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Louwies T, Mohammadi E, Greenwood-Van Meerveld B. Epigenetic mechanisms underlying stress-induced visceral pain: Resilience versus vulnerability in a two-hit model of early life stress and chronic adult stress. Neurogastroenterol Motil 2023; 35:e14558. [PMID: 36893055 DOI: 10.1111/nmo.14558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/16/2022] [Accepted: 02/19/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND Women with a history of early life stress (ELS) have a higher risk of developing irritable bowel syndrome (IBS). In addition, chronic stress in adulthood can exacerbate IBS symptoms such as abdominal pain due to visceral hypersensitivity. We previously showed that sex and the predictability of ELS determine whether rats develop visceral hypersensitivity in adulthood. In female rats, unpredictable ELS confers vulnerability and results in visceral hypersensitivity, whereas predictable ELS induces resilience and does not induce visceral hypersensitivity in adulthood. However, this resilience is lost after exposure to chronic stress in adulthood leading to an exacerbation of visceral hypersensitivity. Evidence suggests that changes in histone acetylation at the promoter regions of glucocorticoid receptor (GR) and corticotrophin-releasing factor (CRF) in the central nucleus of the amygdala (CeA) underlie stress-induced visceral hypersensitivity. Here, we aimed to investigate the role of histone acetylation in the CeA on visceral hypersensitivity in a two-hit model of ELS followed by chronic stress in adulthood. METHODS Male and female neonatal rats were exposed to unpredictable, predictable ELS, or odor only (no stress control) from postnatal days 8 to 12. In adulthood, rats underwent stereotaxic implantation of indwelling cannulas. Rats were exposed to chronic water avoidance stress (WAS, 1 h/day for 7 days) or SHAM stress and received infusions of vehicle, the histone deacetylase inhibitor trichostatin A (TSA) or the histone acetyltransferase inhibitor garcinol (GAR) after each WAS session. 24 h after the final infusion, visceral sensitivity was assessed and the CeA was removed for molecular experiments. RESULTS In the two-hit model (ELS + WAS), female rats previously exposed to predictable ELS, showed a significant reduction in histone 3 lysine 9 (H3K9) acetylation at the GR promoter and a significant increase in H3K9 acetylation at the CRF promoter. These epigenetic changes were associated with changes in GR and CRF mRNA expression in the CeA and an exacerbation of stress-induced visceral hypersensitivity in female animals. TSA infusions in the CeA attenuated the exacerbated stress-induced visceral hypersensitivity, whereas GAR infusions only partially ameliorated ELS+WAS induced visceral hypersensitivity. CONCLUSION The two-hit model of ELS followed by WAS in adulthood revealed that epigenetic dysregulation occurs after exposure to stress in two important periods of life and contributes to the development of visceral hypersensitivity. These aberrant underlying epigenetic changes may explain the exacerbation of stress-induced abdominal pain in IBS patients.
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Affiliation(s)
- Tijs Louwies
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | - Ehsan Mohammadi
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
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Blin J, Gautier C, Aubert P, Durand T, Oullier T, Aymeric L, Naveilhan P, Masson D, Neunlist M, Bach-Ngohou K. Psychological stress induces an increase in cholinergic enteric neuromuscular pathways mediated by glucocorticoid receptors. Front Neurosci 2023; 17:1100473. [PMID: 36866332 PMCID: PMC9971731 DOI: 10.3389/fnins.2023.1100473] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
Introduction Repeated acute stress (RASt) is known to be associated with gastrointestinal dysfunctions. However, the mechanisms underlying these effects have not yet been fully understood. While glucocorticoids are clearly identified as stress hormones, their involvement in RASt-induced gut dysfunctions remains unclear, as does the function of glucocorticoid receptors (GR). The aim of our study was to evaluate the involvement of GR on RASt-induced changes in gut motility, particularly through the enteric nervous system (ENS). Methods Using a murine water avoidance stress (WAS) model, we characterized the impact of RASt upon the ENS phenotype and colonic motility. We then evaluated the expression of glucocorticoid receptors in the ENS and their functional impact upon RASt-induced changes in ENS phenotype and motor response. Results We showed that GR were expressed in myenteric neurons in the distal colon under basal conditions, and that RASt enhanced their nuclear translocation. RASt increased the proportion of ChAT-immunoreactive neurons, the tissue concentration of acetylcholine and enhanced cholinergic neuromuscular transmission as compared to controls. Finally, we showed that a GR-specific antagonist (CORT108297) prevented the increase of acetylcholine colonic tissue level and in vivo colonic motility. Discussion Our study suggests that RASt-induced functional changes in motility are, at least partly, due to a GR-dependent enhanced cholinergic component in the ENS.
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Affiliation(s)
- Justine Blin
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France,Nantes Université, CHU Nantes, Department of Biochemistry, Nantes, France,*Correspondence: Justine Blin,
| | - Camille Gautier
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France
| | - Philippe Aubert
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France
| | - Tony Durand
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France
| | - Thibauld Oullier
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France
| | - Laetitia Aymeric
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France,Université d’Angers, Department of Biology, Angers, France
| | - Philippe Naveilhan
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France
| | - Damien Masson
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France,Nantes Université, CHU Nantes, Department of Biochemistry, Nantes, France
| | - Michel Neunlist
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France,Michel Neunlist,
| | - Kalyane Bach-Ngohou
- Nantes Université, CHU Nantes, INSERM, The Enteric Nervous System in Gut and Brain Disorders, IMAD, Nantes, France,Nantes Université, CHU Nantes, Department of Biochemistry, Nantes, France,Kalyane Bach-Ngohou,
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Alam MJ, Chen JDZ. Electrophysiology as a Tool to Decipher the Network Mechanism of Visceral Pain in Functional Gastrointestinal Disorders. Diagnostics (Basel) 2023; 13:627. [PMID: 36832115 PMCID: PMC9955347 DOI: 10.3390/diagnostics13040627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 01/27/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
Abdominal pain, including visceral pain, is prevalent in functional gastrointestinal (GI) disorders (FGIDs), affecting the overall quality of a patient's life. Neural circuits in the brain encode, store, and transfer pain information across brain regions. Ascending pain signals actively shape brain dynamics; in turn, the descending system responds to the pain through neuronal inhibition. Pain processing mechanisms in patients are currently mainly studied with neuroimaging techniques; however, these techniques have a relatively poor temporal resolution. A high temporal resolution method is warranted to decode the dynamics of the pain processing mechanisms. Here, we reviewed crucial brain regions that exhibited pain-modulatory effects in an ascending and descending manner. Moreover, we discussed a uniquely well-suited method, namely extracellular electrophysiology, that captures natural language from the brain with high spatiotemporal resolution. This approach allows parallel recording of large populations of neurons in interconnected brain areas and permits the monitoring of neuronal firing patterns and comparative characterization of the brain oscillations. In addition, we discussed the contribution of these oscillations to pain states. In summary, using innovative, state-of-the-art methods, the large-scale recordings of multiple neurons will guide us to better understanding of pain mechanisms in FGIDs.
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Affiliation(s)
- Md Jahangir Alam
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jiande D. Z. Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
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Louwies T, Greenwood-Van Meerveld B. Chronic stress increases DNA methylation of the GR promoter in the central nucleus of the amygdala of female rats. Neurogastroenterol Motil 2022; 34:e14377. [PMID: 35411658 DOI: 10.1111/nmo.14377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/17/2022] [Accepted: 03/26/2022] [Indexed: 02/08/2023]
Abstract
The central pathophysiological mechanisms underlying irritable bowel syndrome (IBS), a female-predominant gastrointestinal disorder characterized by abdominal pain and abnormal bowel habits, remain poorly understood. IBS patients often report that chronic stress exacerbates their symptoms. Brain imaging studies have revealed that the amygdala, a stress-responsive brain region, of IBS patients is overactive when compared to healthy controls. Previously, we demonstrated that downregulation of the glucocorticoid receptor (GR) in the central nucleus of the amygdala (CeA) underlies stress-induced visceral hypersensitivity in female rats. In the current study, we aimed to evaluate in the CeA of female rats whether chronic water avoidance stress (WAS) alters DNA methylation of the GR exon 17 promoter region, a region homologous to the human GR promoter. As histone deacetylase (HDAC) inhibitors are able to change DNA methylation, we also evaluated whether administration of the HDAC inhibitor trichostatin A (TSA) directly into the CeA prevented WAS-induced increases in DNA methylation of the GR exon 17 promoter. We found that WAS increased overall and specific CpG methylation of the GR promoter in the CeA of female rats, which persisted for up to 28 days. Administration of the TSA directly into the CeA prevented these stress-induced changes of DNA methylation at the GR promoter. Our results suggest that, in females, changes in DNA methylation are involved in the regulation of GR expression in the CeA. These changes in DNA methylation may contribute to the central mechanisms responsible for stress-induced visceral hypersensitivity.
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Affiliation(s)
- Tijs Louwies
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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Cantu DJ, Kaur S, Murphy AZ, Averitt DL. Sex Differences in the Amygdaloid Projections to the Ventrolateral Periaqueductal Gray and Their Activation During Inflammatory Pain in the Rat. J Chem Neuroanat 2022; 124:102123. [PMID: 35738454 DOI: 10.1016/j.jchemneu.2022.102123] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/16/2022] [Accepted: 06/17/2022] [Indexed: 10/18/2022]
Abstract
Preclinical and clinical studies have reported sex differences in pain and analgesia. These differences may be linked to anatomical structures of the central nervous system pain modulatory circuitry, and/or hormonal milieu. The midbrain periaqueductal gray is a critical brain region for descending inhibition of pain. The PAG projects to the rostral ventromedial medulla (RVM), which projects bilaterally to the spinal cord to inhibit pain. In addition to pain, this descending circuit (or pathway) can be engaged by endogenous opioids (i.e., endorphins) or exogenous opioids (i.e., morphine), and we have previously reported sex differences in the activation of this circuit during pain and analgesia. Forebrain structures, including the amygdala, project to and engage the PAG-RVM circuit during persistent inflammatory pain. However, there are limited studies in females detailing this amygdalar-PAG pathway and its involvement during persistent inflammatory pain. The objective of the present study was to delineate the neural projections from the amygdala to the PAG in male and female rats to determine if they are sexually distinct in their anatomical organization. We also examined the activation of this pathway by inflammatory pain and the co-localization of receptors for estrogen. Injection of the retrograde tracer fluorogold (FG) into the ventrolateral PAG (vlPAG) resulted in dense retrograde labeling in both the central amygdala (CeA) and medial amygdala (MeA). While the number of CeA-vlPAG neurons were comparable between the sexes, there were more MeA-vlPAG neurons in females. Inflammatory pain resulted in greater activation of the amygdala in males; however, females displayed higher Fos expression within CeA-vlPAG projection neurons. Females expressed higher ERα in the MeA and CeA and the same was true of the projection neurons. Together, these data indicate that although the MeA-vlPAG projections are denser in females, inflammatory pain does not significantly activate these projections. In contrast, inflammatory pain resulted in a greater activation of the CeA-vlPAG pathway in females. As females experience a greater number of chronic pain syndromes, the CeA-vlPAG pathway may play a facilitatory (and not inhibitory) role in pain modulation.
