Skip to main content

Advertisement

SpringerLink
Log in

Disrupted functional connectivity density in irritable bowel syndrome patients

  • Original Research
  • Published:
Brain Imaging and Behavior Aims and scope Submit manuscript

Abstract

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder resulting from a dysregulation of the brain-gut axis. However, its exact neural substrate still remains unclear. This study investigated the changes of intrinsic whole brain functional connectivity pattern in IBS using functional connectivity density (FCD). We acquired resting-state functional magnetic resonance imaging (rs-fMRI) data from thirty-two IBS patients and thirty-two healthy controls. Functional connectivity density, a data-driven algorithm, was used to compute the long-range and short-range FCD values for each voxel in the brain of each subject, implying the amount of distant and local functional connections of cortical hubs. The FCD maps were compared between IBS patients and healthy controls. Pearson correlations analysis was also performed between abnormal FCD values and clinical/psychometric scores in patients. Compared to healthy controls, IBS patients showed concurrently decreased long- and short-range FCD in bilateral anterior midcingulate cortices (aMCC) and inferior parietal lobules (IPL), and decreased long-range FCD in right anterior insula, and decreased short-range FCD in bilateral prefrontal cortices, subgenual anterior cingulate cortices and caudates. IBS patients also had concurrently increased long- and short-range FCD mainly in primary sensorimotor cortices, as well as increased long-range FCD in right supplementary motor area and increased short-range FCD in occipital lobe. In addition, some regions with altered FCD showed abnormal functional connectivity in brain regions involved in pain matrix of IBS patients. Furthermore, the abnormal FCD values in right anterior insula and left caudate showed significant correlation with severity of symptoms and disease duration of IBS patients respectively. In conclusion, patients with IBS have widely disrupted FCD, which decreased in brain regions involved in homeostatic afferent network, emotional arouse, and cognitive regulation, while increased in regions associated with sensorimotor modulation. And the observed functional connectivity alterations unveiled complicated working patterns of pain matrix in IBS patients. This study may provide us with new insight into the underlying brain network topology of IBS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aizawa, E., Sato, Y., Kochiyama, T., Saito, N., Izumiyama, M., Morishita, J., et al. (2012). Altered cognitive function of prefrontal cortex during error feedback in patients with irritable bowel syndrome, based on FMRI and dynamic causal modeling. Gastroenterology, 143(5), 1188–1198.

    Article  PubMed  Google Scholar 

  • Apkarian, A. V., Bushnell, M. C., Treede, R. D., & Zubieta, J. K. (2005). Human brain mechanisms of pain perception and regulation in health and disease. European Journal of Pain, 9(4), 463–484.

    Article  PubMed  Google Scholar 

  • Berman, S. M., Naliboff, B. D., Suyenobu, B., Labus, J. S., Stains, J., Ohning, G., et al. (2008). Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome. The Journal of Neuroscience, 28(2), 349–359.

    Article  CAS  PubMed  Google Scholar 

  • Beucke, J. C., Sepulcre, J., Talukdar, T., Linnman, C., Zschenderlein, K., Endrass, T., et al. (2013). Abnormally high degree connectivity of the orbitofrontal cortex in obsessive-compulsive disorder. JAMA Psychiatry, 70(6), 619–929.

    Article  PubMed  Google Scholar 

  • Brody, A. L., Barsom, M. W., Bota, R. G., & Saxena, S. (2001). Prefrontal-subcortical and limbic circuit mediation of major depressive disorder. Seminars in Clinical Neuropsychiatry, 6(2), 102–112.

    Article  CAS  PubMed  Google Scholar 

  • Buckner, R. L., Sepulcre, J., Talukdar, T., Krienen, F. M., Liu, H., et al. (2009). Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheirmer’s disease. The Journal of Neuroscience, 29(6), 1860–1873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buckner, R. L., Krienen, F. M., & Yeo, B. T. (2013). Opportunities and limitations of intrinsic functional connectivity MRI. Nature Neuroscience, 16(7), 832–837.

