Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation

Many Veterans exposed to physical and psychological trauma experience symptoms of posttraumatic stress disorder (PTSD). As the etiology of PTSD symptoms is complex, a better understanding of the underlying biological mechanisms may improve preventative care and treatment for PTSD. Recent findings from the fields of neuroimaging and epigenetics offer important insights into the potential brain structures and biochemical pathways of modified gene expression associated with PTSD. We combined neuroimaging and epigenetic measures to assess current PTSD symptoms by measuring overall hippocampal volume and methylation of the glucocorticoid receptor (GR) gene (promoter region). Multiple regression analyses indicated that the hippocampal volume/GR methylation interaction was a predictor of PTSD symptoms. Our findings suggest that neuroimaging and epigenetic measures contribute interactively to PTSD symptoms. Incorporation of these metrics may aid in the identification and treatment of PTSD patients.

[1]  F. Holsboer,et al.  Stress and the brain: from adaptation to disease , 2005, Nature Reviews Neuroscience.

[2]  Michael B. Stadler,et al.  Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome , 2007, Nature Genetics.

[3]  J. Krystal.  Trauma and the Vietnam War Generation , 1992, The Yale Journal of Biology and Medicine.

[4]  Norbert Schuff,et al.  Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. , 2010, Archives of general psychiatry.

[5]  S. Southwick,et al.  MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. , 1995, The American journal of psychiatry.

[6]  K. Moors,et al.  Reproducibility and intraindividual variation over days in buccal cell DNA methylation of two asthma genes, interferon γ (IFNγ) and inducible nitric oxide synthase (iNOS) , 2012, Clinical Epigenetics.

[7]  E. Blanchard,et al.  Psychometric properties of the PTSD Checklist (PCL). , 1996, Behaviour research and therapy.

[8]  R. Kikinis,et al.  Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder , 1996, Biological Psychiatry.

[9]  Michael J. Meaney,et al.  Lower Methylation of Glucocorticoid Receptor Gene Promoter 1F in Peripheral Blood of Veterans with Posttraumatic Stress Disorder , 2015, Biological Psychiatry.

[10]  B. Ham,et al.  Association between Glucocorticoid Receptor Methylation and Hippocampal Subfields in Major Depressive Disorder , 2014, PloS one.

[11]  M E Shenton,et al.  Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. , 2001, The American journal of psychiatry.

[12]  Kendall C. Wilkins,et al.  Synthesis of the psychometric properties of the PTSD checklist (PCL) military, civilian, and specific versions , 2011, Depression and anxiety.

[13]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[14]  E. Aronica,et al.  Glucocorticoid receptor protein expression in human hippocampus; stability with age , 2013, Neurobiology of Aging.

[15]  Yi Zhang,et al.  TET enzymes, TDG and the dynamics of DNA demethylation , 2013, Nature.

[16]  R. Yehuda,et al.  Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: systematic review of contributing factors , 2014, Front. Neurosci..

[17]  J. Sweatt,et al.  Interindividual Variability in Stress Susceptibility: A Role for Epigenetic Mechanisms in PTSD , 2013, Front. Psychiatry.

[18]  I. Weaver,et al.  Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Anders M. Dale,et al.  Sequence-independent segmentation of magnetic resonance images , 2004, NeuroImage.

[20]  Christianna S. Williams,et al.  Course of Posttraumatic Stress Disorder 40 Years After the Vietnam War: Findings From the National Vietnam Veterans Longitudinal Study. , 2015, JAMA psychiatry.

[21]  J. Buxbaum,et al.  Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD , 2013, Front. Psychiatry.

[22]  Han K. Kang,et al.  Illnesses among United States veterans of the Gulf War: a population-based survey of 30,000 veterans. , 2000, Journal of occupational and environmental medicine.

[23]  Fred J. Helmstetter,et al.  Chronic stress selectively reduces hippocampal volume in rats: a longitudinal magnetic resonance imaging study , 2009, Neuroreport.

