Skip to main content

Advertisement

SpringerLink
Log in

Abnormal structure and functional connectivity of the anterior insula at pain-free periovulation is associated with perceived pain during menstruation

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

Abstract

Neuroimaging studies have demonstrated the critical role of the insula in pain pathways and its close relation with the perceived intensity of nociceptive stimuli. We aimed to identify the structural and functional characteristics of the insula during periovulatory phase in women with primary dysmenorrhea (PDM), and further investigate its association with the intensity of perceived pain during menstruation. Optimized voxel-based morphometry and functional connectivity (FC) analyses were applied by using 3-dimensional T1-weighted and resting functional magnetic resonance imaging (fMRI) in 36 patients at the peri-ovulation phase and 29 age-, education-, and gender-matched healthy controls (HC). A visual analogue scale (VAS) was used to examine the intensity of the abdominal pain at periovulation and menstruation. In our results, PDM patients had significant higher VAS-rating during menstruaion than periovulation. Compared with the HC, PDM patients had lower gray matter density in the left anterior insula (aINS). Taken the left aINS as a seed region, we further found hypoconnectivity between aINS and medial prefrontal cortex (mPFC), which showed negative relation with the VAS during menstruation. As the aINS is a key site of the salience network (SN) and the mPFC is a critical region in the default mode network (DMN), it’s implicated a trait-related central-alteration that communications between pain attention and perception networks were disrupted without the ongoing menstrual pain. Moreover, result of correlation analysis, at least in part, suggested a possible role of altered FC (pain-free period) in predicting pain perception (menstruation).

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

Similar content being viewed by others

References

  • Amodio, D. M., & Frith, C. D. (2006). Meeting of minds: the medial frontal cortex and social cognition. Nature Reviews. Neuroscience, 7(4), 268–277.

    Article  CAS  PubMed  Google Scholar 

  • Andersson, J. L., Jenkinson, M. & Smith, S. (2007a) Non-linear optimisation. FMRIB Analysis Group Technical Reports. TR07JA1. Oxford: University of Oxford.

  • Andersson, J. L. R., Jenkinson, M., & Smith, S. (2007b). Non-linear registration, aka spatial normalisation FMRIB technical report TR07JA2. FMRIB Analysis Group of the University of Oxford.

  • Andrews-Hanna, J. R., Smallwood, J., & Spreng, R. N. (2014). The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Annals of the New York Academy of Sciences, 1316(1), 29–52.

    Article  PubMed  PubMed Central  Google Scholar 

  • Augustine, J. R. (1985). The insular lobe in primates including humans. Neurological Research, 7(1), 2–10.

    Article  CAS  PubMed  Google Scholar 

  • Baliki, M. N., & Apkarian, A. V. (2015). Nociception, pain, negative moods, and behavior selection. Neuron, 87(3), 474–491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baliki, M. N., Geha, P. Y., & Apkarian, A. V. (2009). Parsing pain perception between nociceptive representation and magnitude estimation. Journal of Neurophysiology, 101(2), 875–887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baliki, M. N., Petre, B., Torbey, S., Herrmann, K. M., Huang, L., Schnitzer, T. J., et al. (2012). Corticostriatal functional connectivity predicts transition to chronic back pain. Nature Neuroscience, 15(8), 1117–1119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baliki, M. N., Mansour, A. R., Baria, A. T., & Apkarian, A. V. (2014). Functional reorganization of the default mode network across chronic pain conditions. PloS One, 9(9), e106133.

    Article  PubMed  PubMed Central  Google Scholar 

  • Biswal, B. B., Mennes, M., Zuo, X. N., Gohel, S., Kelly, C., Smith, S. M., et al. (2010). Toward discovery science of human brain function. Proceedings of the National Academy of Sciences of the United States of America, 107(10), 4734–4739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Borsook, D., Edwards, R., Elman, I., Becerra, L., & Levine, J. (2013). Pain and analgesia: the value of salience circuits. Progress in Neurobiology, 10493–10105.