    Article  PubMed  Google Scholar 

  • Cashman, M. D., Martin, D. K., Dhillon, S., & Puli, S. R. (2016). Irritable bowel syndrome: a clinical review. Current Rheumatology Reviews, 12(1), 13–26.

    Article  PubMed  Google Scholar 

  • Chen, K. H., Rusch, M. L., Dawson, J. D., Rizzo, M., & Anderson, S. W. (2015). Susceptibility to social pressure following ventromedial prefrontal cortex damage. Social Cognitive and Affective Neuroscience, 10(11), 1469–1476.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cifre, I., Sitges, C., Fraiman, D., Munoz, M. A., Balenzuela, P., Gonzalez-Roldan, A., et al. (2012). Disrupted functional connectivity of the pain network in fibromyalgia. Psychosomatic Medicine, 74(1), 55–62.

    Article  PubMed  Google Scholar 

  • Craggs, J. G., Price, D. D., Verne, G. N., Perlstein, W. M., & Robinson, M. M. (2007). Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia. NeuroImage, 38(4), 720–729.

    Article  PubMed  PubMed Central  Google Scholar 

  • Drossman, D. A. (2006). The functional gastrointestinal disorders and the Rome III process. Gastroenterology, 130(5), 1377–1390.

    Article  PubMed  Google Scholar 

  • Elsenbruch, S. (2011). Abdominal pain in irritable bowel syndrome: a review of putative psychological, neural and neuro-immune mechanisms. Brain, Behavior, and Immunity, 25(3), 386–394.

    Article  CAS  PubMed  Google Scholar 

  • Erpelding, N., Moayedi, M., & Davis, K. D. (2012). Cortical thickness correlates of pain and temperature sensitivity. Pain, 153(8), 1602–1609.

    Article  PubMed  Google Scholar 

  • Fadgyas-Stanculete, M., Buga, A. M., Popa-Wagner, A., & Dumitrascu, D. L. (2014). The relationship between irritable bowel syndrome and psychiatric disorders: from molecular changes to clinical manifestations. Journal of Molecular Psychiatry, 2(1), 4.

    Article  PubMed  PubMed Central  Google Scholar 

  • Folstein, M. F., Robins, L. N., & Helzer, J. E. (1983). The mini-mental state examination. Archives of General Psychiatry, 40(7), 812.

    Article  CAS  PubMed  Google Scholar 

  • Fox, M. D., & Raichle, M. E. (2007). Spontaneous fluations in brain activity observed with functional magnetic resonance imaging. Nature reviews. Neuroscience, 8(9), 700–711.

    CAS  PubMed  Google Scholar 

  • Fox, M. D., Snyder, A. Z., Vincent, J. L., Corbetta, M., Van Essen, D. C., & Raichle, M. E. (2005). The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proceedings of the National Academy of Sciences of the United States of America, 102(27), 9673–9678.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Francis, C. Y., Morris, J., & Whorwell, P. J. (1997). The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Alimentary Pharmacology & Therapeutics, 11(2), 395–402.

    Article  CAS  Google Scholar 

  • Friebel, U., Eickhoff, S. B., & Lotze, M. (2011). Coordinate-based meta-analysis of experimentally induced and chronic persistent neuropathic pain. NeuroImage, 58(4), 1070–1080.

    Article  PubMed  Google Scholar 

  • Gao, Q., Xu, F., Jiang, C., Chen, Z., Chen, H., Liao, H., et al. (2016). Decreased functional connectivity density in pain-related brain regions of female migraine patients without Aura. Brain Research, 1632, 73–81.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Campayo, J., Fayed, N., Serrano-Blanco, A., & Roca, M. (2009). Brain dysfunction behind functional symptoms: neuroimaging and somatoform, conversive, and dissociative disorders. Current Opinion in Psychiatry, 22(2), 224–231.

