrated abnormalities in regions, figure 3. Preliminary data suggest correlations of regional brain on September 27, 2021 by guest. Protected copyright. as well as in resting state and task related networks related to structural differences with gut microbial taxa,51 even though default mode (DMN),34 35 emotional arousal,7 23 36–38 central similar to the situation with clinical metadata, it is currently not autonomic control,17 18 20 22 central executive control,17 20 38 possible to draw conclusions about causality from these results. sensorimotor processing39–42 and salience detection.43 44 (table 1). IBS-related alterations in these networks have provided plausible How do brain signatures differ between male and