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Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma



In animals, exposure to severe stress can damage the hippocampus. Recent human studies show smaller hippocampal volume in individuals with the stress-related psychiatric condition posttraumatic stress disorder (PTSD). Does this represent the neurotoxic effect of trauma, or is smaller hippocampal volume a pre-existing condition that renders the brain more vulnerable to the development of pathological stress responses? In monozygotic twins discordant for trauma exposure, we found evidence that smaller hippocampi indeed constitute a risk factor for the development of stress-related psychopathology. Disorder severity in PTSD patients who were exposed to trauma was negatively correlated with the hippocampal volume of both the patients and the patients' trauma-unexposed identical co-twin. Furthermore, severe PTSD twin pairs—both the trauma-exposed and unexposed members—had significantly smaller hippocampi than non-PTSD pairs.

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  1. 1

    Sapolsky, R.M., Uno, H., Rebert, C.S. & Finch, C.E. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J. Neurosci. 10, 2897–2902 (1990).

  2. 2

    McEwen, B.S. in The Cognitive Neurosciences (ed. Gazzaniga, M.S.) 1117–1135 (MIT Press, Cambridge, Massachusetts, 1995).

  3. 3

    Squire, L.R. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev. 99, 195–231 (1992).

  4. 4

    Zola-Morgan, S. & Squire, L.R. Neuroanatomy of memory. Annu. Rev. Neurosci. 16, 547–563 (1993).

  5. 5

    Bremner, J.D. et al. MRI-based measurements of hippocampal volume in combat-related posttraumatic stress disorder. Am. J. Psychiatry 152, 973–978 (1995).

  6. 6

    Gurvits, T.V. et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol. Psychiatry 40, 1091–1099 (1996).

  7. 7

    Bremner, J.D. 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 41, 23–32 (1997).

  8. 8

    Stein, M.B., Koverola, C., Hanna, C., Torchia, M.G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).

  9. 9

    Pitman, R.K. Hippocampal diminution in PTSD: more (or less?) than meets the eye. Hippocampus 11, 73–74 (2001).

  10. 10

    Bremner, J.D. 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 11, 75–81 (2001).

  11. 11

    McEwen, B.S. Commentary on PTSD discussion. Hippocampus 11, 82–84 (2001).

  12. 12

    Yehuda, R. Are glucocortoids responsible for putative hippocampal damage in PTSD? How and when to decide. Hippocampus 11, 85–89 (2001).

  13. 13

    Kulka, R.A. et al. Trauma and the Vietnam War Generation: Report of Findings from the National Vietnam Veterans Readjustment Study (Brunner/Mazel, New York, 1990).

  14. 14

    Kessler, R.C., Sonnega, A., Bromet, E., Huges, M. & Nelson, C.B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 1048–1060 (1995).

  15. 15

    Crusio, W.E., Schwegler, H. & & van Abeelen, J.H.F. Behavioral responses to novelty and structural variation of the hippocampus in mice. II. Multivariate genetic analysis. Behav. Brain Res. 32, 81–88 (1989).

  16. 16

    Wimer, C.C., Wimer, R.E. & Roderick, T.H. Some behavioral differences associated with relative size of hippocampus in the mouse. J. Comp. Physiol. Psychol. 76, 57–65 (1971).

  17. 17

    Schwegler, H. & Lipp, H.P. Hereditary covariations of neuronal circuitry and behavior: correlations between the proportions of hippocampal synaptic fields in the regio inferior and two-way avoidance in mice and rats. Behav. Brain Res. 7, 1–38 (1983).

  18. 18

    Lyons, D.M., Yang, C., Sawyer-Glover, A.M., Moseley, M.E. & Schatzberg, A.F. Early life stress and inherited variation in monkey hippocampal volumes. Arch. Gen. Psychiatry 58, 1145–1151 (2001).

  19. 19

    Freeman, T.W., Cardwell, D., Karson, C.N. & Komoroski, R.A. In vivo proton magnetic resonance spectroscopy of the medial temporal lobes of subjects with combat-related posttraumatic stress disorder. Magn. Reson. Med. 40, 66–71 (1998).

  20. 20

    Schuff, N. et al. Reduced hippocampal volume and n-acetyl aspartate in posttraumatic stress disorder. Ann. NY Acad. Sci. 821, 516–520 (1997).

  21. 21

    Keane, T.M. & Kaloupek, D.G. Comorbid psychiatric disorders in PTSD: implications for research. Ann. NY Acad. Sci. 821, 24–34 (1997).

  22. 22

    Bremner, J. et al. Hippocampal volume reduction in major depression. Am. J. Psychiatry 157, 115–127 (2000).

  23. 23

    Laakso, M.P. et al. A volumetric MRI study of the hippocampus in type 1 and 2 alcoholism. Behav. Brain Res. 109, 177–186 (2000).

  24. 24

    Sheline, Y., Sanghavi, M., Mintin, M. & Gado, M. Depression duration but not age predicts hippocampal volume loss in medical healthy women with recurrent major depression. J. Neurosci. 19, 5034–5041 (1999).

  25. 25

    De Bellis, M.D. et al. Hippocampal volume in adolescent-onset alcohol use disorders. Am. J. Psychiatry 157, 737–744 (2000).

  26. 26

    Miller, G.A. & Chapman, J.P. Misunderstanding analysis of covariance. J. Abnorm. Psychol. 110, 40–48 (2001).

