Advertisement

Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms

Published:November 22, 2010DOI:https://doi.org/10.1016/j.biopsych.2010.09.044

      Background

      Decreased hippocampal volume is described in posttraumatic stress disorder (PTSD) and depression. However, it is not known whether it is a risk factor for the development of PTSD or a consequence of PTSD. We sought to determine the effects of PTSD and depressive symptoms on hippocampal volume.

      Methods

      Clinical and magnetic resonance imaging data were collected in a cross sectional study of 244 Gulf War veterans. Measures included lifetime and current Clinician Administered PTSD Scale, Hamilton Depression Scale, Life Stressor Checklist, and Lifetime Drinking History. Magnetic resonance imaging data were acquired with a 1.5-T scanner and analyzed with automated and semiautomated image processing techniques.

      Results

      Eighty-two veterans had lifetime PTSD, 44 had current PTSD, and 38 had current depression. In the linear regression analysis, current PTSD symptoms (standardized coefficient β = −.25, p = .03) but neither lifetime PTSD symptoms nor current depression were associated with smaller hippocampal volume. Gender, age, history of early life trauma, education, lifetime and current alcohol use, current marijuana use, and treatment with antidepressants did not have independent effects. Participants with chronic PTSD had, on average, a smaller hippocampus compared with those with remitted PTSD.

      Conclusions

      The finding that current but not lifetime PTSD symptom severity explains hippocampal size raises two possibilities: either a small hippocampus is a risk factor for lack of recovery from PTSD (trait) or PTSD effects on hippocampal volume are reversible once PTSD symptoms remit and the patient recovers (state).