  • Borsook, D., Veggeberg, R., Erpelding, N., Borra, R., Linnman, C., Burstein, R., et al. (2015). The insula: a "hub of activity" in migraine. The Neuroscientist. doi:10.1177/1073858415601369.

    PubMed  Google Scholar 

  • Buhle, J. T., Silvers, J. A., Wager, T. D., Lopez, R., Onyemekwu, C., Kober, H., et al. (2014). Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cerebral Cortex, 24(11), 2981–2990.

    Article  PubMed  Google Scholar 

  • Cauda, F., Palermo, S., Costa, T., Torta, R., Duca, S., Vercelli, U., et al. (2014). Gray matter alterations in chronic pain: a network-oriented meta-analytic approach. Neuroimage Clin, 4, 676–686.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cerliani, L., Thomas, R. M., Jbabdi, S., Siero, J. C., Nanetti, L., Crippa, A., et al. (2012). Probabilistic tractography recovers a rostrocaudal trajectory of connectivity variability in the human insular cortex. Human Brain Mapping, 33(9), 2005–2034.

    Article  PubMed  Google Scholar 

  • Cloutman, L. L., Binney, R. J., Drakesmith, M., Parker, G. J., & Lambon Ralph, M. A. (2012). The variation of function across the human insula mirrors its patterns of structural connectivity: evidence from in vivo probabilistic tractography. NeuroImage, 59(4), 3514–3521.

    Article  PubMed  Google Scholar 

  • Crombez, G., Van Damme, S., & Eccleston, C. (2005). Hypervigilance to pain: an experimental and clinical analysis. Pain, 116(1–2), 4–7.

    Article  PubMed  Google Scholar 

  • Dawood, M. Y. (2006). Primary dysmenorrhea: advances in pathogenesis and management. Obstetrics and Gynecology, 108(2), 428–441.

    Article  PubMed  Google Scholar 

  • Douaud, G., Smith, S., Jenkinson, M., Behrens, T., Johansen-Berg, H., Vickers, J., et al. (2007). Anatomically related grey and white matter abnormalities in adolescent-onset schizophrenia. Brain, 130(Pt 9), 2375–2386.

    Article  PubMed  Google Scholar 

  • Duerden, E. G., & Albanese, M. C. (2013). Localization of pain-related brain activation: a meta-analysis of neuroimaging data. Human Brain Mapping, 34(1), 109–149.

    Article  PubMed  Google Scholar 

  • Dun, W., Yang, J., Yang, L., Ma, S., Guo, C., Zhang, X., et al. (2016). Abnormal white matter integrity during pain-free periovulation is associated with pain intensity in primary dysmenorrhea. Brain Imaging and Behavior. doi:10.1007/s11682-016-9582-x.

    Google Scholar 

  • Elsenbruch, S., Schmid, J., Kullmann, J. S., Kattoor, J., Theysohn, N., Forsting, M., et al. (2014). Visceral sensitivity correlates with decreased regional gray matter volume in healthy volunteers: a voxel-based morphometry study. Pain, 155(2), 244–249.

    Article  PubMed  Google Scholar 

  • Fritz, H.-C., McAuley, J. H., Wittfeld, K., Hegenscheid, K., Schmidt, C. O., Langner, S., et al. (2015). Chronic back pain is associated with decreased prefrontal and anterior insular gray matter: results from a population-based cohort study. The Journal of Pain, 17(1), 111–118.

    Article  PubMed  Google Scholar 

  • Geha, P., & Waxman, S. G. (2016). Pain perception: multiple matrices or one? JAMA Neurology, 73(6), 628–630.

    Article  PubMed  Google Scholar 

  • Geha, P. Y., Baliki, M. N., Harden, R. N., Bauer, W. R., Parrish, T. B., & Apkarian, A. V. (2008). The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron, 60(4), 570–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Good, C. D., Johnsrude, I. S., Ashburner, J., Henson, R. N., Friston, K. J., & Frackowiak, R. S. (2001). A voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage, 14(1 Pt 1), 21–36.