    Article  PubMed  Google Scholar 

  • Hong, J. Y., Kilpatrick, L. A., Labus, J. S., Gupta, A., Katibian, D., Ashe-McNalley, C., et al. (2014). Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain. The Journal of Neuroscience, 34(43), 14252–14259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu, C., & Jiang, X. (2014). An emotion regulation role of ventromedial prefrontal cortex in moral judgment. Frontiers in Human Neuroscience, 8, 873.

    PubMed  PubMed Central  Google Scholar 

  • Hubbard, C. S., Hong, J., Jiang, Z., Ebrat, B., Suyenobu, B., Smith, S., et al. (2015). Increased attentional network functioning related to symptom severity measures in females with irritable bowel syndrome. Neurogastroenterology and Motility, 27(9), 1282–1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke, J., Qi, R., Liu, C., Xu, Q., Wang, F., Zhang, L., et al. (2015). Abnormal regional homogeneity in patients with irritable bowel syndrome: a resting-state functional MRI study. Neurogastroenterology and Motility, 27(12), 1796–1803.

    Article  CAS  PubMed  Google Scholar 

  • Kennedy, P. J., Clarke, G., Quigley, E. M., Groeger, J. A., Dinan, T. G., & Cryan, J. F. (2012). Gut memories: towards a cognitive neurobiology of irritable bowel syndrome. Neuroscience and Biobehavioral Reviews, 36(1), 310–340.

    Article  PubMed  Google Scholar 

  • Keszthelyi, D, Troost, FJ, Masclee, AA., et al. (2012). Irritable bowel syndrom: methods, mechanisms, and pathophysiology. Methods to visceral hypersenstivity in irritable bowel syndrome. American Journal of Physiology. Gastrointestinal and Liver Physiology 303(2), 141–154.

  • Legrain, V., Iannetti, G. D., Plaghki, L., & Mouraux, A. (2011). The pain matrix reloaded: a salience detection system for the body. Progress in Neurobiology, 93(1), 111–124.

    Article  PubMed  Google Scholar 

  • Letzen, J. E., Craggs, J. G., Perlstein, W. M., Price, D. D., & Robinson, M. E. (2013). Functional connectivity of the default mode network and its association with pain networks in irritable bowel patients assessed via lidocaine treatment. The Journal of Pain, 14(10), 1077–1087.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu, X., Silverman, A., Kein, M., Ward, B. D., Li, S. J., Shaker, R., et al. (2016). Excessive coupling of the salience network with intrinsic neurocognitive pain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminay report. Neurogastroenterology and Motility, 28(1), 43–53.

    Article  CAS  PubMed  Google Scholar 

  • Longstreth, G. F., Wilson, A., Knight, K., Wong, J., Chiou, C. F., Barghout, V., et al. (2003). Irritable bowel syndrome, health care use, and costs: a U.S. managed care perspective. The American Journal of Gastroenterology, 98(3), 600–607.

    Article  PubMed  Google Scholar 

  • Ma, X., Li, S., Tian, J., Jiang, G., Wen, H., Wang, T., et al. (2015). Altered brain spontaneous activity and connectivity network in irritable bowel syndrome patients: a resting-state fMRI study. Clinical Neurophysiology, 126(6), 1190–1197.

    Article  PubMed  Google Scholar 

  • Mayer, E. A., & Tillisch, K. (2011). The brain-gut axis in abdominal pain syndromes. Annual Review of Medicine, 62, 381–396.

    Article  CAS  PubMed  Google Scholar 

  • Nasreddine, Z. S., Phillips, N. A., Bedirian, V., Charbonneau, S., Whitehead, V., Collin, I., et al. (2005). The Montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society, 53(4), 695–699.

