Abstract
While a variety of peripheral candidate biomarkers related to functional gastrointestinal disorders (FGIDs) continue to be investigated, none appear to account for a large proportion of the symptom variance in this heterogeneous set of syndromes. At the same time, a model for FGIDs that includes a prominent role for brain-gut interactions has emerged and holds promise for helping to elucidate what are likely complex interrelationships between gastrointestinal sensation, motility, immune function, and gut microbes with sensory, cognitive, and affective circuitry in the brain. Brain imaging technologies have been become a standard in the investigation of the pathophysiology of a number of health problems in neurology and psychiatry, as well as various chronic pain conditions, including the FGIDs, where subjective symptom reports are often relied on as primary disease outcomes. Neuroimaging research has often confirmed long-held hypotheses of altered interoceptive, emotional, and cognitive function in FGIDs and increasingly is used to develop a more comprehensive understanding of the interplay between the behavioral aspects of the disorders and their physical symptoms. In this chapter, we will highlight the contributions neuroimaging has made to the understanding of the pathophysiology of the most commonly studied FGIDs, irritable bowel syndrome and functional dyspepsia, and some of the most promising avenues for neuroimaging research of FGIDs in the future.
Keywords
Functional GI disorders, Irritable bowel syndrome, Functional dyspepsia, Brain imaging, Brain networks
Acknowledgments
Thanks to Cathy Liu and Christine Canilao for assistance with manuscript preparation.
Grant support: National Center for Complementary and Integrative Health R01 R01AT007137 (KT and BDN); NIDDKP50 DK064539 (EAM); NIDDK P30 DK041301.
18.1
Introduction
While a variety of peripheral candidate biomarkers related to functional gastrointestinal disorders (FGIDs) continue to be investigated, none appear to account for a large proportion of the symptom variance in this heterogeneous set of syndromes. At the same time, a model for FGIDs that includes a prominent role for brain-gut interactions has emerged and holds promise for helping to elucidate what are likely complex interrelationships between gastrointestinal sensation, motility, immune function, and gut microbes with sensory, cognitive, and affective circuitry in the brain. Brain imaging technologies have been become a standard in the investigation of the pathophysiology of a number of health problems in neurology and psychiatry, as well as various chronic pain conditions, including the FGIDs, where subjective symptom reports are often relied on as primary disease outcomes. Neuroimaging research has often confirmed long-held hypotheses of altered interoceptive, emotional, and cognitive function in FGIDs and increasingly is used to develop a more comprehensive understanding of the interplay between the behavioral aspects of the disorders and their physical symptoms. Fig. 18.1 shows the interaction of the brain and gut in the context of external and internal environmental stimuli. In this chapter, we will highlight the contributions neuroimaging has made to the understanding of the pathophysiology of the most commonly studied FGIDs, irritable bowel syndrome (IBS) and functional dyspepsia (FD), and some of the most promising avenues for neuroimaging research of FGIDs in the future.
18.2
The Current Role of Neuroimaging in FGIDs
The FGIDs are defined by symptom clusters, rather than objective markers of pathophysiology. In fact, there is growing consensus that no single pathophysiological process can adequately characterize any of the individual FGIDs. It is therefore likely that symptoms in a specific patient result from alterations in one or more peripheral and central processes and that this mix varies across individuals and perhaps over time within the same individual. Although there are objective measures for some of the potential peripheral processes (e.g., motility, visceral sensitivity, altered microbiome), subjective responses have been the only measures to determine such factors as illness severity, symptom-related distress or vigilance, and overall response to medications or placebo. Although patient reports remain the gold standard for clinical outcomes, more objective measures are needed to elucidate the brain processes underlying central pathophysiology or a medication’s mechanism of action. Pain is the signature symptom of the most prevalent FGIDs, IBS, and FD. The study of FGIDs without including the brain limits our understanding to that of peripheral pain reflex pathways, nonspecific autonomic responses, and symptom reports. Unlike preclinical studies in organic gastrointestinal disorders, animal models of FGIDs remain limited in their predictive value, as surrogate markers for the complex range of symptoms and distress seen in humans with FGIDs are largely not accessible in rodents. This likely explains why such models have largely failed to predict treatment responses of FGIDs in humans. The predominance of higher cortical modulation of subcortical systems seen in humans is not readily replicated in the animal models, and such activity is likely involved in the generation and maintenance of FGID symptoms. Imaging the brain allows us to evaluate the input from the periphery via the interoceptive circuitry in the brain, as well as assess the emotional and cognitive factors in the modulation of the afferent input. Neuroimaging provides a route to objectively assess the central response to a variety of variables including medications, symptoms, gastrointestinal sensations, and psychosocial stress.