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Karl A.
        • Schaefer M.
        • Malta L.S.
        • Dorfel D.
        • Rohleder N.
        • Werner A.
        A meta-analysis of structural brain abnormalities in PTSD.
        Neurosci Biobehav Rev. 2006; 30: 1004-1031
        • Kitayama N.
        • Vaccarino V.
        • Kutner M.
        • Weiss P.
        • Bremner J.D.
        Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: A meta-analysis.
        J Affect Disord. 2005; 88: 79-86
        • Smith M.E.
        Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: A meta-analysis of structural MRI studies.
        Hippocampus. 2005; 15: 798-807
        • Sala M.
        • Perez J.
        • Soloff P.
        • Ucelli di Nemi S.
        • Caverzasi E.
        • Soares J.C.
        • Brambilla P.
        Stress and hippocampal abnormalities in psychiatric disorders.
        Eur Neuropsychopharmacol. 2004; 14: 393-405
        • De Kloet E.R.
        • Vreugdenhil E.
        • Oitzl M.S.
        • Joels M.
        Brain corticosteroid receptor balance in health and disease.
        Endocr Rev. 1998; 19: 269-301
        • McEwen B.S.
        • Gould E.A.
        • Sakai R.R.
        The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress.
        Br J Psychiatry Suppl. 1992; : 18-23
        • Dickerson B.C.
        • Eichenbaum H.
        The episodic memory system: Neurocircuitry and disorders.
        Neuropsychopharmacology. 2010; 35: 86-104
        • Pitman R.
        • Shalev A.
        • Orr S.
        Posttraumatic stress disorder: Emotion, conditioning, and memory.
        in: Corbetta M. Gazzaniga M. The New Cognitive Neurosciences. 2nd ed. Plenum Press, New York2000: 687-700
        • Magarinos A.M.
        • McEwen B.S.
        Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors.
        Neuroscience. 1995; 69: 89-98
        • Abrous D.N.
        • Koehl M.
        • Le Moal M.
        Adult neurogenesis: from precursors to network and physiology.
        Physiol Rev. 2005; 85: 523-569
        • Sapolsky R.M.
        Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders.
        Arch Gen Psychiatry. 2000; 57: 925-935
        • McEwen B.S.
        • Angulo J.
        • Cameron H.
        • Chao H.M.
        • Daniels D.
        • Gannon M.N.
        • et al.
        Paradoxical effects of adrenal steroids on the brain: Protection versus degeneration.
        Biol Psychiatry. 1992; 31: 177-199
        • Moghaddam B.
        Stress activation of glutamate neurotransmission in the prefrontal cortex: Implications for dopamine-associated psychiatric disorders.
        Biol Psychiatry. 2002; 51: 775-787
        • Smith M.A.
        • Makino S.
        • Kvetnansky R.
        • Post R.M.
        Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus.
        J Neurosci. 1995; 15: 1768-1777
        • Sunanda
        • Rao M.S.
        • Raju T.R.
        Effect of chronic restraint stress on dendritic spines and excrescences of hippocampal CA3 pyramidal neurons—a quantitative study.
        Brain Res. 1995; 694: 312-317
        • Magarinos A.M.
        • McEwen B.S.
        • Flugge G.
        • Fuchs E.
        Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews.
        J Neurosci. 1996; 16: 3534-3540
        • Stewart M.G.
        • Davies H.A.
        • Sandi C.
        • Kraev I.V.
        • Rogachevsky V.V.
        • Peddie C.J.
        • et al.
        Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: A three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities.
        Neuroscience. 2005; 131: 43-54
        • Gould E.
        • Tanapat P.
        • McEwen B.S.
        • Flugge G.
        • Fuchs E.
        Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress.
        Proc Natl Acad Sci U S A. 1998; 95: 3168-3171
        • Sapolsky R.M.
        • Uno H.
        • Rebert C.S.
        • Finch C.E.
        Hippocampal damage associated with prolonged glucocorticoid exposure in primates.
        J Neurosci. 1990; 10: 2897-2902
        • Felmingham K.
        • Williams L.M.
        • Whitford T.J.
        • Falconer E.
        • Kemp A.H.
        • Peduto A.
        • Bryant R.A.
        Duration of posttraumatic stress disorder predicts hippocampal grey matter loss.
        Neuroreport. 2009; 20: 1402-1406
        • Vermetten E.
        • Vythilingam M.
        • Southwick S.M.
        • Charney D.S.
        • Bremner J.D.
        Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder.
        Biol Psychiatry. 2003; 54: 693-702
        • Gilbertson M.W.
        • Shenton M.E.
        • Ciszewski A.
        • Kasai K.
        • Lasko N.B.
        • Orr S.P.
        • Pitman R.K.
        Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma.
        Nat Neurosci. 2002; 5: 1242-1247
        • Bryant R.A.
        • O'Donnell M.L.
        • Creamer M.
        • McFarlane A.C.
        • Clark C.R.
        • Silove D.
        The psychiatric sequelae of traumatic injury.
        Am J Psychiatry. 2010; 167: 312-320
        • Kessler R.C.
        • Sonnega A.
        • Bromet E.
        • Hughes M.
        • Nelson C.B.
        Posttraumatic stress disorder in the National Comorbidity Survey.
        Arch Gen Psychiatry. 1995; 52: 1048-1060
        • Koolschijn P.C.
        • van Haren N.E.
        • Lensvelt-Mulders G.J.
        • Hulshoff Pol H.E.
        • Kahn R.S.
        Brain volume abnormalities in major depressive disorder: A meta-analysis of magnetic resonance imaging studies.
        Hum Brain Mapp. 2009; 30: 3719-3735
        • McKinnon M.C.
        • Yucel K.
        • Nazarov A.
        • MacQueen G.M.
        A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder.
        J Psychiatry Neurosci. 2009; 34: 41-54
        • Videbech P.
        • Ravnkilde B.
        Hippocampal volume and depression: A meta-analysis of MRI studies.
        Am J Psychiatry. 2004; 161: 1957-1966
        • Lorenzetti V.
        • Allen N.B.
        • Fornito A.
        • Yucel M.
        Structural brain abnormalities in major depressive disorder: A selective review of recent MRI studies.
        J Affect Disord. 2009; 117: 1-17
      1. Weiner MW, Meyerhoff DJ, Neylan TC, Hlavin J, Ramage ER, McCoy D, et al. (in press): The relationship between gulf war illness, brain N-acetyl aspartate and post-traumatic stress disorder. Mil Med.

