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Amlashi FI, Besharat S, Jahanshahi M, Shirzad-Aski H, Torshizi FN. Colitis can reduce the cingulate cortex neuronal density in rats. BMC Gastroenterol 2025; 25:171. [PMID: 40082771 PMCID: PMC11907912 DOI: 10.1186/s12876-025-03745-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/28/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND AND AIM Hyperalgesia and hypersensitivity in patients with Inflammatory Bowel Disease (IBD) can be related to central nervous system (CNS) changes, particularly in the pain pathways. The objective of this study was to examine the neuronal density of the cingulate cortex area (CC) and amygdala in an animal model of colitis. MATERIALS AND METHODS In this experiment, 13 male Wistar rats were subjected to study. Colitis was induced in the rats by transrectally administering 1 cc of acetic acid 3% under sedation with xylazine 10% (5 mg/kg). After 14 days of colitis, the rats were euthanized under high doses of anesthesia with ketamine (50 mg/kg), xylazine (10 mg/kg), and diazepam (2.5 mg/kg). Their brains were then removed surgically. Six-micrometer-thick brain slices were stained with cresyl violet, and the neuronal density of the amygdala, area 1 of the cingulate cortex area (CC1), and area 2 of the cingulate cortex area (CC2) was assessed via microscopic imaging. RESULTS The mean ± standard deviation (SD) of the neuronal density in CC1 was significantly decreased in rats with colitis compared to the control group in both the right CC1 (43.53 ± 9.63 vs. 62.7 ± 11.89; p-value ˂ 0.001), and left CC1 (41.19 ± 9.05 and 63.1 ± 7.44; p-value ˂ 0.001). Additionally, the neuronal density of CC2 in the colitis group was found to be significantly lower than that of the controls in both the right CC2 (57.8 ± 13.23 vs. 87.95 ± 8.76; p-value ˂ 0.001), and left CC2 (55.42 ± 11.3 vs. 98 ± 8.99; p-value ˂ 0.001). Furthermore, the amygdala had a lower neuronal density in both hemispheres in rats with colitis in comparison to the controls bilaterally: right hemisphere (24.51 ± 5.49 and 36.3 ± 7.44; p-value = 0.360), and left hemisphere (24.52 ± 5.53 VS. 35.25 ± 5.6; P-value = 0.869). CONCLUSION This study showed that colitis can reduce the neuronal density within cortical areas and amygdala of both hemispheres. Considering the cingulate cortex's role in suppressing pain perception, any harm inflicted upon this region of the brain can has the ability to impact the cognitive and sensory aspects of pain.
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Affiliation(s)
- Fazel Isapanah Amlashi
- Golestan Research Center of Gastroenterology and Hepatology, GolestanUniversity of Medical Sciences, Gorgan, Iran
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sima Besharat
- Golestan Research Center of Gastroenterology and Hepatology, GolestanUniversity of Medical Sciences, Gorgan, Iran
| | - Mehrdad Jahanshahi
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Hesamaddin Shirzad-Aski
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, 49178-67439, Iran.
| | - Fatemeh Nassaj Torshizi
- Clinical Research Development Unit (CRDU), Sayad Shirazi Hospital, Golestan University of Medical Sciences, Gorgan, Iran
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Yue KC, Zhu YY, Sun JW, Wu XT, Liu WJ, Shi HF. Imaging characteristics of brain microstructure and cerebral perfusion in Crohn's disease patients with anxiety: A prospective comparative study. World J Gastroenterol 2025; 31:99014. [PMID: 39877713 PMCID: PMC11718645 DOI: 10.3748/wjg.v31.i4.99014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/13/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Anxiety is a common comorbidity in patients with Crohn's disease (CD). Data on the imaging characteristics of brain microstructure and cerebral perfusion in CD with anxiety are limited. AIM To compare the imaging characteristics of brain microstructure and cerebral perfusion among CD patients with or without anxiety and healthy individuals. METHODS This prospective comparative study enrolled consecutive patients with active CD and healthy individuals who visited the study hospital between January 2022 and January 2023. Anxiety was measured using the Hospital Anxiety and Depression Scale-Anxiety. The imaging characteristics of brain microstructure and cerebral perfusion were measured by diffusion kurtosis imaging and intravoxel incoherent motion. RESULTS A total of 57 participants were enrolled. Among the patients with active CD, 16 had anxiety. Compared with healthy individuals, patients with active CD demonstrated significantly lower radial kurtosis values in the right cerebellar region 6, lower axial kurtosis (AK) values in the right insula, left superior temporal gyrus, and right thalamus, and higher slow and fast apparent diffusion coefficients (ADCslow and ADCfast) in the bilateral frontal lobe, bilateral temporal lobe, and bilateral insular lobe (all P < 0.05). Compared with patients with CD without anxiety, patients with CD and anxiety exhibited significantly higher ADCslow values in the left insular lobe and lower AK values in the right insula and right anterior cuneus (all P < 0.05). CONCLUSION There are variations in brain microstructure and perfusion among CD patients with/without anxiety and healthy individuals, suggesting potential use in assessing anxiety-related changes in active CD.
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Affiliation(s)
- Ke-Cen Yue
- Dalian Medical University, Dalian 116044, Liaoning Province, China
- Department of Radiology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou 213000, Jiangsu Province, China
| | - Ying-Yin Zhu
- Department of Radiology, Suzhou 100 Hospital, Suzhou 215000, Jiangsu Province, China
| | - Jing-Wen Sun
- Department of Radiology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou 213000, Jiangsu Province, China
| | - Xin-Tong Wu
- Dalian Medical University, Dalian 116044, Liaoning Province, China
- Department of Radiology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou 213000, Jiangsu Province, China
| | - Wen-Jia Liu
- Department of Gastroenterology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou 213000, Jiangsu Province, China
| | - Hai-Feng Shi
- Department of Radiology, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Changzhou 213000, Jiangsu Province, China
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Huang M, Ma G, Zou Y, Ma H, Fan W, Li X, Zhu L, Han P, Wang H, Shi H. A potential brain functional biomarker distinguishing patients with Crohn's disease with different disease stages: a resting-state fMRI study. Front Neurosci 2024; 18:1361320. [PMID: 38500485 PMCID: PMC10945013 DOI: 10.3389/fnins.2024.1361320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 02/23/2024] [Indexed: 03/20/2024] Open
Abstract
Background The previous studies have demonstrated that patients with Crohn's disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohn's disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF). Methods 121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohn's disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ≥150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages. Results There were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (beta = 5.138, p = 0.031), PC_R (beta = 1.876, p = 0.002) and OFG_L (beta = 3.937, p = 0.044) was disease stages predictors. Conclusion The results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD.