18.3
Brain Networks in FGIDs
Initial efforts using magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning compared patients and controls by identifying activation in individual brain regions discovered in whole brain analyses or in regions that were selected a priori for their hypothesized relevance to FGIDs. Gradually, the field of neurogastroenterology has advanced from the focus on localized regional activity to directly characterizing regions within brain networks altered in FGIDs compared to healthy controls, and by examining interactions between brain networks. These networks consist of sets of sometimes widely dispersed regions involved in a specific process or function. Based on prior research, clinically driven hypotheses, and primate studies of anatomical connectivity, several networks have been of particular interest in FGIDs. The most consistent brain networks described in FGIDs and other chronic pain syndromes include emotional arousal, central executive control, sensorimotor processing, and salience networks. The emotional arousal network is driven by the amygdala, in communication with the anterior cingulate and prefrontal cortex and extension to the hippocampus and locus ceruleus. It is the network involved in fear-related responses and anxiety related to FGIDs. The central executive network is represented by cortical modulatory regions including the dorsolateral prefrontal cortex and posterior parietal cortex. Impaired function in this network may be associated with diminished cortico-limbic modulation to the emotional arousal network. The sensorimotor network consists of the sensorimotor cortex, posterior insula, basal ganglia, and thalamus which are regions which process somatic and visceral sensation. The salience network is a collection of brain regions working in concert to evaluate the importance of internal or external stimuli and to assist in the coordination of the brain’s response to those stimuli. Its main hub is the anterior insula with connection to the anterior mid-cingulate cortex. Descriptions of the salience network can often include additional regions, chiefly the medial prefrontal and orbitofrontal cortex, and amygdala. In FGIDs, the salience network is considered a key region in amplifying the importance of potentially benign body sensations. In the following sections, we will review findings from multiple modalities of neuroimaging and both regional and network-focused studies with an emphasis on these key networks for FGIDs ( Fig. 18.2 ).
Several types of imaging techniques have been used to elucidate brain networks in FGIDs including: (a) functional MRI or PET imaging of task-specific evoked responses or intrinsic connectivity of the brain during a resting state, (b) gray matter morphometric parameters such as cortical thickness, volume, and surface area from structural MRI (sMRI), and (c) diffusion-weighted tensor imaging of microstructural properties of white matter and region to region connectivity. Imaging studies performed in FGID patients using each of these modalities have demonstrated alterations in the above-described brain networks.
The characterization of brain networks requires application of more sophisticated analytical techniques than were used in the early imaging studies. Functional networks and their circuits are analyzed using effective connectivity multivariate pattern analysis including sparse partial least squares and independent component analysis or multivariate regression quantifying the association between voxel-to-voxel or region-to-region activity during evoked responses or time series across the resting state. Using these methods in IBS and, to some extent, in FD studies have generally shown increased activity in emotional arousal and signal salience networks as well as altered sensory processing and diminished corticolimbic inhibition from central executive networks.
18.4
Utilization of Different Imaging Modalities to Understand FGIDs
18.4.1
Task-Based Neuroimaging Studies
Functional neuroimaging often utilizes an experimental task, or stimulus to evoke the brain response of interest. Task-based studies generally utilize fMRI or PET imaging and focus on comparing an active condition to a neutral control condition. Early neuroimaging studies in FGIDs focused predominantly on visceral stimulation using balloon inflation in the sigmoid colon or rectum (in IBS) or the stomach (in FD). While the initial concept that such stimulation represented a biomarker of “visceral sensitivity” or mimics clinical symptoms has been discarded, these studies have been useful in both characterizing the central pathways through which interoceptive stimuli are processed and for reinforcing the essential role of anticipation of pain in FGIDs. Further, powerful quantitative metaanalytic approaches have been used to cumulate information from many smaller imaging studies, showing clear patterns of activation in brain regions and networks involved in processing visceral sensation, emotional arousal, and cognitive modulation in patients with IBS and healthy subjects. Additional work has utilized cognitive and emotional tasks to evaluate brain differences not related to visceral sensation.