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Affiliation(s)
- Daisy J Cantu
- Division of Biology, School of the Sciences, Texas Woman's University, Denton, TX 76204
| | - Sukhbir Kaur
- Division of Biology, School of the Sciences, Texas Woman's University, Denton, TX 76204
| | - Anne Z Murphy
- Neuroscience Institute, Georgia State University, Atlanta, GA 30303
| | - Dayna L Averitt
- Division of Biology, School of the Sciences, Texas Woman's University, Denton, TX 76204.
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Guan L, Shi X, Tang Y, Yan Y, Chen L, Chen Y, Gao G, Lin C, Chen A. Contribution of Amygdala Histone Acetylation in Early Life Stress-Induced Visceral Hypersensitivity and Emotional Comorbidity. Front Neurosci 2022; 16:843396. [PMID: 35600618 PMCID: PMC9120649 DOI: 10.3389/fnins.2022.843396] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 04/19/2022] [Indexed: 01/04/2023] Open
Abstract
Patients with irritable bowel syndrome (IBS) experience not only enhanced visceral pain but also emotional comorbidities, such as anxiety and depression. Early life stress (ELS) is a high-risk for the development of IBS. Literatures have reported an important epigenetic modulation in sustaining extrinsic phenotypes. The amygdala is closely related to the regulation of visceral functions and emotional experiences. In this study, we hypothesized that ELS-induced reprogramming inappropriate adaptation of histone acetylation modification in the amygdala may result in visceral hypersensitivity and anxiety-like behaviors in ELS rats. To test this hypothesis, the model of ELS rats was established by neonatal colorectal dilatation (CRD). Visceral hypersensitivity was assessed based on the electromyography response of the abdominal external oblique muscle to CRD. Emotional comorbidities were examined using the elevated plus maze test, open field test, and sucrose preference test. Trichostatin A (TSA) and C646 were microinjected into the central amygdala (CeA) individually to investigate the effects of different levels of histone acetylation modification on visceral hypersensitivity and emotion. We found neonatal CRD resulted in visceral hypersensitivity and anxiety-like behaviors after adulthood. Inhibiting histone deacetylases (HDACs) in the CeA by TSA enhanced visceral sensitivity but did not affect anxiety-like behaviors, whereas inhibiting HAT by C646 attenuated visceral hypersensitivity in ELS rats. Interestingly, CeA treatment with TSA induced visceral sensitivity and anxiety-like behaviors in the control rats. Western blot showed that the expressions of acetylated 9 residue of Histone 3 (H3K9) and protein kinase C zeta type (PKMζ) were higher in the ELS rats compared to those of the controls. The administration of the PKMζ inhibitor ZIP into the CeA attenuated visceral hypersensitivity of ELS rats. Furthermore, the expression of amygdala PKMζ was enhanced by TSA treatment in control rats. Finally, western blot and immunofluorescence results indicated the decrease of HDAC1 and HDAC2 expressions, but not HDAC3 expression, contributed to the enhancement of histone acetylation in ELS rats. Our results support our hypothesis that amygdala-enhanced histone acetylation induced by stress in early life results in visceral hypersensitivity and anxiety-like behaviors in ELS rats, and reversing the abnormal epigenetic mechanisms may be crucial to relieve chronic symptoms in ELS rats.
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Affiliation(s)
- Le Guan
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
| | - Xi Shi
- Department of Medical Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Ying Tang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
| | - Yan Yan
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
| | - Liang Chen
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
| | - Yu Chen
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
| | - Guangcheng Gao
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
| | - Chun Lin
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
- Department of Pediatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- *Correspondence: Chun Lin,
| | - Aiqin Chen
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Pain Research Institute, Fujian Medical University, Fuzhou, China
- Department of Medical Oncology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Aiqin Chen,
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Matisz C, Gruber A. Neuroinflammatory remodeling of the anterior cingulate cortex as a key driver of mood disorders in gastrointestinal disease and disorders. Neurosci Biobehav Rev 2022; 133:104497. [DOI: 10.1016/j.neubiorev.2021.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 11/10/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
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Yuan T, Orock A, Greenwood-VanMeerveld B. An enriched environment reduces chronic stress-induced visceral pain through modulating microglial activity in the central nucleus of the amygdala. Am J Physiol Gastrointest Liver Physiol 2022; 322:G223-G233. [PMID: 34877892 PMCID: PMC8793868 DOI: 10.1152/ajpgi.00307.2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Cognitive behavioral therapy (CBT) improves the quality of life for patients with brain-gut disorders; however, the underlying mechanisms of CBT remain to be explored. Previously, we showed that environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, ameliorates chronic stress-induced visceral hypersensitivity in a rodent model via mechanisms involving altered activity in the central nucleus of amygdala (CeA). In the present study, we investigated whether microglia-mediated synaptic plasticity in the CeA is a potential mechanism underlying the protective effects of EE against stress-induced visceral hypersensitivity. We stereotaxically implanted corticosterone (CORT) micropellets onto the dorsal margin of the CeA shown previously to induce colonic hypersensitivity. Animals were housed in EE cages or standard cages for 14 days after CORT implantation. Visceral sensitivity was assessed via visceromotor behavioral response to colorectal distension. Microglial morphology, microglia-mediated synaptic engulfment, and the expression of synaptic pruning-related signals complement component 1q (C1q), complement component 3 (C3), and C3 receptor (C3R) were measured using immunofluorescence and RNAscope assay. We found that housing CORT implanted rats in EE cages for 14 days attenuated visceral hypersensitivity in both male and female rats as compared with control rats maintained in standard housing. EE reduced CORT-induced microglial remodeling and microglia-mediated synaptic pruning with reduced C1q and CR3, but not C3, expression. Our data suggest that exposure to EE is sufficient to ameliorate stress-induced visceral pain via reducing amygdala microglia-modulated neuronal plasticity.NEW & NOTEWORTHY Clinical studies show that cognitive behavioral therapy (CBT) is effective in ameliorating visceral pain in patient with irritable bowel syndrome (IBS), yet the underlying mechanisms remain unexplored. By using environmental enrichment (EE), an experimental paradigm that mirrors positive behavioral intervention, we demonstrated that microglia-mediated synaptic plasticity in the CeA explains, plays a role, at least in part, in the positive effects of EE to reduce visceral hypersensitivity.
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Affiliation(s)
- Tian Yuan
- 1Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Albert Orock
- 1Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Beverley Greenwood-VanMeerveld
- 1Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma,2Oklahoma City Veterans Affairs Health Care System, Oklahoma City, Oklahoma
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Louwies T, Orock A, Greenwood-Van Meerveld B. Stress-induced visceral pain in female rats is associated with epigenetic remodeling in the central nucleus of the amygdala. Neurobiol Stress 2021; 15:100386. [PMID: 34584907 PMCID: PMC8456109 DOI: 10.1016/j.ynstr.2021.100386] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/23/2021] [Accepted: 08/28/2021] [Indexed: 12/19/2022] Open
Abstract
Stress and anxiety contribute to the pathophysiology of irritable bowel syndrome (IBS), a female-predominant disorder of the gut-brain axis, characterized by abdominal pain due to heightened visceral sensitivity. In the current study, we aimed to evaluate in female rats whether epigenetic remodeling in the limbic brain, specifically in the central nucleus of the amygdala (CeA), is a contributing factor in stress-induced visceral hypersensitivity. Our results showed that 1 h exposure to water avoidance stress (WAS) for 7 consecutive days decreased histone acetylation at the GR promoter and increased histone acetylation at the CRH promoter in the CeA. Changes in histone acetylation were mediated by the histone deacetylase (HDAC) SIRT-6 and the histone acetyltransferase CBP, respectively. Administration of the HDAC inhibitor trichostatin A (TSA) into the CeA prevented stress-induced visceral hypersensitivity through blockade of SIRT-6 mediated histone acetylation at the GR promoter. In addition, HDAC inhibition within the CeA prevented stress-induced histone acetylation of the CRH promoter. Our results suggest that, in females, epigenetic modifications in the limbic brain regulating GR and CRH expression contribute to stress-induced visceral hypersensitivity and offer a potential explanation of how stress can trigger symptoms in IBS patients.
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Affiliation(s)
- Tijs Louwies
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Albert Orock
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Beverley Greenwood-Van Meerveld
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma City VA Medical Center, Oklahoma City, OK, USA
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Lyubashina OA, Sivachenko IB, Busygina II. Amygdalofugal Modulation of Visceral Nociceptive Transmission in the Rat Caudal Ventrolateral Medulla under Normal Conditions and Intestinal Inflammation. J EVOL BIOCHEM PHYS+ 2021. [DOI: 10.1134/s0022093021050161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Orock A, Louwies T, Yuan T, Greenwood-Van Meerveld B. Environmental enrichment prevents chronic stress-induced brain-gut axis dysfunction through a GR-mediated mechanism in the central nucleus of the amygdala. Neurogastroenterol Motil 2020; 32:e13826. [PMID: 32084303 PMCID: PMC7906280 DOI: 10.1111/nmo.13826] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 02/04/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cognitive behavioral therapy (CBT) improves quality of life of patients with irritable bowel syndrome (IBS), a disorder characterized by chronic visceral pain and abnormal bowel habits. Whether CBT can actually improve visceral pain in IBS patients is still unknown. The aim of this study is to evaluate whether environment enrichment (EE), the animal analog of CBT, can prevent stress-induced viscero-somatic hypersensitivity through changes in glucocorticoid receptor (GR) signaling within the central nucleus of the amygdala (CeA). METHODS Rats were housed in either standard housing (SH) or EE for 7 days before and during daily water avoidance stress (WAS) exposure (1-h/d for 7 days). In the first cohort, visceral and somatic sensitivity were assessed via visceromotor response to colorectal distention and von Frey Anesthesiometer 24 hous and 21 days after WAS. In another cohort, the CeA was isolated for GR mRNA quantification. KEY RESULTS Environment enrichment for 7 days before and during the 7 days of WAS persistently attenuated visceral and somatic hypersensitivity when compared to rats placed in SH. Environment enrichment exposure also prevented the WAS-induced decrease in GR expression in the CeA. CONCLUSION & INFERENCES Pre-exposure to short-term EE prevents the stress-induced downregulation of GR, and inhibits visceral and somatic hypersensitivity induced by chronic stress. These results suggest that a positive environment can ameliorate stress-induced pathology and provide a non-pharmacological therapeutic option for disorders such as IBS.