        • First M.
        • Spitzer R.
        • Gibbon M.
        • Williams J.
        Structured Clinical Interview for DSM-IV Axis 1 Disorders—Non-Patient Edition (SCID-I/NP, Version 2.0).
        Biometrics Research Department, New York State Psychiatric Institute, New York1996
        • Blake D.D.
        • Weathers F.W.
        • Nagy L.M.
        • Kaloupek D.G.
        • Gusman F.D.
        • Charney D.S.
        • Keane T.M.
        The development of a Clinician-Administered PTSD Scale.
        J Trauma Stress. 1995; 8: 75-90
        • Weathers F.W.
        • Keane T.M.
        • Davidson J.R.
        Clinician-administered PTSD scale: A review of the first ten years of research.
        Depress Anxiety. 2001; 13: 132-156
        • Hamilton M.
        A rating scale for depression.
        J Neurol Neurosurg Psychiatry. 1960; 23: 56-62
        • Wolfe J.
        • Kimerling R.
        • Brown P.J.
        • Chresman K.R.
        • Levin K.
        Psychometric Review of the Life Stressor Checklist-Revised.
        Sidran Publishing Group, Lutherville, Maryland1996
        • Wolfe J.
        • Kimerling R.
        Gender issues in the assessment of posttraumatic stress disorder.
        in: Wilson J. Keane T.M. Assessing Psychological Trauma and PTSD. Guilford, New York1997: 192-238
        • Skinner H.A.
        • Sheu W.J.
        Reliability of alcohol use indices.
        J Stud Alcohol. 1982; 43: 1157-1170
        • Hsu Y.Y.
        • Schuff N.
        • Du A.T.
        • Mark K.
        • Zhu X.
        • Hardin D.
        • Weiner M.W.
        Comparison of automated and manual MRI volumetry of hippocampus in normal aging and dementia.
        J Magn Reson Imaging. 2002; 16: 305-310
        • Christensen G.E.
        • Joshi S.C.
        • Miller M.I.
        Volumetric transformation of brain anatomy.
        IEEE Trans Med Imaging. 1997; 16: 864-877
        • Gazdzinski S.
        • Durazzo T.C.
        • Yeh P.H.
        • Hardin D.
        • Banys P.
        • Meyerhoff D.J.
        Chronic cigarette smoking modulates injury and short-term recovery of the medial temporal lobe in alcoholics.
        Psychiatry Res. 2008; 162: 133-145
        • Buckner R.L.
        • Head D.
        • Parker J.
        • Fotenos A.F.
        • Marcus D.
        • Morris J.C.
        • Snyder A.Z.
        A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: Reliability and validation against manual measurement of total intracranial volume.
        Neuroimage. 2004; 23: 724-738
        • Dale A.M.
        • Fischl B.
        • Sereno M.I.
        Cortical surface-based analysis.
        Neuroimage. 1999; 9: 179-194
        • Pereira A.C.
        • Huddleston D.E.
        • Brickman A.M.
        • Sosunov A.A.
        • Hen R.
        • McKhann G.M.
        • et al.
        An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.
        Proc Natl Acad Sci U S A. 2007; 104: 5638-5643
        • Pajonk F.G.
        • Wobrock T.
        • Gruber O.
        • Scherk H.
        • Berner D.
        • Kaizl I.
        • et al.
        Hippocampal plasticity in response to exercise in schizophrenia.
        Arch Gen Psychiatry. 2010; 67: 133-143
        • Boldrini M.
        • Underwood M.D.
        • Hen R.
        • Rosoklija G.B.
        • Dwork A.J.
        • John Mann J.
        • Arango V.
        Antidepressants increase neural progenitor cells in the human hippocampus.
        Neuropsychopharmacology. 2009; 34: 2376-2389
        • Chen F.
        • Madsen T.M.
        • Wegener G.
        • Nyengaard J.R.
        Imipramine treatment increases the number of hippocampal synapses and neurons in a genetic animal model of depression.
        Hippocampus. 2009; ([published online ahead of print November 17])
        • Dranovsky A.
        • Hen R.
        Hippocampal neurogenesis: Regulation by stress and antidepressants.
        Biol Psychiatry. 2006; 59: 1136-1143
        • Warner-Schmidt J.L.
        • Duman R.S.
        Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment.
        Hippocampus. 2006; 16: 239-249
        • Lucassen P.J.
        • Meerlo P.
        • Naylor A.S.
        • van Dam A.M.
        • Dayer A.G.
        • Fuchs E.
        • et al.
        Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action.
        Eur Neuropsychopharmacol. 2010; 20: 1-17
        • Duman R.S.
        • Nakagawa S.
        • Malberg J.
        Regulation of adult neurogenesis by antidepressant treatment.
        Neuropsychopharmacology. 2001; 25: 836-844
        • Koolschijn P.C.
        • van Haren N.E.
        • Cahn W.
        • Schnack H.G.
        • Janssen J.
        • Klumpers F.
        • et al.
        Hippocampal volume change in schizophrenia.
        J Clin Psychiatry. 2010; 71: 737-744
        • Wang Z.
        • Neylan T.C.
        • Mueller S.G.
        • Lenoci M.
        • Truran D.
        • Marmar C.R.
        • et al.
        Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder.
        Arch Gen Psychiatry. 2010; 67: 296-303
        • Neylan T.C.
        • Mueller S.G.
        • Wang Z.
        • Metzler T.J.
        • Lenoci M.
        • Truran D.
        • et al.
        Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield.
        Biol Psychiatry. 2010; 68: 494-496
        • Duan X.
        • Kang E.
        • Liu C.Y.
        • Ming G.L.
        • Song H.
        Development of neural stem cell in the adult brain.
        Curr Opin Neurobiol. 2008; 18: 108-115
        • Ehninger D.
        • Kempermann G.
        Neurogenesis in the adult hippocampus.
        Cell Tissue Res. 2008; 331: 243-250
        • Pitman R.K.
        • Gilbertson M.W.
        • Gurvits T.V.
        • May F.S.
        • Lasko N.B.
        • Metzger L.J.
        • et al.
        Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure.
        Ann N Y Acad Sci. 2006; 1071: 242-254
        • Macklin M.L.
        • Metzger L.J.
        • Litz B.T.
        • McNally R.J.
        • Lasko N.B.
        • Orr S.P.
        • Pitman R.K.
        Lower precombat intelligence is a risk factor for posttraumatic stress disorder.
        J Consult Clin Psychol. 1998; 66: 323-326
        • Pitman R.K.
        Posttraumatic stress disorder and dementia: What is the origin of the association?.
        JAMA. 2010; 303 (9): 2287-2288
        • Bonne O.
        • Brandes D.
        • Gilboa A.
        • Gomori J.M.
        • Shenton M.E.
        • Pitman R.K.
        • Shalev A.Y.
        Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD.
        Am J Psychiatry. 2001; 158: 1248-1251
        • Lindauer R.J.
        • Vlieger E.J.
        • Jalink M.
        • Olff M.
        • Carlier I.V.
        • Majoie C.B.
        • et al.
        Effects of psychotherapy on hippocampal volume in out-patients with post-traumatic stress disorder: A MRI investigation.
        Psychol Med. 2005; 35: 1421-1431
        • De Bellis M.D.
        • Hall J.
        • Boring A.M.
        • Frustaci K.
        • Moritz G.
        A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder.
        Biol Psychiatry. 2001; 50: 305-309
        • Tottenham N.
        • Sheridan M.A.
        A review of adversity, the amygdala and the hippocampus: A consideration of developmental timing.
        Front Hum Neurosci. 2009; 3: 68
        • Woon F.L.
        • Hedges D.W.
        Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: A meta-analysis.
        Hippocampus. 2008; 18: 729-736
      2. Cardenas V, Samuelson K, Lenoci M, Studholme C, Neylan T, Marmar C, et al. (in press): Changes in brain anatomy during the course of PTSD. Psychiatry Res.

