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Decreased functional connectivity of hippocampal subregions and methylation of the NR3C1 gene in Han Chinese adults who lost their only child

Published online by Cambridge University Press:  27 January 2020

Rongfeng Qi Open the ORCID record for Rongfeng Qi [Opens in a new window] ,
Yifeng Luo ,
Li Zhang ,
Yifei Weng ,
Wesley Surento ,
Qiang Xu ,
Neda Jahanshad ,
Lingjiang Li ,
Zhihong Cao  and
Guang Ming Lu
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Rongfeng Qi
Affiliation:
Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, 90292, USA
Yifeng Luo
Affiliation:
Department of Radiology, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, 75 Tongzhenguan Road, 214200, Wuxi, China
Li Zhang
Affiliation:
Mental Health Institute, the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan, 410011, China
Yifei Weng
Affiliation:
Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
Wesley Surento
Affiliation:
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, 90292, USA
Qiang Xu
Affiliation:
Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
Neda Jahanshad
Affiliation:
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, 90292, USA
Lingjiang Li
Affiliation:
Mental Health Institute, the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, Changsha, Hunan, 410011, China
Zhihong Cao*
Affiliation:
Department of Radiology, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, 75 Tongzhenguan Road, 214200, Wuxi, China
Guang Ming Lu*
Affiliation:
Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
Paul M. Thompson
Affiliation:
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, CA, 90292, USA
*
Author for correspondence: Guangming Lu, E-mail: [email protected]; Zhihong Cao, E-mail: [email protected]
Author for correspondence: Guangming Lu, E-mail: [email protected]; Zhihong Cao, E-mail: [email protected]
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Abstract

Background

Losing one's only child is a major traumatic life event that may lead to post-traumatic stress disorder (PTSD); however, the underlying mechanisms of its psychological consequences remain poorly understood. Here, we investigated subregional hippocampal functional connectivity (FC) networks based on resting-state functional magnetic resonance imaging and the deoxyribonucleic acid methylation of the human glucocorticoid receptor gene (NR3C1) in adults who had lost their only child.

Methods

A total of 144 Han Chinese adults who had lost their only child (51 adults with PTSD and 93 non-PTSD adults [trauma-exposed controls]) and 50 controls without trauma exposure were included in this fMRI study (age: 40–67 years). FCs between hippocampal subdivisions (four regions in each hemisphere: cornu ammonis1 [CA1], CA2, CA3, and dentate gyrus [DG]) and methylation levels of the NR3C1 gene were compared among the three groups.

Results

Trauma-exposed adults, regardless of PTSD diagnosis, had weaker positive FC between the left hippocampal CA1, left DG, and the posterior cingulate cortex, and weaker negative FC between the right CA1, right DG, and several frontal gyri, relative to healthy controls. Compared to non-PTSD adults, PTSD adults showed decreased negative FC between the right CA1 region and the right middle/inferior frontal gyri (MFG/IFG), and decreased negative FC between the right DG and the right superior frontal gyrus and left MFG. Both trauma-exposed groups showed lower methylation levels of the NR3C1 gene.

Conclusions

Adults who had lost their only child may experience disrupted hippocampal network connectivity and NR3C1 methylation status, regardless of whether they have developed PTSD.

Keywords

Functional connectivityhippocampusloss of only childNR3C1 methylationpost-traumatic stress disorder
Type
Original Articles
Information
Psychological Medicine , Volume 51 , Issue 8 , June 2021 , pp. 1310 - 1319
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Copyright
Copyright © Cambridge University Press 2020

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Footnotes

*

Rongfeng Qi and Yifeng Luo contributed equally to this work.

