Review
A meta-analysis of structural brain abnormalities in PTSD

https://doi.org/10.1016/j.neubiorev.2006.03.004Get rights and content

Abstract

This series of meta-analyses examined structural abnormalities of the hippocampus and other brain regions in persons with PTSD compared to trauma-exposed and non-exposed control groups. The findings were significantly smaller hippocampal volumes in persons with PTSD compared to controls with and without trauma exposure, but group differences were moderated by MRI methodology, PTSD severity, medication, age and gender. Trauma-exposed persons without PTSD also showed significantly smaller bilateral hippocampal compared to non-exposed controls. Meta-analyses also found significantly smaller left amygdala volumes in adults with PTSD compared to both healthy and trauma-exposed controls, and significantly smaller anterior cingulate cortex compared to trauma-exposed controls. Pediatric samples with PTSD exhibited significantly smaller corpus callosum and frontal lobe volumes compared to controls, but there were no group differences in hippocampal volume. The overall findings suggested a dimensional, developmental psychopathology systems model in which: (1) hippocampal volumetric differences covary with PTSD severity; (2) hippocampal volumetric differences do not become apparent until adulthood; and (3) PTSD is associated with abnormalities in multiple frontal–limbic system structures.

Introduction

Exposure to trauma can precipitate the development of posttraumatic stress disorder (PTSD), a complex syndrome comprising re-experiencing symptoms (e.g., nightmares, flashbacks) hyperarousal symptoms (e.g., insomnia), numbing symptoms (e.g., restricted affect, anhedonia), and avoidance symptoms (e.g., avoiding trauma-related stimuli) (DSM-IV, American Psychiatric Association, 1994) in addition to poor concentration and difficulty explicitly recalling aspects of the traumatic event (DSM-IV, American Psychiatric Association, 1994). PTSD may be accompanied by other types of mild cognitive impairment, such as relatively impoverished autobiographic memory for positive events (Harvey et al., 1998; McNally et al., 1995) as well as problems with attention, working memory (Vasterling et al., 1998, Vasterling et al., 2002), and learning novel word associations (Golier et al., 2002). Studies of electro-encephalographic activity (Karl et al., 2006) have found that PTSD is associated with enhanced processing of trauma-related stimuli and reduced processing of neutral stimuli. Converging evidence from neuroimaging research suggests that this altered information processing is associated with differential functional neuroanatomical activity in PTSD (Bremner et al., 1999b, Bremner et al., 2003b; Clark et al., 2003; Matsuo et al., 2003; Rauch et al., 1996; Shaw et al., 2002; Shin et al., 2004a, Shin et al., 2004b).

Studies of structural brain abnormalities in PTSD have focused in particular on the hippocampus, a grey matter structure in the limbic system that is critically involved in explicit (declarative) memory, working memory (O’Keefe and Nadel, 1978; Squire, 1992), and memory for episodic events (Eldridge et al., 2000; Tulving, 1985; Wheeler and Buckner, 2004). The hippocampus also has an important role in the regulation of stress (Jacobson and Sapolsky, 1991), and findings from animal research suggest that chronic stress may affect the hippocampus through excess release of glucocorticoids (Sapolsky et al., 1990), corticotropin-releasing hormone (Brunson et al., 2001), and glutamate (Moghaddam, 2002; Moghaddam and Bolinao, 1994), inhibition of neurogenesis (Gould et al., 1997); impaired long-term potentiation induction (Li et al., 2005); inhibition of brain-derived neurotrophic factor (BDNF, Duric and McCarson, 2005) and altered serotonergic receptor function (Harvey et al., 2003).

Because of its critical role in learning and memory as well as stress regulation, alterations in the hippocampus have been proposed as contributing to the etiology of PTSD (Bremner, 2001; Sapolsky, 2000). However, findings from PTSD neuroimaging research are equivocal (Jelicic and Merckelbach, 2004). Some cross-sectional studies find reduced hippocampal volumes (e.g., Bremner et al., 1995; Gurvits et al., 1996; Stein et al., 1997) in PTSD but others do not (e.g., Pederson et al., 2004; Schuff et al., 2001). Right-sided (Bremner et al., 1995), left-sided (Gurvits et al., 1996) as well as bilateral (Bremner et al., 2003a) volumetric reductions have been reported. One longitudinal study failed to find reduced hippocampal volume at 6 months post-trauma (Bonne et al., 2001), but the sample in this study experienced only a single incident trauma rather than chronic trauma exposure. Smaller hippocampal volumes have been associated with longer time since trauma (Villarreal et al., 2002) as well as trauma severity (Bremner et al., 1997; Gurvits et al., 1996; Winter and Irle, 2004) but there are negative findings as well (Stein et al., 1997). Winter and colleagues (Winter and Irle, 2004) found reduced hippocampal volumes in burn survivors with and without PTSD, compared to non-exposed healthy controls, which suggests that trauma exposure may produce reductions in hippocampal volumes in the absence of a PTSD diagnosis. In contrast, in Gilbertson et al.'s (2002) twin study, smaller hippocampal volumes were only found in combat veterans with more severe PTSD compared to non-exposed controls, with no significant differences when veterans with less severe PTSD were included in the analyses. Perhaps most critically, they found no significant difference in hippocampal volumes between monozygotic twin pairs with and without PTSD, and concluded that smaller hippocampal volume is a premorbid risk factor for severe and chronic PTSD, rather than a consequence of PTSD or trauma exposure.