    Article  CAS  PubMed  Google Scholar 

  • Guenot, M., Isnard, J., & Sindou, M. (2004). Surgical anatomy of the insula. Advances and Technical Standards in Neurosurgery, 2, 9265–9288.

    Google Scholar 

  • Hashmi, J. A., Baliki, M. N., Huang, L., Baria, A. T., Torbey, S., Hermann, K. M., et al. (2013). Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain, 136(Pt 9), 2751–2768.

    Article  PubMed  PubMed Central  Google Scholar 

  • Isnard, J., Magnin, M., Jung, J., Mauguiere, F., & Garcia-Larrea, L. (2011). Does the insula tell our brain that we are in pain? Pain, 152(4), 946–951.

    Article  PubMed  Google Scholar 

  • Jenkinson, M., & Smith, S. (2001). A global optimisation method for robust affine registration of brain images. Medical Image Analysis, 5(2), 143–156.

    Article  CAS  PubMed  Google Scholar 

  • Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage, 17(2), 825–841.

    Article  PubMed  Google Scholar 

  • Kuchinad, A., Schweinhardt, P., Seminowicz, D. A., Wood, P. B., Chizh, B. A., & Bushnell, M. C. (2007). Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? The Journal of Neuroscience, 27(15), 4004–4007.

    Article  CAS  PubMed  Google Scholar 

  • Kucyi, A., & Davis, K. D. (2015). The dynamic pain connectome. Trends in Neurosciences, 38(2), 86–95.

    Article  CAS  PubMed  Google Scholar 

  • Kucyi, A., Salomons, T. V., & Davis, K. D. (2013). Mind wandering away from pain dynamically engages antinociceptive and default mode brain networks. Proceedings of the National Academy of Sciences of the United States of America, 110(46), 18692–18697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kurth, F., Zilles, K., Fox, P. T., Laird, A. R., & Eickhoff, S. B. (2010). A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis. Brain Structure & Function, 214(5–6), 519–534.

    Article  Google Scholar 

  • Lee, L. C., Tu, C. H., Chen, L. F., Shen, H. D., Chao, H. T., Lin, M. W., et al. (2014). Association of brain-derived neurotrophic factor gene Val66Met polymorphism with primary dysmenorrhea. PloS One, 9(11), e112766.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lisofsky, N., Martensson, J., Eckert, A., Lindenberger, U., Gallinat, J., & Kuhn, S. (2015). Hippocampal volume and functional connectivity changes during the female menstrual cycle. NeuroImage, 118, 154–162.

    Article  PubMed  Google Scholar 

  • Liu, P., Yang, J., Wang, G., Liu, Y., Liu, X., Jin, L., et al. (2015). Altered regional cortical thickness and subcortical volume in women with primary dysmenorrhoea. European Journal of Pain, 20(4), 512–520.

    Article  PubMed  Google Scholar 

  • Maleki, N., Becerra, L., Brawn, J., Bigal, M., Burstein, R., & Borsook, D. (2012). Concurrent functional and structural cortical alterations in migraine. Cephalalgia, 32(8), 607–620.

    Article  PubMed  Google Scholar 

  • Mayer, E. A., Gupta, A., Kilpatrick, L. A. & Hong, J. Y. (2015). Imaging brain mechanisms in chronic visceral pain. Pain, 156 Suppl 1S50–63.

  • Menon, V., & Uddin, L. Q. (2010). Saliency, switching, attention and control: a network model of insula function. Brain Structure & Function, 214(5–6), 655–667.

    Article  Google Scholar 

  • Mesulam, M. M., & Mufson, E. J. (1982). Insula of the old world monkey. III: efferent cortical output and comments on function. The Journal of Comparative Neurology, 212(1), 38–52.

    Article  CAS  PubMed  Google Scholar 

  • Moayedi, M., Weissman-Fogel, I., Crawley, A. P., Goldberg, M. B., Freeman, B. V., Tenenbaum, H. C., et al. (2011). Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder. NeuroImage, 55(1), 277–286.