References

Akiki, T. J., Averill, C. L., Wrocklage, K. M., Scott, J. C., Averill, L. A., Schweinsburg, B., … Abdallah, C. G. (2018). Default mode network abnormalities in posttraumatic stress disorder: A novel network-restricted topology approach. Neuroimage, 176, 489–498.CrossRefGoogle ScholarPubMed
Basten, S., & Jiang, Q. (2014). China's family planning policies: Recent reforms and future prospects. Studies in Family Planning, 45, 493–509.CrossRefGoogle ScholarPubMed
Bauer, M. (2018). Cell-type-specific disturbance of DNA methylation pattern: A chance to get more benefit from and to minimize cohorts for epigenome-wide association studies. International Journal of Epidemiology. https://www.ncbi.nlm.nih.gov/pubmed/29506027, Epub ahead of print. doi: 10.1093/ije/dyy029.CrossRefGoogle ScholarPubMed
Bluhm, R. L., Williamson, P. C., Osuch, E. A., Frewen, P. A., Stevens, T. K., Boksman, K., … Lanius, R. A. (2009). Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma. Journal of Psychiatry & Neuroscience, 34, 187–194.Google ScholarPubMed
Braun, K. (2011). The prefrontal-limbic system: Development, neuroanatomy, function, and implications for socioemotional development. Clinics in Perinatology, 38, 685–702.CrossRefGoogle ScholarPubMed
Bremner, J. D., Innis, R. B., Ng, C. K., Staib, L. H., Salomon, R. M., Bronen, R. A., … Charney, D. S. (1997). Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Archives Of General Psychiatry, 54, 246–254.CrossRefGoogle ScholarPubMed
Chen, A. C., & Etkin, A. (2013). Hippocampal network connectivity and activation differentiates post-traumatic stress disorder from generalized anxiety disorder. Neuropsychopharmacology, 38, 1889–1898.CrossRefGoogle ScholarPubMed
Cheng, Y., Liu, C., Mao, C., Qian, J., Liu, K., & Ke, G. (2008). Social support plays a role in depression in Parkinson's disease: A cross-section study in a Chinese cohort. Parkinsonism & Related Disorders, 14, 43–45.CrossRefGoogle Scholar
Ding, M., Chen, Y., & Bressler, S. L. (2006). Granger causality: Basic theory and application to neuroscience. In Schelter, B., Winterhalder, W. & Timmer, J. (Eds.), Handbook of time series analysis: Recent theoretical developments and applications (pp. 437–460). Berlin: Wiley-VCH Verlag.CrossRefGoogle Scholar
Eickhoff, S. B., Stephan, K. E., Mohlberg, H., Grefkes, C., Fink, G. R., Amunts, K., & Zilles, K. (2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage, 25, 1325–1335.CrossRefGoogle ScholarPubMed
Etkin, A., & Wager, T. D. (2007). Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. American Journal of Psychiatry, 164, 1476–1488.CrossRefGoogle ScholarPubMed
Fayed, N., Torres, C., Morales, H., & Viguera, L. (2019). Neuroimaging studies in psychotic disorders. In Gargiulo, P. Á. & Mesones-Arroyo, H. L. (Eds.), Psychiatry and neuroscience Update (pp. 371–378). Switzerland: Springer.CrossRefGoogle Scholar
First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. (2002). Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition. SCID-I/P New York, NY.Google Scholar
Folstein, M. F., Robins, L. N., & Helzer, J. E. (1983). The mini-mental state examination. Archives of General Psychiatry, 40, 812.CrossRefGoogle ScholarPubMed
Geweke, J. F. (1984). Measures of conditional linear dependence and feedback between time series. Journal of the American Statistical Association, 79, 907–915.CrossRefGoogle Scholar
Godsil, B. P., Kiss, J. P., Spedding, M., & Jay, T. M. (2013). The hippocampal-prefrontal pathway: The weak link in psychiatric disorders? European Neuropsychopharmacology, 23, 1165–1181.CrossRefGoogle ScholarPubMed
Hagan, M. J., Luecken, L. J., Sandler, I. N., & Tein, J. Y. (2010). Prospective effects of post-bereavement negative events on cortisol activity in parentally bereaved youth. Developmental Psychobiology, 52, 394–400.CrossRefGoogle ScholarPubMed
Hamilton, M. (1959). The assessment of anxiety states by rating. British Journal of Medical Psychology, 32, 50–55.CrossRefGoogle ScholarPubMed
Hamilton, M. (1960). A rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 23, 56.CrossRefGoogle ScholarPubMed
Hesketh, T., Lu, L., & Xing, Z. W. (2005). The effect of China's one-child family policy after 25 years. The New England Journal of Medicine, 353, 1171–1176.CrossRefGoogle ScholarPubMed
Im, J. J., Namgung, E., Choi, Y., Kim, J. Y., Rhie, S. J., & Yoon, S. (2016). Molecular neuroimaging in posttraumatic stress disorder. Experimental Neurobiology, 25, 277–295.CrossRefGoogle ScholarPubMed
