Biological studies of post-traumatic stress disorder

Key Points

  • Perhaps the most well-replicated biological finding in post-traumatic stress disorder (PTSD) is higher autonomic (heart rate and skin conductance) and facial electromyography responding during internal, mental imagery of the traumatic event and upon exposure to external, trauma-related cues.

  • Higher heart rate responding to sudden loud tones in PTSD probably reflects an acquired sensitization of the nervous system.

  • Diminished volumes of the hippocampus and anterior cingulate cortex are the most frequently replicated neuroanatomic findings in patients with PTSD. These do not appear to be fully explained by comorbid conditions such as substance abuse and depression.

  • Some evidence exists to support both pre-existing vulnerability and neurotoxicity as origins of brain volume reductions in PTSD. On the basis of present data, it is going too far to say that stress damages the brain, but there is no doubt that it changes it.

  • Functional neuroimaging studies suggest that the amygdala and dorsal anterior cingulate cortex are hyper(re)active, whereas the ventral medial prefrontal cortex is hypo(re)active, in PTSD. These abnormalities are likely to underlie the attentional bias towards threat, impaired emotion regulation and persistence of fear memories in this disorder.

  • The classic model of stress based on chronic hyperactivity of the hypothalamus–pituitary–adrenal cortical axis does not characterize PTSD.

  • A number of neurotransmitters and neuroendocrinological factors interact to influence PTSD risk, symptom profiles and severity. These factors vary across individuals owing to genetic and epigenetic factors, as well as within individuals over time in response to environmental influences, including exposure to psychological trauma.

  • As with other mental disorders, genetic vulnerability to PTSD is likely to involve the sum of contributions from multiple alleles, each with small effects.

  • The full range of molecular genetic factors, which include genotype, methylation, histone deacetylation and gene expression, probably influence or accompany the development of PTSD. However, at this time, there are no definitive findings for any one gene or gene system in the aetiology of the disorder.

  • Animal models have identified important molecular pathways that are likely to contribute to the pathophysiology of PTSD and may constitute promising therapeutic targets.

Abstract

Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

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Figure 1: Assessing structural abnormalities in post-traumatic stress disorder using a combat-discordant identical-twin design.
Figure 2: Brain regions implicated in post-traumatic stress disorder functional neuroimaging studies.
Figure 3: Contributions of prefrontal regions to fear regulation and expression.
Figure 4: Putative brain-state shift relevant to post-traumatic stress disorder.
Figure 5: Behavioural and physiological changes in a post-traumatic stress disorder animal model.

References

  1. 1

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 3rd edn (American Psychiatric Association, 1980).

  2. 2

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Press, 2000).

  3. 3

    Dobbs, D. & Wilson, W. P. Observations on persistence of war neurosis. Dis. Nerv. Syst. 21, 686–691 (1960).

    CAS  PubMed  Google Scholar 

  4. 4

    Orr, S. P., Metzger, L. J., Miller, M. W. & Kaloupek, D. G. in Assessing Psychological Trauma and PTSD: A Handbook for Practicioners 2nd edn (eds Wilson, J. P. & Keane, T. M.) 289–343 (Guilford Publications, 2004).

    Google Scholar 

  5. 5

    Metzger, L. J., Gilbertson, M. W. & Orr, S. P. in Neuropsychology of PTSD: Biological, Clinical, and Cognitive Perspectives (eds Vasterling, J. & Brewin, C.) 83–102 (Guilford Publications, 2005).

    Google Scholar 

  6. 6

    Pole, N. The psychophysiology of posttraumatic stress disorder: a meta-analysis. Psychol. Bull. 133, 725–746 (2007). A comprehensive review and meta-analysis of the most important psychophysiological research in PTSD as of that date.

    Article  PubMed  Google Scholar 

  7. 7

    Keane, T. M. et al. Utility of psychophysiological measurement in the diagnosis of posttraumatic stress disorder: results from a Department of Veterans Affairs Cooperative Study. J. Consult. Clin. Psychol. 66, 914–923 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. 8

    Pitman, R. K., Orr, S. P., Forgue, D. F., de Jong, J. B. & Claiborn, J. M. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch. Gen. Psychiatry 44, 970–975 (1987). This study introduced a novel symptom provocation technique for PTSD that has come into widespread psychophysiologic, neuroimaging and other research use.

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Blanchard, E. B. et al. Psychophysiology of posttraumatic stress disorder related to motor vehicle accidents: replication and extension. J. Consult Clin. Psychol. 64, 742–751 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Kleim, B., Wilhelm, F. H., Glucksman, E. & Ehlers, A. Sex differences in heart rate responses to script-driven imagery soon after trauma and risk of posttraumatic stress disorder. Psychosom. Med. 72, 917–924 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Orr, S. P. et al. Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch. Gen. Psychiatry 60, 283–288 (2003).

    Article  PubMed  Google Scholar 

  12. 12

    Shalev, A. Y. et al. Auditory startle response in trauma survivors with posttraumatic stress disorder: a prospective study. Am. J. Psychiatry 157, 255–261 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Pitman, R. K. et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51, 189–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Griffin, M. G., Resick, P. A. & Galovski, T. E. Does physiologic response to loud tones change following cognitive-behavioral treatment for posttraumatic stress disorder? J. Trauma Stress. 25, 25–32 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Peri, T., Ben-Shakhar, G., Orr, S. P. & Shalev, A. Y. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol. Psychiatry 47, 512–519 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Blechert, J., Michael, T., Vriends, N., Margraf, J. & Wilhelm, F. H. Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behav. Res. Ther. 45, 2019–2033 (2007).