    Article  PubMed  Google Scholar 

  • Pan, Y. J., Wang, D. X., Yang, J., He, X. L., Xiao, N. M., Ma, R. Q., et al. (2016). Oxytocin in hypothalamic supraoptic nucleus is transferred to the caudate nucleus to influence pain modulation. Neuropeptides, 58, 61–65.

    Article  CAS  PubMed  Google Scholar 

  • Patrick, D. L., Drossman, D. A., Frederick, I. O., DiCesare, J., & Puder, K. L. (1998). Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Digestive Diseases and Sciences, 43(2), 400–411.

    Article  CAS  PubMed  Google Scholar 

  • Pessoa, L. (2008). On the relationship between emotion and cognition. Nature Reviews. Neuroscience, 9(2), 148–158.

    Article  CAS  PubMed  Google Scholar 

  • Price, D. D. (2000). Psychological and neural mechanisms of the affective dimension of pain. Science, 288(5472), 1769–1772.

    Article  CAS  PubMed  Google Scholar 

  • Price, D. D., Bush, F. M., Long, S., & Harkins, S. W. (1994). A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain, 56(2), 217–226.

    Article  CAS  PubMed  Google Scholar 

  • Price, D. D., Zhou, Q., Moshiree, B., Robinson, M. E., & Verne, G. N. (2006). Peripheral and central contributions to hyperalgesia in irritable bowel syndrome. The Journal of Pain, 7(8), 529–535.

    Article  PubMed  Google Scholar 

  • Qi, R., Liu, C., Ke, J., Xu, Q., Zhong, J., Wang, F., et al. (2015). Intrinsic brain abnormalities in irritable bowel syndrome and effect of anxiety and depression. Brain Imaging and Behavior. doi:10.1007/s11682-015-9478-1.

    Google Scholar 

  • Qi, R., Liu, C., Ke, J., Xu, Q., Ye, Y., Jia, L., et al. (2016). Abnormal amygdala resting-state functional connectivity in irritable bowel syndrome. AJNR. American Journal of Neuroradiology, 37(6), 1139–1145.

    Article  CAS  PubMed  Google Scholar 

  • Rapps, N., Van Oudenhove, L., Enck, P., & Aziz, Q. (2008). Brain imaging of visceral functions in healthy volunteers and IBS patients. Journal of Psychosomatic Research, 64(6), 599–604.

  • Seminowicz, D. A., Labus, J. S., Bueller, J. A., Tillisch, K., Naliboff, B. D., Bushnell, M. C., et al. (2010). Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology, 139(1), 48–57.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sepulcre, J., Liu, H., Talukdar, T., Martincorena, I., Yeo, B. T., & Buckner, R. L. (2010). The organization of local and distant functional connectivity in the human brain. PLoS Computational Biology, 6(6), e1000808.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stasi, C., Rosselli, M., Bellini, M., Laffi, G., & Milani, S. (2012). Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. Journal of Gastroenterology, 47(11), 1177–11857.

    Article  CAS  PubMed  Google Scholar 

  • Stufflebeam, S. M., Liu, H., Sepulcre, J., Tanaka, N., Buckner, R. L., & Madsen, J. R. (2011). Localization of focal epileptic discharges using functional connectivity magnetic resonance imaging. Journal of Neurosurgery, 114(6), 1693–1697.

    Article  PubMed  PubMed Central  Google Scholar 

  • Su, A. M., Shih, W., Presson, A. P., & Chang, L. (2014). Characterization of symptoms in irritable bowel syndrome with mixed bowel habit pattern. Neurogastroenterology and Motility, 26(1), 36–45.

    Article  CAS  PubMed  Google Scholar 

  • Tillisch, K., Mayer, E. A., & Labus, J. S. (2011). Quantitative meta-analysis identifies brain regions activated during rectal distension in irritable bowel syndrome. Gastroenterology, 140(1), 91–100.

