Functional connectivity density abnormalities and anxiety in primary insomnia patients

Abstract

Primary insomnia (PI) is strongly associated with emotional dysregulation. However, the neurobiological pathology of the association between PI and emotional dysregulation is limited. Previous studies have indicated an impact of PI on the emotional regulatory system, but the specificity of this finding remains to be confirmed. A sample of 27 primary insomnia patients (PIs) and 32 matched healthy controls (HCs) was recruited for this study. The functional connectivity density (FCD) was used to assess the spontaneous functional brain organization in PIs. Then, we identified whether the local (lFCD) and global FCD (gFCD) abnormalities can be the potential biomarker for emotion level in PIs. Our findings suggested that PIs exhibited higher levels of anxiety and depression, and the levels of anxiety and depression is associated with the insomnia severity. We also found that PIs showed both lower lFCD and gFCD in several regions (i.e. thalamus, anterior cingulate cortex (ACC), insula). Furthermore, the lower gFCD values of left ACC and right insula were associated with their anxiety level in PIs, which demonstrated their potential biomarker for anxiety in PIs. Our results demonstrated that the relationship between the insomnia severity and the anxiety level could be partially mediated by gFCD of the ACC and insula. The current study improved our understanding of the anxiety in PIs and provided helpful information for future therapeutic development for PIs.

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References

  1. Ancoli-Israel, S., & Roth, T. (1999). Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation survey I. Sleep, 22, S347–S353.

    PubMed  Google Scholar 

  2. BøRge, S., Paula, S., Arnstein, M., Mari, H., StåLe, P., Steinar, K., et al. (2012). The bidirectional association between depression and insomnia: the HUNT study. Psychosomatic Medicine, 74(7), 758–765.

    Article  Google Scholar 

  3. Bruno, R. M., & Sakmann, B. (2006). Cortex is driven by weak but synchronously active thalamocortical synapses. Science, 312(5780), 1622–1627.

    CAS  Article  Google Scholar 

  4. Buysse, D. J., Jules, A., Alex, G., Vladeta, A., Dominique, E., & Wulf, R. S. (2008). Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep, 31(4), 473–480.

    Article  Google Scholar 

  5. Cano, G., Mochizuki, T., & Saper, C. B. (2008). Neural circuitry of stress-induced insomnia in rats. Journal of Neuroscience, 28(40), 10167–10184.

    CAS  Article  Google Scholar 

  6. Caparelli, E. C., Tomasi, D., & Ernst, T. (2005). The effect of small rotations on R 2 * measured with echo planar imaging. Neuroimage, 24(4), 1164–1169.

    Article  Google Scholar 

  7. Chen, M. C., Chang, C., Glover, G. H., & Gotlib, I. H. (2014). Increased insula coactivation with salience networks in insomnia. Biological Psychology, 97, 1–8.

    Article  Google Scholar 

  8. Chen, P. J., Huang, C. L., Weng, S. F., Wu, M. P., Ho, C. H., Wang, J. J., et al. (2017). Relapse insomnia increases greater risk of anxiety and depression: evidence from a population-based 4-year cohort study. Sleep Medicine, 38, 122.

    Article  Google Scholar 

  9. Cooper, J. (2001). Diagnostic and statistical manual of mental disorders (4th edn, text revision)(DsM-IV-TR). RCP.

  10. Cordes, D., ., Haughton, V. M., Arfanakis, K., ., Carew, J. D., Turski, P. A., Moritz, C. H., Quigley M.A., Meyerand M.E. (2001). Frequencies contributing to functional connectivity in the cerebral cortex in “resting-state” data. AJNR American Journal of Neuroradiology, 22(7), 1326–1333.

    CAS  PubMed  Google Scholar 

  11. Del Felice, A., Formaggio, E., Storti, S. F., Fiaschi, A., & Manganotti, P. (2012). The gating role of the thalamus to protect sleep: An f-MRI report. Sleep Medicine, 13(4), 447–449.

    Article  Google Scholar 

  12. Desseilles, M., Dang-Vu, T., Schabus, M., Sterpenich, V., Maquet, P., & Schwartz, S. (2008). Neuroimaging insights into the pathophysiology of sleep disorders. Sleep, 31(6), 777–794.