  27. 27

    De Bellis, M.D. et al. Developmental traumatology part II: brain development. Biol. Psychiatry 45, 1271–1284 (1999).

  28. 28

    Schuff, N. et al. Decreased hippocampal n-acetylaspartate in the absence of atrophy in Posttraumatic Stress Disorder. Biol. Psychiatry 50, 952–959 (2001).

  29. 29

    Bonne, O. et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am. J. Psychiatry 158, 1248–1251 (2001).

  30. 30

    Breslau, N. & Davis, G.C. Posttraumatic Stress Disorder in an urban population of young adults: risk factors for chronicity. Am. J. Psychiatry 149, 671–675 (1992).

  31. 31

    Mellman, T.A., Randolph, C.A., Brawman-Mintzer, O., Flores, L.P. & Milanes, F.J. Phenomenology and course of psychiatric disorders associated with combat-related posttraumatic stress disorder. Am. J. Psychiatry 149, 1568–1574 (1992).

  32. 32

    Selden, N.R.W., Everitt, B.J., Jarrard, L.E. & Robbins, T.W. Complementary roles for amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience 42, 335–350 (1991).

  33. 33

    Phillips, R.G. & LeDoux, J.E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

  34. 34

    Falls, W.A. & Davis, M. in Neurobiological and Clinical Consequences of Stress: from Normal Adaptation to Post-Traumatic Stress Disorder (eds. Friedman, D.J., Charney, D.S. & Deutch, A.Y.) 177–202 (Lippincott-Raven, Philadelphia, 1995).

  35. 35

    Antelman, S.M. & Brown, T.S. Hippocampal lesions and shuttlebox avoidance behavior: a fear hypothesis. Physiol. Behav. 9, 15–20 (1972).

  36. 36

    Orr, S.P. et al. De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder. J. Abnorm. Psychol. 109, 290–298 (2000).

  37. 37

    Wimer, R.E. & Wimer, C.C. A biometrical-genetic analysis of granule cell number in the area dentata of house mice. Brain Res. 254, 129–140 (1981).

  38. 38

    Beck, K.D., Powell-Braxton, L., Widmer, H.R., Vlaverde, J. & Hefti, F. Igfl gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14, 717–730 (1995).

  39. 39

    Pennington, B.F. et al. A twin MRI study of size variations in the human brain. J. Cogn. Neurosci. 12, 223–232 (2000).

  40. 40

    Thompson, P.M. et al. Genetic influences on brain structure. Nat. Neurosci. 4, 1253–1258 (2001).

  41. 41

    Eisen, S., Neuman, R., Goldberg, J., Rice, J. & True, W. Determining zygosity in the Vietnam Era Twin Registry: an approach using questionnaires. Clin. Genet. 35, 423–432 (1989).

  42. 42

    Janes, G.R., Goldberg, J., Eisen, S.A. & True, W.R. Reliability and validity of a combat exposure index for Vietnam era veterans. J. Clin. Psychol. 47, 80–86 (1991).

  43. 43

    Eisen, S.A., True, W.R., Goldberg, J., Henderson, W. & Robinette, C.D. The Vietnam Era Twin (VET) Registry: method of construction. Acta Geneticae Medicae et Gemellologiae (Roma) 36, 61–66 (1987).

  44. 44

    Henderson, W.G. et al. The Vietnam Era Twin Registry: a resource for medical research. Public Health Rep. 105, 368–373 (1990).

  45. 45

    Orr, S.P. et al. Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with PTSD. Arch. Gen. Psychiatry (in press).

  46. 46

    Blake, D.D. et al. The development of a clinician-administered PTSD scale. J. Trauma. Stress 8, 75–90 (1995).

  47. 47

    First, M.B., Spitzer, R.L., Gibbon, M. & Williams, J.B.W. Structured Clinical Interview for Axis I DSM-IV Disorders, Version 2.0 (Biometrics Research Department, New York, 1994).

  48. 48

    Selzer, M.L. The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am. J. Psychiatry 127, 1653–1658 (1971).

  49. 49

    Shenton, M.A. et al. Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imagery study. N. Engl. J. Med. 327, 604–612 (1992).

  50. 50

    Weathers, F.W., Ruscio, A.M. & Keane, T.M. Psychometric properties of nine scoring rules for the Clinican-Administered Posttraumatic Stress Disorder Scale. Psychol. Assess. 11, 124–133 (1999).

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This work was supported by Department of Veterans Affairs Merit Review Grants (to M.W.G. and S.P.O.), USPHS Grant R01-MH54636 (to R.K.P.) and USPHS Grant K02-MH01110 (to M.E.S.). The authors would like to thank M. Macklin, K. Sheldon, S. Williston, L. Paulus, H. Croteau and the VA Cooperative Studies VET Registry (M.E. Vitek, K. Bukowski, R. Havlicek, T. Colton, W.E. Nance, R.S. Paffenbarger, Jr., M.M. Weissman and R.R. Williams) for their assistance. We gratefully acknowledge the participation of the veterans of the VET Registry and the non-Registry twin participants.

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The authors declare no competing financial interests.

Correspondence to Mark W. Gilbertson.

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Figure 1: Discordant monozygotic twin paradigm for assessing MRI differences in PTSD.
Figure 2: Hippocampal volume correlations with post-trauma symptoms.
Figure 3: Total hippocampal volumes for four subject groups.