McIver TA, Bernstein CN, Kornelsen J. Current approaches to studying human resting-state function in inflammatory bowel disease. Journal of the Canadian Association of Gastroenterology 2025 Feb 21;8(Suppl 2):S36-S43.

 

Crohn's disease and ulcerative colitis are 2 subtypes of Inflammatory Bowel Disease. The chronic, alternating periods of relapsing, and remitting inflammation of the gastrointestinal tract that underlie these diseases trigger a range of gut-related symptoms, in addition to being related to burdensome psychological and cognitive comorbidities. With advancing knowledge of the brain-gut axis and its dysregulation in diseases such as IBD, understanding IBD-related brain changes is an important focus for current research in this area. "Resting state" function refers to the spontaneous fluctuations in neural activity when a person is awake and resting-not focusing attention on a task or stimulus. The recent surge in human resting-state functional magnetic resonance imaging (rs-fMRI) studies suggest that resting function is altered in IBD, representing a potential neural biomarker to target in the development of novel interventions. There are, however, multiple factors that contribute to the approach of these studies, including factors related to participant sample characteristics (IBD subtype and incorporation of disease activity in group definition and comparison), application of different resting-state metrics to assess resting brain activity (via regional homogeneity or amplitude of low-frequency fluctuations) or functional connectivity (via independent component analysis, region-of-interest, seed-to-voxel, or graph theory analyses) and incorporation of additional, multimodal variables of interest. The present review provides a summary of current approaches to studying resting-state brain function in IBD, the most commonly identified brain regions/networks to exhibit aberrant function, and avenues for advancement that forthcoming research in this field can strive to address.

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McIver TA, Bernstein CN, Figley C, Patel R, Fisk JD, Marrie RA, Kornelsen J. Impact of fatigue in Crohn's disease is negatively related to resting state functional connectivity between the superior parietal lobule and parahippocampal gyrus/hippocampus. Frontiers in Human Neuroscience 2025; April 25;19: 1561421.

 

Introduction: Crohn's disease is one phenotype of inflammatory bowel disease (IBD). Fatigue is a common and burdensome symptom for persons with Crohn's disease. Despite its detrimental impact on health-related quality of life, the pathophysiology of fatigue in Crohn's disease is not fully understood. Specifically, basic research on the difference in brain functioning associated with fatigue in Crohn's disease is scarce. This study aimed to address this knowledge gap by identifying fatigue-related differences in brain resting state functional connectivity. in Crohn's disease.

Methods: Participants included 49 adults with Crohn's Disease (M age 53 yrs, 35 females) and 49 healthy controls (M age 50 yrs, 31 females). The Fatigue Impact Scale  assessed impact of fatigue across three domains (physical, cognitive, and psychosocial) as well as total impact of fatigue. The Harvey-Bradshaw Inventory (HBI) assessed disease activity. Magnetic Resonance Imaging of brain functional connectivity during resting state (i.e.,: wakeful rest) was assessed in relation to scores on the Fatigue Impact Scale   (total and for each domain). Moderation analyses tested whether brain resting state functional connectivity moderates the relationship between disease activity and fatigue.

Results: The Crohn's disease group reported more severe fatigue than the healthy control group in each domain of the Fatigue Impact Scale. For the Crohn's disease group, increasing fatigue was associated with decreasing synchronicity of brain function (i.e., functional connectivity) between the superior parietal lobule and the parahippocampal gyrus/hippocampus. Unlike in the healthy control group, an increasing impact of physical fatigue was associated with decreasing functional connectivity between these Regions of Interest for the Crohn's disease group (TFCE = 16.88, p-FDR = 0.03). Moderation analyses revealed a significant interaction between disease activity, total fatigue, and functional connectivity of the right superior parietal lobule and left anterior parahippocampal gyrus (ΔR2 = 0.058, F = 5.445, p = 0.0245). Higher scores on the Harvey Bradshaw Index were only associated with higher total scores on the Fatigue Impact Scale   in persons with Crohn's disease who exhibited negative functional connectivity between these brain regions.

Discussion: In people with Crohn's disease, fatigue increases as functional connectivity between brain regions involved in sensorimotor integration and memory processing decreases.

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Kornelsen J, McIver T, Figley C, Patel R, Fisk JD, Marrie RA, Bernstein CN. Resting state functional connectivity of the cerebellum differs between persons with inflammatory bowel disease and healthy controls in relation to executive function. Inflammatory Bowel Diseases 2025;31(5):1466-1470. 