In their critical review, Jelicic and Merckelbach (2004) noted that PTSD hippocampus volumetric studies are beset by a number of limitations, including small study sample sizes and low statistical power, methodological heterogeneity (e.g., neuroimaging measurements, type of control sample), and sample heterogeneity (e.g., type and severity of trauma exposure, comorbid psychopathology, medication use). Meta-analysis is a technique that can address some of these limitations, and the results of two recent meta-analyses have provided further evidence of hippocampal volumentric reduction in PTSD. Smith (2005) meta-analyzed 13 studies of adult patients with PTSD and found that persons with PTSD had left and right hippocampal volumes that were 7.2% and 7.0% smaller, respectively, than those of non-exposed controls, and 4.3% and 4.5% smaller, respectively, than those of trauma-exposed controls. Kitayama and associates (2005) also found smaller bilateral hippocampal volume in PTSD compared to both trauma-exposed and non-exposed controls in a meta-analysis of nine studies of adult patients, the majority of whom had chronic trauma exposure (combat veterans and adult survivors of childhood abuse).

The objective of the research that we present in this paper was to quantitatively integrate the literature through a comprehensive series of meta-analyses of structural abnormalities in PTSD. We expanded upon the results of the two previous meta-analyses (Kitayama et al., 2005; Smith, 2005) in the following ways. As recommended by Glass et al. (1981) we did not restrict the study sample to only those studies with the best methodology, which yielded a larger and more inclusive sample of studies. We then used empirical methods to identify sample heterogeneity and to construct homogenous groups for analyses. To examine whether volumetric reductions were specific to PTSD, we also meta-analyzed comparisons of trauma-exposed samples without PTSD versus healthy controls. To address method and sample variance, we conducted an extensive series of analyses examining the effects of moderator variables, including MRI methodology, gender, age and age of trauma exposure, PTSD severity and duration, comorbid disorders, and medication. To examine whether volumetric reductions were restricted to the hippocampus, we meta-analyzed PTSD volumetric studies of other brain regions. For ease of apprehension, we have organized the series of meta-analyses into separate sections punctuated by summaries. In the discussion we summarize the overall results and explicate their implications for the formulation of comprehensive neurobiological models of PTSD.

Section snippets

Studies/samples

Fifty English language candidate studies (23 hippocampus studies; 27 studies of other brain areas) were located through electronic indexes (Medline, PsychInfo; keywords: PTSD and MRI, hippocampal volume, amygdala volume, ACC, corpus callosum) and through perusing relevant journals from 1990 to 2005 (e.g., Neuroimage, Nature Neuroscience, Hippocampus, Biological Psychiatry, Biological Psychology). To address the “file drawer problem” (Hunter and Schmidt, 1990),1

Analyses 1: hippocampal volumetric studies

Studies were grouped according to type of control group: trauma-exposed (non-PTSD) or non-trauma exposed healthy controls (HC); and by hippocampal hemisphere.

PTSD vs. HC: The meta-analysis included 15 studies (Studies # 1–4, 8, 9, 11, 12, 14–17, 25, 26, 35 in Appendix A), N=562. Persons with PTSD had significantly smaller bilateral hippocampal volume; see Table 1 and Fig. 1.

PTSD vs. non-PTSD: The meta-analysis included 12 studies (# 2, 4–7, 10, 13–15, 18, 25, 35 Appendix A), N=379. The

Discussion

The main findings of the meta-analyses were as follows. Compared to control groups with no trauma exposure, samples with PTSD and trauma-exposed samples without PTSD showed significantly smaller hippocampal volume bilaterally. Compared to trauma-exposed controls, persons with PTSD reliably exhibited significantly smaller hippocampal volumes bilaterally only in samples with severe PTSD. MRI methodology differentially moderated results, depending upon the type of method and type of control group.

Acknowledgements

Our current research on PTSD is supported by the Deutsche Forschungsgemeinschaft (KA1476/3). Denise Dörfel was awarded a scholarship by the G.A. Lienert Foundation.

References (121)

  • C.R. Clark et al.

    Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study

    Biological Psychiatry

    (2003)
  • M.D. De Bellis et al.

    A.E. Bennett research award. Developmental traumatology. Part II: brain development

    Biological Psychiatry

    (1999)
  • M.D. De Bellis et al.

    A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder

    Biological Psychiatry

    (2001)
  • M.D. De Bellis et al.

    Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study

    Biological Psychiatry

    (2002)
  • V. Duric et al.

    Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress

    Neuroscience

    (2005)
  • J.L. Eberling et al.

    Preliminary evidence that estrogen protects against age-related hippocampal atrophy

    Neurobiology of Aging

    (2003)
  • C. Fennema-Notestine et al.

    Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder

    Biological Psychiatry

    (2002)
  • T.V. Gurvits et al.

    Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder

    Biological Psychiatry

    (1996)
  • B.H. Harvey et al.

    Endocrine, cognitive and hippocampal/cortical 5HT 1A/2A receptor changes evoked by a time-dependent sensitisation TDS stress model in rats

    Brain Research

    (2003)
  • A. Karl et al.

    Meta-analytic review of event-related potential studies in post-traumatic stress disorder

    Biological Psychology

    (2006)
  • N. Kitayama et al.

    Magnetic resonance imaging MRI measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis

    Journal of Affective Disorders

    (2005)
  • R.J. Lindauer et al.

    Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder

    Biological Psychiatry

    (2004)
  • N. Makris et al.

    MRI-based topographic parcellation of human cerebral white matter and nuclei II. Rationale and applications with systematics of cerebral connectivity

    Neuroimage

    (1999)
  • K. Matsuo et al.

    Hypoactivation of the prefrontal cortex during verbal fluency test in PTSD: a near-infrared spectroscopy study

    Psychiatry Research: Neuroimaging

    (2003)
  • Y. Matsuoka et al.

    A volumetric study of amygdala in cancer survivors with intrusive recollections

    Biological Psychiatry

    (2003)
  • F.S. May et al.

    Cavum septum pellucidum in monozygotic twins discordant for combat exposure: relationship to posttraumatic stress disorder

    Biological Psychiatry

    (2004)
  • R.J. McNally et al.

    Autobiographical memory disturbance in combat-related posttraumatic stress disorder

    Behavioral Research and Therapy

    (1995)
  • B. Moghaddam

    Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders

    Biological Psychiatry

    (2002)
  • M.S. Myslobodsky et al.

    Changes in brain anatomy in patients with posttraumatic stress disorder: a pilot magnetic resonance imaging study

    Psychiatry Research

    (1995)
  • M. Peters et al.

    Unsolved problems in comparing brain sizes in Homo sapiens

    Brain and Cognition

    (1998)
  • N. Raz et al.

    Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume

    Neurobiology of Aging

    (2004)
  • N. Rohleder et al.

    Hypocortisolism and increased glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder

    Biological Psychiatry

    (2004)
  • N. Schuff et al.

    Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder

    Biological Psychiatry

    (2001)
  • M.E. Shaw et al.

    Abnormal functional connectivity in posttraumatic stress disorder

    Neuroimage

    (2002)
  • L.M. Shin et al.

    An fMRI study of anterior cingulate function in posttraumatic stress disorder

    Biological Psychiatry

    (2001)
  • J.P. Aggleton et al.

    Episodic memory, amnesia, and the hippocampal-anterior thalamic axis

    Behavioural Brain Science

    (1999)
  • Diagnostic and Statistical Manual of Mental Disorders, fourth ed. DSM-IV

    (1994)
  • E.D. Bigler et al.

    Hippocampal volume in normal aging and traumatic brain injury

    AJNR American Journal of Neuroradiology

    (1997)
  • D. Blake et al.

    Clinician-Administered PTB Scale

    (1990)
  • O. Bonne et al.

    Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD

    American Journal of Psychiatry

    (2001)
  • J.D. Bremner

    Hypotheses and controversies related to effects of stress on the hippocampus: an argument for stress-induced damage to the hippocampus in patients with posttraumatic stress disorder

    Hippocampus

    (2001)
  • J.D. Bremner et al.

    MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder

    American Journal of Psychiatry

    (1995)
  • J.D. Bremner et al.

    Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder

    American Journal of Psychiatry

    (1999)
  • J.D. Bremner et al.

    MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder

    American Journal of Psychiatry

    (2003)
  • K.L. Brunson et al.

    Long-term, progressive hippocampal cell loss and dysfunction induced by early life administration of corticotropin-releasing hormone reproduce the effects of early life stress

    Proceedings of the National Academy of Sciences of the United States of America

    (2001)
  • T.C. Buckley et al.

    A meta-analytic examination of basal cardiovascular activity in posttraumatic stress disorder

    Psychosomatic Medicine

    (2001)
  • S. Campbell et al.

    Lower hippocampal volume in patients suffering from depression: a meta-analysis

    American Journal of Psychiatry

    (2004)
  • J.M. Canive et al.

    MRI reveals gross structural abnormalities in PTSD

    Annals of New York Academy of Sciences

    (1997)
  • J. Cohen

    Statistical Power Analysis for the Behavioural Sciences

    (1988)
  • L.L. Eldridge et al.

    Remembering episodes: a selective role for the hippocampus during retrieval

    Nature Neuroscience

    (2000)
  • Cited by (696)

    View all citing articles on Scopus
    View full text