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Affiliation(s)
- Mengting Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Guina Ma
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yan Zou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Hui Ma
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Wenliang Fan
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xin Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Liangru Zhu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Han
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Huan Wang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heshui Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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Yang L, He P, Zhang L, Li K. Altered resting-state brain functional activities and networks in Crohn's disease: a systematic review. Front Neurosci 2024; 18:1319359. [PMID: 38332859 PMCID: PMC10851432 DOI: 10.3389/fnins.2024.1319359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/10/2024] [Indexed: 02/10/2024] Open
Abstract
Background Crohn's disease (CD) is a non-specific chronic inflammatory disease of the gastrointestinal tract and is a phenotype of inflammatory bowel disease (IBD). The current study sought to compile the resting-state functional differences in the brain between CD patients and healthy controls. Methods The online databases PubMed, Web of Science Core, and EMBASE were used to find the published neuroimage studies. The search period was from the beginning through December 15, 2023. The predetermined inclusion and exclusion criteria allowed for the identification of the studies. The studies were assembled by two impartial reviewers, who also assessed their quality and bias. Results This review comprised 16 resting-state fMRI studies in total. The included studies generally had modest levels of bias. According to the research, emotional processing and pain processing were largely linked to increased or decreased brain activity in patients with CD. The DMN, CEN, and limbic systems may have abnormalities in patients with CD, according to research on brain networks. Several brain regions showed functional changes in the active CD group compared to the inactive CD group and the healthy control group, respectively. The abnormalities in brain areas were linked to changes in mood fluctuations (anxiety, melancholy) in patients with CD. Conclusion Functional neuroimaging helps provide a better understanding of the underlying neuropathological processes in patients with CD. In this review, we summarize as follows: First, these findings indicate alterations in brain function in patients with CD, specifically affecting brain regions associated with pain, emotion, cognition, and visceral sensation; second, disease activity may have an impact on brain functions in patients with CD; and third, psychological factors may be associated with altered brain functions in patients with CD.
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Affiliation(s)
- Ling Yang
- Radiology Department, Chongqing General Hospital, Chongqing, China
- Department of Radiology Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
| | - Peipei He
- Radiology Department, Chongqing General Hospital, Chongqing, China
| | - Lingqin Zhang
- Radiology Department, Chongqing General Hospital, Chongqing, China
| | - Kang Li
- Radiology Department, Chongqing General Hospital, Chongqing, China
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Wang J, Liu G, Xu K, Ai K, Huang W, Zhang J. The role of neurotransmitters in mediating the relationship between brain alterations and depressive symptoms in patients with inflammatory bowel disease. Hum Brain Mapp 2023; 44:5357-5371. [PMID: 37530546 PMCID: PMC10543356 DOI: 10.1002/hbm.26439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/07/2023] [Accepted: 07/10/2023] [Indexed: 08/03/2023] Open
Abstract
A growing body of evidence from neuroimaging studies suggests that inflammatory bowel disease (IBD) is associated with functional and structural alterations in the central nervous system and that it has a potential link to emotional symptoms, such as anxiety and depression. However, the neurochemical underpinnings of depression symptoms in IBD remain unclear. We hypothesized that changes in cortical gamma-aminobutyric acid (GABA+) and glutamine (Glx) concentrations are related to cortical thickness and resting-state functional connectivity in IBD as compared to healthy controls. To test this, we measured whole-brain cortical thickness and functional connectivity within the medial prefrontal cortex (mPFC), as well as the concentrations of neurotransmitters in the same brain region. We used the edited magnetic resonance spectroscopy (MRS) with the MEGA-PRESS sequence at a 3 T scanner to quantitate the neurotransmitter levels in the mPFC. Subjects with IBD (N = 37) and healthy control subjects (N = 32) were enrolled in the study. Compared with healthy controls, there were significantly decreased GABA+ and Glx concentrations in the mPFC of patients with IBD. The cortical thickness of patients with IBD was thin in two clusters that included the right medial orbitofrontal cortex and the right posterior cingulate cortex. A seed-based functional connectivity analysis indicated that there was higher connectivity of the mPFC with the left precuneus cortex (PC) and the posterior cingulate cortex, and conversely, lower connectivity in the left frontal pole was observed. The functional connectivity between the mPFC and the left PC was negatively correlated with the IBD questionnaire score (r = -0.388, p = 0.018). GABA+ concentrations had a negative correlation with the Hamilton Depression Scale (HAMD) score (r = -0.497, p = 0.002). Glx concentration was negatively correlated with the HAMD score (r = -0.496, p = 0.002) and positively correlated with the Short-Form McGill Pain Questionnaire score (r = 0.330, p = 0.046, uncorrected). There was a significant positive correlation between the ratio of Glx to GABA+ and the HAMD score (r = 0.428, p = 0.008). Mediation analysis revealed that GABA+ significantly mediated the main effect of the relationship between the structural and functional alterations and the severity of depression in patients with IBD. Our study provides initial evidence of neurochemistry that can be used to identify potential mechanisms underlying the modulatory effects of GABA+ on the development of depression in patients with IBD.
