Altered functional connectivity patterns of insular subregions in major depressive disorder after electroconvulsive therapy

  • Lijie Wang
  • Qiang Wei
  • Chao Wang
  • Jinping Xu
  • Kai Wang
  • Yanghua TianEmail author
  • Jiaojian WangEmail author


Although electroconvulsive therapy (ECT) is an efficient treatment for major depressive disorder (MDD), however, it also brings memory impairment. The insula is a critical brain structure for coordinating affective, cognitive memory, saliency processing, and attention switching suggesting functional activity of insula maybe an important indicator to delineate the treatment and side effects of ECT. Here, Resting-state functional connectivity analyses of insular subregions were performed to reveal the changes of connectivity in 23 MDD patients before and after ECT and 25 healthy control (HC) and identified significantly increased functional connectivity of the right ventral anterior insular subregion with bilateral caudate, angular gyrus, and dorsolateral prefrontal cortex after ECT. Granger causality analyses identified significantly increased effective connectivity from dorsolateral prefrontal cortex to right angular gyrus in MDD patients after ECT. Furthermore, increased effective connectivity from dorsolateral prefrontal cortex to right angular gyrus exhibited significantly positive correlation with changed Hamilton Rating Scale for Depression scores. These results showed that ECT can normalize abnormal functional connectivity and effective connectivity in MDD. Our findings also indicated that the right ventral anterior insula and effective connectivity from dorsolateral prefrontal cortex to right angular gyrus are biomarkers of antidepressant effects during ECT of MDD.


ECT MDD Insular subregions Resting-state Granger causality analyses 



This work was supported by the Natural Science Foundation of China (31500867, 81601187, 81671354, and 81471117), the National Basic Research Program of China (973 program, 2015CB856400).

Supplementary material

11682_2018_13_MOESM1_ESM.docx (40 kb)
ESM 1 (DOCX 39 kb)


  1. Allen, M., Fardo, F., Dietz, M. J., Hillebrandt, H., Friston, K. J., Rees, G., & Roepstorff, A. (2016). Anterior insula coordinates hierarchical processing of tactile mismatch responses. Neuroimage, 127, 34–43.CrossRefGoogle Scholar
  2. Andreano, J. M., Touroutoglou, A., Dickerson, B. C., & Barrett, L. F. (2017). Resting connectivity between salience nodes predicts recognition memory. Social Cognitive and Affective Neuroscience, 12, 948–955.CrossRefGoogle Scholar
  3. Bastos, A. M., Usrey, W. M., Adams, R. A., Mangun, G. R., Fries, P., & Friston, K. J. (2012). Canonical microcircuits for predictive coding. Neuron, 76, 695–711.CrossRefGoogle Scholar
  4. Berman, M. G., Peltier, S., Nee, D. E., Kross, E., Deldin, P. J., & Jonides, J. (2011). Depression, rumination and the default network. Social Cognitive and Affective Neuroscience, 6, 548–555.CrossRefGoogle Scholar
  5. Biedermann, S. V., Bumb, J. M., Demirakca, T., Ende, G., & Sartorius, A. (2016). Improvement in verbal memory performance in depressed in-patients after treatment with electroconvulsive therapy. Acta Psychiatrica Scandinavica, 134, 461–468.CrossRefGoogle Scholar
  6. Bora, E., Harrison, B. J., Davey, C. G., Yucel, M., & Pantelis, C. (2012). Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder. Psychological Medicine, 42, 671–681.CrossRefGoogle Scholar
  7. Bouckaert, F., De Winter, F. L., Emsell, L., Dols, A., Rhebergen, D., Wampers, M., Sunaert, S., Stek, M., Sienaert, P., & Vandenbulcke, M. (2016). Grey matter volume increase following electroconvulsive therapy in patients with late life depression: A longitudinal MRI study. Journal of Psychiatry & Neuroscience, 41, 105–114.CrossRefGoogle Scholar