    Article  PubMed  Google Scholar 

  17. 17

    Lissek, S. & Grillon, C. in The Oxford Handbook of Traumatic Stress Disorders (eds Beck, J. G. & Sloan, D. M.) 175–190 (Oxford Univ. Press, 2012).

    Google Scholar 

  18. 18

    Wessa, M. & Flor, H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. Am. J. Psychiatry 164, 1684–1692 (2007).

    Article  PubMed  Google Scholar 

  19. 19

    Milad, M. R. et al. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J. Psychiatr. Res. 42, 515–520 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Metzger, L. J., Pitman, R. K., Miller, G. A., Paige, S. R. & Orr, S. P. Intensity dependence of auditory P2 in monozygotic twins discordant for Vietnam combat: associations with posttraumatic stress disorder. J. Rehabil. Res. Dev. 45, 437–449 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Grillon, C. & Morgan, C. A. Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. J. Abnorm. Psychol. 108, 134–142 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Griffin, M. G. A prospective assessment of auditory startle alterations in rape and physical assault survivors. J. Trauma. Stress 21, 91–99 (2008).

    Article  PubMed  Google Scholar 

  23. 23

    Buhlmann, U. et al. Physiologic responses to loud tones in individuals with obsessive-compulsive disorder. Psychosom. Med. 69, 166–172 (2007).

    Article  PubMed  Google Scholar 

  24. 24

    Guthrie, R. M. & Bryant, R. A. Auditory startle response in firefighters before and after trauma exposure. Am. J. Psychiatry 162, 283–290 (2005).

    Article  PubMed  Google Scholar 

  25. 25

    Guthrie, R. M. & Bryant, R. A. Extinction learning before trauma and subsequent posttraumatic stress. Psychosom. Med. 68, 307–311 (2006).

    Article  PubMed  Google Scholar 

  26. 26

    Orr, S. P. et al. Predicting post-trauma stress symptoms from pre-trauma psychophysiologic reactivity, personality traits and measures of psychopathology. Biol. Mood Anxiety Disord. 2, 8 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    O'Donnell, M. L., Creamer, M., Elliott, P. & Bryant, R. Tonic and phasic heart rate as predictors of posttraumatic stress disorder. Psychosom. Med. 69, 256–261 (2007).

    Article  PubMed  Google Scholar 

  28. 28

    Suendermann, O., Ehlers, A., Boellinghaus, I., Gamer, M. & Glucksman, E. Early heart rate responses to standardized trauma-related pictures predict posttraumatic stress disorder: a prospective study. Psychosom. Med. 72, 301–308 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Shalev, A. Y. et al. A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. Arch. Gen. Psychiatry 55, 553–559 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Kobayashi, I., Boarts, J. M. & Delahanty, D. L. Polysomnographically measured sleep abnormalities in PTSD: a meta-analytic review. Psychophysiology 44, 660–669 (2007).

    Article  PubMed  Google Scholar 

  31. 31

    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).

    Article  CAS  PubMed  Google Scholar 

  32. 32

    Bremner, J. D. et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am. J. Psychiatry 152, 973–981 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    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).

    Article  CAS  Google Scholar 

  35. 35

    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. 88, 79–86 (2005).

    Article  PubMed  Google Scholar 

  36. 36

    Wang, Z. et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch. Gen. Psychiatry 67, 296–303 (2010). This was the first study in humans to use high-resolution sMRI to determine more specific volume diminutions within selected hippocampal subfields and to delineate those regions specific to PTSD versus ageing effects.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Smith, M. E. Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 15, 798–807 (2005).

    Article  PubMed  Google Scholar 

  38. 38

    Karl, A. et al. A meta-analysis of structural brain abnormalities in PTSD. Neurosci. Biobehav. Rev. 30, 1004–1031 (2006).

    Article  PubMed  Google Scholar 

  39. 39

    Woon, F. & Hedges, D. W. Gender does not moderate hippocampal volume deficits in adults with posttraumatic stress disorder: a meta-analysis. Hippocampus 21, 243–252 (2011).

    Article  PubMed  Google Scholar 

  40. 40

    Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nature Neurosci. 5, 1242–1247 (2002). This study used data from monozygotic twins discordant for combat exposure and PTSD to suggest that smaller hippocampal volume in PTSD represents a pre-existing vulnerability factor.

    Article  CAS  PubMed  Google Scholar 

  41. 41

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Fennema-Notestine, C. Stein, M. B., Kennedy, C. M., Archibald, S. L. & Jernigan, T. L. Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder. Biol. Psychiatry 52, 1089–1101 (2002).

    Article  PubMed  Google Scholar 

  43. 43

    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 50, 305–309 (2001).

    Article  CAS  Google Scholar 

  44. 44

    Emdad, R. et al. Morphometric and psychometric comparisons between non-substance-abusing patients with posttraumatic stress disorder and normal controls. Psychother. Psychosom. 75, 122–132 (2006).

