Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia

BACKGROUND Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

Paul M. Thompson | David H. Salat | Emily L. Dennis | Anthony P. King | Israel Liberzon | Dick J. Veltman | Neda Jahanshad | Justin T. Baker | Margaret A. Sheridan | William P. Milberg | Regina E. McGlinchey | Jeffrey M. Spielberg | Rajendra A. Morey | Dan J Stein | Ifat Levy | Kerry J. Ressler | John H. Krystal | Katie A. McLaughlin | Miranda Olff | Richard A. Bryant | Dan J. Stein | Mark W. Miller | Chadi G. Abdallah | Kristen M. Wrocklage | Jim Lagopoulos | Staci A. Gruber | Maria Densmore | Tanja Jovanovic | Mark W. Logue | Jonathan Ipser | Xin Wang | Ilan Harpaz-Rotem | Jennifer S. Stevens | Elbert Geuze | Laura Nawijn | M. Bennett | N. Jahanshad | P. Thompson | K. Ressler | D. Salat | S. Gruber | Ifat Levy | J. Krystal | I. Liberzon | J. Lagopoulos | R. Lanius | M. Densmore | D. Veltman | M. Korgaonkar | W. Milberg | J. Baker | M. Sheridan | T. Jovanović | M. Miller | P. Boedhoe | R. Morey | C. Haswell | A. King | Xin Wang | S. Koch | R. Bryant | M. Logue | C. Abdallah | E. Geuze | J. Ipser | J. Hayes | M. Kaufman | E. Wolf | K. McLaughlin | Matthew Peverill | J. Spielberg | M. Olff | J. Frijling | M. Zuiden | R. McGlinchey | K. Wrocklage | I. Harpaz-Rotem | K. Thomaes | L. Lebois | S. Winternitz | Jonathan D. Wolff | L. Nawijn | S. V. Rooij | Saskia B.J. Koch | Jessie L. Frijling | S. Koopowitz | Sarah L. Davis | J. Stevens | L. O'Connor | Jasmeet P. Hayes | Sanne J.H. van Rooij | Courtney C. Haswell | Mayuresh Korgaonkar | Lauren A.M. Lebois | Matthew Peverill | Premika S.W. Boedhoe | Sheri Koopowitz | Lauren O’Connor | Mirjam van Zuiden | Sherry R. Winternitz | Erika J. Wolf | Kristen Wrocklage | Milissa L. Kaufman | Maxwell Bennett | Ruth Lanius | Kathleen Thomaes | J. Wolff | E. Dennis | I. Levy | Mark W. Miller | Sheri M. Koopowitz | P. Thompson | P. Thompson | P. Thompson | P. Thompson

[1]  Jessica D. Nasser,et al.  Amygdala volume changes in posttraumatic stress disorder in a large case-controlled veterans group. , 2012, Archives of general psychiatry.

[2]  R. Sapolsky,et al.  Hippocampal damage associated with prolonged glucocorticoid exposure in primates , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  Larry A. Tupler,et al.  Segmented Hippocampal Volume in Children and Adolescents with Posttraumatic Stress Disorder , 2006, Biological Psychiatry.

[4]  Olga V. Demler,et al.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[5]  N. Schuff,et al.  Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder , 2001, Biological Psychiatry.

[6]  B. Grant,et al.  The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions-III , 2016, Social Psychiatry and Psychiatric Epidemiology.

[7]  K. Luan Phan,et al.  The contextual brain: implications for fear conditioning, extinction and psychopathology , 2013, Nature Reviews Neuroscience.

[8]  R. Kessler,et al.  Posttraumatic stress disorder in the National Comorbidity Survey. , 1995, Archives of general psychiatry.

[9]  B. Dohrenwend,et al.  The Psychological Risks of Vietnam for U.S. Veterans: A Revisit with New Data and Methods , 2006, Science.

[10]  Michael E. Smith Bilateral hippocampal volume reduction in adults with post‐traumatic stress disorder: A meta‐analysis of structural MRI studies , 2005, Hippocampus.

[11]  S. Hooper,et al.  Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder , 2016, Neuropsychopharmacology.

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

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

[14]  I. Melle,et al.  Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium , 2016, Molecular Psychiatry.

[15]  Janice R. Kuo,et al.  Amygdala volume in combat-exposed veterans with and without posttraumatic stress disorder: a cross-sectional study. , 2012, Archives of general psychiatry.

[16]  D. Ramasamy,et al.  Symptoms of posttraumatic stress disorder and exposure to traumatic stressors are related to brain structural volumes and behavioral measures of affective stimulus processing in police officers , 2012, Psychiatry Research: Neuroimaging.

[17]  V. Magnotta,et al.  Hippocampal volume in chronic posttraumatic stress disorder (PTSD): MRI study using two different evaluation methods. , 2006, Journal of affective disorders.

[18]  K. Frustaci,et al.  A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder , 2001, Biological Psychiatry.

[19]  O. Andreassen,et al.  Subcortical volumetric abnormalities in bipolar disorder , 2016, Molecular Psychiatry.

[20]  P. Renshaw,et al.  Hippocampal volume, PTSD, and alcoholism in combat veterans. , 2006, The American journal of psychiatry.

[21]  D. Hommer,et al.  Smaller right amygdala in Caucasian alcohol‐dependent male patients with a history of intimate partner violence: a volumetric imaging study , 2013, Addiction biology.

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

[23]  S. Rauch,et al.  Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder , 2009, Biological Psychiatry.