  8. Chang, L. J., Yarkoni, T., Khaw, M. W., & Sanfey, A. G. (2013). Decoding the role of the insula in human cognition: Functional parcellation and large-scale reverse inference. Cerebral Cortex, 23, 739–749.CrossRefGoogle Scholar
  9. Chiarello, C., Vazquez, D., Felton, A., & Leonard, C. M. (2013). Structural asymmetry of anterior insula: Behavioral correlates and individual differences. Brain and Language, 126, 109–122.CrossRefGoogle Scholar
  10. Craig, A. D. (2009). How do you feel--now? The anterior insula and human awareness. Nature Reviews. Neuroscience, 10, 59–70.CrossRefGoogle Scholar
  11. Cronin, D., Bodley, P., Potts, L., Mather, M. D., Gardner, R. K., & Tobin, J. C. (1970). Unilateral and bilateral ECT: A study of memory disturbance and relief from depression. Journal of Neurology, Neurosurgery, and Psychiatry, 33, 705–713.CrossRefGoogle Scholar
  12. Deen, B., Pitskel, N. B., & Pelphrey, K. A. (2011). Three systems of insular functional connectivity identified with cluster analysis. Cerebral Cortex, 21, 1498–1506.CrossRefGoogle Scholar
  13. Delgado, M. R., Miller, M. M., Inati, S., & Phelps, E. A. (2005). An fMRI study of reward-related probability learning. Neuroimage, 24, 862–873.CrossRefGoogle Scholar
  14. Diener, C., Kuehner, C., Brusniak, W., Ubl, B., Wessa, M., & Flor, H. (2012). A meta-analysis of neurofunctional imaging studies of emotion and cognition in major depression. Neuroimage, 61, 677–685.CrossRefGoogle Scholar
  15. Drevets, W. C., Price, J. L., & Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: Implications for neurocircuitry models of depression. Brain Structure & Function, 213, 93–118.CrossRefGoogle Scholar
  16. Ellard, K.K., Zimmerman, J.P., Kaur, N., Dijk, K.R.A.V., Roffman, J.L., Nierenberg, A.A., Dougherty, D.D., Deckersbach, T., Camprodon, J.A., 2018. Functional connectivity between anterior insula and key nodes of frontoparietal executive control and salience networks distinguish bipolar depression from unipolar depression and healthy controls. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging In Press.Google Scholar
  17. Engelmann, J. B., Berns, G. S., & Dunlop, B. W. (2017). Hyper-responsivity to losses in the anterior insula during economic choice scales with depression severity. Psychological Medicine, 47, 2879–2891.CrossRefGoogle Scholar
  18. Fan, L., Li, H., Zhuo, J., Zhang, Y., Wang, J., Chen, L., Yang, Z., Chu, C., Xie, S., Laird, A. R., Fox, P. T., Eickhoff, S. B., Yu, C., & Jiang, T. (2016). The human Brainnetome atlas: A new brain atlas based on connectional architecture. Cerebral Cortex, 26, 3508–3526.CrossRefGoogle Scholar
  19. Fitzgerald, P. B., Laird, A. R., Maller, J., & Daskalakis, Z. J. (2008). A meta-analytic study of changes in brain activation in depression. Human Brain Mapping, 29, 683–695.CrossRefGoogle Scholar
  20. Gotts, S. J., Saad, Z. S., Jo, H. J., Wallace, G. L., Cox, R. W., & Martin, A. (2013). The perils of global signal regression for group comparisons: A case study of autism Spectrum disorders. Frontiers in Human Neuroscience, 7, 356.CrossRefGoogle Scholar
  21. Goulden, N., Khusnulina, A., Davis, N. J., Bracewell, R. M., Bokde, A. L., McNulty, J. P., & Mullins, P. G. (2014). The salience network is responsible for switching between the default mode network and the central executive network: Replication from DCM. Neuroimage, 99, 180–190.CrossRefGoogle Scholar
  22. Guo, W., Liu, F., Xiao, C., Zhang, Z., Liu, J., Yu, M., Zhang, J., & Zhao, J. (2015). Decreased insular connectivity in drug-naive major depressive disorder at rest. Journal of Affective Disorders, 179, 31–37.CrossRefGoogle Scholar