    Article  PubMed  Google Scholar 

  45. 45

    Bonne, O. et al. Reduced posterior hippocampal volume in posttraumatic stress disorder. J. Clin. Psychiatry 69, 1087–1091 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Schuff, N. et al. Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder. Psychiatry Res. 162, 147–157 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Karl, A. & Werner, A. The use of proton magnetic resonance spectroscopy in PTSD research — meta-analyses of findings and methodological review. Neurosci. Biobehav. Rev. 34, 7–22 (2010).

    Article  PubMed  Google Scholar 

  48. 48

    Myslobodsky, M. S. et al. Changes of brain anatomy in patients with posttraumatic stress disorder: a pilot magnetic resonance imaging study. Psychiatry Res. 58, 259–264 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    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).

    Article  CAS  PubMed  Google Scholar 

  50. 50

    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 54, 693–702 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Woon, F. L., Sood, S. & Hedges, D. W. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1181–1188 (2010).

    Article  PubMed  Google Scholar 

  52. 52

    Kasai, K. et al. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol. Psychiatry 63, 550–556 (2008).

    Article  PubMed  Google Scholar 

  53. 53

    Kitayama, N., Quinn, S. & Bremner, J. D. Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder. J. Affect. Disord. 90, 171–174 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Carrion, V. G., Weems, C. F., Richert, K., Hoffman, B. C. & Reiss, A. L. Decreased prefrontal cortical volume associated with increased bedtime cortisol in traumatized youth. Biol. Psychiatry 68, 491–493 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Kim, S. J. et al. Asymmetrically altered integrity of cingulum bundle in posttraumatic stress disorder. Neuropsychobiology 54, 120–125 (2006).

    Article  PubMed  Google Scholar 

  56. 56

    Sekiguchi, A. et al. Brain structural changes as vulnerability factors and acquired signs of post-earthquake stress. Mol. Psychiatry 22 May 2012 (doi:10.1038/mp.2012.51).

  57. 57

    Morrow, B. A., Elsworth, J. D., Rasmusson, A. M. & Roth, R. H. The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92, 553–564 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Herry, C. et al. Neuronal circuits of fear extinction. Eur. J. Neurosci. 31, 599–612 (2010).

    Article  PubMed  Google Scholar 

  59. 59

    Milad, M. R. & Quirk, G. J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Liberzon, I. et al. Brain activation in PTSD in response to trauma-related stimuli. Biol. Psychiatry 45, 817–826 (1999).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Bremner, J. D. et al. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol. Med. 35, 791–806 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Shin, L. M. et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am. J. Psychiatry 156, 575–584 (1999).

    CAS  Google Scholar 

  64. 64

    Gold, A. L. et al. Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder. Psychol. Med. 41, 2563–2572 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    Felmingham, K. et al. Neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder. J. Abnorm. Psychol. 119, 241–247 (2010).

    Article  PubMed  Google Scholar 

  66. 66

    Shin, L. M. et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch. Gen. Psychiatry 61, 168–176 (2004).

    Article  PubMed  Google Scholar 

  67. 67

    Felmingham, K. et al. Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder. Psychol. Sci. 18, 127–129 (2007). This article used fMRI to reveal functional brain changes in response to cognitive behavioural therapy in PTSD.

    Article  PubMed  Google Scholar 

  68. 68

    Milad, M. R. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Shin, L. M. et al. An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol. Psychiatry 50, 932–942 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Rougemont-Bucking, A. et al. Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci. Ther. 17, 227–236 (2011).

    Article  PubMed  Google Scholar 

  71. 71

    Bryant, R. A. et al. Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study. Biol. Psychiatry 58, 111–118 (2005).

    Article  PubMed  Google Scholar 

  72. 72

    Pannu, H. J., Labar, K. S., Petty, C. M., McCarthy, G. & Morey, R. A. Alterations in the neural circuitry for emotion and attention associated with posttraumatic stress symptomatology. Psychiatry Res. 172, 7–15 (2009).

    Article  Google Scholar 

  73. 73

    Fonzo, G. A. et al. Exaggerated and disconnected insular–amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol. Psychiatry 68, 433–441 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Shin, L. M. et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch. Gen. Psychiatry 66, 1099–1107 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Shin, L. M. et al. Exaggerated activation of dorsal anterior cingulate cortex during cognitive interference: a monozygotic twin study of posttraumatic stress disorder. Am. J. Psychiatry 168, 979–985 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924–932 (2003).

    Article  Google Scholar 

  77. 77

    Shin, L. M. & Liberzon, I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191 (2010).

    Article  Google Scholar 

  78. 78

    Simmons, A. N. et al. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol. Psychiatry 64, 681–690 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Strigo, I. A. et al. Neural correlates of altered pain response in women with posttraumatic stress disorder from intimate partner violence. Biol. Psychiatry 68, 442–450 (2010).

    Article  PubMed  Google Scholar 

  80. 80

    Aupperle, R. L. et al. Dorsolateral prefrontal cortex activation during emotional anticipation and neuropsychological performance in posttraumatic stress disorder. Arch. Gen. Psychiatry 69, 360–371 (2012). This paper linked functional brain activation patterns with neuropsychological test performance in PTSD.