Jiang, X.-R., Du, J.-J., & Dong, R.-Y. (2017). Coping style, job burnout and mental health of university teachers of the millennial generation. Journal of Mathemmatical Science and Technology Education, 13(7), 3379–3392.Google Scholar
Jiao, Q., Lu, G., Zhang, Z., Zhong, Y., Wang, Z., Guo, Y., … Liu, Y. (2011). Granger causal influence predicts BOLD activity levels in the default mode network. Human Brain Mapping, 32, 154–161.CrossRefGoogle ScholarPubMed
Lanius, R. A., Bluhm, R. L., Coupland, N. J., Hegadoren, K. M., Rowe, B., Theberge, J., … Brimson, M. (2010). Default mode network connectivity as a predictor of post-traumatic stress disorder symptom severity in acutely traumatized subjects. Acta Psychiatrica Scandinavica, 121, 33–40.CrossRefGoogle ScholarPubMed
Lazarov, A., Zhu, X., Suarez-Jimenez, B., Rutherford, B. R., & Neria, Y. (2017). Resting-state functional connectivity of anterior and posterior hippocampus in posttraumatic stress disorder. Journal of Psychiatric Research, 94, 15–22.CrossRefGoogle ScholarPubMed
Li, Y., & Wu, S. (2013). Health care for older Chinese people who lose their only child. The Lancet, 381, 536.CrossRefGoogle ScholarPubMed
Liao, W., Chen, H., Feng, Y., Mantini, D., Gentili, C., Pan, Z., … Zhang, W. (2010a). Selective aberrant functional connectivity of resting state networks in social anxiety disorder. Neuroimage, 52, 1549–1558.CrossRefGoogle Scholar
Liao, W., Qiu, C., Gentili, C., Walter, M., Pan, Z., Ding, J., … Chen, H. (2010b). Altered effective connectivity network of the amygdala in social anxiety disorder: A resting-state FMRI study. PLoS ONE, 5, e15238.CrossRefGoogle Scholar
Liu, W., Liu, H., Wei, D., Sun, J., Yang, J., Meng, J., … Qiu, J. (2015). Abnormal degree centrality of functional hubs associated with negative coping in older Chinese adults who lost their only child. Biological Psychology, 112, 46–55.CrossRefGoogle ScholarPubMed
Luo, Y., Liu, Y., Qin, Y., Zhang, X., Ma, T., Wu, W., … Cao, Z. (2017). The atrophy and laterality of the hippocampal subfields in parents with or without posttraumatic stress disorder who lost their only child in China. Neurological Sciences, 38, 1241–1247.CrossRefGoogle ScholarPubMed
Luo, Y., Qi, R., Zhang, L., Qing, Z., Weng, Y., Wang, W., … Lu, G. (2019). Functional brain network topology in parents who lost their only child in China: Post-traumatic stress disorder and sex effects. Journal of Affective Disorders, 257, 632–639.CrossRefGoogle ScholarPubMed
Luo, Y., Shan, H., Liu, Y., Wu, L., Zhang, X., Ma, T., … Cao, Z. (2016). Decreased left hippocampal volumes in parents with or without posttraumatic stress disorder who lost their only child in China. Journal of Affective Disorders, 197, 223–230.CrossRefGoogle ScholarPubMed
Malivoire, B. L., Girard, T. A., Patel, R., & Monson, C. M. (2018). Functional connectivity of hippocampal subregions in PTSD: Relations with symptoms. BMC Psychiatry, 18, 129.CrossRefGoogle ScholarPubMed
McNerney, M. W., Sheng, T., Nechvatal, J. M., Lee, A. G., Lyons, D. M., Soman, S., … Adamson, M. M. (2018). Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation. PLoS ONE, 13, e0192222.CrossRefGoogle ScholarPubMed
Miller, D. R., Hayes, S. M., Hayes, J. P., Spielberg, J. M., Lafleche, G., & Verfaellie, M. (2017). Default mode network subsystems are differentially disrupted in posttraumatic stress disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2, 363–371.Google ScholarPubMed
Mueller, S. G., Chao, L. L., Berman, B., & Weiner, M. W. (2011). Evidence for functional specialization of hippocampal subfields detected by MR subfield volumetry on high resolution images at 4 T. Neuroimage, 56, 851–857.CrossRefGoogle ScholarPubMed
Na, K.-S., Chang, H. S., Won, E., Han, K.-M., Choi, S., Tae, W. S., … Jung, I.-K. (2014). Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder. PLoS ONE, 9, e85425.CrossRefGoogle ScholarPubMed
Palma-Gudiel, H., Córdova-Palomera, A., Leza, J. C., & Fananás, L. (2015). Glucocorticoid receptor gene (NR3C1) methylation processes as mediators of early adversity in stress-related disorders causality: A critical review. Neuroscience & Biobehavioral Reviews, 55, 520–535.CrossRefGoogle ScholarPubMed
Perroud, N., Paoloni-Giacobino, A., Prada, P., Olie, E., Salzmann, A., Nicastro, R., … Malafosse, A. (2011). Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma. Translational Psychiatry, 1, e59.CrossRefGoogle ScholarPubMed