    Article  PubMed  Google Scholar 

  • Morrow, C., & Naumburg, E. H. (2009). Dysmenorrhea. Primary Care, 36(1), 19–32.

    Article  PubMed  Google Scholar 

  • Mufson, E. J., & Mesulam, M. M. (1982). Insula of the old world monkey. II: afferent cortical input and comments on the claustrum. The Journal of Comparative Neurology, 212(1), 23–37.

    Article  CAS  PubMed  Google Scholar 

  • Napadow, V., LaCount, L., Park, K., As-Sanie, S., Clauw, D. J., & Harris, R. E. (2010). Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis and Rheumatism, 62(8), 2545–2555.

    Article  PubMed  PubMed Central  Google Scholar 

  • Nieuwenhuys, R. (2011). The insular cortex: a review. Progress in Brain Research, 195, 123–163.

    Article  Google Scholar 

  • Ploner, M., Lee, M. C., Wiech, K., Bingel, U., & Tracey, I. (2010). Prestimulus functional connectivity determines pain perception in humans. Proceedings of the National Academy of Sciences of the United States of America, 107(1), 355–360.

    Article  CAS  PubMed  Google Scholar 

  • Schweinhardt, P., Glynn, C., Brooks, J., McQuay, H., Jack, T., Chessell, I., et al. (2006). An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients. NeuroImage, 32(1), 256–265.

    Article  PubMed  Google Scholar 

  • Seeley, W. W., Menon, V., Schatzberg, A. F., Keller, J., Glover, G. H., Kenna, H., et al. (2007). Dissociable intrinsic connectivity networks for salience processing and executive control. The Journal of Neuroscience, 27(9), 2349–2356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155.

    Article  PubMed  Google Scholar 

  • Stankewitz, A., & May, A. (2011). Increased limbic and brainstem activity during migraine attacks following olfactory stimulation. Neurology, 77(5), 476–482.

    Article  PubMed  Google Scholar 

  • Starr, C. J., Sawaki, L., Wittenberg, G. F., Burdette, J. H., Oshiro, Y., Quevedo, A. S., et al. (2009). Roles of the insular cortex in the modulation of pain: insights from brain lesions. The Journal of Neuroscience, 29(9), 2684–2694.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tracey, I., & Mantyh, P. W. (2007). The cerebral signature for pain perception and its modulation. Neuron, 55(3), 377–391.

    Article  CAS  PubMed  Google Scholar 

  • Tu, C. H., Niddam, D. M., Chao, H. T., Liu, R. S., Hwang, R. J., Yeh, T. C., et al. (2009). Abnormal cerebral metabolism during menstrual pain in primary dysmenorrhea. NeuroImage, 47(1), 28–35.

    Article  PubMed  Google Scholar 

  • Tu, C. H., Niddam, D. M., Chao, H. T., Chen, L. F., Chen, Y. S., Wu, Y. T., et al. (2010). Brain morphological changes associated with cyclic menstrual pain. Pain, 150(3), 462–468.

    Article  PubMed  Google Scholar 

  • Tu, C. H., Niddam, D. M., Yeh, T. C., Lirng, J. F., Cheng, C. M., Chou, C. C., et al. (2013). Menstrual pain is associated with rapid structural alterations in the brain. Pain, 154(9), 1718–1724.

    Article  PubMed  Google Scholar 

  • Valfre, W., Rainero, I., Bergui, M., & Pinessi, L. (2008). Voxel-based morphometry reveals gray matter abnormalities in migraine. Headache, 48(1), 109–117.

    Article  PubMed  Google Scholar 

  • Vincent, K., Warnaby, C., Stagg, C. J., Moore, J., Kennedy, S., & Tracey, I. (2011). Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain, 152(9), 1966–1975.