  23. Ham, T., Leff, A., de Boissezon, X., Joffe, A., & Sharp, D. J. (2013). Cognitive control and the salience network: An investigation of error processing and effective connectivity. The Journal of Neuroscience, 33, 7091–7098.CrossRefGoogle Scholar
  24. Hamilton, M. (1960). A rating scale for depression. Journal of Neurology Neurosurgery and Psychiatry, 23, 56–62.CrossRefGoogle Scholar
  25. Haq, A. U., Sitzmann, A. F., Goldman, M. L., Maixner, D. F., & Mickey, B. J. (2015). Response of depression to electroconvulsive therapy: A meta-analysis of clinical predictors. The Journal of Clinical Psychiatry, 76, 1374–1384.CrossRefGoogle Scholar
  26. Harvey, P. O., Pruessner, J., Czechowska, Y., & Lepage, M. (2007). Individual differences in trait anhedonia: A structural and functional magnetic resonance imaging study in non-clinical subjects. Molecular Psychiatry, 12(703), 767–775.CrossRefGoogle Scholar
  27. Janeš, I. (2015). Insular cortex - review. Gyrus, 3, 108–114.CrossRefGoogle Scholar
  28. Kellner, C. H., Farber, K. G., Chen, X. R., Mehrotra, A., & Zipursky, G. D. N. (2017). A systematic review of left unilateral electroconvulsive therapy. Acta Psychiatrica Scandinavica, 136, 166–176.CrossRefGoogle Scholar
  29. Kertz, S. J., Koran, J., Stevens, K. T., & Bjorgvinsson, T. (2015). Repetitive negative thinking predicts depression and anxiety symptom improvement during brief cognitive behavioral therapy. Behaviour Research and Therapy, 68, 54–63.CrossRefGoogle Scholar
  30. 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, 519–534.CrossRefGoogle Scholar
  31. Lanzenberger, R., Baldinger, P., Hahn, A., Ungersboeck, J., Mitterhauser, M., Winkler, D., Micskei, Z., Stein, P., Karanikas, G., Wadsak, W., Kasper, S., & Frey, R. (2013). Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET. Molecular Psychiatry, 18, 93–100.CrossRefGoogle Scholar
  32. Liu, Z., Xu, C., Xu, Y., Wang, Y., Zhao, B., Lv, Y., Cao, X., Zhang, K., & Du, C. (2010). Decreased regional homogeneity in insula and cerebellum: A resting-state fMRI study in patients with major depression and subjects at high risk for major depression. Psychiatry Research, 182, 211–215.CrossRefGoogle Scholar
  33. Lui, S., Wu, Q., Qiu, L., Yang, X., Kuang, W., Chan, R. C., Huang, X., Kemp, G. J., Mechelli, A., & Gong, Q. (2011). Resting-state functional connectivity in treatment-resistant depression. The American Journal of Psychiatry, 168, 642–648.CrossRefGoogle Scholar
  34. Menon, V. (2011). Large-scale brain networks and psychopathology: A unifying triple network model. Trends in Cognitive Sciences, 15, 483–506.CrossRefGoogle Scholar
  35. Menon, V., & Uddin, L. Q. (2010). Saliency, switching, attention and control: A network model of insula function. Brain Structure & Function, 214, 655–667.CrossRefGoogle Scholar
  36. Nelson, S. M., Dosenbach, N. U., Cohen, A. L., Wheeler, M. E., Schlaggar, B. L., & Petersen, S. E. (2010). Role of the anterior insula in task-level control and focal attention. Brain Structure & Function, 214, 669–680.CrossRefGoogle Scholar
  37. Oltedal, L., Kessler, U., Ersland, L., Gruner, R., Andreassen, O. A., Haavik, J., Hoff, P. I., Hammar, A., Dale, A. M., Hugdahl, K., & Oedegaard, K. J. (2015). Effects of ECT in treatment of depression: Study protocol for a prospective neuroradiological study of acute and longitudinal effects on brain structure and function. BMC Psychiatry, 15, 94.CrossRefGoogle Scholar
  38. Pizzagalli, D. A., Holmes, A. J., Dillon, D. G., Goetz, E. L., Birk, J. L., Bogdan, R., Dougherty, D. D., Iosifescu, D. V., Rauch, S. L., & Fava, M. (2009). Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. The American Journal of Psychiatry, 166, 702–710.CrossRefGoogle Scholar