    Article  Google Scholar 

  13. Eklund, A., Nichols, T. E., & Knutsson, H. (2016). Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proceedings of the National Academy of Sciences of the United States of America, 113(28), 7900–7905.

    CAS  Article  Google Scholar 

  14. Evans, K. C., Simon, N. M., Dougherty, D. D., Hoge, E. A., Worthington, J. J., Chow, C., Kaufman, R. E., Gold, A. L., Fischman, A. J., Pollack, M. H., & Rauch, S. L. (2009). A PET study of tiagabine treatment implicates ventral medial prefrontal cortex in generalized social anxiety disorder. Neuropsychopharmacology, 34(2), 390–398.

    CAS  Article  Google Scholar 

  15. Foerster, B. U., Dardo, T., & Caparelli, E. C. (2010). Magnetic field shift due to mechanical vibration in functional magnetic resonance imaging. Magnetic Resonance in Medicine, 54(5), 1261–1267.

    Article  Google Scholar 

  16. Ford, D. E., & Kamerow, D. B. (2016). Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention? Jama, 262(11), 1479–1484.

    Article  Google Scholar 

  17. Frewen, P. A., Dozois, D. J., & Lanius, R. A. (2008). Neuroimaging studies of psychological interventions for mood and anxiety disorders: empirical and methodological review. Clinical Psychology Review, 28(2), 228–246.

    Article  Google Scholar 

  18. Gentili, C., Gobbini, M. I., Ricciardi, E., Vanello, N., Pietrini, P., Haxby, J. V., & Guazzelli, M. (2008). Differential modulation of neural activity throughout the distributed neural system for face perception in patients with social phobia and healthy subjects. Brain Research Bulletin, 77(5), 286–292.

    Article  Google Scholar 

  19. Hoehn-Saric, R., Schlund, M. W., & Wong, S. H. (2004). Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder. Psychiatry Research: Neuroimaging, 131(1), 11–21.

    CAS  Article  Google Scholar 

  20. Holzschneider, K., & Mulert, C. (2011). Neuroimaging in anxiety disorders. Dialogues in Clinical Neuroscience, 13(4), 453–461.

    Article  Google Scholar 

  21. Huang, Z., Liang, P., Jia, X., Zhan, S., Li, N., Ding, Y., Lu, J., Wang, Y., & Li, K. (2012). Abnormal amygdala connectivity in patients with primary insomnia: evidence from resting state fMRI. European Journal of Radiology, 81(6), 1288–1295.

    Article  Google Scholar 

  22. Kyle, S. D., Espie, C. A., & Morgan, K. (2010). “ … Not just a minor thing, it is something major, which stops you from functioning daily”: quality of life and daytime functioning in insomnia. Behavioral Sleep Medicine, 8(3), 123–140.

    Article  Google Scholar 

  23. Leppänen, J. M. (2006). Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings. Current Opinion in Psychiatry, 19(1), 34–39.

    Article  Google Scholar 

  24. Levin, B., & Duchowny, M. (1991). Childhood obsessive-compulsive disorder and cingulate epilepsy. Biological Psychiatry, 30(10), 1049–1055.

    CAS  Article  Google Scholar 

  25. Liu, C.-H., Liu, C.-Z., Zhang, J., Yuan, Z., Tang, L.-R., Tie, C.-L., Fan, J., & Liu, Q. Q. (2016). Reduced spontaneous neuronal activity in the insular cortex and thalamus in healthy adults with insomnia symptoms. Brain Research, 1648, 317–324.

    CAS  Article  Google Scholar 

  26. Mayberg, H. S., Liotti, M., Brannan, S. K., McGinnis, S., Mahurin, R. K., Jerabek, P. A., et al. (1999). Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. American Journal of Psychiatry, 156(5), 675–682.

    CAS  Google Scholar 

  27. Min, L., Wang, R., Meng, Z., Zhai, J., Bo, L., Yu, D., et al. (2018). Abnormalities of thalamus volume and resting state functional connectivity in primary insomnia patients. Brain Imaging & Behavior, 1–9.

  28. Monti, J. M., & Monti, D. (2000). Sleep disturbance in generalized anxiety disorder and its treatment. Sleep Medicine Reviews, 4(3), 263–276.