    Article  PubMed  Google Scholar 

  81. 81

    Hayes, J. P., Hayes, S. M. & Mikedis, A. M. Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol. Mood Anxiety Disord. 2, 9 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Elzinga, B. M. & Bremner, J. D. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J. Affect. Disord. 70, 1–17 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Rauch, S. L., Shin, L. M. & Phelps, E. A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol. Psychiatry 60, 376–382 (2006).

    Article  PubMed  Google Scholar 

  84. 84

    Pitman, R. K. Combat effects on mental health: the more things change, the more they remain the same. Arch. Gen. Psychiatry 63, 127–128 (2006).

    Article  PubMed  Google Scholar 

  85. 85

    Geuze, E. et al. Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol. Psychiatry 13, 74–83 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    Murrough, J. W. et al. Reduced amygdala serotonin transporter binding in posttraumatic stress disorder. Biol. Psychiatry 70, 1033–1038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Liberzon, I. et al. Altered central mu-opioid receptor binding after psychological trauma. Biol. Psychiatry 61, 1030–1038 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Murrough, J. W. et al. The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding. Arch. Gen. Psychiatry 68, 892–900 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Southwick, S. M. et al. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol. Psychiatry 46, 1192–1204 (1999).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Pitman, R. K. Post-traumatic stress disorder, hormones, and memory. Biol. Psychiatry 26, 221–223 (1989).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Rasmusson, A. M. et al. Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol. Psychiatry 47, 526–539 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Perry, B. D., Giller, E. L. Jr & Southwick, S. M. Altered platelet α2-adrenergic binding sites in posttraumatic stress disorder. Am. J. Psychiatry 144, 1511–1512 (1987).

    CAS  PubMed  Google Scholar 

  93. 93

    Maes, M. et al. Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression. Neuropsychopharmacology 20, 188–197 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Blanchard, E. B., Kolb, L. C., Prins, A., Gates, S. & McCoy, G. C. Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with posttraumatic stress disorder. J. Nerv. Ment. Dis. 179, 371–373 (1991).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    Southwick, S. M. et al. Abnormal noradrenergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 50, 266–274 (1993).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Mellman, T. A., Kumar, A., Kulick-Bell, R., Kumar, M. & Nolan, B. Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD. Biol. Psychiatry 38, 174–179 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    Liberzon, I., Abelson, J. L., Flagel, S. B., Raz, J. & Young, E. A. Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study. Neuropsychopharmacology 21, 40–50 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Bremner, J. D. et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 246–254 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Taylor, F. B. et al. Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. Biol. Psychiatry 59, 577–581 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Raskind, M. A. et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol. Psychiatry 61, 928–934 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. 101

    Vaiva, G. et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol. Psychiatry 54, 947–949 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Stein, M. B., Kerridge, C., Dimsdale, J. E. & Hoyt, D. B. Pharmacotherapy to prevent PTSD: results from a randomized controlled proof-of-concept trial in physically injured patients. J. Trauma Stress. 20, 923–932 (2007).

    Article  PubMed  Google Scholar 

  103. 103

    Hoge, E. A. et al. Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery. CNS Neurosci. Ther. 18, 21–27 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Southwick, S. M. et al. Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 749–758 (1997).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Baumann, M. H., Mash, D. C. & Staley, J. K. The serotonin agonist m-chlorophenylpiperazine (mCPP) binds to serotonin transporter sites in human brain. Neuroreport 6, 2150–2152 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Murphy, D. L., Lesch, K. P., Aulakh, C. S. & Pigott, T. A. Serotonin-selective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol. Rev. 43, 527–552 (1991).

    CAS  PubMed  Google Scholar 

  107. 107

    Kennett, G. A. et al. Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology 33, 1581–1588 (1994).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Britton, K. T., Akwa, Y., Spina, M. G. & Koob, G. F. Neuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze. Peptides 21, 37–44 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    Zhou, Z. et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 452, 997–1001 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Morgan, C. A. et al. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol. Psychiatry 52, 136–142 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Sah, R. et al. Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder. Biol. Psychiatry 66, 705–707 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Yehuda, R., Brand, S. & Yang, R. K. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol. Psychiatry 59, 660–663 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Dunn, A. J. & Berridge, C. W. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res. Brain Res. Rev. 15, 71–100 (1990).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Baker, D. G. et al. Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder. Am. J. Psychiatry 162, 992–994 (2005).

    Article  PubMed  Google Scholar 

  115. 115

    de Kloet, C. S. et al. Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder. Prog. Brain Res. 167, 287–291 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Geracioti, T. D. Jr et al. Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder. Psychoneuroendocrinology 33, 416–424 (2008).

    Article  CAS  PubMed  Google Scholar 

  117. 117

    Yehuda, R. et al. Low urinary cortisol excretion in patients with posttraumatic stress disorder. J. Nerv. Ment. Dis. 178, 366–369 (1990).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 346, 108–114 (2002). This article reviewed a highly influential body of research involving hyper-responsiveness of glucocorticoid receptors, enhanced negative feedback of the hypothalamus–pituitary–adrenal cortical axis and lower circulating cortisol levels in PTSD.