  39. Rothkirch, M., Tonn, J., Kohler, S., & Sterzer, P. (2017). Neural mechanisms of reinforcement learning in unmedicated patients with major depressive disorder. Brain, 140, 1147–1157.CrossRefGoogle Scholar
  40. Saad, Z. S., Reynolds, R. C., Jo, H. J., Gotts, S. J., Chen, G., Martin, A., & Cox, R. W. (2013). Correcting brain-wide correlation differences in resting-state FMRI. Brain Connectivity, 3, 339–352.CrossRefGoogle Scholar
  41. Seeley, W. W., Merkle, F. T., Gaus, S. E., Craig, A. D., Allman, J. M., & Hof, P. R. (2011). Distinctive neurons of the anterior cingulate and frontoinsular cortex: A historical perspective. Cerebral Cortex, 22, 245–250.CrossRefGoogle Scholar
  42. Semkovska, M., & McLoughlin, D. M. (2010). Objective cognitive performance associated with electroconvulsive therapy for depression: A systematic review and meta-analysis. Biological Psychiatry, 68, 568–577.CrossRefGoogle Scholar
  43. Seth, A. K. (2010). A MATLAB toolbox for granger causal connectivity analysis. Journal of Neuroscience Methods, 186, 262–273.CrossRefGoogle Scholar
  44. Seth, A. K. (2013). Interoceptive inference, emotion, and the embodied self. Trends in Cognitive Sciences, 17, 565–573.CrossRefGoogle Scholar
  45. Spati, J., Chumbley, J., Brakowski, J., Dorig, N., Grosse Holtforth, M., Seifritz, E., & Spinelli, S. (2014). Functional lateralization of the anterior insula during feedback processing. Human Brain Mapping, 35, 4428–4439.CrossRefGoogle Scholar
  46. Sridharan, D., Levitin, D. J., & Menon, V. (2008). A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proceedings of the National Academy of Sciences of the United States of America, 105, 12569–12574.CrossRefGoogle Scholar
  47. Sun, H., Luo, L., Yuan, X., Zhang, L., He, Y., Yao, S., Wang, J., & Xiao, J. (2018). Regional homogeneity and functional connectivity patterns in major depressive disorder, cognitive vulnerability to depression and healthy subjects. Journal of Affective Disorders, 235, 229–235.CrossRefGoogle Scholar
  48. Uddin, L. Q., Kinnison, J., Pessoa, L., & Anderson, M. L. (2014). Beyond the tripartite cognition-emotion-interoception model of the human insular cortex. Journal of Cognitive Neuroscience, 26, 16–27.CrossRefGoogle Scholar
  49. Uddin, L. Q., Nomi, J. S., Hebert-Seropian, B., Ghaziri, J., & Boucher, O. (2017). Structure and function of the human insula. Journal of Clinical Neurophysiology, 34, 300–306.CrossRefGoogle Scholar
  50. van Eijndhoven, P., Mulders, P., Kwekkeboom, L., van Oostrom, I., van Beek, M., Janzing, J., Schene, A., & Tendolkar, I. (2016). Bilateral ECT induces bilateral increases in regional cortical thickness. Translational Psychiatry, 6, e874.CrossRefGoogle Scholar
  51. Wang, L., Hermens, D. F., Hickie, I. B., & Lagopoulos, J. (2012). A systematic review of resting-state functional-MRI studies in major depression. Journal of Affective Disorders, 142, 6–12.CrossRefGoogle Scholar
  52. Wang, J., Fan, L., Wang, Y., Xu, W., Jiang, T., Fox, P. T., Eickhoff, S. B., Yu, C., & Jiang, T. (2015a). Determination of the posterior boundary of Wernicke's area based on multimodal connectivity profiles. Human Brain Mapping, 36, 1908–1924.CrossRefGoogle Scholar
  53. Wang, Y. Q., Li, R., Zhang, M. Q., Zhang, Z., Qu, W. M., & Huang, Z. L. (2015b). The neurobiological mechanisms and treatments of REM sleep disturbances in depression. Current Neuropharmacology, 13, 543–553.CrossRefGoogle Scholar
  54. Wang, J., Tian, Y., Wang, M., Cao, L., Wu, H., Zhang, Y., Wang, K., & Jiang, T. (2016). A lateralized top-down network for visuospatial attention and neglect. Brain Imaging and Behavior, 10, 1029–1037.CrossRefGoogle Scholar