18.4.1.1
Visceral Distension in IBS and FD
As described in the most extensive metaanalysis to date, when experiencing visceral distension, IBS patients show a greater extent of brain activity than healthy subjects in regions associated with visceral afferent processing and emotional arousal. Specifically, IBS patients show engagement of two specific regions associated with an emotional arousal circuit (amygdala, pregenual anterior cingulate cortex) that lack consistent activity in healthy subjects. Additionally, IBS patients show less involvement of the medial and dorsolateral prefrontal cortices, which are brain regions involved in the central executive network. Findings from this metaanalysis also suggested a more consistent activation of medial thalamic regions, including the medial dorsal nucleus in IBS patients. Anatomically, the thalamic nuclei have connectivity with the anterior cingulated and prefrontal cortices; so, these findings are consistent with stronger association of sensorimotor input to affective and motivation processing. This pattern of response during visceral stimulation is consistent with the increased sympathetic arousal, anxiety, and vigilance often associated with IBS and other FGIDs. Indeed, carefully designed studies using visceral stimulation that is threatened but not delivered show that the response to a visceral distension in IBS appears to be more related to the anticipation of the stimulus than the stimulus itself, a finding which can only be revealed by using neuroimaging techniques. Building on this concept, more recent work using visceral distension as an unconditioned stimulus in a fear-conditioning paradigm has shown that IBS patients develop enhanced reinstatement of the conditioned stimulus, along with enhanced hippocampal brain activity compared to controls, exposing the underlying biology of FGID-related hypervigilance.
18.4.1.2
Noninvasive Experimental Neuroimaging Tasks
Several studies have used imaging tasks without visceral stimulation to identify whether the brain network abnormalities described above are specific to the stimulation sites or more generalized. Somatic pain stimuli given in an anticipation of a pain task showed results consistent with visceral distension studies, with IBS patients exhibiting great brain response in affective and salience-related brain regions (amygdala, insula) as well as sensory areas (thalamus) during contextual threat.
In addition to the role of pain processing, the role of emotional and cognitive factors is also of great interest for further research in FGIDs. Several studies have utilized paradigms developed for psychological research to understand the IBS phenotypes beyond the focus on sensory processing. Using a standardized set of negatively valenced emotional faces, fMRI was used to probe the brain’s affective processing regions in IBS compared to healthy subjects. This revealed an increase in brain activity in affective brain regions in men with IBS compared to healthy men and women with and without IBS. In response to emotionally valenced auditory stimuli, unlike healthy subjects, IBS patients did not discriminate between pleasant and distressing sounds, and displayed a pattern that was interpreted as a generalized increase in emotional reactivity. Finally, cognitive flexibility was evaluated in IBS patients using a standardized task, the Wisconsin Card Sorting task. IBS patients had more errors in perseveration and had decreased brain activity in regions associated with cognitive modulation of emotion and sensation, such as the dorsolateral prefrontal cortex, compared to controls. In summary, task-based functional neuroimaging has been able to show that patients with IBS display altered regulation of both sensory and affective central processes. However, the studies described above using regional-based analyses with a variety of task-evoked responses support the hypothesis of alterations in the salience, executive control, and emotional arousal brain networks as key features of FGIDs.
18.4.2
Resting-State Neuroimaging
In contrast to task-based fMRI, resting-state MRI (rsMRI) measures task-independent, spontaneous brain activity acquired during a resting state and capitalizes on the wealth of connectivity versus activation information that can be extracted from the intrinsic fluctuations of the blood oxygen level-dependent (BOLD) signal, without requiring the presence of a task. Intrinsic connectivity patterns can identify alterations in brain organization and coordination. Seed-based functional connectivity analyses and independent components analysis have been used to identify brain regions that show correlated spontaneous low-frequency BOLD signal fluctuations. This pattern of intercorrelations over time can then be attributed to discrete, functionally connected brain networks. Early skepticism that this technique may be unrelated to significant neural processes has been overcome by the large number of studies showing consistent intrinsic brain networks. Biswal and colleagues, for example, have shown the existence of multiple consistent networks in the resting state across 35 centers worldwide, including pooled data for over 1400 subjects. While it is now accepted that reliable intrinsic functional brain networks exist, the significance of such networks remains an area of active investigation.