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Yehuda, R., Boisoneau, D., Lowy, M. T. & Giller, E. L. Jr. Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch. Gen. Psychiatry 52, 583–593 (1995).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Yehuda, R., Lowy, M. T., Southwick, S. M., Shaffer, D. & Giller, E. L. Jr. Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder. Am. J. Psychiatry 148, 499–504 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. 121

    Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 56–69 (2009).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Mehta, D. et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch. Gen. Psychiatry 68, 901–910 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Young, E. A. & Breslau, N. Cortisol and catecholamines in posttraumatic stress disorder: an epidemiologic community study. Arch. Gen. Psychiatry 61, 394–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. 124

    Young, E. A. & Breslau, N. Saliva cortisol in posttraumatic stress disorder: a community epidemiologic study. Biol. Psychiatry 56, 205–209 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Rasmusson, A. M. et al. Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder. Biol. Psychiatry 50, 965–977 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Schelling, G. et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol. Psychiatry 55, 627–633 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Zohar, J. et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur. Neuropsychopharmacol. 21, 796–809 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. 128

    de Quervain, D. J. Glucocorticoid-induced inhibition of memory retrieval: implications for posttraumatic stress disorder. Ann. NY Acad. Sci. 1071, 216–220 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    McIntyre, C. K. & Roozendaal, B. in Neural Plasticity and Memory: From Genes to Brain Imaging (ed. Bermúdez-Rattoni, F.) 265–284 (CRC, 2007).

    Google Scholar 

  130. 130

    Sandi, C. Glucocorticoids act on glutamatergic pathways to affect memory processes. Trends Neurosci. 34, 165–176 (2011).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Hou, Y. T., Lin, H. K. & Penning, T. M. Dexamethasone regulation of the rat 3α-hydroxysteroid/dihydrodiol dehydrogenase gene. Mol. Pharmacol. 53, 459–466 (1998).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    Rasmusson, A. M., Picciotto, M. R. & Krishnan-Sarin, S. Smoking as a complex but critical covariate in neurobiological studies of posttraumatic stress disorders: a review. J. Psychopharmacol. 20, 693–707 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Yehuda, R. et al. Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001. Psychoneuroendocrinology 34, 1304–1313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Rasmusson, A. M., Vythilingam, M. & Morgan, C. A. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr. 8, 651–657 (2003).

    Article  PubMed  Google Scholar 

  135. 135

    Chalbot, S. & Morfin, R. Dehydroepiandrosterone metabolites and their interactions in humans. Drug Metabol. Drug Interact. 22, 1–23 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    Balazs, Z., Schweizer, R. A., Frey, F. J., Rohner-Jeanrenaud, F. & Odermatt, A. DHEA induces 11β–HSD2 by acting on CCAAT/enhancer-binding proteins. J. Am. Soc. Nephrol. 19, 92–101 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Spivak, B. et al. Elevated circulatory level of GABAA — antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol. Med. 30, 1227–1231 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. 138

    Sondergaard, H. P., Hansson, L. O. & Theorell, T. Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: findings from a longitudinal study of refugees in Sweden. Psychother. Psychosom. 71, 298–303 (2002).

    Article  PubMed  Google Scholar 

  139. 139

    Rasmusson, A. M. et al. An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology 29, 1546–1557 (2004).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    Gill, J., Vythilingam, M. & Page, G. G. Low cortisol, high DHEA, and high levels of stimulated TNFα, and IL-6 in women with PTSD. J. Trauma Stress 21, 530–539 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Morgan, C. A. et al. Relationships among plasma dehydroepiandrosterone sulfate and cortisol levels, symptoms of dissociation, and objective performance in humans exposed to acute stress. Arch. Gen. Psychiatry 61, 819–825 (2004).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    Morgan, C. A., Rasmusson, A., Pietrzak, R. H., Coric, V. & Southwick, S. M. Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation, and objective performance in humans exposed to underwater navigation stress. Biol. Psychiatry 66, 334–340 (2009).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Yehuda, R., Brand, S. R., Golier, J. A. & Yang, R. K. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr. Scand. 114, 187–193 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. 144

    Rasmusson, A. M. et al. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol. Psychiatry 60, 704–713 (2006). This article reported deficits in the synthesis of GABAergic neuroactive steroids in PTSD, suggesting a mechanism that may confer resistance to SSRI treatment and contribute to comorbidities, such as depression and chronic pain.

    Article  CAS  PubMed  Google Scholar 

  145. 145

    Genazzani, A. D. et al. Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids. Fertil. Steril. 80, 1495–1501 (2003).

    Article  PubMed  Google Scholar 

  146. 146

    Schmidt, P. J. et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch. Gen. Psychiatry 62, 154–162 (2005).

    Article  CAS  PubMed  Google Scholar 

  147. 147

    Semyanov, A., Walker, M. C., Kullmann, D. M. & Silver, R. A. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Pinna, G., Dong, E., Matsumoto, K., Costa, E. & Guidotti, A. In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc. Natl Acad. Sci. USA 100, 2035–2040 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. 149

    True, W. R. et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch. Gen. Psychiatry 50, 257–264 (1993).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Stein, M. B., Jang, K. L., Taylor, S., Vernon, P. A. & Livesley, W. J. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am. J. Psychiatry 159, 1675–1681 (2002).