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Affiliation(s)
- Jun Wang
- Department of Magnetic ResonanceLanzhou University Second HospitalLanzhouChina
- Second Clinical SchoolLanzhou UniversityLanzhouChina
- Gansu Province Clinical Research Center for Functional and Molecular ImagingLanzhou University Second HospitalLanzhouChina
| | - Guangyao Liu
- Department of Magnetic ResonanceLanzhou University Second HospitalLanzhouChina
- Gansu Province Clinical Research Center for Functional and Molecular ImagingLanzhou University Second HospitalLanzhouChina
| | - Kun Xu
- Department of Magnetic ResonanceLanzhou University Second HospitalLanzhouChina
- Second Clinical SchoolLanzhou UniversityLanzhouChina
- Gansu Province Clinical Research Center for Functional and Molecular ImagingLanzhou University Second HospitalLanzhouChina
| | - Kai Ai
- Deparment of Clinical and Technical Support, Philips HealthcareXi'anChina
| | - Wenjing Huang
- Department of Magnetic ResonanceLanzhou University Second HospitalLanzhouChina
- Second Clinical SchoolLanzhou UniversityLanzhouChina
- Gansu Province Clinical Research Center for Functional and Molecular ImagingLanzhou University Second HospitalLanzhouChina
| | - Jing Zhang
- Department of Magnetic ResonanceLanzhou University Second HospitalLanzhouChina
- Second Clinical SchoolLanzhou UniversityLanzhouChina
- Gansu Province Clinical Research Center for Functional and Molecular ImagingLanzhou University Second HospitalLanzhouChina
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Mao Y, Zhang P, Sun R, Zhang X, He Y, Li S, Yin T, Zeng F. Altered resting-state brain activity in functional dyspepsia patients: a coordinate-based meta-analysis. Front Neurosci 2023; 17:1174287. [PMID: 37250423 PMCID: PMC10213416 DOI: 10.3389/fnins.2023.1174287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 04/14/2023] [Indexed: 05/31/2023] Open
Abstract
Background Neuroimaging studies have identified aberrant activity patterns in multiple brain regions in functional dyspepsia (FD) patients. However, due to the differences in study design, these previous findings are inconsistent, and the underlying neuropathological characteristics of FD remain unclear. Methods Eight databases were systematically searched for literature from inception to October 2022 with the keywords "Functional dyspepsia" and "Neuroimaging." Thereafter, the anisotropic effect size signed the differential mapping (AES-SDM) approach that was applied to meta-analyze the aberrant brain activity pattern of FD patients. Results A total of 11 articles with 260 FD patients and 202 healthy controls (HCs) were included. The AES-SDM meta-analysis demonstrated that FD patients manifested increased activity in the bilateral insula, left anterior cingulate gyrus, bilateral thalamus, right precentral gyrus, left supplementary motor area, right putamen, and left rectus gyrus and decreased functional activity in the right cerebellum compared to the HCs. Sensitivity analysis showed that all these above regions were highly reproducible, and no significant publication bias was detected. Conclusion The current study demonstrated that FD patients had significantly abnormal activity patterns in several brain regions involved in visceral sensation perception, pain modulation, and emotion regulation, which provided an integrated insight into the neuropathological characteristics of FD.
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Affiliation(s)
- Yangke Mao
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Pan Zhang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ruirui Sun
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyue Zhang
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuqi He
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Siyang Li
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Yin
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Fang Zeng
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Acupuncture and Brain Science Research Center, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Key Laboratory of Sichuan Province for Acupuncture and Chronobiology, Chengdu, China
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Nass BYS, Dibbets P, Markus CR. Impact of the COVID‐19 pandemic on inflammatory bowel disease: The role of emotional stress and social isolation. Stress Health 2022; 38:222-233. [PMID: 34273129 PMCID: PMC8420478 DOI: 10.1002/smi.3080] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/01/2021] [Accepted: 07/06/2021] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic health condition exacerbated by negative emotional stress experiences. In the current study, we examined whether the outbreak of the COVID-19 pandemic coincided with an increase in stress experiences and accordingly an aggravation of disease activity in IBD patients. Sixty-three IBD patients (30 Crohn's disease or CD, 33 ulcerative colitis) completed an online survey during the COVID-19-related lockdown, assessing clinical disease activity, disease-related quality of life, presence of functional gastrointestinal symptoms, social isolation and stress experiences. Scores were then compared to pre-lockdown baseline screening. The pandemic yielded a significant baseline-to-lockdown increase in emotional stress and social isolation. Stress increments, particularly those occasioned by interpersonal tension and excessive interpersonal proximity, were associated with a worsening of functional gastrointestinal symptoms. Exacerbations of loneliness coincided with an escalation of CD activity, functional gastrointestinal symptoms and a decline in subjective health. Lastly, COVID-19 anxiety was significantly related to CD symptom severity and social dysfunction. The findings show that shifts in IBD expression are closely linked to changes in emotional stress experiences and interpersonal relatedness. As such, they contribute to a better understanding of inter-individual differences in IBD progression and provide leads for therapeutic interventions.
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Affiliation(s)
- Boukje Yentl Sundari Nass
- Department of Neuropsychology and PsychopharmacologyFaculty of Psychology and NeuroscienceMaastricht UniversityMaastrichtThe Netherlands,Dr. Rath Health FoundationHeerlenThe Netherlands
| | - Pauline Dibbets
- Clinical Psychological ScienceMaastricht UniversityMaastrichtThe Netherlands
| | - C. Rob Markus
- Department of Neuropsychology and PsychopharmacologyFaculty of Psychology and NeuroscienceMaastricht UniversityMaastrichtThe Netherlands
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McGing JJ, Radford SJ, Francis ST, Serres S, Greenhaff PL, Moran GW. Review article: The aetiology of fatigue in inflammatory bowel disease and potential therapeutic management strategies. Aliment Pharmacol Ther 2021; 54:368-387. [PMID: 34228817 DOI: 10.1111/apt.16465] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/30/2020] [Accepted: 05/20/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Fatigue is the inability to achieve or maintain an expected work output resulting from central or peripheral mechanisms. The prevalence of inflammatory bowel disease (IBD) fatigue can reach 86% in active disease, persisting in 50%-52% of patients with mild to inactive disease. Fatigue is the commonest reason for work absence in IBD, and patients often report fatigue burden to be greater than that of primary disease symptoms. Relatively few evidence-based treatment options exist, and the aetiology is poorly understood. AIM To review the available data and suggest a possible aetiology of IBD fatigue and to consider the efficacy of existing management strategies and highlight potential future interventions. METHODS We reviewed fatigue-related literature in IBD using PubMed database. RESULTS Disease related factors such as inflammation and pharmacological treatments negatively impact skeletal muscle and brain physiology, likely contributing to fatigue symptoms. Secondary factors such as malnutrition, anaemia, sleep disturbance and psychological comorbidity are potential determinants. Immune profile, faecal microbiota composition and physical fitness differ significantly between fatigued and non-fatigued patients, suggesting these may be aetiological factors. Solution-focused therapy, high-dosage thiamine supplementation and biological therapy may reduce fatigue perception in IBD. The effect of physical activity interventions is inconclusive. CONCLUSIONS A multimodal approach is likely required to treat IBD fatigue. Established reversible factors like anaemia, micronutrient deficiencies and active disease should initially be resolved. Psychosocial intervention shows potential efficacy in reducing fatigue perception in quiescent disease. Restoring physical deconditioning by exercise training intervention may further improve fatigue burden.