Alternative approaches to analyzing rsFMRI include measures of amplitude and regional homogeneity (ReHo). Amplitude measures such as fractional amplitude of low-frequency fluctuation (fALFF) represents the relative contribution of specific oscillations to the whole detectable frequency range. Variations of (f)ALFF provide information about the spectral content of the spontaneous signal fluctuations present in a region during rest. ReHo is a voxel-based measure of the coherence and synchrony of the BOLD signal fluctuations in adjacent voxels. Preliminary evidence suggests that variation in ReHo is associated with neurovascular coupling. Both IBS and FD patients have been studied using these techniques, showing altered spontaneous neural activity and abnormal local functioning compared to healthy controls.
In IBS, resting state studies have shown alteration in the functional and intrinsic connectivity regions comprising of default mode, emotional arousal, sensorimotor, and salience networks. In particular, in multiple studies the functional connectivity of the anterior insula, a key region in salience computation, has been shown to be altered and associated with interoceptive awareness and rectal pain-perception thresholds. In addition, compared with healthy controls, IBS has higher positive resting-state functional connectivity between the amygdala and salience and sensorimotor regions that was associated with reported pain intensity and symptom severity scores. Alterations in the resting-state functional connectivity of the default mode and central executive networks have also be observed in adolescents with IBS. Furthermore, alteration in the intrinsic connectivity of salience and sensorimotor networks have been shown to be specific to IBS in comparison to another commonly comorbid chronic pain disorder, provoked vulvodynia.
Compared to healthy controls, IBS patients have shown alterations in intensity (amplitude) of spontaneous signal fluctuations at rest in regions comprising the default mode and emotional arousal, salience, and somatosensory networks. Using ReHo as a marker of the local functional connectivity, coherence of spontaneous brain, activity has been shown to be altered compared to healthy subjects in sensorimotor, default mode, and emotional arousal regions. Applying network analysis using graph theory, decreased global efficiency of the default mode network has been reported in IBS compared to healthy subjects.
In parallel with the increased number of IBS resting-state studies published over the past 5 years, a large number of resting-state studies of FD have been published. These studies demonstrate alterations in similar brain networks that are correlated with symptoms in FD. To date, no formal direct comparisons have been made to determine the similarities and difference between these two disorders. Interestingly, preliminary data indicate that whole brain functional connectivity may be useful in classifying FD patients from healthy subjects indicating that functional connectivity plays an important role in reflecting the disease pathophysiology underlying FD.
Functional connectivity and spectral characteristics of spontaneous fluctuation activity of brain regions and networks during rest may represent endophenotypes associated with disease vulnerability, or alternatively, alterations in these networks may be a consequence of disease and may be amenable to therapy. Initial results in a small sample of chronic pain patients indicate that cognitive behavior therapy alters the intrinsic connectivity of regions comprising sensorimotor, default, and central executive networks.
18.4.3
Structural Neuroimaging
While functional imaging dominated the early years of brain imaging in FGIDs, as the spatial resolution of scanners has increased, structural imaging of both gray and white matter has become a standard part of many imaging studies. The promise of sMRI datasets is to not only provide means to assess differences between patient and healthy groups, but also to assess central nervous system effects of treatments (both pharmacological and nonpharmacological) in FGID patients.
18.4.3.1
Gray-Matter Imaging
High-resolution sMRI can be used to produce structural imaging datasets comprised of global (whole-brain), regional, and voxel-level indices of gray-matter volume and cortical thickness (neuronal density in the cortical mantle). Initially, sMRI analysis was limited to neurological disorders with clear-cut brain lesions (e.g., stroke, Alzheimer’s disease). However, improved MRI acquisition and new analysis techniques have begun to show subtle stable differences in brain morphometry across individuals and groups. Additionally, the recognition that gray matter plasticity can be measured and can occur over relatively short periods of time has made this technique attractive for studying treatment effects in chronic disease. Contrary to the notion that anatomical structures of the brain are fixed in adulthood, dynamic alterations in brain structure have been observed in as little as 5 days. Research utilizing sMRI has demonstrated replicable changes in gray- and white-matter structure under environmental demands including learning, aging, and illness. Early life stressors experienced by patients with persistent pain disorders such as IBS may even impact brain structures during development, potentially creating a vulnerability for developing FGIDs if the symptoms are induced and maintained by conditioned fear of gastrointestinal sensations, symptoms, and the context in which these visceral sensations and symptoms occur. This is supported by recent reports of cortical thinning of prefrontal regulatory brain regions in children with IBS compared to healthy subjects.