    Article  PubMed  Google Scholar 

  151. 151

    Sartor, C. E. et al. Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychol. Med. 41, 1497–1505 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Lyons, M. J. et al. Do genes influence exposure to trauma? A twin study of combat. Am. J. Med. Genet. 48, 22–27 (1993).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Jang, K. L., Stein, M. B., Taylor, S., Asmundson, G. J. & Livesley, W. J. Exposure to traumatic events and experiences: aetiological relationships with personality function. Psychiatry Res. 120, 61–69 (2003).

    Article  PubMed  Google Scholar 

  154. 154

    Cornelis, M. C., Nugent, N. R., Amstadter, A. B. & Koenen, K. C. Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Curr. Psychiatry Rep. 12, 313–326 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Sartor, C. E. et al. Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Arch. Gen. Psychiatry 69, 293–299 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).

    CAS  PubMed  Google Scholar 

  157. 157

    Ressler, K. J. et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470, 492–497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Chang, S. C. et al. No association between ADCYAP1R1 and post-traumatic stress disorder in two independent samples. Mol. Psychiatry 17, 239–241 (2012).

    Article  CAS  PubMed  Google Scholar 

  159. 159

    Segman, R. H. et al. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol. Psychiatry 10, 500–513 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. 160

    Zieker, J. et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol. Psychiatry 12, 116–118 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. 161

    Yehuda, R. et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol. Psychiatry 66, 708–711 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. 162

    Uddin, M. et al. Gene expression and methylation signatures of MAN2C1 are associated with PTSD. Dis. Markers 30, 111–121 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Kilpatrick, D. G. et al. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am. J. Psychiatry 164, 1693–1699 (2007). This was the first study to document a genotype by environment interaction in risk of PTSD. The data suggested that the low expression variant of the serotonin transporter gene increases risk of PTSD under conditions of high stress and low social support but not under low stress conditions.

    Article  PubMed  Google Scholar 

  164. 164

    Binder, E. B. et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299, 1291–1305 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Uddin, M. et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 107, 9470–9475 (2010). This study provided evidence of a biological model of PTSD aetiology in which an externally experienced traumatic event induces downstream alterations in immune function by reducing methylation levels of immune-related genes.

    Article  PubMed  Google Scholar 

  166. 166

    Smith, A. K. et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 700–708 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Xie, P. et al. Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch. Gen. Psychiatry 66, 1201–1209 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Xie, P., Kranzler, H. R., Farrer, L. & Gelernter, J. Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 159B, 644–652 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Koenen, K. C. et al. Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment. Am. J. Epidemiol. 169, 704–711 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Philibert, R. A. et al. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 543–549 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. 171

    Koenen, K. C. et al. SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depress. Anxiety 28, 639–647 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Trollope, A. F. et al. Stress, epigenetic control of gene expression and memory formation. Exp. Neurol. 233, 3–11 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. 173

    El-Sayed, A. M., Halossim, M. R., Galea, S. & Koenen, K. C. Epigenetic modifications associated with suicide and common mood and anxiety disorders: a systematic review of the literature. Biol. Mood Anxiety Disord. 2, 10 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Pitman, R. K., Orr, S. P. & Shalev, A. Y. Once bitten, twice shy: beyond the conditioning model of PTSD. Biol. Psychiatry 33, 145–146 (1993).

    Article  CAS  PubMed  Google Scholar 

  175. 175

    Adamec, R. E. & Shallow, T. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol. Behav. 54, 101–109 (1993). An early and influential study of the PredEx animal model for PTSD.

    Article  CAS  PubMed  Google Scholar 

  176. 176

    Zoladz, P. R., Conrad, C. D., Fleshner, M. & Diamond, D. M. Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder. Stress 11, 259–281 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Cohen, H., Zohar, J. & Matar, M. The relevance of differential response to trauma in an animal model of posttraumatic stress disorder. Biol. Psychiatry 53, 463–473 (2003).

    Article  PubMed  Google Scholar 

  178. 178

    Mesches, M. H., Fleshner, M., Heman, K. L., Rose, G. M. & Diamond, D. M. Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro. J. Neurosci. 19, RC18 (1999).

    Article  CAS  PubMed  Google Scholar 

  179. 179

    Liberzon, I., Lopez, J. F., Flagel, S. B., Vazquez, D. M. & Young, E. A. Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J. Neuroendocrinol. 11, 11–17 (1999). This study demonstrated the construct validity of the SPS animal model of PTSD.

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Kohda, K. et al. Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model. Neuroscience 148, 22–33 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    Servatius, R. J., Ottenweller, J. E., Bergen, M. T., Soldan, S. & Natelson, B. H. Persistent stress-induced sensitization of adrenocortical and startle responses. Physiol Behav. 56, 945–954 (1994).

    Article  CAS  PubMed  Google Scholar 

  182. 182

    Pynoos, R. S., Ritzmann, R. F., Steinberg, A. M., Goenjian, A. & Prisecaru, I. A behavioral animal model of posttraumatic stress disorder featuring repeated exposure to situational reminders. Biol. Psychiatry 39, 129–134 (1996).