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Affiliation(s)
- Jordan J McGing
- School of Medicine, University of Nottingham, Nottingham, UK.,Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK
| | - Shellie Jean Radford
- School of Medicine, University of Nottingham, Nottingham, UK.,National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK
| | - Susan T Francis
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK
| | - Sébastien Serres
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Paul L Greenhaff
- National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK.,MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre, School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Gordon W Moran
- School of Medicine, University of Nottingham, Nottingham, UK.,National Institute of Health Research Nottingham Biomedical Research Centre (NIHR), Nottingham University Hospitals and University of Nottingham, Nottingham, UK
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Li L, Ma J, Xu J, Zheng Y, Xie Q, Rong L, Liang Z. Brain functional changes in patients with Crohn's disease: A resting-state fMRI study. Brain Behav 2021; 11:e2243. [PMID: 34124857 PMCID: PMC8413760 DOI: 10.1002/brb3.2243] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Crohn's disease (CD) is a chronic recurrent intestinal inflammatory disease, often accompanied by poor adaptation and excessive stress response. However, the potential neurological mechanisms of these symptoms have not yet been studied in-depth. OBJECTIVE To investigate alterations in brain activity in patients with Crohn's disease and study the relationship between altered regions and clinical indices. METHODS A total of 15 CD patients and 26 matched healthy controls were recruited. All participants underwent fMRI scans. The amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) assessed differences in spontaneous regional brain activity. Differences between the groups were selected as seeds for functional connectivity (FC) analyses. Correlations between disease duration and ALFF/ReHo/FC values in abnormal regions were analyzed. RESULTS Patients with CD had significantly higher ALFF values in the left superior frontal gyrus, anterior cingulate cortex, and supplementary motor area, and lower values in the left hippocampus. They also had higher ReHo values in the left anterior cingulate cortex, supplementary motor area, putamen, and the bilateral superior frontal gyri. FC strength in the left precentral and middle temporal gyri was found to be increased when the left superior frontal gyrus was used as the seed point. FC strength was also observed to be increased in the left postcentral, middle frontal gyri, inferior frontal orbital cortex, and right rolandic operculum when the left anterior cingulate cortex was used as the seed point. CONCLUSION CD demonstrated abnormal neural activity and FC in various regions primarily associated with emotional, pain and cognitive-related functions, which provides more information to further understand the neural mechanisms of the disease.
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Affiliation(s)
- Lu Li
- Department of Radiology, Jing'an District Centre Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Jie Ma
- School of Rehabilitation ScienceShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jian‐Guang Xu
- School of Rehabilitation ScienceShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Yan‐Ling Zheng
- Department of Radiology, Jing'an District Centre Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Qian Xie
- Department of Radiology, Jing'an District Centre Hospital of ShanghaiFudan UniversityShanghaiChina
| | - Lan Rong
- Department of Gastroenterology, Huashan HospitalFudan UniversityShanghaiChina
| | - Zong‐Hui Liang
- Department of Radiology, Jing'an District Centre Hospital of ShanghaiFudan UniversityShanghaiChina
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10
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Engel F, Berens S, Gauss A, Schaefert R, Eich W, Tesarz J. Higher Levels of Psychological Burden and Alterations in Personality Functioning in Crohn's Disease and Ulcerative Colitis. Front Psychol 2021; 12:671493. [PMID: 34248767 PMCID: PMC8264053 DOI: 10.3389/fpsyg.2021.671493] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/03/2021] [Indexed: 12/19/2022] Open
Abstract
Aims: Is there evidence for increased psychological distress and alterations in personality functioning in patients with Crohn’s disease (CD) and ulcerative colitis (UC) compared to healthy controls (HCs)? Background: In patients with CD and UC, perceived stress is closely associated with changes in disease activity. The stress response is influenced by psychological burden and personality functioning, but only little is known about these factors in inflammatory bowel diseases (IBD). Study: A total of 62 patients with an endoscopic ensured CD/UC without remission (n = 31 per group) and 31 HC were included. Patients with an active CD/UC and HC were individually matched (n = 93, 31 per group) for age, sex, education, and disease activity. Depression and anxiety were assessed to evaluate the effect of psychological burden (Patient Health Questionnaire-9/PHQ-9, Generalized Anxiety Disorder-7/GAD-7). Personality functioning was measured by validated questionnaires for psychodynamic structural characteristics, mentalization, and attachment (Operationalized Psychodynamic Diagnosis-Structure Questionnaire/OPD-SQ, Mentalization Questionnaire/MZQ, and Experiences in Close Relationships scale/ECR-RD 12). Results: Levels of depression and anxiety were higher in CD/UC patients than in HC with large effect sizes. Comparing personality functioning in CD/UC with HC, psychodynamic structural characteristics differed between CD/UC and HC with medium effect sizes, with structural differences occurring primarily in the domain of self-perception and regulation. Only minor differences were found regarding mentalization and attachment. CD and UC differed only with small effect sizes. Conclusion: Our data show that compared to HC, patients with CD/UC are characterized by a higher level of psychological burden and structural alterations in the domain of self.