 

We hypothesized that there would be a difference between IBD and healthy controls in their relationship between cerebellar resting-state functional connectivity and scores on a separately performed executive function task. Establishing if executive function is associated with different resting-state functional connectivity of cerebellar regions for persons with IBD will expand our understanding of brain–gut axis dysregulation in IBD and support future investigation of executive function impairment as a comorbidity of the disease. We hypothesized that there will be a difference between IBD and healthy controls in their relationship between cerebellar resting-state functional connectivity and scores on a separately performed executive function task. Establishing if executive function is associated with different resting-state functional connectivity of cerebellar regions for persons with IBD will expand our understanding of brain–gut axis dysregulation in IBD and support future investigation of executive function impairment as a comorbidity of the disease. 72 persons with IBD and 90 healthy controls underwent whole-brain anatomical and resting-state functional imaging which were acquired on a 3T Siemens TIM Trio MRI system

The present study provides further support for an association between executive functioning and cerebellar functional connectivity, in addition to highlighting the role of cerebellar VIIa in distinguishing functional connectivity differences between persons with IBD and healthy controls. Limitations of the current study include the participant sample heterogeneity and the use of various disease-modifying medications within the IBD group. Nonetheless, this study provides valuable insight into the role of the cerebellum and the potential neural underpinnings of cognition in IBD.

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Patel R, Marrie RA, Bernstein CN, Bolton JM. Graff LA, Marriott JJ, Figley CR, Kornelsen J, Mazerolle EL, Helmick C, Uddin N, Fisk JD. Vascular disease is associated with differences in brain structure and lower cognitive functioning in inflammatory bowel disease: A cross-sectional study. Inflammatory Bowel Diseases 2024; 30(8):1309-1318.

 

Background: Vascular disease and cognitive impairment have been increasingly documented in IBD, and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning.

Methods: Eighty-four IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression-based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling.

Results: Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure.

Conclusions: Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.

 

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Wang H, Labus JS, Griffin F, Gupta A, Bhatt RR, Sauk JS, Turkiewicz J, Bernstein CN, Kornelsen J, Mayer EA. Functional Brain Rewiring and Altered Cortical Stability in Ulcerative Colitis. Molecular Psychiatry 2022; 27:1792-1804.

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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 IBD. 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, irritable bowel syndrome, and healthy controls, N = 74 each) to investigate the alterations in functional brain wiring and cortical stability in ulcerative colitis compared to the two control groups and identify possible correlations of these alterations with clinical parameters. Globally, ulcerative colitis participants showed increased functional connectivity and decreased modularity compared to IBS and healthy controls groups. Regionally, ulcerative colitis showed decreased eigenvector centrality in the executive control network (ulcerative colitis < irritable bowel syndrome < healthy controls) and increased eigenvector centrality in the visual network (ulcerative colitis > irritable bowel syndrome > healthy controls). Ulcerative colitis also showed increased connectivity in dorsal attention, somatomotor network, and visual networks, and these enhanced subnetwork connectivities were able to distinguish ulcerative colitis participants from healthy controls and IBS with high accuracy. Dynamic functional connectome analysis revealed that ulcerative colitis 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 ulcerative colitis.

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Uddin MD, Figley TD, Kornelsen J, Mazerolle EL, Helmick CA, O’Grady CB, Pirzada S, Patel R, Carter S, Wong K, Essig MR, Graff LA, Bolton JM, Marriott JJ, Bernstein CN, Fisk JD, Marrie RA, Figley CR. The Comorbidity and Cognition in Multiple Sclerosis (CCOMS) neuroimaging protocol: study rationale, MRI acquisition and minimal image processing pipelines. Frontiers in Neuroimaging 2022 Aug 24:1:970385.

 

The Comorbidity and Cognition in Multiple Sclerosis (CCOMS) study represents a coordinated effort by a team of clinicians, neuropsychologists, and neuroimaging experts to investigate the neural basis of cognitive changes and their association with comorbidities among persons with multiple sclerosis (MS). The objectives are to determine the relationships among psychiatric (e.g., depression or anxiety) and vascular (e.g., diabetes, hypertension, etc.) comorbidities, cognitive performance, and MRI measures of brain structure and function, including changes over time. Because neuroimaging forms the basis for several investigations of specific neural correlates that will be reported in future publications, the goal of the current manuscript is to briefly review the CCOMS study design and baseline characteristics for participants enrolled in the three study cohorts (MS, psychiatric control, and healthy control), and provide a detailed description of the MRI hardware, neuroimaging acquisition parameters, and image processing pipelines for the volumetric, microstructural, functional, and perfusion MRI data.

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Kornelsen J, Witges K, Labus J, Mayer EA, Bernstein CN. Brain structure and function changes in inflammatory bowel disease. NeuroImage Reports 2022; 2 (2): 10009.