  55. Wang, C., Wu, H., Chen, F., Xu, J., Li, H., Li, H., & Wang, J. (2017a). Disrupted functional connectivity patterns of the insula subregions in drug-free major depressive disorder. Journal of Affective Disorders, 234, 297–304.CrossRefGoogle Scholar
  56. Wang, J., Wei, Q., Bai, T., Zhou, X., Sun, H., Becker, B., Tian, Y., Wang, K., & Kendrick, K. (2017b). Electroconvulsive therapy selectively enhanced feedforward connectivity from fusiform face area to amygdala in major depressive disorder. Social Cognitive and Affective Neuroscience, 12, 1983–1992.CrossRefGoogle Scholar
  57. Wang, J., Wei, Q., Yuan, X., Jiang, X., Xu, J., Zhou, X., Tian, Y., & Wang, K. (2017c). Local functional connectivity density is closely associated with the response of electroconvulsive therapy in major depressive disorder. Journal of Affective Disorders, 225, 658–664.CrossRefGoogle Scholar
  58. Wang, J., Wei, Q., Wang, L., Zhang, H., Bai, T., Cheng, L., Tian, Y., & Wang, K. (2018). Functional reorganization of intra- and internetwork connectivity in major depressive disorder after electroconvulsive therapy. Human Brain Mapping, 39, 1403–1411.CrossRefGoogle Scholar
  59. Wei, Q., Tian, Y., Yu, Y., Zhang, F., Hu, X., Dong, Y., Chen, Y., Hu, P., Hu, X., & Wang, K. (2014). Modulation of interhemispheric functional coordination in electroconvulsive therapy for depression. Translational Psychiatry, 4, e453.CrossRefGoogle Scholar
  60. Wu, Q. Z., Li, D. M., Kuang, W. H., Zhang, T. J., Lui, S., Huang, X. Q., Chan, R. C., Kemp, G. J., & Gong, Q. Y. (2011). Abnormal regional spontaneous neural activity in treatment-refractory depression revealed by resting-state fMRI. Human Brain Mapping, 32, 1290–1299.CrossRefGoogle Scholar
  61. Wu, H., Sun, H., Xu, J., Wu, Y., Wang, C., Xiao, J., She, S., Huang, J., Zou, W., Peng, H., Lu, X., Huang, G., Jiang, T., Ning, Y., & Wang, J. (2016). Changed hub and corresponding functional connectivity of Subgenual anterior cingulate cortex in major depressive disorder. Frontiers in Neuroanatomy, 10, 120.PubMedPubMedCentralGoogle Scholar
  62. Wu, H., Sun, H., Wang, C., Yu, L., Li, Y., Peng, H., Lu, X., Hu, Q., Ning, Y., Jiang, T., Xu, J., & Wang, J. (2017). Abnormalities in the structural covariance of emotion regulation networks in major depressive disorder. Journal of Psychiatric Research, 84, 237–242.CrossRefGoogle Scholar
  63. Zhang, W. N., Chang, S. H., Guo, L. Y., Zhang, K. L., & Wang, J. (2013). The neural correlates of reward-related processing in major depressive disorder: A meta-analysis of functional magnetic resonance imaging studies. Journal of Affective Disorders, 151, 531–539.CrossRefGoogle Scholar
  64. Zhang, X., Di, X., Lei, H., Yang, J., Xiao, J., Wang, X., Yao, S., & Rao, H. (2016). Imbalanced spontaneous brain activity in orbitofrontal-insular circuits in individuals with cognitive vulnerability to depression. Journal of Affective Disorders, 198, 56–63.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Lab for NeuroinformationUniversity of Electronic Science and Technology of ChinaChengduChina
  2. 2.School of life Science and technologyUniversity of Electronic Science and Technology of ChinaChengduChina
  3. 3.Department of NeurologyThe First Hospital of Anhui Medical UniversityHefeiChina
  4. 4.College of Psychology and SociologyShenzhen UniversityShenzhenChina
  5. 5.Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenChina
  6. 6.Department of Medical PsychologyAnhui Medical UniversityHefeiChina
  7. 7.Anhui Province Key Laboratory of Cognition and Neuropsychiatric DisordersHefeiChina
  8. 8.Collaborative Innovation Center for Neuropsychiatric Disorders and Mental HealthHefeiChina

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