    Article  CAS  PubMed  Google Scholar 

  183. 183

    Rau, V. & Fanselow, M. S. Exposure to a stressor produces a long lasting enhancement of fear learning in rats. Stress 12, 125–133 (2009).

    Article  PubMed  Google Scholar 

  184. 184

    Li, X., Han, F., Liu, D. & Shi, Y. Changes of Bax, Bcl-2 and apoptosis in hippocampus in the rat model of post-traumatic stress disorder. Neurol. Res. 32, 579–586 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Kozlovsky, N., Matar, M. A., Kaplan, Z., Zohar, J. & Cohen, H. A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder. Eur. Neuropsychopharmacol. 19, 759–771 (2009).

    Article  CAS  PubMed  Google Scholar 

  186. 186

    Zhe, D., Fang, H. & Yuxiu, S. Expressions of hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the single-prolonged stress-rats. Acta Histochem. Cytochem. 41, 89–95 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187

    Adamec, R., Muir, C., Grimes, M. & Pearcey, K. Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress. Behav. Brain Res. 179, 192–207 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. 188

    Adamec, R., Fougere, D. & Risbrough, V. CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD. Int. J. Neuropsychopharmacol. 13, 747–757 (2010).

    Article  CAS  PubMed  Google Scholar 

  189. 189

    Cohen, H., Matar, M. A., Buskila, D., Kaplan, Z. & Zohar, J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol. Psychiatry 64, 708–717 (2008).

    Article  CAS  PubMed  Google Scholar 

  190. 190

    Kaouane, N. et al. Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335, 1510–1513 (2012).

    Article  CAS  PubMed  Google Scholar 

  191. 191

    Knox, D., Perrine, S. A., George, S. A., Galloway, M. P. & Liberzon, I. Single prolonged stress decreases glutamate, glutamine, and creatine concentrations in the rat medial prefrontal cortex. Neurosci. Lett. 480, 16–20 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192

    Harvey, B. H., Oosthuizen, F., Brand, L., Wegener, G. & Stein, D. J. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl.) 175, 494–502 (2004).

    Article  CAS  Google Scholar 

  193. 193

    Yamamoto, S. et al. Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder. J. Psychiatr. Res. 44, 1069–1074 (2010).

    Article  PubMed  Google Scholar 

  194. 194

    Yamamoto, S. et al. Effects of single prolonged stress and d-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology 33, 2108–2116 (2008).

    Article  CAS  PubMed  Google Scholar 

  195. 195

    Blundell, J. & Adamec, R. The NMDA receptor antagonist CPP blocks the effects of predator stress on pCREB in brain regions involved in fearful and anxious behavior. Brain Res. 1136, 59–76 (2007).

    Article  CAS  PubMed  Google Scholar 

  196. 196

    Adamec, R., Holmes, A. & Blundell, J. Vulnerability to lasting anxiogenic effects of brief exposure to predator stimuli: sex, serotonin and other factors-relevance to PTSD. Neurosci. Biobehav. Rev. 32, 1287–1292 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 197

    Harvey, B. H., Brand, L., Jeeva, Z. & Stein, D. J. Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder. Physiol. Behav. 87, 881–890 (2006).

    Article  CAS  PubMed  Google Scholar 

  198. 198

    Kesner, Y. et al. WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model. Mol. Psychiatry 14, 86–94 (2009).

    Article  CAS  PubMed  Google Scholar 

  199. 199

    Luo, F. F., Han, F. & Shi, Y. X. Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder. Mol. Med. Report. 4, 843–847 (2011).

    CAS  Google Scholar 

  200. 200

    Harvey, B. H., Naciti, C., Brand, L. & Stein, D. J. Endocrine, cognitive and hippocampal/cortical 5HT1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats. Brain Res. 983, 97–107 (2003).

    Article  CAS  PubMed  Google Scholar 

  201. 201

    Wang, H. T., Han, F. & Shi, Y. X. Activity of the 5-HT1A receptor is involved in the alteration of glucocorticoid receptor in hippocampus and corticotropin-releasing factor in hypothalamus in SPS rats. Int. J. Mol. Med. 24, 227–231 (2009).

    CAS  PubMed  Google Scholar 

  202. 202

    Harada, K., Yamaji, T. & Matsuoka, N. Activation of the serotonin 5-HT2C receptor is involved in the enhanced anxiety in rats after single-prolonged stress. Pharmacol. Biochem. Behav. 89, 11–16 (2008).

    Article  CAS  PubMed  Google Scholar 

  203. 203

    Olson, V. G. et al. The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder. Biol. Psychiatry 70, 441–448 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Takei, S. et al. Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder. J. Psychiatr. Res. 45, 460–468 (2011).

    Article  PubMed  Google Scholar 

  205. 205

    Kozlovsky, N. et al. Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int. J. Neuropsychopharmacol. 10, 741–758 (2007).

    Article  CAS  PubMed  Google Scholar 

  206. 206

    Roth, T. L., Zoladz, P. R., Sweatt, J. D. & Diamond, D. M. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J. Psychiatr. Res. 45, 919–926 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  207. 207

    Pitman, R. K. & Orr, S. P. in Posttraumatic Stress Disorder in Litigation: Guidelines for Forensic Assessment (ed. Simon, R. I.) 207–223 (American Psychiatric Press, 2003).