[24]  E. Shirtcliff,et al.  Not all biofluids are created equal: chewing over salivary diagnostics and the epigenome. , 2015, Clinical therapeutics.

[25]  S. Chattarji,et al.  Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons , 2002, The Journal of Neuroscience.

[26]  F. Champagne,et al.  Maternal prenatal depressive symptoms predict infant NR3C1 1F and BDNF IV DNA methylation , 2015, Epigenetics.

[27]  Han K. Kang,et al.  Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans. , 2003, American journal of epidemiology.

[28]  Michael Papsdorf,et al.  Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses , 2008, Epigenetics.

[29]  G. Ehninger,et al.  Buccal swabs but not mouthwash samples can be used to obtain pretransplant DNA fingerprints from recipients of allogeneic bone marrow transplants , 2000, Bone Marrow Transplantation.

[30]  P. Calhoun,et al.  The diagnostic accuracy of the PTSD checklist: a critical review. , 2010, Clinical psychology review.

[31]  R. Sapolsky,et al.  Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. , 2000, Archives of general psychiatry.

[32]  R. Yehuda,et al.  The relevance of epigenetics to PTSD: implications for the DSM-V. , 2009, Journal of traumatic stress.

[33]  M. Verfaellie,et al.  Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume. , 2017, Journal of psychiatric research.

[34]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[35]  J W Mason,et al.  Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder. , 1993, The American journal of psychiatry.

[36]  G. Fan,et al.  DNA Methylation and Its Basic Function , 2013, Neuropsychopharmacology.

[37]  R. Yehuda.  POST-TRAUMATIC STRESS DISORDER , 1985, The Lancet.

[38]  Achim Tresch,et al.  Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns , 2010, Nucleic acids research.

[39]  M. Meaney,et al.  Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome , 2005, Dialogues in clinical neuroscience.

[40]  P. Schnurr,et al.  Combat exposure, posttraumatic stress disorder symptoms, and health behaviors as predictors of self-reported physical health in older veterans. , 1999, The Journal of nervous and mental disease.

[41]  Michael D. Nelson,et al.  Posttraumatic stress disorder symptom severity is associated with left hippocampal volume reduction: a meta-analytic study , 2016, CNS Spectrums.

[42]  A. Sawa,et al.  Environmental Stressors and Epigenetic Control of the Hypothalamic-Pituitary-Adrenal Axis , 2014, Neuroendocrinology.

[43]  Jacob Cohen.  Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[44]  S. Pollak,et al.  Associations Between Early Life Stress and Gene Methylation in Children , 2014, Child development.

[45]  B. McEwen,et al.  Glucocorticoid-sensitive hippocampal neurons are involved in terminating the adrenocortical stress response. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[46]  J. Raz,et al.  Neuroendocrine and Psychophysiologic Responses in PTSD: A Symptom Provocation Study , 1999, Neuropsychopharmacology.

[47]  R. Kahn,et al.  Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder , 2015, Psychological Medicine.

[48]  J. Herman,et al.  Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. , 1995, Neuroendocrinology.

[49]  T. Elbert,et al.  Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors , 2014, The Journal of Neuroscience.

[50]  Ilya M. Veer,et al.  Evidence for smaller right amygdala volumes in posttraumatic stress disorder following childhood trauma , 2015, Psychiatry Research: Neuroimaging.

[51]  H. Greinix,et al.  Genetic fingerprinting in mouthwashes of patients after allogeneic bone marrow transplantation , 1999, Bone Marrow Transplantation.

[52]  R. Bryant,et al.  PAGES_ 12_AG_1004_BA.qxd:DCNS#50 , 2011 .

[53]  Terri Tanielian,et al.  Invisible Wounds of War. Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery , 2008 .

[54]  Gustavo Turecki,et al.  Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse , 2009, Nature Neuroscience.

[55]  R. Ruff,et al.  Mild traumatic brain injury in U.S. soldiers returning from Iraq. , 2008, The New England journal of medicine.