    Article  PubMed  Google Scholar 

  • Wager, T. D., Atlas, L. Y., Lindquist, M. A., Roy, M., Woo, C. W., & Kross, E. (2013). An fMRI-based neurologic signature of physical pain. The New England Journal of Medicine, 368(15), 1388–1397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei, S. Y., Chao, H. T., Tu, C. H., Li, W. C., Low, I., Chuang, C. Y., et al. (2016). Changes in functional connectivity of pain modulatory systems in women with primary dysmenorrhea. Pain, 157(1), 92–102.

    Article  PubMed  Google Scholar 

  • Wiech, K., Lin, C. S., Brodersen, K. H., Bingel, U., Ploner, M., & Tracey, I. (2010). Anterior insula integrates information about salience into perceptual decisions about pain. The Journal of Neuroscience, 30(48), 16324–16331.

    Article  CAS  PubMed  Google Scholar 

  • Willis, W. D., Al-Chaer, E. D., Quast, M. J., & Westlund, K. N. (1999). A visceral pain pathway in the dorsal column of the spinal cord. Proceedings of the National Academy of Sciences of the United States of America, 96(14), 7675–7679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woo, C. W., Roy, M., Buhle, J. T., & Wager, T. D. (2015). Distinct brain systems mediate the effects of nociceptive input and self-regulation on pain. PLoS Biology, 13(1), e1002036.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu, T. H., Tu, C. H., Chao, H. T., Li, W. C., Low, I., Chuang, C. Y., et al. (2016). Dynamic changes of functional pain connectome in women with primary dysmenorrhea. Scientific Reports, 6, 624543.

    Google Scholar 

  • Xue, T., Yuan, K., Zhao, L., Yu, D., Zhao, L., Dong, T., et al. (2012). Intrinsic brain network abnormalities in migraines without aura revealed in resting-state fMRI. PloS One, 7(12), e52927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan, K., Zhao, L., Cheng, P., Yu, D., Zhao, L., Dong, T., et al. (2013). Altered structure and resting-state functional connectivity of the basal ganglia in migraine patients without aura. The Journal of Pain, 14(8), 836–844.

    Article  PubMed  Google Scholar 

  • Zahradnik, H. P., Hanjalic-Beck, A., & Groth, K. (2010). Nonsteroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review. Contraception, 81(3), 185–196.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. Medical Imaging, IEEE Transactions on, 20(1), 45–57.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Imaging, First Affiliated Hospital of Xi’an Jiaotong University, No. 277, West Yanta Road, Xi’an, 710061, Shaanxi-Province, People’s Republic of China

    Wang-huan Dun, Jing Yang, Ling Yang, Dun Ding, Xue-ying Ma, Feng-Li Liang, Shao-hui Ma, Xiao-ling Xu & Ming Zhang

  2. School of Life Science and Technology, Xidian University, Xi’an, 710071, China

    Karen M. von Deneen & Jixin Liu

Authors
  1. Wang-huan Dun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dun Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xue-ying Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng-Li Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Karen M. von Deneen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shao-hui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiao-ling Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jixin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jixin Liu or Ming Zhang.

Ethics declarations

Conflict of interest

Wanghuan Dun, Jing Yang, Ling Yang, Dun Ding, Shaohui Ma, Feng-Li Liang, Karen M. von Deneen, and Xiao-ling Xu critically reviewed the content and approved the final version for publication. They declared no conflict of interest.

Ethical approval

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

Ethical statements

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

Funding sources

This work was supported by the National Natural Science Foundation of China (Grant No. 81,371,530, 81,571,640 and 81,471,737) and the Research Funds of the First Affiliated Hospital of Xi’an Jiaotong University, College of Medicine (Grant No. 2014YK1).

Additional information

Wanghuan Dun and Jing Yang contributed equally to this work and should be considered co-first authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dun, Wh., Yang, J., Yang, L. et al. Abnormal structure and functional connectivity of the anterior insula at pain-free periovulation is associated with perceived pain during menstruation. Brain Imaging and Behavior 11, 1787–1795 (2017). https://doi.org/10.1007/s11682-016-9646-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-016-9646-y

Keywords

Search

Navigation