[24]  Robert W. Williams,et al.  Variation in Mouse Basolateral Amygdala Volume is Associated With Differences in Stress Reactivity and Fear Learning , 2008, Neuropsychopharmacology.

[25]  M. Bennett,et al.  A systematic review and meta-analysis of magnetic resonance imaging measurement of structural volumes in posttraumatic stress disorder , 2015, Psychiatry Research: Neuroimaging.

[26]  M. Shenton,et al.  Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma , 2002, Nature Neuroscience.

[27]  Loretta S. Malta,et al.  A meta-analysis of structural brain abnormalities in PTSD , 2006, Neuroscience & Biobehavioral Reviews.

[28]  D. Paré,et al.  Intra-amygdaloid projections of the basolateral and basomedial nuclei in the cat: Phaseolus vulgaris-leucoagglutinin anterograde tracing at the light and electron microscopic level , 1995, Neuroscience.

[29]  B. Mcewen,et al.  Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Viola Vaccarino,et al.  Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. , 2005, Journal of affective disorders.

[31]  Margot J. Taylor,et al.  Neuroanatomical features in soldiers with post-traumatic stress disorder , 2016, BMC Neuroscience.

[32]  D. Tate,et al.  Reduced Hippocampal Volume in Alcohol and Substance Naïve Vietnam Combat Veterans with Posttraumatic Stress Disorder , 2003, Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology.

[33]  E. Phelps Human emotion and memory: interactions of the amygdala and hippocampal complex , 2004, Current Opinion in Neurobiology.

[34]  D. Hedges,et al.  Hippocampal and amygdala volumes in children and adults with childhood maltreatment‐related posttraumatic stress disorder: A meta‐analysis , 2008, Hippocampus.

[35]  Lachlan T. Strike,et al.  Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group , 2015, Molecular Psychiatry.

[36]  Tieliang Ma,et al.  Decreased left hippocampal volumes in parents with or without posttraumatic stress disorder who lost their only child in China. , 2016, Journal of affective disorders.

[37]  C. Nievergelt,et al.  The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration , 2015, Neuropsychopharmacology.

[38]  Michael Davis,et al.  Posttraumatic stress disorder may be associated with impaired fear inhibition: Relation to symptom severity , 2009, Psychiatry Research.

[39]  M. Stein,et al.  Hippocampal volume in women victimized by childhood sexual abuse , 1997, Psychological Medicine.

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

[41]  Matcheri S. Keshavan,et al.  Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study , 2002, Biological Psychiatry.

[42]  B. Brkljačić,et al.  Smaller right hippocampus in war veterans with posttraumatic stress disorder , 2007, Psychiatry Research: Neuroimaging.

[43]  Jerome Joseph Maller,et al.  Caudate volumes in public transportation workers exposed to trauma in the Stockholm train system , 2009, Psychiatry Research: Neuroimaging.

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

[45]  Cathy L Pederson,et al.  Hippocampal Volume and Memory Performance in a Community-Based Sample of Women with Posttraumatic Stress Disorder Secondary to Child Abuse , 2004, Journal of traumatic stress.

[46]  M. Joëls,et al.  Brain corticosteroid receptor balance in health and disease. , 1998, Endocrine reviews.

[47]  Orin C. Davis,et al.  Amygdala volume associated with alcohol abuse relapse and craving. , 2008, The American journal of psychiatry.

[48]  C. Fennema-Notestine,et al.  Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder , 2002, Biological Psychiatry.

[49]  Matcheri S Keshavan,et al.  Right amygdala volume in adolescent and young adult offspring from families at high risk for developing alcoholism , 2001, Biological Psychiatry.

[50]  J. Markowitz,et al.  Greater hippocampal volume is associated with PTSD treatment response , 2016, Psychiatry Research: Neuroimaging.

[51]  Silvia Brem,et al.  Distinct Subcortical Volume Alterations in Pediatric and Adult OCD: A Worldwide Meta- and Mega-Analysis. , 2017, The American journal of psychiatry.

[52]  L. Rowland,et al.  Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder , 2002, Biological Psychiatry.

[53]  A. Etkin,et al.  Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. , 2007, The American journal of psychiatry.

[54]  S. Garfinkel,et al.  Impaired Contextual Modulation of Memories in PTSD: An fMRI and Psychophysiological Study of Extinction Retention and Fear Renewal , 2014, The Journal of Neuroscience.

[55]  Miranda Olff,et al.  Gender differences in posttraumatic stress disorder. , 2007, Psychological bulletin.

[56]  J. Bremner,et al.  MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed , 2005, Molecular Psychiatry.

[57]  E. Irle,et al.  Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. , 2004, The American journal of psychiatry.

[58]  B. Penninx,et al.  Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology , 2016, Social cognitive and affective neuroscience.

[59]  Norbert Schuff,et al.  Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms , 2011, Biological Psychiatry.

[60]  S. Santi,et al.  Absence of hippocampal volume differences in survivors of the Nazi Holocaust with and without posttraumatic stress disorder , 2005, Psychiatry Research: Neuroimaging.

[61]  R. Sapolsky,et al.  How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. , 2000, Endocrine reviews.

[62]  M. Phillips,et al.  Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans , 2012, Psychiatry Research: Neuroimaging.

[63]  S. Southwick,et al.  MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. , 2003, The American journal of psychiatry.

[64]  Bruce S. McEwen,et al.  Stress, memory and the amygdala , 2009, Nature Reviews Neuroscience.