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., & Shulman, G. L. (2001). A default mode of brain function. Proceedings of the National Academy of Sciences of the United States of America, 98, 676–682.CrossRefGoogle ScholarPubMed
Romens, S. E., McDonald, J., Svaren, J., & Pollak, S. D. (2015). Associations between early life stress and gene methylation in children. Child Development, 86, 303–309.CrossRefGoogle ScholarPubMed
Schechter, D. S., Moser, D. A., Paoloni-Giacobino, A., Stenz, L., Gex-Fabry, M., Aue, T., … Manini, A. (2015). Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure. Frontiers in Psychology, 6, 690.CrossRefGoogle ScholarPubMed
Scholtens, L. H., & van den Heuvel, M. P. (2018). Multimodal connectomics in psychiatry: Bridging scales from micro to macro. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 3, 767–776.Google ScholarPubMed
Schumacher, A., Vlassov, E., & Ito, R. (2016). The ventral hippocampus, but not the dorsal hippocampus is critical for learned approach-avoidance decision making. Hippocampus, 26, 530–542.CrossRefGoogle Scholar
Song, Y. (2014). Losing an only child: The one-child policy and elderly care in China. Reproductive Health Matters, 22, 113–124.CrossRefGoogle ScholarPubMed
Sun, X., Tian, Y., Zheng, Q., Zheng, R., Lin, A., Chen, T., … Lai, M. (2018). A novel discriminating colorectal cancer model for differentiating normal and tumor tissues. Epigenomics, 10, 1463–1475.CrossRefGoogle ScholarPubMed
Szeszko, P. R., Lehrner, A., & Yehuda, R. (2018). Glucocorticoids and hippocampal structure and function in PTSD. Harvard Review of Psychiatry, 26, 142–157.CrossRefGoogle ScholarPubMed
Tyrka, A. R., Price, L. H., Marsit, C., Walters, O. C., & Carpenter, L. L. (2012). Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults. PLoS ONE, 7, e30148.CrossRefGoogle ScholarPubMed
Vitlic, A., Khanfer, R., Lord, J. M., Carroll, D., & Phillips, A. C. (2014). Bereavement reduces neutrophil oxidative burst only in older adults: Role of the HPA axis and immunesenescence. Immunity & Ageing, 11, 13.CrossRefGoogle ScholarPubMed
Vukojevic, V., Kolassa, I. T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., … de Quervain, D. J. (2014). Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. Journal of Neuroscience, 34, 10274–10284.CrossRefGoogle ScholarPubMed
Weaver, I. C., Meaney, M. J., & Szyf, M. (2006). Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proceedings of the National Academy of Sciences of the United States of America, 103, 3480–3485.CrossRefGoogle ScholarPubMed
Wei, Y., Jiang, Q., & Gietel-Basten, S. (2016). The well-being of bereaved parents in an only-child society. Death Studies, 40, 22–31.CrossRefGoogle Scholar
Woodward, N. D., & Cascio, C. J. (2015). Resting-state functional connectivity in psychiatric disorders. JAMA Psychiatry, 72, 743–744.CrossRefGoogle ScholarPubMed
Yehuda, R., Flory, J. D., Bierer, L. M., Henn-Haase, C., Lehrner, A., Desarnaud, F., … Meaney, M. J. (2015). Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biological Psychiatry, 77, 356–364.CrossRefGoogle ScholarPubMed
Zarei, M., Beckmann, C. F., Binnewijzend, M. A., Schoonheim, M. M., Oghabian, M. A., Sanz-Arigita, E. J., … Barkhof, F. (2013). Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease. Neuroimage, 66, 28–35.CrossRefGoogle ScholarPubMed
Zhang, Y., & Jia, X. (2018). A qualitative study on the grief of people who lose their only child: From the perspective of familism culture. Frontiers in Psychology, 9, 869.CrossRefGoogle ScholarPubMed
Zheng, Y., Lawson, T. R., & Anderson Head, B. (2017). ‘Our only child has died’ – A study of bereaved older Chinese parents. OMEGA-Journal of Death and Dying, 74, 410–425.CrossRefGoogle Scholar
Zhong, Y. M., Yukie, M., & Rockland, K. S. (2006). Distinctive morphology of hippocampal CA1 terminations in orbital and medial frontal cortex in macaque monkeys. Experimental Brain Research, 169, 549–553.CrossRefGoogle ScholarPubMed
Zhou, S., Cai, B., Zhang, Z., Zhang, Y., Wang, L., Liu, K., … Xu, G. (2017). CDKN2B methylation and aortic arch calcification in patients with ischemic stroke. Journal of Atherosclerosis and Thrombosis, 24, 609–620.CrossRefGoogle ScholarPubMed
Zhu, H., Zhang, J., Zhan, W., Qiu, C., Wu, R., Meng, Y., … Zhang, W. (2014). Altered spontaneous neuronal activity of visual cortex and medial anterior cingulate cortex in treatment-naive posttraumatic stress disorder. Comprehensive Psychiatry, 55, 1688–1695.CrossRefGoogle ScholarPubMed
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