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Affiliation(s)
- A Orock
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - T Louwies
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - T Yuan
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - B Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK,,Department of Veterans Affairs Health Care System, Oklahoma City, OK.,Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Louwies T, Greenwood-Van Meerveld B. Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress. Neurogastroenterol Motil 2020; 32:e13751. [PMID: 31667916 PMCID: PMC8628638 DOI: 10.1111/nmo.13751] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 09/11/2019] [Accepted: 09/28/2019] [Indexed: 01/28/2023]
Abstract
BACKGROUND We previously reported that early life stress (ELS) dysregulated glucocorticoid receptor (GR) and corticotrophin-releasing hormone (CRH) expression in the central nucleus of the amygdala (CeA). Epigenetic modifications serve as memories of adverse events that occurred during early life. Therefore, we hypothesized that epigenetic mechanisms alter GR and CRH expression in the CeA and underlie chronic visceral pain after ELS. METHODS Neonatal rats were exposed to unpredictable, predictable ELS, or odor only (no stress control) from postnatal days 8 to 12. In adulthood, visceral sensitivity was assessed or the CeA was isolated for Western blot or ChiP-qPCR to study histone modifications at the GR and CRH promoters. Female adult rats underwent stereotaxic implantation of indwelling cannulas for microinjections of garcinol (HAT inhibitor) into the CeA. After 7 days of microinjections, visceral sensitivity was assessed or the CeA was isolated for ChIP-qPCR assays. RESULTS Unpredictable ELS increased visceral sensitivity in adult female rats, but not in male counterparts. ELS increased histone 3 lysine 9 (H3K9) acetylation in the CeA and H3K9 acetylation levels at the GR promoter in the CeA of adult female rats. After unpredictable ELS, H3K9 acetylation was increased and GR binding was decreased at the CRH promoter. Administration of garcinol in the CeA of adult females, that underwent unpredictable ELS, normalized H3K9 acetylation and restored GR binding at the CRH promoter. CONCLUSION Dysregulated histone acetylation and GR binding at the CRH promoter in the CeA are an important mechanism for "memorizing" ELS events mediating visceral pain in adulthood.
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Affiliation(s)
- Tijs Louwies
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Beverley Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA,Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA,VA Medical Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Insula Activity to Visceral Stimulation and Endocrine Stress Responses as Associated With Alexithymia in Patients With Irritable Bowel Syndrome. Psychosom Med 2020; 82:29-38. [PMID: 31609924 DOI: 10.1097/psy.0000000000000729] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Few studies have investigated associations between alexithymia and physiological mechanisms in psychosomatic diseases. We examined associations between alexithymia and 1) perception and brain processing of visceral stimulation and 2) the endocrine responses to corticotrophin-releasing hormone (CRH) in healthy individuals and patients with irritable bowel syndrome (IBS). METHODS The study included 29 patients with IBS and 35 age- and sex-matched healthy controls (HCs). Alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Brain responses to rectal distention and its anticipation were measured by functional magnetic resonance imaging and analyzed at a voxel-level threshold of puncorrected < .001 combined with a cluster-level threshold of pFWE-corrected < .05. On a different day, plasma adrenocorticotropic hormone and cortisol responses after intravenous CRH administration were measured. RESULTS TAS-20 scores did not differ significantly between patients with IBS and HCs (p = .18). TAS-20 scores correlated positively with the individual rectal discomfort thresholds (βrobust = 0.49, p = .03) and negatively with the rating of fear before rectal distention (βrobust = -1.63, p = .04) in patients with IBS but not in HCs. Brain responses to rectal distention in the right insula and other brain regions were positively associated with TAS-20 scores to a greater extent in patients with IBS than in HCs. Individuals with higher TAS-20 scores (both patients with IBS and HCs) demonstrated stronger adrenocorticotropic hormone responses to CRH administration (F(4,224) = 3.54, p = .008). CONCLUSION Higher alexithymia scores are associated with stronger physiological responses, but lower anticipatory fear ratings and higher discomfort thresholds, particularly in patients with IBS.
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Bonaz B, Sinniger V, Pellissier S. Vagus Nerve Stimulation at the Interface of Brain-Gut Interactions. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a034199. [PMID: 30201788 DOI: 10.1101/cshperspect.a034199] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The vagus nerve, a key component of the cross-communication between the gut and the brain, is a major element of homeostasis sensing the "milieu intérieur" and boosting the nervous and endocrine responses to maintain the gastrointestinal health status. This nerve has anti-inflammatory properties regulating the gut through the activation of the hypothalamic-pituitary-adrenal axis and the release of cortisol and through a vagovagal reflex, which has an anti-tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway. Stimulating this nerve is an interesting tool as a nondrug therapy for the treatment of gastrointestinal diseases in which brain-gut communication is dysfunctional, such as inflammatory bowel disorders and others. This review presents the rationale of vagal gastrointestinal physiology and diseases and the most recent advances in vagus nerve stimulation. It also highlights the main issues to be addressed in the future to improve this bioelectronic therapy for gastrointestinal disorders.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato-Gastroenterology, Grenoble University Hospital, 38043 Grenoble Cedex 09, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Valérie Sinniger
- Division of Hepato-Gastroenterology, Grenoble University Hospital, 38043 Grenoble Cedex 09, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Sonia Pellissier
- University Grenoble Alpes, University Savoie Mont Blanc, 38000 Grenoble, France
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Fakhfouri G, Rahimian R, Dyhrfjeld-Johnsen J, Zirak MR, Beaulieu JM. 5-HT 3 Receptor Antagonists in Neurologic and Neuropsychiatric Disorders: The Iceberg Still Lies beneath the Surface. Pharmacol Rev 2019; 71:383-412. [PMID: 31243157 DOI: 10.1124/pr.118.015487] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
5-HT3 receptor antagonists, first introduced to the market in the mid-1980s, are proven efficient agents to counteract chemotherapy-induced emesis. Nonetheless, recent investigations have shed light on unappreciated dimensions of this class of compounds in conditions with an immunoinflammatory component as well as in neurologic and psychiatric disorders. The promising findings from multiple studies have unveiled several beneficial effects of these compounds in multiple sclerosis, stroke, Alzheimer disease, and Parkinson disease. Reports continue to uncover important roles for 5-HT3 receptors in the physiopathology of neuropsychiatric disorders, including depression, anxiety, drug abuse, and schizophrenia. This review addresses the potential of 5-HT3 receptor antagonists in neurology- and neuropsychiatry-related disorders. The broad therapeutic window and high compliance observed with these agents position them as suitable prototypes for the development of novel pharmacotherapeutics with higher efficacy and fewer adverse effects.
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Affiliation(s)
- Gohar Fakhfouri
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Reza Rahimian
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Jonas Dyhrfjeld-Johnsen
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Mohammad Reza Zirak
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
| | - Jean-Martin Beaulieu
- Department of Psychiatry and Neuroscience, Faculty of Medicine, CERVO Brain Research Centre, Laval University, Quebec, Quebec, Canada (G.F., R.R.); Sensorion SA, Montpellier, France (J.D.-J.); Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran (M.R.Z.); and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada (J.-M.B.)
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Toossi V, Zivaljevic A, Shi B, S. Tam E. Treatment of visceral pain associated with irritable bowel syndrome using acupuncture: Mechanism of action. WORLD JOURNAL OF TRADITIONAL CHINESE MEDICINE 2019. [DOI: 10.4103/wjtcm.wjtcm_24_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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17
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Sugawara N, Sato K, Takahashi I, Satake R, Fukuda S, Nakaji S, Yasui-Furukori N. Irritable bowel syndrome and quality of life in a community-dwelling population in Japan. Int J Psychiatry Med 2018; 53:159-170. [PMID: 29280689 DOI: 10.1177/0091217417749791] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objective Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and is characterized by recurrent abdominal pain or abnormal defecation. This investigation evaluated the relationship between IBS and self-reported quality of life in a community-dwelling population in Japan. Methods For this cross-sectional survey, we enrolled 1002 volunteers who participated in the Iwaki Health Promotion Project in 2013. IBS symptoms were evaluated using the criteria from the Japanese version of the Rome III Questionnaire. The assessments included an interview to obtain sociodemographic data, the second version of the Short-Form Health Survey (SF-36), and the Center for Epidemiologic Studies Depression Scale. Multiple regression analysis was used to assess the relationship between IBS symptoms and scores on the SF-36. Results A total of 59 subjects (5.9%) were classified as having IBS. Scores for all eight domains of the SF-36, the physical component summary, and the mental component summary were significantly and negatively associated with the Center for Epidemiologic Studies Depression scores. Physical functioning, role physical, vitality, mental health, and physical component summary scores were significantly and negatively associated with IBS. Conclusions The burden of IBS symptoms affects both physical and mental wellbeing, even after adjusting for confounders. Our findings suggest that screening for IBS symptoms and evaluating the need for medical care is important for community health workers.
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Affiliation(s)
- Norio Sugawara
- 1 Department of Clinical Epidemiology, Translational Medical Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.,2 Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Ken Sato
- 3 Department of Gastroenterology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Ippei Takahashi
- 4 Department of Social Medicine, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Ryu Satake
- 3 Department of Gastroenterology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Shinsaku Fukuda
- 3 Department of Gastroenterology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Shigeyuki Nakaji
- 4 Department of Social Medicine, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
| | - Norio Yasui-Furukori
- 2 Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
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18
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Mugie SM, Koppen IJN, van den Berg MM, Groot PFC, Reneman L, de Ruiter MB, Benninga MA. Brain processing of rectal sensation in adolescents with functional defecation disorders and healthy controls. Neurogastroenterol Motil 2018; 30. [PMID: 28975729 DOI: 10.1111/nmo.13228] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 09/14/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Decreased sensation of urge to defecate is often reported by children with functional constipation (FC) and functional nonretentive fecal incontinence (FNRFI). The aim of this cross-sectional study was to evaluate cerebral activity in response to rectal distension in adolescents with FC and FNRFI compared with healthy controls (HCs). METHODS We included 15 adolescents with FC, 10 adolescents with FNRFI, and 15 young adult HCs. Rectal barostat was performed prior to functional magnetic resonance imaging (fMRI) to determine individual pressure thresholds for urge sensation. Subjects received 2 sessions of 5 × 30 seconds of barostat stimulation during the acquisition of blood oxygenation level-dependent fMRI. Functional magnetic resonance imaging signal differences were analyzed using SPM8 in Matlab. KEY RESULTS Functional constipation and FNRFI patients had higher thresholds for urgency than HCs (P < .001). During rectal distension, FC patients showed activation in the anterior cingulate cortex, dorsolateral prefrontal cortex, inferior parietal lobule, and putamen. No activations were observed in controls and FNRFI patients. Functional nonretentive fecal incontinence patients showed deactivation in the hippocampus, parahippocampal gyrus, fusiform gyrus (FFG), lingual gyrus, posterior parietal cortex, and precentral gyrus. In HCs, deactivated areas were detected in the hippocampus, amygdala, FFG, insula, thalamus, precuneus, and primary somatosensory cortex. In contrast, no regions with significant deactivation were detected in FC patients. CONCLUSIONS & INFERENCES Children with FC differ from children with FNRFI and HCs with respect to patterns of cerebral activation and deactivation during rectal distension. Functional nonretentive fecal incontinence patients seem to resemble HCs when it comes to brain processing of rectal distension.