        • Agartz I.
        • Momenan R.
        • Rawlings R.R.
        • Kerich M.J.
        • Hommer D.W.
        Hippocampal volume in patients with alcohol dependence.
        Arch Gen Psychiatry. 1999; 56: 356-363
        • Laakso M.P.
        • Vaurio O.
        • Savolainen L.
        • Repo E.
        • Soininen H.
        • Aronen H.J.
        • Tiihonen J.
        A volumetric MRI study of the hippocampus in type 1 and 2 alcoholism.
        Behav Brain Res. 2000; 109: 177-186
        • Richardson H.N.
        • Chan S.H.
        • Crawford E.F.
        • Lee Y.K.
        • Funk C.K.
        • Koob G.F.
        • Mandyam C.D.
        Permanent impairment of birth and survival of cortical and hippocampal proliferating cells following excessive drinking during alcohol dependence.
        Neurobiol Dis. 2009; 36: 1-10
        • Vythilingam M.
        • Heim C.
        • Newport J.
        • Miller A.H.
        • Anderson E.
        • Bronen R.
        • et al.
        Childhood trauma associated with smaller hippocampal volume in women with major depression.
        Am J Psychiatry. 2002; 159: 2072-2080
        • Bremner J.D.
        • Randall P.
        • Vermetten E.
        • Staib L.
        • Bronen R.A.
        • Mazure C.
        • et al.
        Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report.
        Biol Psychiatry. 1997; 41: 23-32
        • Driessen M.
        • Herrmann J.
        • Stahl K.
        • Zwaan M.
        • Meier S.
        • Hill A.
        • et al.
        Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization.
        Arch Gen Psychiatry. 2000; 57: 1115-1122
        • Rao U.
        • Chen L.A.
        • Bidesi A.S.
        • Shad M.U.
        • Thomas M.A.
        • Hammen C.L.
        Hippocampal changes associated with early-life adversity and vulnerability to depression.
        Biol Psychiatry. 2010; 67: 357-364
        • Frodl T.
        • Reinhold E.
        • Koutsouleris N.
        • Reiser M.
        • Meisenzahl E.M.
        Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression.
        J Psychiatr Res. 2010; 44: 799-807
        • Teicher M.H.
        • Tomoda A.
        • Andersen S.L.
        Neurobiological consequences of early stress and childhood maltreatment: Are results from human and animal studies comparable?.
        Ann N Y Acad Sci. 2006; 1071: 313-323
        • Malberg J.E.
        • Eisch A.J.
        • Nestler E.J.
        • Duman R.S.
        Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
        J Neurosci. 2000; 20: 9104-9110
        • Balu D.T.
        • Lucki I.
        Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology.
        Neurosci Biobehav Rev. 2009; 33: 232-252