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Affiliation(s)
- Felicitas Engel
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Sabrina Berens
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany.,Institute of Psychology, Heidelberg University, Heidelberg, Germany
| | - Annika Gauss
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Rainer Schaefert
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany.,Division of Internal Medicine, Department of Psychosomatic Medicine, University Hospital Basel, Basel, Switzerland
| | - Wolfgang Eich
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
| | - Jonas Tesarz
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
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11
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Structural and functional changes in the brain of patients with Crohn's disease: an activation likelihood estimation meta-analysis. Brain Imaging Behav 2021; 15:807-818. [PMID: 32333318 DOI: 10.1007/s11682-020-00291-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Multiple reports for brain functional and structural alterations in patients with Crohn's disease (CD) were published. The current study aimed to meta-analyze the existing neuroimaging data and hence produce a brain map revealing areas with functional and structural differences between patients with CD and healthy controls. Original studies published until 2019 were identified from Scopus, Web of Science and PubMed databases, and included into the analysis if they reported relevant results from task-related or resting state functional magnetic resonance imaging (fMRI or rsfMRI) or voxel-based morphometry (VBM), in the form of standardized brain coordinates based on whole-brain analysis. The brain coordinates and sample size of significant results were extracted from eligible studies to be meta-analyzed with the activation likelihood estimation method using the GingerALE software. Sixteen original studies comprised of a total of 865 participants fulfilled the inclusion criteria. Compared to healthy controls, patients with CD had reduced resting state brain connectivity in the paracentral lobule and cingulate gyrus as well as reduced grey matter volume in the medial frontal gyrus. No significant results were found vice versa. These neural correlates allow a better understanding on the effects of CD on the pain expectation, emotion, and quality of life of patients and potentially serve as useful biomarkers for evaluating treatment efficacy.
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12
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Thomaidou MA, Peerdeman KJ, Koppeschaar MI, Evers AWM, Veldhuijzen DS. How Negative Experience Influences the Brain: A Comprehensive Review of the Neurobiological Underpinnings of Nocebo Hyperalgesia. Front Neurosci 2021; 15:652552. [PMID: 33841092 PMCID: PMC8024470 DOI: 10.3389/fnins.2021.652552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 03/05/2021] [Indexed: 01/06/2023] Open
Abstract
This comprehensive review summarizes and interprets the neurobiological correlates of nocebo hyperalgesia in healthy humans. Nocebo hyperalgesia refers to increased pain sensitivity resulting from negative experiences and is thought to be an important variable influencing the experience of pain in healthy and patient populations. The young nocebo field has employed various methods to unravel the complex neurobiology of this phenomenon and has yielded diverse results. To comprehend and utilize current knowledge, an up-to-date, complete review of this literature is necessary. PubMed and PsychInfo databases were searched to identify studies examining nocebo hyperalgesia while utilizing neurobiological measures. The final selection included 22 articles. Electrophysiological findings pointed toward the involvement of cognitive-affective processes, e.g., modulation of alpha and gamma oscillatory activity and P2 component. Findings were not consistent on whether anxiety-related biochemicals such as cortisol plays a role in nocebo hyperalgesia but showed an involvement of the cyclooxygenase-prostaglandin pathway, endogenous opioids, and dopamine. Structural and functional neuroimaging findings demonstrated that nocebo hyperalgesia amplified pain signals in the spinal cord and brain regions involved in sensory and cognitive-affective processing including the prefrontal cortex, insula, amygdala, and hippocampus. These findings are an important step toward identifying the neurobiological mechanisms through which nocebo effects may exacerbate pain. Results from the studies reviewed are discussed in relation to cognitive-affective and physiological processes involved in nocebo and pain. One major limitation arising from this review is the inconsistency in methods and results in the nocebo field. Yet, while current findings are diverse and lack replication, methodological differences are able to inform our understanding of the results. We provide insights into the complexities and involvement of neurobiological processes in nocebo hyperalgesia and call for more consistency and replication studies. By summarizing and interpreting the challenging and complex neurobiological nocebo studies this review contributes, not only to our understanding of the mechanisms through which nocebo effects exacerbate pain, but also to our understanding of current shortcomings in this field of neurobiological research.
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Affiliation(s)
- Mia A. Thomaidou
- Health, Medical & Neuropsychology Unit, Leiden University, Leiden, Netherlands
- Leiden Institute for Brain and Cognition, Leiden, Netherlands
| | - Kaya J. Peerdeman
- Health, Medical & Neuropsychology Unit, Leiden University, Leiden, Netherlands
- Leiden Institute for Brain and Cognition, Leiden, Netherlands
| | | | - Andrea W. M. Evers
- Health, Medical & Neuropsychology Unit, Leiden University, Leiden, Netherlands
- Leiden Institute for Brain and Cognition, Leiden, Netherlands
- Medical Delta Healthy Society, Leiden University, Technical University Delft, & Erasmus UniversityRotterdam, Netherlands
- Department of Psychiatry, Leiden University Medical Centre, Leiden, Netherlands
| | - Dieuwke S. Veldhuijzen
- Health, Medical & Neuropsychology Unit, Leiden University, Leiden, Netherlands
- Leiden Institute for Brain and Cognition, Leiden, Netherlands
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13
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Kong N, Gao C, Xu M, Gao X. Changes in the anterior cingulate cortex in Crohn's disease: A neuroimaging perspective. Brain Behav 2021; 11:e02003. [PMID: 33314765 PMCID: PMC7994700 DOI: 10.1002/brb3.2003] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Evidence suggests that Crohn's disease (CD) pathophysiology goes beyond the gastrointestinal tract and is also strongly associated with the brain. In particular, the anterior cingulate cortex (ACC), which plays an integral role in the first brain as part of the default mode network (DMN) and pain matrix, shows abnormalities using multiple neuroimaging modalities. This review summarizes nine related studies that investigated changes in the ACC using structural magnetic resonance imaging, resting-state functional magnetic resonance imaging, and magnetic resonance spectroscopy. METHODS An extensive PubMed literature search was conducted from 1980 to August 2020. In a review of the articles identified, particular attention was paid to analysis methods, technical protocol characteristics, and specific changes in the ACC. RESULTS In terms of morphology, a decrease in gray matter volume and cortical thickness was observed along with an increase in local gyrification index. In terms of function, functional connectivity (FC) within the DMN was increased. FC between the ACC and the amygdala was decreased. Higher amplitudes of low-frequency fluctuation and graph theory results, including connectivity strength, clustering coefficient, and local efficiency, were detected. In terms of neurotransmitter changes, the concentrations of glutamate increased along with a decrease in gamma-aminobutyric acid, providing a rational explanation for abdominal pain. These changes may be attributed to stress, pain, and negative emotions, as well as changes in gut microbiota. CONCLUSIONS For patients with CD, the ACC demonstrates structural, functional, and metabolic changes. In terms of clinical findings, the ACC plays an important role in the onset of depression/anxiety and abdominal pain. Therefore, successful modulation of this pathway may guide treatment.