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Affiliation(s)
- S M Mugie
- Department of Pediatric Gastroenterology and Nutrition, Academic Medical Center, Emma Children's Hospital, Amsterdam, The Netherlands
| | - I J N Koppen
- Department of Pediatric Gastroenterology and Nutrition, Academic Medical Center, Emma Children's Hospital, Amsterdam, The Netherlands
| | - M M van den Berg
- Department of Pediatrics, Haaglanden Medical Centre, The Hague, The Netherlands
| | - P F C Groot
- Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
| | - L Reneman
- Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
| | - M B de Ruiter
- Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
| | - M A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Academic Medical Center, Emma Children's Hospital, Amsterdam, The Netherlands
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Radovanovic-Dinic B, Tesic-Rajkovic S, Grgov S, Petrovic G, Zivkovic V. Irritable bowel syndrome - from etiopathogenesis to therapy. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:1-9. [PMID: 29358788 DOI: 10.5507/bp.2017.057] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 12/12/2017] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic and relapsing functional gastrointestinal disorder that affects 9-23% of the population across the world. Patients with IBS are often referred to gastroenterology, undergo various investigations, take various medicines, take time off work and have a poor quality of life. The pathophysiology of IBS is not yet completely understood and seems to be multifactorial. Many pathogenetic factors, in various combinations, and not all necessarily present in each patient, can play an important role. Discomfort or abdominal pain relieived by defacation, asociated with a change in stool form, is a typical clinical manifestation of IBS. Many factors, such as emotional stress and eating, may exacerbate the symptoms. A timely diagnosis of IBS is important so that treatment which will provide adequate symptomatic relief (diarrhoea, constipation, pain and boaring) can be introduced. The diagnosis of IBS is not confirmed by a specific test or structural abnormality. It is made using criteria based on clinical symptoms such as Rome criteria, unless the symptoms are thought to be atypical. Today the Rome Criteria IV is the current gold-standard for the diagnoses of IBS. Treatment of patients with IBS requires a multidisciplinary approach. Some patients respond well to non-pharmacological treatment, while others also require pharmacological treatment. This review will provide a summary of pathophysiology, diagnostic criteria and therapies for IBS.
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Affiliation(s)
- Biljana Radovanovic-Dinic
- Clinic for Gastroenterology and Hepatology, Clinical Centre Nis, Serbia.,Faculty of Medicine, University of Nis, Serbia
| | | | | | - Gordana Petrovic
- Clinic for Gastroenterology and Hepatology, Clinical Centre Nis, Serbia
| | - Valentina Zivkovic
- Faculty of Medicine, University of Nis, Serbia.,Institute for Treatment and Rehabilitation, Niska Banja, Serbia
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20
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Abstract
The amygdala is a limbic brain region that plays a key role in emotional processing, neuropsychiatric disorders, and the emotional-affective dimension of pain. Preclinical and clinical studies have identified amygdala hyperactivity as well as impairment of cortical control mechanisms in pain states. Hyperactivity of basolateral amygdala (BLA) neurons generates enhanced feedforward inhibition and deactivation of the medial prefrontal cortex (mPFC), resulting in pain-related cognitive deficits. The mPFC sends excitatory projections to GABAergic neurons in the intercalated cell mass (ITC) in the amygdala, which project to the laterocapsular division of the central nucleus of the amygdala (CeLC; output nucleus) and serve gating functions for amygdala output. Impairment of these cortical control mechanisms allows the development of amygdala pain plasticity. Mechanisms of abnormal amygdala activity in pain with particular focus on loss of cortical control mechanisms as well as new strategies to correct pain-related amygdala dysfunction will be discussed in the present review.
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21
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Guleria A, Karyampudi A, Singh R, Khetrapal CL, Verma A, Ghoshal UC, Kumar D. Mapping of Brain Activations to Rectal Balloon Distension Stimuli in Male Patients with Irritable Bowel Syndrome Using Functional Magnetic Resonance Imaging. J Neurogastroenterol Motil 2017; 23:415-427. [PMID: 28192648 PMCID: PMC5503292 DOI: 10.5056/jnm16148] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/25/2016] [Accepted: 12/26/2016] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Irritable bowel syndrome (IBS) is associated with exaggerated cerebral response including emotional processing following visceral stimulation; though data on this issue is available in female IBS patients, it is scanty among males. Hence, we aimed to study brain response of male IBS patients following rectal balloon distension as compared to healthy controls using functional magnetic resonance imaging (fMRI). Data between diarrhea and constipation predominant IBS (IBS-D and IBS-C) were also compared. Methods Rectal balloon distension threshold was assessed in 20 male IBS patients (10 IBS-C and 10 IBS-D) and 10 age-matched male healthy controls. Subsequently, fMRI on all the participants was performed at their respective rectal pain threshold. The fMRI data were analysed using the Statistical Parametric Mapping software. Results IBS patients showed greater cerebral activations in insula, middle temporal gyrus, and cerebellum in the left hemisphere compared to healthy controls. Neural activation was found in bilateral precuneus/superior parietal lobules in controls but not in patients with IBS. The brain activation differed among IBS-C and IBS-D patients; while the right mid-cingulate cortex was activated in IBS-C, the left inferior orbito-frontal cortex, left calcarine, and bilateral fusiform gyri were activated among patients with IBS-D following rectal balloon distension. Conclusions Brain response to rectal balloon distension differed among male patients with IBS and controls and among patients with IBS-C and IBS-D. Differential activation among patients with IBS-C and IBS-D was seen in the brain regions controlling affective motivation, homeostatic emotions, and autonomic responses to pain.
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Affiliation(s)
- Anupam Guleria
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Arun Karyampudi
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Rajan Singh
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Chunni L Khetrapal
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
| | - Abhai Verma
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Dinesh Kumar
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, Uttar Pradesh, India
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22
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Lee IS, Preissl H, Enck P. How to Perform and Interpret Functional Magnetic Resonance Imaging Studies in Functional Gastrointestinal Disorders. J Neurogastroenterol Motil 2017; 23:197-207. [PMID: 28256119 PMCID: PMC5383114 DOI: 10.5056/jnm16196] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 12/19/2016] [Indexed: 12/20/2022] Open
Abstract
Functional neuroimaging studies have revealed the importance of the role of cognitive and psychological factors and the dysregulation of the brain-gut axis in functional gastrointestinal disorder patients. Although only a small number of neuroimaging studies have been conducted in functional gastrointestinal disorder patients, and despite the fact that the neuroimaging technique requires a high level of knowledge, the technique still has a great deal of potential. The application of functional magnetic resonance imaging (fMRI) technique in functional gastrointestinal disorders should provide novel methods of diagnosing and treating patients. In this review, basic knowledge and technical/practical issues of fMRI will be introduced to clinicians.
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Affiliation(s)
- In-Seon Lee
- Psychosomatic Medicine and Psychotherapy Department, University of Tübingen, Tübingen, Germany.,Graduate Training Centre of Neuroscience, International Max Planck Research School, University of Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.,Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany
| | - Paul Enck
- Psychosomatic Medicine and Psychotherapy Department, University of Tübingen, Tübingen, Germany
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23
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Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood‐Van Meerveld B, Cryan JF. Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome. CNS Neurosci Ther 2016; 22:102-17. [PMID: 26662472 PMCID: PMC6492884 DOI: 10.1111/cns.12490] [Citation(s) in RCA: 253] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 11/05/2015] [Accepted: 11/05/2015] [Indexed: 02/06/2023] Open
Abstract
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.
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Affiliation(s)
- Rachel D. Moloney
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Present address:
Oklahoma Center for NeuroscienceUniversity of Oklahoma Health Science CenterOklahoma CityOKUSA
| | - Anthony C. Johnson
- Oklahoma Center for NeuroscienceUniversity of Oklahoma Health Science CenterOklahoma CityOKUSA
| | - Siobhain M. O'Mahony
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Department of Anatomy and NeuroscienceUniversity College CorkCorkIreland
| | - Timothy G. Dinan
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Department of Psychiatry and Neurobehavioural ScienceUniversity College CorkCorkIreland
| | - Beverley Greenwood‐Van Meerveld
- Oklahoma Center for NeuroscienceUniversity of Oklahoma Health Science CenterOklahoma CityOKUSA
- V.A. Medical CenterOklahoma CityOKUSA
| | - John F. Cryan
- Laboratory of NeurogastroenterologyAPC Microbiome InstituteUniversity College CorkCorkIreland
- Department of Anatomy and NeuroscienceUniversity College CorkCorkIreland
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Abstract
Accumulating evidence suggests an important contribution of reactive oxygen species (ROS) to pain and neuropsychiatric disorders, but their role in pain-related plasticity in the brain is largely unknown. Neuroplasticity in the central nucleus of the amygdala (CeA) correlates positively with pain behaviors in different models. Little is known, however, about mechanisms of visceral pain-related amygdala changes. The electrophysiological and behavioral studies reported here addressed the role of ROS in the CeA in a visceral pain model induced by intracolonic zymosan. Vocalizations to colorectal distension and anxiety-like behavior increased after intracolonic zymosan and were inhibited by intra-CeA application of a ROS scavenger (tempol, a superoxide dismutase mimetic). Tempol also induced a place preference in zymosan-treated rats but not in controls. Single-unit recordings of CeA neurons in anesthetized rats showed increases of background activity and responses to visceral stimuli after intracolonic zymosan. Intra-CeA application of tempol inhibited the increased activity but had no effect under normal conditions. Whole-cell patch-clamp recordings of CeA neurons in brain slices from zymosan-treated rats showed that tempol decreased neuronal excitability and excitatory synaptic transmission of presumed nociceptive inputs from the brainstem (parabrachial area) through a combination of presynaptic and postsynaptic actions. Tempol had no effect in brain slices from sham controls. The results suggest that ROS contribute to visceral pain-related hyperactivity of amygdala neurons and amygdala-dependent behaviors through a mechanism that involves increased excitatory transmission and excitability of CeA neurons.
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26
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Hungin APS, Becher A, Cayley B, Heidelbaugh JJ, Muris JWM, Rubin G, Seifert B, Russell A, De Wit NJ. Irritable bowel syndrome: an integrated explanatory model for clinical practice. Neurogastroenterol Motil 2015; 27:750-63. [PMID: 25703486 DOI: 10.1111/nmo.12524] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 01/13/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Although irritable bowel syndrome (IBS) is a symptom-based diagnosis, clinicians' management of and communication about the disorder is often hampered by an unclear conceptual understanding of the nature of the problem. We aimed to elucidate an integrated explanatory model (EM) for IBS from the existing literature for pragmatic use in the clinical setting. METHODS Systematic and exploratory literature searches were performed in PubMed to identify publications on IBS and EMs. KEY RESULTS The searches did not identify a single, integrated EM for IBS. However, three main hypotheses were elucidated that could provide components with which to develop an IBS EM: (i) altered peripheral regulation of gut function (including sensory and secretory mechanisms); (ii) altered brain-gut signaling (including visceral hypersensitivity); and (iii) psychological distress. Genetic polymorphisms and epigenetic changes may, to some degree, underlie the etiology and pathophysiology of IBS and could increase the susceptibility to developing the disorder. The three model components also fit into one integrated explanation for abdominal symptoms and changes in stool habit. Additionally, IBS may share a common pathophysiological mechanism with other associated functional syndromes. CONCLUSIONS & INFERENCES It was possible to elucidate an integrated, three-component EM as a basis for clinicians to conceptualize the nature of IBS, with the potential to contribute to better diagnosis and management, and dialog with sufferers.