Patterns of increased and decreased gray-matter volume and/or cortical thickness have been described in both FD and IBS. Specifically, regions in the prefrontal cortex and insula tend to show decreased gray matter compared to healthy controls supporting an abnormality in the salience and executive networks that have historically shown disease-related differences in functional studies. Some, but not all, studies have suggested an increase in the cortical thickness of the somatosensory cortex in IBS, a finding consistent with the pattern seen in other pain populations. There has been some evidence that the somatosensory cortex is related to pain sensitivity more generally, and may be a predictor of pain sensitivity and potential vulnerability to chronic pain. In some sMRI studies in FGIDs, controlling for anxiety and depression diminishes the differences between patients with IBS and controls, whereas the differences in the prefrontal cortex appear to be more specific. This combination of overlapping and disease-specific structural findings is consistent with the close relationship of FGIDs with mood disorders and presents an ongoing challenge when studying the brain. Pain catastrophizing, another common psychological trait in IBS and FD, also appears to be correlated with brain structure. Pain catastrophizing was negatively correlated with degree of cortical thickness in the prefrontal cortex. The correlation of catastrophizing with decreased cortical thickness in the dorsolateral prefrontal cortex may suggest a pathway for this psychological characteristic to alter the ability to mobilize descending pain inhibition as this area is one of the initiation areas for such modulation.
Clearly, these studies of sMRI provide intriguing hypotheses linking brain structure to clinical variables in FGIDs. Only larger scale studies that follow the brain and symptoms together over long spans of time will be able to more definitively test these relationships. The gray-matter findings in IBS patients support the hypothesized brain networks that were largely established in functional imaging studies, in particular, the central executive network, the sensorimotor network, and the salience network. What remains unknown in most cases is whether these changes are preexisting risk factors for disease or whether they are secondary changes due to active symptoms. Also, the biological substrate underlying these gray-matter changes are unknown at the moment; they may involve changes in glial cell volume, neuroinflammation, changes in dendritic spines or synapses, or less likely, neural degeneration.
18.4.3.2
White-Matter Imaging
Diffusion tensor imaging (DTI) is a noninvasive MRI technique used to quantify the subvoxel, microstructural properties and organization within brain tissue by probing the behavior of randomly diffusing water molecules. In particular, measures of fractional anisotropy (FA) can be used to estimate the degree of directional coherence of the underlying tissue structures within an image voxel, reflecting the strength of axonal or dendritic projections, while mean diffusivity (MD) can be used to estimate relative tissue compactness and degree of myelination. Water molecules that are unconstrained by cellular architecture, such as in the CSF, are isotropic and thus have an FA value of 0. Because they are constrained to move in the direction of axons, water molecules in dense, parallel white-matter tracts have high FA values. Decreases in the FA of white-matter tracts can occur due to decreased axonal number, myelin integrity, or axonal cytoskeleton integrity.
Studies have found differences in both FA and MD in several chronic pain conditions. A recent study by Ellingson et al. reported less directional coherence (decrease in FA) and higher MD in regions comprising cortico- thalamic-basal ganglia circuits in IBS compared to healthy subjects. IBS compared to healthy subjects also had lower FA in thalamic regions, the basal ganglia and sensory/motor association/integration regions, suggestive of differences in axon/dendritic density. In another study, IBS had alterations in the FA of fiber tracts innervating the viscerotopic portion of the primary somatosensory region indicating differences in fiber diameter and/or myelination. Alterations in FA of major output tracts associated with the emotional arousal system, salience, and sensorimotor networks have also been found to be correlated with IBS symptom severity.
As our approach to neuroimaging relies increasingly on brain networks, the connectivity between gray-matter regions via white-matter tracts is of great interest. Impairment in functional connectivity and region morphometry are in part due to alterations in anatomical connectivity and microstructural properties of white-matter tracts. Another DTI method, quantitative fiber tracking or probabilistic tractography, allows identification of specific fiber tracts between brain regions, and can be useful for confirming anatomical connectivity between regions determined to be functionally connected based on fMRI studies. While functional MRI results are often interpreted in the context of neuroanatomical studies in primates, the use of tractography can assess the anatomic connectivity of functionally determined regions within individual subjects or groups. One such study established connectivity between regions associated with response to visceral distension in healthy volunteers. Additionally, using tractography, Ellingson et al. found that IBS symptom severity was associated with decreased connectivity between the thalamus and both primary sensory cortex as well as insular regions, suggesting that white-matter tracts can also be used to describe the key brain networks of interest in FGIDs.