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Affiliation(s)
- Ning Kong
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.,Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Chen Gao
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.,Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Maosheng Xu
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.,Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Xuning Gao
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.,Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
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14
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Brenner L, Zerlin L, Tan LL. Functional disruption of cortical cingulate activity attenuates visceral hypersensitivity and anxiety induced by acute experimental colitis. Sci Rep 2021; 11:2103. [PMID: 33483524 PMCID: PMC7822936 DOI: 10.1038/s41598-021-81256-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 01/04/2021] [Indexed: 12/26/2022] Open
Abstract
Visceral pain is a highly complex experience and is the most common pathological feature in patients suffering from inflammatory gastrointestinal disorders. Whilst it is increasingly recognized that aberrant neural processing within the gut-brain axis plays a key role in development of neurological symptoms, the underlying mechanisms remain largely unknown. Here, we investigated the cortical activation patterns and effects of non-invasive chemogenetic suppression of cortical activity on visceral hypersensitivity and anxiety-related phenotypes in a well-characterized mouse model of acute colitis induced by dextran sulfate sodium (DSS). We found that within the widespread cortical network, the mid-cingulate cortex (MCC) was consistently highly activated in response to innocuous and noxious mechanical stimulation of the colon. Furthermore, during acute experimental colitis, impairing the activity of the MCC successfully alleviated visceral hypersensitivity, anxiety-like behaviors and visceromotor responses to colorectal distensions (CRDs) via downregulating the excitability of the posterior insula (PI), somatosensory and the rostral anterior cingulate cortices (rACC), but not the prefrontal or anterior insula cortices. These results provide a mechanistic insight into the central cortical circuits underlying painful visceral manifestations and implicate MCC plasticity as a putative target in cingulate-mediated therapies for bowel disorders.
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Affiliation(s)
- Lukas Brenner
- Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany
| | - Leah Zerlin
- Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany
| | - Linette Liqi Tan
- Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
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15
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Colonnello V, Agostini A. Disease course, stress, attachment, and mentalization in patients with inflammatory bowel disease. Med Hypotheses 2020; 140:109665. [PMID: 32155541 DOI: 10.1016/j.mehy.2020.109665] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/18/2020] [Accepted: 03/03/2020] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, are chronic intestinal disorders that requires lifelong treatments. IBD are associated with perceived stress, poor quality of life, and psychopathological disorders. Previous studies have documented that psychological distress and depression are risk factors for IBD. On the other hand, IBD itself might be a source of psychological stress. IBD negatively affect individuals' daily social interactions and close interpersonal relationships. Despite IBD's detrimental effects on quality of life, patients' adherence to medicaments remains low, increasing the risk of relapses and the subsequent worsening of the clinical condition. Drawing on attachment and mentalization theories, we aim to contribute to understanding of the mechanisms involved in the poor quality of social relationships and the tendency for medication non-adherence in patients with IBD. We hypothesize a bidirectional link between IBD and attachment style and related mentalization abilities, where an individual's attachment style refers to a complex and characteristic pattern of relating to self and others and mentalization refers to the process of inferring one's own and others' mental and physical states. This hypothesized link between IBD and insecure attachment style, mediated by reduced mentalizing abilities, may be a risk factor for developing both IBD-related psychological disorders and reduced medication adherence, which could then lead to worsening disease management and prognoses for the disease course. The medication nonadherence is here considered as both an outcome and a risk factor of this vicious circle. We share the view that preventing the worsening of the IBD condition and promoting patients' medication adherence would be possible by considering the circular relationship between IBD, attachment, and mentalization and by promoting reflective functioning in patients with IBD, from the onset of the disease.
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Affiliation(s)
- Valentina Colonnello
- Department of Experimental, Diagnostic, and Specialty Medicine DIMES St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Alessandro Agostini
- Department of Experimental, Diagnostic, and Specialty Medicine DIMES St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
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16
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Nocebo Effects and Experimental Models in Visceral Pain. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2018; 138:285-306. [PMID: 29681331 DOI: 10.1016/bs.irn.2018.01.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite its clinical relevance and the potential to extend insights into the processing and modulation of pain derived from investigations of placebo phenomena, the nocebo effect has received comparably little attention over the past decades. Research from experimental and clinical studies is only beginning to unravel the behavioral, functional, and psychoneurobiological mechanisms underlying the nocebo effect. Herein, we summarize current evidence regarding nocebo effects in the field of pain, with a particular emphasis on visceral pain. We provide an overview over behavioral and neuroimaging findings on the impact of expectations and learning and propose promising future directions to help fostering the transition of experimental research from bench to bedside.