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Affiliation(s)
- A P S Hungin
- School of Medicine, Pharmacy and Health, Durham University, Stockton-on-Tees, UK
| | - A Becher
- School of Medicine, Pharmacy and Health, Durham University, Stockton-on-Tees, UK.,Research and Evaluation Unit, Oxford PharmaGenesis Ltd, Oxford, UK
| | - B Cayley
- Department of Family Medicine, University of Wisconsin, Madison, WI, USA
| | - J J Heidelbaugh
- Departments of Family Medicine and Urology, Medical School, University of Michigan, Ann Arbor, MI, USA
| | - J W M Muris
- Department of Family Medicine, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
| | - G Rubin
- School of Medicine, Pharmacy and Health, Durham University, Stockton-on-Tees, UK
| | - B Seifert
- Institute of General Practice, Charles University, Praha, Czech Republic
| | - A Russell
- Department of Anthropology, Durham University, Durham, UK
| | - N J De Wit
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
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Knockdown of steroid receptors in the central nucleus of the amygdala induces heightened pain behaviors in the rat. Neuropharmacology 2015; 93:116-23. [PMID: 25656477 DOI: 10.1016/j.neuropharm.2015.01.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 11/25/2014] [Accepted: 01/21/2015] [Indexed: 01/25/2023]
Abstract
Previously we demonstrated that exposure of the central nucleus of the amygdala (CeA) to elevated corticosterone (CORT) induces nociceptive behaviors that are reversed by glucocorticoid and/or mineralocorticoid (GR/MR) receptor antagonism. Here we test the hypothesis that in a cholesterol (CHOL)-implanted control rat, selective knockdown of GR/MR in the CeA would, via a corticotropin-releasing factor (CRF)-mediated mechanism, replicate the nociceptive behaviors produced by elevated amygdala CORT. Micropellets of CHOL or CORT were stereotaxically placed on the dorsal margin of the CeA. Cannulae were implanted into the CeA for the delivery of vehicle or oligodeoxynucleotide (ODN) of either antisense (ASO) or random sequences (RSO) targeting GR or MR. Visceromotor behavioral response quantified visceral sensitivity in response to colonic distension, while von Frey filaments assessed somatic sensitivity. Receptor expression was determined with qRT-PCR. In CHOL implanted controls, knockdown of GR in the CeA increased both colonic and somatic sensitivity, whereas selective knockdown of MR in the CeA induced colonic hypersensitivity without affecting somatic sensitivity. CRF expression in the CeA was increased in CHOL-implanted rats treated with GR or MR ASO and resembled the augmented CRF expression seen in the CORT-implanted rats. This is the first study to demonstrate that decreasing either GR or MR within the CeA is sufficient to induce visceral hypersensitivity whereas somatic hypersensitivity developed after only GR knockdown. The loss of either GR or MR was associated with an increased CRF expression, and may represent a common mechanism for the development of CeA-mediated nociceptive behaviors.
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Rubio A, Van Oudenhove L, Pellissier S, Ly HG, Dupont P, Lafaye de Micheaux H, Tack J, Dantzer C, Delon-Martin C, Bonaz B. Uncertainty in anticipation of uncomfortable rectal distension is modulated by the autonomic nervous system--a fMRI study in healthy volunteers. Neuroimage 2014; 107:10-22. [PMID: 25479021 DOI: 10.1016/j.neuroimage.2014.11.043] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 10/17/2014] [Accepted: 11/20/2014] [Indexed: 12/23/2022] Open
Abstract
The human brain responds both before and during the application of aversive stimuli. Anticipation allows the organism to prepare its nociceptive system to respond adequately to the subsequent stimulus. The context in which an uncomfortable stimulus is experienced may also influence neural processing. Uncertainty of occurrence, timing and intensity of an aversive event may lead to increased anticipatory anxiety, fear, physiological arousal and sensory perception. We aimed to identify, in healthy volunteers, the effects of uncertainty in the anticipation of uncomfortable rectal distension, and the impact of the autonomic nervous system (ANS) activity and anxiety-related psychological variables on neural mechanisms of anticipation of rectal distension using fMRI. Barostat-controlled uncomfortable rectal distensions were preceded by cued uncertain or certain anticipation in 15 healthy volunteers in a fMRI protocol at 3T. Electrocardiographic data were concurrently registered by MR scanner. The low frequency (LF)-component of the heart rate variability (HRV) time-series was extracted and inserted as a regressor in the fMRI model ('LF-HRV model'). The impact of ANS activity was analyzed by comparing the fMRI signal in the 'standard model' and in the 'LF-HRV model' across the different anticipation and distension conditions. The scores of the psychological questionnaires and the rating of perceived anticipatory anxiety were included as covariates in the fMRI data analysis. Our experiments led to the following key findings: 1) the subgenual anterior cingulate cortex (sgACC) is the only activation site that relates to uncertainty in healthy volunteers and is directly correlated to individual questionnaire score for pain-related anxiety; 2) uncertain anticipation of rectal distension involved several relevant brain regions, namely activation of sgACC and medial prefrontal cortex and deactivation of amygdala, insula, thalamus, secondary somatosensory cortex, supplementary motor area and cerebellum; 3) most of the brain activity during anticipation, but not distension, is associated with activity of the central autonomic network. This approach could be applied to study the ANS impact on brain activity in various pathological conditions, namely in patients with chronic digestive conditions characterized by visceral discomfort and ANS imbalance such as irritable bowel syndrome or inflammatory bowel diseases.
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Affiliation(s)
- Amandine Rubio
- INSERM, U836, F-38000 Grenoble, France; Univ. Grenoble Alpes, GIN, F-38000 Grenoble, France; CHU de Grenoble, Clinique Universitaire de Pédiatrie, F-38000 Grenoble, France.
| | - Lukas Van Oudenhove
- University Psychiatric Centre, Liaison Psychiatry, University Hospital Gasthuisberg, B-3000 Leuven, Belgium; Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Diseases, University of Leuven, B-3000 Leuven, Belgium
| | - Sonia Pellissier
- INSERM, U836, F-38000 Grenoble, France; Univ. Grenoble Alpes, GIN, F-38000 Grenoble, France; Univ. Savoie, F-73000 Chambery, France
| | - Huynh Giao Ly
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Diseases, University of Leuven, B-3000 Leuven, Belgium
| | - Patrick Dupont
- University Psychiatric Centre, Liaison Psychiatry, University Hospital Gasthuisberg, B-3000 Leuven, Belgium; Laboratory for Cognitive Neurology, KU Leuven, B-3000 Leuven, Belgium; Medical Imaging Research Centre, KU Leuven, B-3000 Leuven, Belgium
| | | | - Jan Tack
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Diseases, University of Leuven, B-3000 Leuven, Belgium
| | | | - Chantal Delon-Martin
- INSERM, U836, F-38000 Grenoble, France; Univ. Grenoble Alpes, GIN, F-38000 Grenoble, France
| | - Bruno Bonaz
- INSERM, U836, F-38000 Grenoble, France; Univ. Grenoble Alpes, GIN, F-38000 Grenoble, France; Clinique Universitaire d'Hépato-Gastroentérologie, CHU de Grenoble, Hôpital Albert Michallon, F-38000 Grenoble, France
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Kleinstäuber M, Witthöft M, Steffanowski A, van Marwijk H, Hiller W, Lambert MJ, Cochrane Common Mental Disorders Group. Pharmacological interventions for somatoform disorders in adults. Cochrane Database Syst Rev 2014; 2014:CD010628. [PMID: 25379990 PMCID: PMC11023023 DOI: 10.1002/14651858.cd010628.pub2] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions. OBJECTIVES To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults. SEARCH METHODS We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation & Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field. SELECTION CRITERIA We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder. DATA COLLECTION AND ANALYSIS One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment. MAIN RESULTS We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95% CI -0.39 to 0.13; 2 studies, 239 participants; I(2) = 2%; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95% CI -1.36 to -0.46; 3 studies, 243 participants; I(2) = 63%). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95% CI -0.97 to -0.51; 2 studies, 322 participants; I(2) = 0%).One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95% CI -0.55 to 0.23; 3 studies, 177 participants; I(2) = 42%; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95% CI -0.45 to 0.14; 4 studies, 182 participants; I(2) = 0%).Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95% CI 0.32 to 1.22; 2 studies, 107 participants; I(2) = 23%).Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95% CI 0.64 to 1.61; 2 studies, 163 participants; I(2) = 0%; low-quality evidence) or NPs and placebo (RR 0.85, 95% CI 0.40 to 1.78; 3 studies, 506 participants; I(2) = 0%; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95% CI 0.59 to 3.72; 8 studies, 556 participants; I(2) =14%; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95% CI 0.25 to 2.52; 2 studies, 118 participants; I(2) = 0%; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0% to 32%), but low for NPs (0% to 1.7%).The risk of bias was high in many domains across studies. Seventeen trials (65.4%) gave no information about random sequence generation and only two (7.7%) provided information about allocation concealment. Eighteen studies (69.2%) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise. AUTHORS' CONCLUSIONS The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.
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Affiliation(s)
- Maria Kleinstäuber
- Philipps‐University MarburgDepartment of Clinical Psychology and PsychotherapyGutenbergstr. 18MarburgHessenGermanyD‐35032
| | - Michael Witthöft
- Johannes Gutenberg‐University MainzDepartment of Clinical Psychology and PsychotherapyWallstr. 3MainzRheinland‐PfalzGermanyD‐55122
| | - Andrés Steffanowski
- University of MannheimDepartment of PsychologySchloss Ehrenhof Ost (2.OG)MannheimBaden‐WürttembergGermanyD‐68131
| | - Harm van Marwijk
- VU University Medical CenterDepartment of General Practice and Elderly Care Medicine, EMGO Institute for Health and Care ResearchPO Box 7057AmsterdamNetherlands1007 MB
| | - Wolfgang Hiller
- Johannes Gutenberg‐University MainzDepartment of Clinical Psychology and PsychotherapyWallstr. 3MainzRheinland‐PfalzGermanyD‐55122
| | - Michael J Lambert
- Brigham Young UniversityDepartment of PsychologyOffice TLRB 2721001 Kimball TowerProvoUtahUSAUT 84602‐5543
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Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain. Neuropsychopharmacology 2014; 39:2633-45. [PMID: 24853772 PMCID: PMC4207343 DOI: 10.1038/npp.2014.117] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Revised: 05/16/2014] [Accepted: 05/16/2014] [Indexed: 12/12/2022]
Abstract
Corticotropin-releasing factor (CRF)-mediated mechanisms in the bed nucleus of the stria terminalis (BNST) have a pivotal role in stress-induced anxiety and hyperalgesia. Although CRF is known to activate two receptor subtypes, CRF1 and CRF2, attempts to delineate the specific role of each subtype in modulating anxiety and nociception have been inconsistent. Here we test the hypothesis that CRF1 and CRF2 receptor activation in the anteriolateral BNST (BNSTAL) facilitates divergent mechanisms modulating comorbid anxiety and hyperalgesia. Microinfusions of the specific antagonists CP376395 and Astressin2B into the BNSTAL were used to investigate CRF1 and CRF2 receptor functions, respectively. We found that CRF1 and CRF2 receptors in the BNSTAL had opposing effects on exploratory behavior in the elevated plus-maze, somatic mechanical threshold, and the autonomic and endocrine response to stress. However, CRF1 or CRF2 receptor antagonism in the BNSTAL revealed complementary roles in facilitating the acoustic startle and visceromotor reflexes. Our results suggest that the net effect of CRF1 and CRF2 receptor activation in the BNSTAL is pathway-dependent and provides important insight into the CRF receptor-associated circuitry that likely underpins stress-induced pathologies.