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As the importance of the brain-gut axis in the pathobiology of IBD continues to evolve, a greater understanding of brain structure and functional connectivity is necessary. In this magnetic resonance imaging (MRI) study, we investigated differences in brain structure and in functional connectivity of brain regions in 111 participants with IBD (76 ulcerative colitis (UC) and 35 Crohn's disease (CD)) and 74 healthy controls. Significant differences between IBD and healthy controls were observed in the three analyses used (voxel based morphometry, region-of-interest, and independent component analysis) in brain regions of the default mode, cerebellar, and visual networks. Significant differences between IBD subtypes (UC, CD) were found. The results of the current study establish that a relationship between brain functional connectivity and the brain-gut axis exists in IBD.

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Marrie RA, Patel R, Figley CR, Kornelsen J, Bolton J, Graff LA, Mazerolle EL, Helmick C, O’Grady C, Uddin N, Marriott JJ, Bernstein CN, Fisk JD for the Comorbidity and Cognition in Multiple Sclerosis (CCOMS) Study Group. Effects of vascular comorbidity on cognition in multiple sclerosis are partially mediated by changes in brain structure. Frontiers in Neurology 2022; Apr 14; 13: 874724.

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Vascular comorbidities are associated with reduced cognitive performance and with changes in brain structure in people with multiple sclerosis. Understanding causal pathways is necessary to support the design of interventions to mitigate the impacts of comorbidities, and to monitor their effectiveness. We assessed the inter-relationships among vascular comorbidity, cognition and brain structure in people with multiple sclerosis. Adults with neurologist-confirmed multiple sclerosis reported comorbidities, and underwent assessment of their blood pressure, HbA1c, and cognitive functioning (i.e., Symbol Digit Modalities Test, California Verbal Learning Test, Brief Visuospatial Memory Test-Revised, and verbal fluency). Test scores were converted to age-, sex-, and education-adjusted z-scores. Whole brain magnetic resonance imaging (MRI) was completed, from which measures of thalamic and hippocampal volumes, and mean diffusivity of gray matter and normal-appearing white matter were converted to age and sex-adjusted z-scores. Canonical correlation analysis was used to identify linear combinations of cognitive measures (cognitive variate) and MRI measures (MRI variate) that accounted for the most correlation between the cognitive and MRI measures. Regression analyses were used to test whether MRI measures mediated the relationships between the number of vascular comorbidities and cognition measures. Results: Of 105 participants, most were women (84.8%) with a mean (SD) age of 51.8 (12.8) years and age of symptom onset of 29.4 (10.5) years. Vascular comorbidity was common, with 35.2% of participants reporting one, 15.2% reporting two, and 8.6% reporting three or more. Canonical correlation analysis of the cognitive and MRI variables identified one pair of variates (Pillai's trace = 0.45, p = 0.0035). The biggest contributors to the cognitive variate were the Symbol Digit Modalities Test and California Verbal Learning Test-II, and to the MRI variate were gray matter MD and thalamic volume. The correlation between cognitive and MRI variates was 0.50; these variates were used in regression analyses. On regression analysis, vascular comorbidity was associated with the MRI variate, and with the cognitive variate. After adjusting for the MRI variate, vascular comorbidity was not associated with the cognitive variate. Conclusion: Vascular comorbidity is associated with lower cognitive function in people with multiple sclerosis and this association is partially mediated via changes in brain macrostructure and microstructure.

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Kornelsen J, McIver T,  Uddin MN,  Figley CR,  Marrie RA, Patel R, Fisk JD , Carter S, Graff LA,  Mazerolle E,  Bernstein CN. Altered voxel-based and surface-based morphometry in inflammatory bowel disease. Brain Research Bulletin 2023 Oct 15:203:110771.

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 IBD is a disorder of the brain-gut axis. Neuroimaging studies of brain function and structure have helped better understand the relationships between the brain, gut, and comorbidity in IBD. Studies of brain structure have primarily employed voxel-based morphometry to measure grey matter volume and surface-based morphometry to measure cortical thickness. Far fewer studies have employed other surface-based morphometry metrics such as gyrification, cortical complexity, and sulcal depth. In this study, brain structure differences between 72 adults with IBD and 90 healthy controls were assessed using all five metrics. Significant differences were found for cortical thickness with the IBD group showing extensive left-lateralized thinning, and for cortical complexity with the IBD group showing greater complexity in the left fusiform and right posterior cingulate. No significant differences were found in grey matter volume, gyrification, or sulcal depth. Within the IBD group, a post hoc analysis identified that disease duration is associated with cortical complexity of the right supramarginal gyrus, albeit with a more lenient threshold applied.

 

 

Carter SL, Patel R, Fisk JD, Figley CR, Marrie RA, Mazerolle EL, Uddin N, Wong K,  Graff LA,  Bolton JM,  Marriott JM,  Bernstein CN, Kornelsen J. Differences in resting state functional connectivity relative to multiple sclerosis and impaired information processing speed. Frontiers in Neurology 2023 Oct 19:14:1250894.