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17
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Agostini A, Ballotta D, Righi S, Moretti M, Bertani A, Scarcelli A, Sartini A, Ercolani M, Nichelli P, Campieri M, Benuzzi F. Stress and brain functional changes in patients with Crohn's disease: A functional magnetic resonance imaging study. Neurogastroenterol Motil 2017; 29:1-10. [PMID: 28560758 DOI: 10.1111/nmo.13108] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2016] [Accepted: 04/17/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND In Crohn's disease (CD) patients, stress is believed to influence symptoms generation. Stress may act via central nervous system pathways to affect visceral sensitivity and motility thus exacerbating gastrointestinal symptoms. The neural substrate underpinning these mechanisms needs to be investigated in CD. We conducted an explorative functional magnetic resonance imaging (fMRI) study in order to investigate potential differences in the brain stress response in CD patients compared to controls. METHODS 17 CD patients and 17 healthy controls underwent a fMRI scan while performing a stressful task consisting in a Stroop color-word interference task designed to induce mental stress in the fMRI environment. KEY RESULTS Compared to controls, in CD patients the stress task elicited greater blood oxygen level dependent (BOLD) signals in the midcingulate cortex (MCC). CONCLUSIONS & INFERENCES The MCC integrate "high" emotional processes with afferent sensory information ascending from the gut. In light of these integrative functions, the stress-evoked MCC hyperactivity in CD patients might represent a plausible neural substrate for the association between stress and symptomatic disease. The MCC dysfunction might be involved in mechanisms of central disinhibition of nociceptive inputs leading to amplify the visceral sensitivity. Finally, the stress-evoked MCC hyperactivity might affect the regulation of intestinal motility resulting in exacerbation of disease symptoms and the autonomic and neuroendocrine regulation of inflammation resulting in enhanced inflammatory activity.
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Affiliation(s)
- A Agostini
- Department of Experimental, Diagnostic, and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.,Department of Psychology, University of Bologna, Bologna, Italy
| | - D Ballotta
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - S Righi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - M Moretti
- Department of Experimental, Diagnostic, and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - A Bertani
- Department of Gastroenterology, IBD Unit, Policlinico Hospital, Modena, Italy
| | - A Scarcelli
- Department of Gastroenterology, IBD Unit, Policlinico Hospital, Modena, Italy
| | - A Sartini
- Department of Gastroenterology, IBD Unit, Policlinico Hospital, Modena, Italy
| | - M Ercolani
- Department of Experimental, Diagnostic, and Specialty Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.,Department of Psychology, University of Bologna, Bologna, Italy
| | - P Nichelli
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - M Campieri
- Department of Clinical Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - F Benuzzi
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
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18
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Regueiro M, Greer JB, Szigethy E. Etiology and Treatment of Pain and Psychosocial Issues in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152:430-439.e4. [PMID: 27816599 DOI: 10.1053/j.gastro.2016.10.036] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 10/07/2016] [Accepted: 10/27/2016] [Indexed: 12/15/2022]
Abstract
There is increasing evidence that brain-gut interactions are altered during development of inflammatory bowel diseases (IBDs). Understanding the relationship between the neurobiology, psychological symptoms, and social ramifications of IBD can guide comprehensive care for the whole patient. The most common psychological conditions in patients with IBD are chronic abdominal pain, anxiety, and depression. We review the evidence-based data and rates of these conditions and their respective relationship to IBD and the diagnostic approaches to identify patients with these conditions. Different treatment options for pain and psychosocial conditions are discussed, and new models of team-based IBD care are introduced. Providing the health care provider with tools to diagnose and manage psychological conditions in patients with Crohn's disease or ulcerative colitis is necessary for their total care and should be part of quality-improvement initiatives.
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Affiliation(s)
- Miguel Regueiro
- Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Julia B Greer
- Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eva Szigethy
- Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
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19
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Altered Markers of Brain Development in Crohn's Disease with Extraintestinal Manifestations - A Pilot Study. PLoS One 2016; 11:e0163202. [PMID: 27655165 PMCID: PMC5031401 DOI: 10.1371/journal.pone.0163202] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Accepted: 09/06/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Alterations of brain morphology in Crohn's disease have been reported, but data is scarce and heterogenous and the possible impact of disease predisposition on brain development is unknown. Assuming a systemic course of the disease, brain involvement seems more probable in presence of extraintestinal manifestations, but this question has not yet been addressed. The present study examined the relationship between Crohn's disease and brain structure and focused on the connection with extraintestinal manifestations and markers of brain development. METHODS In a pilot study, brains of 15 patients with Crohn's disease (of which 9 had a history of extraintestinal manifestations, i.e. arthritis, erythema nodosum and primary sclerosing cholangitis) were compared to matched healthy controls using high resolution magnetic resonance imaging. Patients and controls were tested for depression, fatigue and global cognitive function. Cortical thickness, surface area and folding were determined via cortical surface modeling. RESULTS The overall group comparison (i.e. all patients vs. controls) yielded no significant results. In the patient subgroup with extraintestinal manifestations, changes in cortical area and folding, but not thickness, were identified: Patients showed elevated cortical surface area in the left middle frontal lobe (p<0.05) and hypergyrification in the left lingual gyrus (p<0.001) compared to healthy controls. Hypogyrification of the right insular cortex (p<0.05) and hypergyrification of the right anterior cingulate cortex (p<0.001) were detected in the subgroup comparison of patients with against without extraintestinal manifestations. P-values are corrected for multiple comparisons. CONCLUSIONS Our findings lend further support to the hypothesis that Crohn's disease is associated with aberrant brain structure and preliminary support for the hypothesis that these changes are associated with a systemic course of the disease as indicated by extraintestinal manifestations. Changes in cortical surface area and folding suggest a possible involvement of Crohn's disease or its predisposition during brain development.