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Liu P, Zeng F, Yang F, Wang J, Liu X, Wang Q, Zhou G, Zhang D, Zhu M, Zhao R, Wang A, Gong Q, Liang F. Altered structural covariance of the striatum in functional dyspepsia patients. Neurogastroenterol Motil 2014; 26:1144-54. [PMID: 24865440 DOI: 10.1111/nmo.12372] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 05/01/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND Functional dyspepsia (FD) is thought to be involved in dysregulation within the brain-gut axis. Recently, altered striatum activation has been reported in patients with FD. However, the gray matter (GM) volumes in the striatum and structural covariance patterns of this area are rarely explored. The purpose of this study was to examine the GM volumes and structural covariance patterns of the striatum between FD patients and healthy controls (HCs). METHODS T1-weighted magnetic resonance images were obtained from 44 FD patients and 39 HCs. Voxel-based morphometry (VBM) analysis was adopted to examine the GM volumes in the two groups. The caudate- or putamen-related regions identified from VBM analysis were then used as seeds to map the whole brain voxel-wise structural covariance patterns. Finally, a correlation analysis was used to investigate the effects of FD symptoms on the striatum. KEY RESULTS The results showed increased GM volumes in the bilateral putamen and right caudate. Compared with the structural covariance patterns of the HCs, the FD-related differences were mainly located in the amygdala, hippocampus/parahippocampus (HIPP/paraHIPP), thalamus, lingual gyrus, and cerebellum. And significant positive correlations were found between the volumes in the striatum and the FD duration in the patients. CONCLUSIONS & INFERENCES These findings provided preliminary evidence for GM changes in the striatum and different structural covariance patterns in patients with FD. The current results might expand our understanding of the pathophysiology of FD.
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Affiliation(s)
- P Liu
- Life Science Research Center, School of Life Science and Technology, Xidian University, Xi'an, China
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Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 2014; 277:32-48. [PMID: 25078296 DOI: 10.1016/j.bbr.2014.07.027] [Citation(s) in RCA: 1259] [Impact Index Per Article: 114.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/08/2014] [Accepted: 07/16/2014] [Indexed: 12/14/2022]
Abstract
The brain-gut axis is a bidirectional communication system between the central nervous system and the gastrointestinal tract. Serotonin functions as a key neurotransmitter at both terminals of this network. Accumulating evidence points to a critical role for the gut microbiome in regulating normal functioning of this axis. In particular, it is becoming clear that the microbial influence on tryptophan metabolism and the serotonergic system may be an important node in such regulation. There is also substantial overlap between behaviours influenced by the gut microbiota and those which rely on intact serotonergic neurotransmission. The developing serotonergic system may be vulnerable to differential microbial colonisation patterns prior to the emergence of a stable adult-like gut microbiota. At the other extreme of life, the decreased diversity and stability of the gut microbiota may dictate serotonin-related health problems in the elderly. The mechanisms underpinning this crosstalk require further elaboration but may be related to the ability of the gut microbiota to control host tryptophan metabolism along the kynurenine pathway, thereby simultaneously reducing the fraction available for serotonin synthesis and increasing the production of neuroactive metabolites. The enzymes of this pathway are immune and stress-responsive, both systems which buttress the brain-gut axis. In addition, there are neural processes in the gastrointestinal tract which can be influenced by local alterations in serotonin concentrations with subsequent relay of signals along the scaffolding of the brain-gut axis to influence CNS neurotransmission. Therapeutic targeting of the gut microbiota might be a viable treatment strategy for serotonin-related brain-gut axis disorders.
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Stasi C, Bellini M, Bassotti G, Blandizzi C, Milani S. Serotonin receptors and their role in the pathophysiology and therapy of irritable bowel syndrome. Tech Coloproctol 2014; 18:613-621. [PMID: 24425100 DOI: 10.1007/s10151-013-1106-8] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Accepted: 12/02/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by abdominal discomfort, pain and changes in bowel habits, often associated with psychological/psychiatric disorders. It has been suggested that the development of IBS may be related to the body's response to stress, which is one of the main factors that can modulate motility and visceral perception through the interaction between brain and gut (brain-gut axis). The present review will examine and discuss the role of serotonin (5-hydroxytryptamine, 5-HT) receptor subtypes in the pathophysiology and therapy of IBS. METHODS Search of the literature published in English using the PubMed database. RESULTS Several lines of evidence indicate that 5-HT and its receptor subtypes are likely to have a central role in the pathophysiology of IBS. 5-HT released from enterochromaffin cells regulates sensory, motor and secretory functions of the digestive system through the interaction with different receptor subtypes. It has been suggested that pain signals originate in intrinsic primary afferent neurons and are transmitted by extrinsic primary afferent neurons. Moreover, IBS is associated with abnormal activation of central stress circuits, which results in altered perception during visceral stimulation. CONCLUSIONS Altered 5-HT signaling in the central nervous system and in the gut contributes to hypersensitivity in IBS. The therapeutic effects of 5-HT agonists/antagonists in IBS are likely to be due also to the ability to modulate visceral nociception in the central stress circuits. Further studies are needed in order to develop an optimal treatment.
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Affiliation(s)
- C Stasi
- Department of Experimental and Clinical Medicine, University of Florence, Viale G.B. Morgagni, 85, 50134, Florence, Italy,
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Abstract
Irritable bowel syndrome (IBS) is a common disorder in children and adults. The pathogenesis and pathophysiology of IBS remains incompletely understood. The biopsychosocial model, which conceptualizes chronic pain as a dysregulation of the gut-brain-homeostasis with peripheral and central factors mutually influencing each other, is the most accepted framework to explain IBS. Twin and family aggregation studies suggest a genetic component that does not exclusively explain the higher prevalence of IBS in certain families. Social learning (environmental factors) and maladaptive coping predispose children to develop IBS with greater disability and more frequent medical consultations. Early-life events constitute an additional risk factor for the development of IBS and other functional gastrointestinal disorders (FGIDs). Children with a history of cow's milk protein hypersensitivity or abdominal surgeries have a higher prevalence of IBS and other FGIDs years later. IBS frequently follows an episode of acute gastrointestinal inflammation (infectious or non-infectious). This article discusses the importance, known pathophysiological mechanisms, clinical approach, and evidence-based therapeutic options for the management of IBS in children and adolescents.
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Melchior C, Gourcerol G, Chastan N, Verin E, Menard JF, Ducrotte P, Leroi AM. Effect of transcranial magnetic stimulation on rectal sensitivity in irritable bowel syndrome: a randomized, placebo-controlled pilot study. Colorectal Dis 2014; 16:O104-11. [PMID: 24119239 DOI: 10.1111/codi.12450] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2013] [Accepted: 09/04/2013] [Indexed: 12/19/2022]
Abstract
AIM Repetitive transcranial magnetic stimulation (rTMS) applied to the motor cortex can induce analgesic effects in patients with chronic pain syndromes through its effect on central pain-modulatory systems. Our aim was to evaluate the effect of rTMS on rectal sensitivity in irritable bowel syndrome (IBS) patients. METHOD In this randomized, sham-controlled, proof-of concept trial, 21 IBS patients (11 women and 10 men; mean age 44.0 ± 12.6 years) were randomized, using a double-blind crossover protocol, to active or sham rTMS for 5 days of treatment. The primary outcome was the increase in the pressure pain threshold after rTMS. Secondary outcomes were the changes in maximum tolerated rectal volume, rectal compliance and average pain intensity between baseline and the end of the treatments. RESULTS There were no statistically significant differences between active and sham rTMS in terms of an increase in the pressure pain threshold, maximum tolerated volume and rectal compliance at the end of the treatments compared with baseline. However, in the subgroup of patients with the most marked rectal hypersensitivity, the volume threshold was significantly improved by active, but not by sham, rTMS (P = 0.03). Patients experienced a significant improvement in pain regardless of the type of stimulation. CONCLUSION This pilot study failed to demonstrate any benefit of rTMS on our primary end-point. However, the effect of rTMS on rectal tolerated volume in the most hypersensitive patients was encouraging enough to plan more powered studies.
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Affiliation(s)
- C Melchior
- INSERM U1073, CIC Rouen University Hospital, Rouen, France
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Zhao F, Williams M, Bowlby M, Houghton A, Hargreaves R, Evelhoch J, Williams DS. Qualification of fMRI as a biomarker for pain in anesthetized rats by comparison with behavioral response in conscious rats. Neuroimage 2013; 84:724-32. [PMID: 24064074 DOI: 10.1016/j.neuroimage.2013.09.036] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 09/07/2013] [Accepted: 09/13/2013] [Indexed: 10/26/2022] Open
Abstract
fMRI can objectively measure pain-related neural activities in humans and animals, providing a valuable tool for studying the mechanisms of nociception and for developing new analgesics. However, due to its extreme sensitivity to subject motion, pain fMRI studies are performed in animals that are immobilized, typically with anesthesia. Since anesthesia could confound the nociceptive processes, it is unknown how well nociceptive-related neural activities measured by fMRI in anesthetized animals correlate with nociceptive behaviors in conscious animals. The threshold to vocalization (VT) in response to an increasing noxious electrical stimulus (NES) was implemented in conscious rats as a behavioral measure of nociception. The antinociceptive effect of systemic (intravenous infusion) lidocaine on NES-induced fMRI signals in anesthetized rats was compared with the corresponding VT in conscious rats. Lidocaine infusion increased VT and suppressed the NES-induced fMRI signals in most activated brain regions. The temporal characteristics of the nociception signal by fMRI and by VT in response to lidocaine infusion were highly correlated with each other, and with the pharmacokinetics (PK) of lidocaine. These results indicate that the fMRI activations in these regions may be used as biomarkers of acute nociception in anesthetized rats. Interestingly, systemic lidocaine had no effect on NES-induced fMRI activations in the primary somatosensory cortex (S1), a result that warrants further investigation.