    Article  PubMed  Google Scholar 

  • Tomasi, D., & Volkow, N. D. (2010). Functional connectivity density mapping. Proceedings of the National Academy of Sciences of the United States of America, 107(21), 9885–9890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomasi, D., & Volkow, N. D. (2014). Mapping small-world properties through development in the human brain: disruption in schizophrenia. PloS One, 9(4), e96176.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tracy, J., Goyal, N., Flanders, A., Weening, R., Laskas, J., Natale, P., et al. (2007). Functional magnetic resonance imaging analysis of attention to one's heartbeat. Psychosomatic Medicine, 69(9), 952–960.

    Article  PubMed  Google Scholar 

  • Wiech, K., & Tracey, I. (2013). Pain, decisions, and actions: a motivational perspective. Frontiers in Neuroscience, 7, 46. doi:10.3389/fnins.2013.00046.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xia, M., Wang, J., & He, Y. (2013). BrainNet viewer: a network visualization tool for human brain connectomics. PloS One, 8(7), e68910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yager, L. M., Garcia, A. F., Wunsch, A. M., & Ferguson, S. M. (2015). The ins and outs of the striatum: role in drug addiction. Neuroscience, 301, 529–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, X. D., Wen, J. Q., Xu, Q., Qi, R. F., Chen, H. J., Kong, X., et al. (2015). Altered long- and short-range functional connectivity in the patients with end-stage renal disease: a resting-state functional MRI study. Metabolic Brain Disease, 30(5), 1175–1186.

    Article  CAS  PubMed  Google Scholar 

  • Zhu, L., Li, Y., Wang, Y., Li, R., Zhang, Z., Lu, G. M., et al. (2016). Aberrant long-range functional connectivity density in generalized tonic-clonic seizures. Medicine, 95(24), e3893.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zung, W. W. (1971). A rating instrument for anxiety disorders. Psychosomatics, 12(6), 371–379.

    Article  CAS  PubMed  Google Scholar 

  • Zung, W. W., Richards, C. B., & Short, M. J. (1965). Self-rating depression scale in an outpatient clinic. Further validation of the SDS. Archives of General Psychiatry, 13(6), 508–515.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the Natural Scientific Foundation of China [Grant Nos. 81322020, 81230032 and 81171313 for Long Jiang Zhang, Grant Nos. 81301209 and 81671672 for Rongfeng Qi], the Program for New Century Excellent Talents in the University (NCET-12-0260 for Long Jiang Zhang), and the Chinese Key Program (Grant Nos. BWS11J063 and 10z026 for Guang Ming Lu).

Author information

Authors and Affiliations

  1. Department of Medical Imaging, Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Xuanwu District, Nanjing, Jiangsu Province, 210002, China

    Yifei Weng, Rongfeng Qi, Jun Ke, Qiang Xu, Long Jiang Zhang & Guang Ming Lu

  2. Department of Gastroenterology, Jinling Hospital, Nanjing University School of Medicine, 305 Zhongshan East Road, Xuanwu District, Nanjing, Jiangsu Province, 210002, China

    Chang Liu & Fangyu Wang

Authors
  1. Yifei Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rongfeng Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fangyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Long Jiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guang Ming Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Long Jiang Zhang or Guang Ming Lu.

Ethics declarations

Conflict of interest statement

Yifei Weng declares that she has no conflict of interest.

Rongfeng Qi declares that he has no conflict of interest.

Chang Liu declares that she has no conflict of interest.

Jun Ke declares that he has no conflict of interest.

Qiang Xu declares that he has no conflict of interest.

Fangyu Wang declares that he has no conflict of interest.

Long Jiang Zhang declares that he has no conflict of interest.

Guang Ming Lu declares that he has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Yifei Weng, Rongfeng Qi and Chang Liu contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weng, Y., Qi, R., Liu, C. et al. Disrupted functional connectivity density in irritable bowel syndrome patients. Brain Imaging and Behavior 11, 1812–1822 (2017). https://doi.org/10.1007/s11682-016-9653-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-016-9653-z

Keywords

Search

Navigation