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20
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From Pavlov to pain: How predictability affects the anticipation and processing of visceral pain in a fear conditioning paradigm. Neuroimage 2016; 130:104-114. [DOI: 10.1016/j.neuroimage.2016.01.064] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 11/24/2015] [Accepted: 01/16/2016] [Indexed: 01/19/2023] Open
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21
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Schmid J, Bingel U, Ritter C, Benson S, Schedlowski M, Gramsch C, Forsting M, Elsenbruch S. Neural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers. Neuroimage 2015; 120:114-22. [DOI: 10.1016/j.neuroimage.2015.06.060] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 06/17/2015] [Accepted: 06/20/2015] [Indexed: 12/16/2022] Open
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22
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Nan J, Liu J, Mu J, Zhang Y, Zhang M, Tian J, Liang F, Zeng F. Anatomically related gray and white matter alterations in the brains of functional dyspepsia patients. Neurogastroenterol Motil 2015; 27:856-64. [PMID: 25825020 DOI: 10.1111/nmo.12560] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 03/03/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND Previous studies summarized altered brain functional patterns in functional dyspepsia (FD) patients, but how the brain structural patterns are related to FD remains largely unclear. The objective of this study was to determine the brain structural characteristics in FD patients. METHODS Optimized voxel-based morphometry and tract-based spatial statistics were employed to investigate the changes in gray matter (GM) and white matter (WM) respectively in 34 FD patients with postprandial distress syndrome and 33 healthy controls based on T1-weighted and diffusion-weighted imaging. The Pearson's correlation evaluated the link among GM alterations, WM abnormalities, and clinical variables in FD patients. The optimal brain structural parameters for identifying FD were explored using the receiver operating characteristic curve. KEY RESULTS Compared to controls, FD patients exhibited a decrease in GM density (GMD) in the right posterior insula/temporal superior cortex (marked as pINS), right inferior frontal cortex (IFC), and left middle cingulate cortex, and an increase in fractional anisotropy (FA) in the posterior limb of the internal capsule, posterior thalamic radiation, and external capsule (EC). Interestingly, the GMD in the pINS was significantly associated with GMD in the IFC and FA in the EC. Moreover, the EC adjacent to the pINS provided the best performance for distinguishing FD patients from controls. CONCLUSIONS & INFERENCES Our results showed pINS-related structural abnormalities in FD patients, indicating that GM and WM parameters were not affected independently. These findings would lay the foundation for probing an efficient target in the brain for treating FD.
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Affiliation(s)
- J Nan
- School of Life Science and Technology, Xidian University, Xi'an, China
| | - J Liu
- School of Life Science and Technology, Xidian University, Xi'an, China
| | - J Mu
- School of Life Science and Technology, Xidian University, Xi'an, China
| | - Y Zhang
- School of Life Science and Technology, Xidian University, Xi'an, China
| | - M Zhang
- Department of Medical Imaging, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - J Tian
- School of Life Science and Technology, Xidian University, Xi'an, China
| | - F Liang
- The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - F Zeng
- The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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23
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Kennedy PJ, Clarke G, O‘Neill A, Groeger JA, Quigley EMM, Shanahan F, Cryan JF, Dinan TG. Cognitive performance in irritable bowel syndrome: evidence of a stress-related impairment in visuospatial memory. Psychol Med 2014; 44:1553-1566. [PMID: 23985155 PMCID: PMC3967841 DOI: 10.1017/s0033291713002171] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 07/30/2013] [Accepted: 08/04/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Central nervous system (CNS) dysfunction is a prominent feature of the functional gastrointestinal (GI) disorder, irritable bowel syndrome (IBS). However, the neurobiological and cognitive consequences of key pathophysiological features of IBS, such as stress-induced changes in hypothalamic-pituitary-adrenal (HPA)-axis functioning, is unknown. Our aim was to determine whether IBS is associated with cognitive impairment, independently of psychiatric co-morbidity, and whether cognitive performance is related to HPA-axis function. METHOD A cross-sectional sample of 39 patients with IBS, a disease control group of 18 patients with Crohn's disease (CD) in clinical remission and 40 healthy age- and IQ-matched control participants were assessed using the Paired Associates Learning (PAL), Intra-Extra Dimensional Set Shift (IED) and Spatial Working Memory (SWM) tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and a computerized Stroop test. HPA-axis function was determined by measuring the cortisol awakening response (CAR). RESULTS IBS patients exhibited a subtle visuospatial memory deficit at the PAL six- pattern stage (p = 0.03), which remained after psychiatric co-morbidity was controlled for (p = 0.04). Morning cortisol levels were lower in IBS (p = 0.04) and significantly associated with visuospatial memory performance within IBS only (p = 0.02). CONCLUSIONS For the first time, altered cognitive function on a hippocampal-mediated test of visuospatial memory, which was related to cortisol levels and independent of psychiatric co-morbidity, has been identified in IBS. Visuospatial memory impairment may be a common, but currently neglected, component of IBS. Further elucidation of the nature of this impairment may lead to a greater understanding of the underlying pathophysiology of IBS, and may provide novel therapeutic approaches.
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Affiliation(s)
- P. J. Kennedy
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
- Department of Psychiatry, University College Cork, Ireland
| | - G. Clarke
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
- Department of Psychiatry, University College Cork, Ireland
| | - A. O‘Neill
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
| | | | - E. M. M. Quigley
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
- Department of Medicine, University College Cork, Ireland
| | - F. Shanahan
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
- Department of Medicine, University College Cork, Ireland
| | - J. F. Cryan
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Ireland
| | - T. G. Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Ireland
- Department of Psychiatry, University College Cork, Ireland
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24
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Filipovic BR, Filipovic BF. Psychiatric comorbidity in the treatment of patients with inflammatory bowel disease. World J Gastroenterol 2014; 20:3552-3563. [PMID: 24707138 PMCID: PMC3974522 DOI: 10.3748/wjg.v20.i13.3552] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/20/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn’s disease, commonly known as inflammatory bowel disease (IBD), draw attention from specialists of various disorders, including gastroenterology, psychiatry, and radiology. The involvement of a cortical influence in the brain-gut axis as well as the interaction of the hypothalamic-pituitary-adrenal axis and the peripheral nervous system provide an initial explanation of the psychological symptoms associated with IBD. The involvement of structures the limbic system, such as the anterior cingulate cortex, the prefrontal cortex, and the amygdala, paves the way for the discovery of the mechanisms underlying depression depression, anxiety, alexithymia, personality traits, and other psychological impairments following the onset of IBD. Psychiatric therapy in IBD patients is almost as important as the gastroenterological approach and consists of pharmacological treatment and psychotherapy. Neither of the available psychiatric treatment methods is considered the golden standard because both methods have side effects, and psychotropic medication can provoke the worsening of IBD symptoms. Thus, both approaches must be applied with awareness of the possibility of side effects. We suggest that psychiatrists and gastroenterologists work together to reach a consensus on IBD therapy to ensure success and to reduce side effects and relapse to the lowest possible rates.
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