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Kleinstäuber M, Witthöft M, Steffanowski A, Lambert M, Meinhardt G, Lieb K, Hiller W. Pharmacological interventions for somatoform disorders in adults. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2013. [DOI: 10.1002/14651858.cd010628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Veinante P, Yalcin I, Barrot M. The amygdala between sensation and affect: a role in pain. J Mol Psychiatry 2013; 1:9. [PMID: 25408902 PMCID: PMC4223879 DOI: 10.1186/2049-9256-1-9] [Citation(s) in RCA: 223] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 05/11/2013] [Indexed: 01/15/2023] Open
Abstract
The amygdala is a structure of the temporal lobe thought to be involved in assigning emotional significance to environmental information and triggering adapted physiological, behavioral and affective responses. A large body of literature in animals and human implicates the amygdala in fear. Pain having a strong affective and emotional dimension, the amygdala, especially its central nucleus (CeA), has also emerged in the last twenty years as key element of the pain matrix. The CeA receives multiple nociceptive information from the brainstem, as well as highly processed polymodal information from the thalamus and the cerebral cortex. It also possesses the connections that allow influencing most of the descending pain control systems as well as higher centers involved in emotional, affective and cognitive functions. Preclinical studies indicate that the integration of nociceptive inputs in the CeA only marginally contributes to sensory-discriminative components of pain, but rather contributes to associated behavior and affective responses. The CeA doesn’t have a major influence on responses to acute nociception in basal condition, but it induces hypoalgesia during aversive situation, such as stress or fear. On the contrary, during persistent pain states (inflammatory, visceral, neuropathic), a long-lasting functional plasticity of CeA activity contributes to an enhancement of the pain experience, including hyperalgesia, aversive behavioral reactions and affective anxiety-like states.
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Affiliation(s)
- Pierre Veinante
- Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 21 Rue René Descartes, 67084 Strasbourg Cedex, France ; Université de Strasbourg, 21 Rue René Descartes, 67084 Strasbourg Cedex, France
| | - Ipek Yalcin
- Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 21 Rue René Descartes, 67084 Strasbourg Cedex, France ; Université de Strasbourg, 21 Rue René Descartes, 67084 Strasbourg Cedex, France
| | - Michel Barrot
- Institut des Neurosciences Cellulaires et Intégratives, UPR3212, Centre National de la Recherche Scientifique, 21 Rue René Descartes, 67084 Strasbourg Cedex, France ; Université de Strasbourg, 21 Rue René Descartes, 67084 Strasbourg Cedex, France
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Chaloner A, Greenwood-Van Meerveld B. Early life adversity as a risk factor for visceral pain in later life: importance of sex differences. Front Neurosci 2013; 7:13. [PMID: 23407595 PMCID: PMC3570767 DOI: 10.3389/fnins.2013.00013] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/23/2013] [Indexed: 12/17/2022] Open
Abstract
A history of early life adversity (ELA) has health-related consequences that persist beyond the initial maltreatment and into adulthood. Childhood adversity is associated with abnormal glucocorticoid signaling within the hypothalamic-pituitary-adrenal (HPA) axis and the development of functional pain disorders such as the irritable bowel syndrome (IBS). IBS and many adult psychopathologies are more frequently diagnosed in women, and ovarian hormones have been shown to modulate pain sensitivity. Therefore, the sexually dimorphic effects of ELA and the role of ovarian hormones in visceral pain perception represent critical research concepts to enhance our understanding of the etiology of IBS. In this review, we discuss current animal models of ELA and the potential mechanisms through which ovarian hormones modulate the HPA axis to alter nociceptive signaling pathways and induce functionally relevant changes in pain behaviors following ELA.
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Affiliation(s)
- Aaron Chaloner
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center Oklahoma City, OK, USA
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Stasi C, Rosselli M, Bellini M, Laffi G, Milani S. Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. J Gastroenterol 2012; 47:1177-1185. [PMID: 22766747 DOI: 10.1007/s00535-012-0627-7] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 06/04/2012] [Indexed: 02/06/2023]
Abstract
The interaction between the brain and the gut as a pathological mechanism of functional gastrointestinal disorders has been recently recognized in the pathophysiology of the irritable bowel syndrome. Communication between central nervous system and enteric nervous system is two-directional: the brain can influence the function of the enteric nervous system and the gut can influence the brain via vagal and sympathetic afferents. In patients with irritable bowel syndrome, symptoms may be caused by alterations either primarily in the central nervous system (top-down model), or in the gut (bottom-up model), or in a combination of both. The brain-gut axis may be stimulated by various stressors either directed to the central nervous system (exteroreceptive stress) or to the gut (interoceptive stress). Particularly, clinical evidence suggest that in complex and multifactorial diseases such as irritable bowel syndrome, psychological disorders represent significant factors in the pathogenesis and course of the syndrome. Neuroimaging techniques have shown functional differences between central process in healthy subjects and patients with irritable bowel syndrome. Moreover, a high prevalence of psychological/psychiatric disorders have been reported in IBS patients compared to controls. Several data also suggest an alteration of neuro-endocrine and autonomic output to the periphery in these patients. This review will examine and discuss the complex interplay of neuro-endocrine-immune pathways, closely associated with neuropsychiatric disorders.
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Affiliation(s)
- Cristina Stasi
- Dipartimento di Medicina Interna, University of Florence, Viale GB Morgagni, 85, 50134 Florence, Italy.
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Chu WC, Wu JC, Yew DT, Zhang L, Shi L, Yeung DK, Wang D, Tong RK, Chan Y, Lao L, Leung PC, Berman BM, Sung JJ. Does acupuncture therapy alter activation of neural pathway for pain perception in irritable bowel syndrome?: a comparative study of true and sham acupuncture using functional magnetic resonance imaging. J Neurogastroenterol Motil 2012; 18:305-16. [PMID: 22837879 PMCID: PMC3400819 DOI: 10.5056/jnm.2012.18.3.305] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 02/16/2012] [Accepted: 02/18/2012] [Indexed: 12/13/2022] Open
Abstract
Background/Aims Patients with irritable bowel syndrome (IBS) are characterized by abnormal central processing with altered brain activation in response to visceral nociceptive signals. The effect of electroacupuncture (EA) on IBS patients is unclear. The study is set to study the effect of EA on brain activation during noxious rectal distension in IBS patients using a randomized sham-controlled model. Methods Thirty IBS-diarrhea patients were randomized to true electroacupuncture or sham acupuncture. Functional MRI was performed to evaluate cerebral activation at the following time points: (1) baseline when there was rectal distension only, (2) rectal distension during application of EA, (3) rectal distension after cessation of EA and (4) EA alone with no rectal distension. Group comparison was made under each condition using SPM5 program. Results Rectal distension induced significant activation of the anterior cingulated cortex, prefrontal cortex, thalamus, temporal regions and cerebellum at baseline. During and immediately after EA, increased cerebral activation from baseline was observed in the anterior cingulated cortex, bilateral prefrontal cortex, thalamus, temporal regions and right insula in both groups. However, true electroacupuncture led to significantly higher activation at right insula, as well as pulvinar and medial nucleus of the thalamus when compared to sham acupuncture. Conclusions We postulate that acupuncture might have the potential effect of pain modulation in IBS by 2 actions: (1) modulation of serotonin pathway at insula and (2) modulation of mood and affection in higher cortical center via ascending pathway at the pulvinar and medial nucleus of the thalamus.
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Affiliation(s)
- Winnie Cw Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
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Chu WC, Wu JC, Yew DT, Zhang L, Shi L, Yeung DK, Wang D, Tong RK, Chan Y, Lao L, Leung PC, Berman BM, Sung JJ. Does acupuncture therapy alter activation of neural pathway for pain perception in irritable bowel syndrome?: a comparative study of true and sham acupuncture using functional magnetic resonance imaging. J Neurogastroenterol Motil 2012. [PMID: 22837879 DOI: 10.5056/jnm] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Patients with irritable bowel syndrome (IBS) are characterized by abnormal central processing with altered brain activation in response to visceral nociceptive signals. The effect of electroacupuncture (EA) on IBS patients is unclear. The study is set to study the effect of EA on brain activation during noxious rectal distension in IBS patients using a randomized sham-controlled model. METHODS Thirty IBS-diarrhea patients were randomized to true electroacupuncture or sham acupuncture. Functional MRI was performed to evaluate cerebral activation at the following time points: (1) baseline when there was rectal distension only, (2) rectal distension during application of EA, (3) rectal distension after cessation of EA and (4) EA alone with no rectal distension. Group comparison was made under each condition using SPM5 program. RESULTS Rectal distension induced significant activation of the anterior cingulated cortex, prefrontal cortex, thalamus, temporal regions and cerebellum at baseline. During and immediately after EA, increased cerebral activation from baseline was observed in the anterior cingulated cortex, bilateral prefrontal cortex, thalamus, temporal regions and right insula in both groups. However, true electroacupuncture led to significantly higher activation at right insula, as well as pulvinar and medial nucleus of the thalamus when compared to sham acupuncture. CONCLUSIONS We postulate that acupuncture might have the potential effect of pain modulation in IBS by 2 actions: (1) modulation of serotonin pathway at insula and (2) modulation of mood and affection in higher cortical center via ascending pathway at the pulvinar and medial nucleus of the thalamus.
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Affiliation(s)
- Winnie Cw Chu
- Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
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Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O'Donnell DE. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012; 185:435-52. [PMID: 22336677 PMCID: PMC5448624 DOI: 10.1164/rccm.201111-2042st] [Citation(s) in RCA: 1191] [Impact Index Per Article: 91.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases. Since the ATS published a consensus statement on dyspnea in 1999, there has been enormous growth in knowledge about the neurophysiology of dyspnea and increasing interest in dyspnea as a patient-reported outcome. PURPOSE The purpose of this document is to update the 1999 ATS Consensus Statement on dyspnea. METHODS An interdisciplinary committee of experts representing ATS assemblies on Nursing, Clinical Problems, Sleep and Respiratory Neurobiology, Pulmonary Rehabilitation, and Behavioral Science determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant expertise. The final content of this statement was agreed upon by all members. RESULTS Progress has been made in clarifying mechanisms underlying several qualitatively and mechanistically distinct breathing sensations. Brain imaging studies have consistently shown dyspnea stimuli to be correlated with activation of cortico-limbic areas involved with interoception and nociception. Endogenous and exogenous opioids may modulate perception of dyspnea. Instruments for measuring dyspnea are often poorly characterized; a framework is proposed for more consistent identification of measurement domains. CONCLUSIONS Progress in treatment of dyspnea has not matched progress in elucidating underlying mechanisms. There is a critical need for interdisciplinary translational research to connect dyspnea mechanisms with clinical treatment and to validate dyspnea measures as patient-reported outcomes for clinical trials.
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Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O'Donnell DE. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 2012. [PMID: 22336677 DOI: 10.1164/rccm.201111–2042st] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases. Since the ATS published a consensus statement on dyspnea in 1999, there has been enormous growth in knowledge about the neurophysiology of dyspnea and increasing interest in dyspnea as a patient-reported outcome. PURPOSE The purpose of this document is to update the 1999 ATS Consensus Statement on dyspnea. METHODS An interdisciplinary committee of experts representing ATS assemblies on Nursing, Clinical Problems, Sleep and Respiratory Neurobiology, Pulmonary Rehabilitation, and Behavioral Science determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant expertise. The final content of this statement was agreed upon by all members. RESULTS Progress has been made in clarifying mechanisms underlying several qualitatively and mechanistically distinct breathing sensations. Brain imaging studies have consistently shown dyspnea stimuli to be correlated with activation of cortico-limbic areas involved with interoception and nociception. Endogenous and exogenous opioids may modulate perception of dyspnea. Instruments for measuring dyspnea are often poorly characterized; a framework is proposed for more consistent identification of measurement domains. CONCLUSIONS Progress in treatment of dyspnea has not matched progress in elucidating underlying mechanisms. There is a critical need for interdisciplinary translational research to connect dyspnea mechanisms with clinical treatment and to validate dyspnea measures as patient-reported outcomes for clinical trials.