18.4.4
Neuroimaging to Probe Specific Receptor Systems: PET
Utilization of PET imaging to assess task-related functional brain activity has decreased due to the ready availability, noninvasive nature, and better temporal resolution of fMRI. However, despite its drawbacks, the ability to use radio-labeled ligands to probe specific receptor systems continues to make PET imaging an attractive tool for specific hypotheses. The study of receptor activity during tasks and to assess differences between patients and healthy subjects has been performed with a number of relevant ligands. Using a serotonin transporter (SERT) ligand, patients with FD have been shown to have increased binding potential in sensory regions, with thalamic binding correlating with abdominal pain and indigestion scores. FD is also characterized by increased cannabinoid receptor availability in brain regions associated with pain processing. In the study of pain and placebo, these techniques have also been used to describe the endogenous opioid and dopamine reward systems in healthy controls. Less work has been done in IBS, though early studies have targeted receptors in dopamine and neurokinin-1 (NK1) receptor systems. PET is also used to study labeled pharmaceuticals to determine the distribution of binding as well as to identify patient subgroups with potentially differential benefit from a given compound. The use of PET remains limited by cost, the difficulty in generating relevant ligands, and the radiation exposure, which limits the number of studies that can be performed on an individual. Despite these shortcomings, PET will likely continue to play a limited but important role in drug development for centrally targeted compounds.
18.4.5
Emerging Technologies and Analytic Techniques
One of the difficulties with human neuroimaging has been the inability to determine what specific neurochemical processes are taking place when we look at the output of functional neuroimaging studies, the BOLD contrast signal. Increasingly magnetic resonance spectroscopy (MRS) is being used to localize these neurochemical processes by targeting neurometabolites such as glutamate. One such study aimed to evaluate stress responsiveness in IBS patients by imaging glutamate-glutamine levels in the hippocampus, a key region for inhibition of the hypothalamic- pituitary axis. They found a localized hippocampal reduction in glutamate-glutamine, suggesting hypofunction of this regulatory system in IBS, and showed a correlation between neurometabolites and reported stress levels in the patients. Glutamate levels have also been studied in FD, with increased levels in the somatosensory cortex compared to healthy subjects; further, these levels correlated with FD symptom severity as well as anxiety suggesting clinical relevance of the findings. As the technology used in MRS acquisition and analysis advances, allowing examination of more metabolites across multiple relevant brain networks, it is likely that a greater mechanistic understanding of the neurobiology of FGIDs will be achieved.
Another challenge of interpreting neuroimaging results is the physical disconnect between the brain and the gut. The brainstem nuclei of the autonomic nervous system are too small for standardized imaging protocols to delineate and are subject to significant physiological artifact. The gastrointestinal branches of the autonomic nervous system have been similarly difficult to study. In addition, sensory pathways in the spinal cord have not been targets of functional imaging until recently. As structural imaging becomes more precise, using more sophisticated 3 Tesla acquisition protocols and moving to the use of 7 Tesla scanners in humans, we anticipate an increased focus on imaging the brain stem and spinal cord in FGIDs, potentially improving our ability to assess top-down versus bottom-up pathways of communication.
Paralleling the increased sophistication of technology has been an explosion of new analysis techniques that are applied to large-scale neuroimaging data and associated clinical and biological metadata. Complex network analyses conceptualize the brain as multiple distinct interacting networks characterized by topological and physical network properties that reflect centrality, integration, and segregation such as the number of connections that link a brain region to other regions (degree), global and local efficiency, and clustering, to name a few. Brain regions can be characterized by measures that quantify their contribution to the structural integrity and information flow in the whole brain. For example, hub regions of a brain network have a high degree of connectivity with other brain regions, provide the infrastructure for integrative information processing and adaptive behavior, and can be assessed by a combination of network indices of centrality, integration, and segregation. Topological resting-state network analysis in FD to date has suggested that key nodes within the integrated networks are related to pain modulation.
With the advent of computationally efficient tools for big data, it has also become possible to combine large datasets from neuroimaging with the equally large datasets generated from study of the gut’s microbiota and metabolites. These analyses allow our emerging understanding of the role of gut microbes in IBS to be informed by correlation with specific brain structures or networks. In one such analysis, IBS and healthy subjects were clustered by their gut microbial composition, and these clusters exhibited distinct differences in brain structure in regions linked to salience and sensory networks. As additional studies combine large sets of central and peripheral biological data, a fuller understanding of the brain-gut axis will emerge.
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