    Article  Google Scholar 

  29. Nofzinger, E. A., Buysse, D. J., Miewald, J. M., Meltzer, C. C., Price, J. C., Sembrat, R. C., et al. (2002). Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking. Brain, 125(5), 1105–1115.

    Article  Google Scholar 

  30. Nofzinger, E. A., Buysse, D. J., Germain, A., Price, J. C., Miewald, J. M., & Kupfer, D. J. (2004). Functional neuroimaging evidence for hyperarousal in insomnia. American Journal of Psychiatry, 161(11), 2126–2128.

    Article  Google Scholar 

  31. Nofzinger, E. A., Nissen, C., Germain, A., Moul, D., Hall, M., Price, J. C., Miewald, J. M., & Buysse, D. J. (2006). Regional cerebral metabolic correlates of WASO during NREM sleep in insomnia. Journal of Clinical Sleep Medicine, 2(3), 316–322.

    Article  Google Scholar 

  32. Paulus, M. P., & Stein, M. B. (2006). An insular view of anxiety. Biological Psychiatry, 60(4), 383–387.

    Article  Google Scholar 

  33. Paulus, M. P., & Stein, M. B. (2010). Interoception in anxiety and depression. Brain Structure and Function, 214(5–6), 451–463.

    Article  Google Scholar 

  34. Périco, C. A.-M., Skaf, C. R., Yamada, A., Duran, F., Buchpiguel, C. A., Castro, C. C., et al. (2005). Relationship between regional cerebral blood flow and separate symptom clusters of major depression: a single photon emission computed tomography study using statistical parametric mapping. Neuroscience letters, 384(3), 265-270.

  35. Plante, D. T., Jensen, J. E., Schoerning, L., & Winkelman, J. W. (2012). Reduced γ-aminobutyric acid in occipital and anterior cingulate cortices in primary insomnia: a link to major depressive disorder? Neuropsychopharmacology, 37(6), 1548–1557.

    CAS  Article  Google Scholar 

  36. Riemann, D., Spiegelhalder, K., Feige, B., Voderholzer, U., Berger, M., Perlis, M., & Nissen, C. (2010). The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Medicine Reviews, 14(1), 19–31.

    Article  Google Scholar 

  37. Rive, M. M., van Rooijen, G., Veltman, D. J., Phillips, M. L., Schene, A. H., & Ruhé, H. G. (2013). Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. Neuroscience & Biobehavioral Reviews, 37(10), 2529–2553.

    Article  Google Scholar 

  38. Shin, L. M., Dougherty, D. D., Orr, S. P., Pitman, R. K., Lasko, M., Macklin, M. L., Alpert, N. M., Fischman, A. J., & Rauch, S. L. (2000). Activation of anterior paralimbic structures during guilt-related script-driven imagery. Biological Psychiatry, 48(1), 43–50.

    CAS  Article  Google Scholar 

  39. Stoffers, D., Moens, S., Benjamins, J. S., Van Tol, M., Penninx, B. W. J. H., Veltman, D. J., et al. (2012). Orbitofrontal gray matter relates to early morning awakening: a neural correlate of insomnia complaints? Frontiers in Neurology, 3, 105–105.

    Article  Google Scholar 

  40. 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.

    CAS  Article  Google Scholar 

  41. Wang, T., Li, S., Jiang, G., Lin, C., Li, M., Ma, X., Zhan, W., Fang, J., Li, L., Li, C., & Tian, J. (2016). Regional homogeneity changes in patients with primary insomnia. European Radiology, 26(5), 1292–1300.

    Article  Google Scholar 

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Acknowledgements

The study was supported by the academic capability and leaders training program supported by Hebei province Foundation.

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Correspondence to Yifei Zhu or Ming Zhang.

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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.

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Zhu, Y., Zhao, X., Yin, H. et al. Functional connectivity density abnormalities and anxiety in primary insomnia patients. Brain Imaging and Behavior 15, 114–121 (2021). https://doi.org/10.1007/s11682-019-00238-w

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Keywords

  • Insomnia
  • Functional connectivity density
  • Anxiety
  • Anterior cingulate cortex
  • Insula