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Salari P, Abdollahi M. Systematic review of modulators of benzodiazepine receptors in irritable bowel syndrome: Is there hope? World J Gastroenterol 2011; 17:4251-7. [PMID: 22090780 PMCID: PMC3214699 DOI: 10.3748/wjg.v17.i38.4251] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Revised: 05/20/2011] [Accepted: 05/27/2011] [Indexed: 02/06/2023] Open
Abstract
Several drugs are used in the treatment of irritable bowel syndrome (IBS) but all have side effects and variable efficacy. Considering the role of the gut-brain axis, immune, neural, and endocrine pathways in the pathogenesis of IBS and possible beneficial effects of benzodiazepines (BZD) in this axis, the present systematic review focuses on the efficacy of BZD receptor modulators in human IBS. For the years 1966 to February 2011, all literature was searched for any articles on the use of BZD receptor modulators and IBS. After thorough evaluation and omission of duplicate data, 10 out of 69 articles were included. BZD receptor modulators can be helpful, especially in the diarrhea-dominant form of IBS, by affecting the inflammatory, neural, and psychologic pathways, however, controversies still exist. Recently, a new BZD receptor modulator, dextofisopam was synthesized and studied in human subjects, but the studies are limited to phase IIb clinical trials. None of the existing trials considered the neuroimmunomodulatory effect of BZDs in IBS, but bearing in mind the concentration-dependent effect of BZDs on cytokines and cell proliferation, future studies using pharmacodynamic and pharmacokinetic approaches are highly recommended.
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Frøkjær JB, Olesen SS, Graversen C, Andresen T, Lelic D, Drewes AM. Neuroimaging of the human visceral pain system–A methodological review. Scand J Pain 2011; 2:95-104. [DOI: 10.1016/j.sjpain.2011.02.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 02/25/2011] [Indexed: 12/13/2022]
Abstract
Abstract
During the last decades there has been a tremendous development of non-invasive methods for assessment of brain activity following visceral pain. Improved methods for neurophysiological and brain imaging techniques have vastly increased our understanding of the central processing of gastrointestinal sensation and pain in both healthy volunteers as well as in patients suffering from gastrointestinal disorders. The techniques used are functional magnetic resonance imaging (fMRI), positron emission tomography (PET), electroencephalography (EEG)/evoked brain potentials (EPs), magnetoencephalography (MEG), single photon emission computed tomography (SPECT), and the multimodal combinations of these techniques. The use of these techniques has brought new insight into the complex brain processes underlying pain perception, including a number of subcortical and cortical regions, and paved new ways in our understanding of acute and chronic pain. The pathways are dynamic with a delicate balance between facilitatory and inhibitory pain mechanisms, and with modulation of the response to internal or external stressors with a high degree of plasticity. Hence, the ultimate goal in imaging of pain is to follow the stimulus response throughout the neuraxis.
Brain activity measured by fMRI is based on subtracting regional changes in blood oxygenation during a resting condition from the signal during a stimulus condition, and has high spatial resolution but low temporal resolution. SPECT and PET are nuclear imaging techniques where radiolabeled molecules are injected with visualization of the distribution, density and activity of receptors in the brain allowing not only assessment of brain activity but also study of receptor sites. EEG is based on assessment of electrical activity in the brain, and recordings of the resting EEG and evoked potentials following an external stimulus are used to study normal visceral pain processing, alterations of pain processing in different patient groups and the effect of pharmacological intervention. EEG has high temporal resolution, but relative poor spatial resolution, which however to some extent can be overcome by applying inverse modelling algorithms and signal decomposition procedures. MEG is based on recording the magnetic fields produced by electrical currents in the brain, has high spatial resolution and is especially suitable for the study cortical activation.
The treatment of chronic abdominal pain is often ineffective and dissapointing, which leads to search for optimized treatment achieved on the basis of a better understanding of underlying pain mechanisms. Application of the recent improvements in neuroimaging on the visceral pain system may likely in near future contribute substantially to our understanding of the functional and structural pathophysiology underlying chronic visceral pain disorders, and pave the road for optimized individual and mechanism based treatments.
The purpose of this review is to give a state-of-the-art overview of these methods, with focus on EEG, and especially the advantages and limitations of the single methods in clinical gastrointestinal pain esearch including examples from relevant studies.
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Affiliation(s)
- Jens Brøndum Frøkjær
- Mech-Sense , Department of Gastroenterology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
- Department of Radiology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
| | - Søren Schou Olesen
- Mech-Sense , Department of Gastroenterology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
| | - Carina Graversen
- Mech-Sense , Department of Gastroenterology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
| | - Trine Andresen
- Mech-Sense , Department of Gastroenterology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
| | - Dina Lelic
- Mech-Sense , Department of Gastroenterology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense , Department of Gastroenterology , Aalborg Hospital , Aarhus University Hospital , Aalborg , Denmark
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Sheehan J, Gaman A, Vangel M, Kuo B. Pooled analysis of brain activity in irritable bowel syndrome and controls during rectal balloon distension. Neurogastroenterol Motil 2011; 23:336-46, e158. [PMID: 21118328 PMCID: PMC3105166 DOI: 10.1111/j.1365-2982.2010.01635.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Brain-imaging literature of irritable bowel syndrome (IBS) suggests an abnormal brain-gut communication. We analyzed the literature to evaluate and compare the aspects of brain activity in individuals with IBS and control subjects experiencing controlled rectal stimulation. METHODS PubMed was searched until September 2010. Data from 16 articles reporting brain activity during rectal balloon distensions in IBS compared to control groups was analyzed. Prevalence rates and pairwise activations were assessed using binomial distributions for 11 selected regions of interest. The data were aggregated to adjust for center effect. KEY RESULTS There was considerable variability in the literature regarding regions and their activity patterns in controls and individuals with IBS. There was no significant difference found in the thalamus, anterior cingulate cortex, posterior cingulate cortex, and prefrontal cortex, however, results show limited evidence of consensus for the anterior insula (AI) (P = 0.22). Pairwise activity results suggest that pairs involving the AI tend to have more consistent activity together than pairs which do not involve the AI (posterior insula and AI, P = 0.08; posterior cingulate cortex and AI, P = 0.16), however, no pairwise evaluation reached significance. CONCLUSIONS & INFERENCES Our pooled analysis demonstrates that the literature reports are quite heterogeneous but there is some evidence that there may be patterns of higher activity more common in individuals with IBS than in controls. A consensus, though, regarding study designs, analysis approach and reporting could create a clearer understanding of brain involvement in IBS pathophysiology.
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Affiliation(s)
- J Sheehan
- Department of Medicine, GI Unit, Massachusetts General Hospital, Harvard Medical School, Martinos Center for Biomedical Imaging, Boston, MA 02114, USA
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Abstract
IBS is a chronic, fluctuating disorder that continues to be the subject of considerable research. 2010 saw some key advances across all aspects of IBS, including further advances in our understanding of the pathophysiology, diagnosis and treatment of this condition.
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Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology 2011; 140:91-100. [PMID: 20696168 PMCID: PMC3253553 DOI: 10.1053/j.gastro.2010.07.053] [Citation(s) in RCA: 321] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 07/21/2010] [Accepted: 07/30/2010] [Indexed: 12/02/2022]
Abstract
BACKGROUND AND AIMS The responsiveness of the central nervous system is altered in patients with irritable bowel syndrome (IBS). However, because of variations in experimental paradigms, analytic techniques, and reporting practices, little consensus exists on brain responses to visceral stimulation. We aimed to identify brain regions consistently activated by supraliminal rectal stimulation in IBS patients and healthy subjects (controls) by performing a quantitative meta-analysis of published studies. METHODS Significant foci from within-group statistical parametric maps were extracted from published neuroimaging studies that employed rectal distension. Voxel-based activation likelihood estimation was applied, pooling the results and comparing them across groups. RESULTS Across studies, there was consistent activation in regions associated with visceral afferent processing (ie, thalamus, insula, anterior midcingulate) among IBS patients and controls, but considerable differences in the extent and specific location of foci. IBS patients differed from controls in that there were more consistent activations in regions associated with emotional arousal (pregenual anterior cingulate cortex, amygdala) and activation of a midbrain cluster, a region playing a role in endogenous pain modulation. Controls showed more consistent activation of the medial and lateral prefrontal cortex. CONCLUSIONS Patients with IBS have greater engagement of regions associated with emotional arousal and endogenous pain modulation, but similar activation of regions involved in processing of visceral afferent information. Controls have greater engagement of cognitive modulatory regions. These results support a role for central nervous system dysregulation in IBS. These findings provide specific targets for guiding development of future neuroimaging protocols to more clearly define altered brain-gut interactions in IBS.
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Gwee KA, Bak YT, Ghoshal UC, Gonlachanvit S, Lee OY, Fock KM, Chua ASB, Lu CL, Goh KL, Kositchaiwat C, Makharia G, Park HJ, Chang FY, Fukudo S, Choi MG, Bhatia S, Ke M, Hou X, Hongo M. Asian consensus on irritable bowel syndrome. J Gastroenterol Hepatol 2010; 25:1189-1205. [PMID: 20594245 DOI: 10.1111/j.1440-1746.2010.06353.x] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIMS Many of the ideas on irritable bowel syndrome (IBS) are derived from studies conducted in Western societies. Their relevance to Asian societies has not been critically examined. Our objectives were to bring to attention important data from Asian studies, articulate the experience and views of our Asian experts, and provide a relevant guide on this poorly understood condition for doctors and scientists working in Asia. METHODS A multinational group of physicians from Asia with special interest in IBS raised statements on IBS pertaining to symptoms, diagnosis, epidemiology, infection, pathophysiology, motility, management, and diet. A modified Delphi approach was employed to present and grade the quality of evidence, and determine the level of agreement. RESULTS We observed that bloating and symptoms associated with meals were prominent complaints among our IBS patients. In the majority of our countries, we did not observe a female predominance. In some Asian populations, the intestinal transit times in healthy and IBS patients appear to be faster than those reported in the West. High consultation rates were observed, particularly in the more affluent countries. There was only weak evidence to support the perception that psychological distress determines health-care seeking. Dietary factors, in particular, chili consumption and the high prevalence of lactose malabsorption, were perceived to be aggravating factors, but the evidence was weak. CONCLUSIONS This detailed compilation of studies from different parts of Asia, draws attention to Asian patients' experiences of IBS.
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Affiliation(s)
- Kok-Ann Gwee
- Stomach Liver and Bowel Clinic, Gleneagles Hospital, Singapore.
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