 

51% of individuals with multiple sclerosis develop cognitive impairment in information processing speed. Although information processing speed scores are associated with health and well-being, neural changes that underlie information processing speed impairments in multiple sclerosis are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with multiple sclerosis. We aimed to assess functional connectivity differences in (i) persons with multiple sclerosis compared to healthy controls, (ii) persons with both multiple sclerosis and cognitive impairment compared to healthy controls, (iii) persons with multiple sclerosis that are cognitively preserved compared to healthy controls, (iv) multiple sclerosis-cognitively impaired compared to multiple sclerosis-cognitively preserved, and (v) in relation to cognition within the multiple sclerosis group.  We included 107 participants with multiple sclerosis (age 49.5 ± 12.9, 82% women), and 94 controls (age 37.9 ± 15.4, 66% women). Each participant was administered the Symbol Digit Modalities Test and underwent a resting state fMRI scan. The multiple sclerosis-cognitively impaired group was created by applying a z-score cut-off of ≤≤-1.5 to locally normalized Symbol Digit Modalities Test scores. The multiple sclerosis-cognitively preserved group was created by applying a z-score of ≥0. Control groups were based on the nearest age-matched healthy controls participants. A whole-brain Region of Interest to Region of Interest (ROI-to-ROI) analysis was performed followed by specific contrasts and a regression. Results: Individuals with multiple sclerosis showed functional connectivity differences compared to healthy controls that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The multiple sclerosis-cognitively impaired showed functional connectivity differences compared to healthy controls that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. Symbol Digit Modalities Test scores were correlated with functional connectivity between the cerebellum and lateral occipital cortex in multiple sclerosis. No differences were observed between the multiple sclerosis-cognitively preserved and healthy controls or multiple sclerosis-cognitively impaired and multiple sclerosis-cognitively preserved groups. Conclusions: Our findings emphasize functional connectivity changes of cerebellar, visual, and language-associated areas in persons with multiple sclerosis. These differences were apparent for (i) all multiple sclerosis participants compared to healthy controls, (ii) multiple sclerosis-cognitively impaired subgroup and their matched controls, and (iii) the association between functional connectivity and Symbol Digit Modalities Test scores within the multiple sclerosis group. Our findings strongly suggest that future work that examines the associations between functional connectivity and information processing speed impairments in multiple sclerosis should focus on the involvement of these regions.

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Patel R, Marrie RA, Bernstein CN, Bolton JM, Graff LA,, Marriott JJ , Figley CR, Kornelsen J,  Mazerolle EL, Uddin MN, Fisk JD. Vascular Disease Is Associated With Differences in Brain Structure and Lower Cognitive Functioning in Inflammatory Bowel Disease: A Cross-Sectional Study. Inflammatory Bowel Diseases 2024; 30(8):1309-1318.

 

Vascular disease and cognitive impairment have been increasingly documented in IBD, and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning. 84 IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression-based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling. Results: Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure. Conclusions: Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.

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Zhu F, Zhao Y, Arnold D, Bar-Or A, Bernstein CN, Bonner C, Graham M, Hart J, Knox N,  Marrie RA,  Mirza AI, O'Mahony J, Van Domselaar G, Yeh EA, Banwell B, Waubant E , Tremlett H; US Network of Pediatric MS Centers, the Canadian Pediatric Demyelinating Disease Network. A cross-sectional study of MRI features and the gut microbiome in pediatric-onset multiple sclerosis. Annals of Clinical Translational Neurology 2024 Feb;11(2):486-496.

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To identify gut microbiome features associated with MRI lesion burden in persons with pediatric-onset multiple sclerosis (symptom onset under 18 years). A cross-sectional study involving the Canadian Paediatric Demyelinating Disease Network study participants. Gut microbiome features (alpha diversity, phylum- and genus-level taxa) were derived using 16S rRNA sequencing from stool samples. T1- and T2-weighted lesion volumes were measured on brain MRI obtained within 6 months of stool sample procurement. Associations between the gut microbiota and MRI metrics (cube-root-transformed) were assessed using standard and Lasso regression models. Results: 34 participants were included; mean ages at symptom onset and MRI were 15.1 and 19.0 years, respectively, and 79% were female. The T1- and T2-weighted lesion volumes were not significantly associated with alpha diversity (age and sex-adjusted p > 0.08). At the phylum level, high Tenericutes (relative abundance) was associated with higher T1 and T2 volumes (β coefficient = 0.25, 0.37) and high Firmicutes, Patescibacteria or Actinobacteria with lower lesion volumes (β coefficient = -0.30 to -0.07). At the genus level, high Ruminiclostridium, whereas low Coprococcus 3 and low Erysipelatoclostridium were associated with higher lesion volumes. Conclusions: Our study characterized the gut microbiota features associated with MRI lesion burden in pediatric-onset MS, shedding light onto possible pathophysiological mechanisms.

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