    Google Scholar 

  208. 208

    Yehuda, R., McFarlane, A. C. & Shalev, A. Y. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol. Psychiatry 44, 1305–1313 (1998).

    Article  CAS  PubMed  Google Scholar 

  209. 209

    Delahanty, D. L., Raimonde, A. J. & Spoonster, E. Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol. Psychiatry 48. 940–947 (2000).

    Article  CAS  PubMed  Google Scholar 

  210. 210

    Brunet, A. et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42, 503–506 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  211. 211

    Brunet, A. et al. Trauma reactivation under the influence of propranolol decreases posttraumatic stress symptoms and disorder: 3 open-label trials. J. Clin. Psychopharmacol. 31, 547–550 (2011).

    Article  PubMed  Google Scholar 

  212. 212

    Schiller, D. et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53 (2010).

    Article  CAS  PubMed  Google Scholar 

  213. 213

    Milad, M. R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).

    Article  PubMed  Google Scholar 

  214. 214

    Milad, M. R. et al. A role for the human dorsal anterior cingulate cortex in fear expression. Biol. Psychiatry 62, 1191–1194 (2007).

    Article  PubMed  Google Scholar 

  215. 215

    Goldstein, L. E., Rasmusson, A. M., Bunney, B. S. & Roth, R. H. Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat. J. Neurosci. 16, 4787–4798 (1996).

    Article  CAS  PubMed  Google Scholar 

  216. 216

    Arnsten, A. F. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Rev. Neurosci. 10, 410–422 (2009).

    Article  CAS  Google Scholar 

  217. 217

    Rosenkranz, J. A. & Grace, A. A. Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J. Neurosci. 22, 324–337 (2002).

    Article  CAS  Google Scholar 

  218. 218

    Chhatwal, J. P., Myers, K. M., Ressler, K. J. & Davis, M. Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction. J. Neurosci. 25, 502–506 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. 219

    Heldt, S. A. & Ressler, K. J. Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear. Eur. J. Neurosci. 26, 3631–3644 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  220. 220

    Rosenkranz, J. A. & Grace, A. A. Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. J. Neurosci. 21, 4090–4103 (2001).

    Article  CAS  Google Scholar 

  221. 221

    Braga, M. F., Aroniadou-Anderjaska, V., Manion, S. T., Hough, C. J. & Li, H. Stress impairs α1A adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala. Neuropsychopharmacology 29, 45–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  222. 222

    Buffalari, D. M. & Grace, A. A. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of α-2 and β receptor activation. J. Neurosci. 27, 12358–12366 (2007).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Roger K. Pitman.

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Supplementary information S1 (table)

Summary of Candidate Genes Studied in Relation to Posttraumatic Stress Disorder (PDF 138 kb)

Glossary

Skin conductance

A measure of sweat activity recorded from two adjacent fingers and/or the thenar and hypothenar eminences of the palm of the hand. It is thought to be primarily under sympathetic nervous system influence.

Event-related potentials

(ERPs). Electrical potentials that are generated in the brain as a consequence of the synchronized activation of neuronal networks by external stimuli. These evoked potentials are recorded at the scalp and consist of precisely timed sequences of waves or 'components'.

Extinction

A procedure by which a conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, resulting in diminution of the conditioned response.

P3b

An electroencephalographic event-related potential response that is positive and reaches its maximum deflection approximately 300ms after a stimulus is presented. It is thought to reflect the amount of attentional resources allocated to the stimulus.

Fear conditioning

An experimental paradigm that teaches an animal or human to associate a previously neutral conditioned stimulus (CS; for example, a light or a tone) with an aversive unconditioned stimulus (for example, an electric shock), the latter of which produces an aversive unconditioned response. Eventually, because of the association, the CS alone comes to elicit a fear response.

Extinction retention

Memory that a conditioned stimulus has been previously extinguished, expressed as a continuing reduction of the conditioned response. It is also called extinction recall.

Fear-potentiated startle

An increased electromyographic responsiveness to a startling stimulus that occurs when an animal or human is afraid.

P2

An electroencephalographic event-related potential response that is positive and reaches its maximum deflection approximately 200ms after a stimulus is presented. It is thought to reflect 'tuning' of a mechanism that regulates the amount of sensory input to the cortex.

Conditioned fear

Fear that is elicited by a conditioned stimulus (or cue) following fear conditioning. Typical measures include freezing in rodents, skin conductance in humans and potentiated startle in both.

Corrugator EMG

A measure of electromyographic activity associated with contraction of the corrugator supercilii muscle, which draws the inner brow inward and downward during negatively valenced emotion.

Structural MRI

(sMRI). A non-invasive diagnostic and research procedure that uses a magnetic field and radio waves to create detailed sectional images of the internal structure of the body, including the brain.

Ventromedial prefrontal cortex

(vmPFC). A region within the medial wall of prefrontal cortex that roughly corresponds to Brodmann area 10. Some studies treat portions of adjacent Brodmann areas as part of the vmPFC.

CA3

A sector of the cornu ammonis subfield of the hippocampus and a major target of glucocorticoids.

Dentate gyrus

A subfield of the hippocampus that contains adult neural stem cells and is an important site of neurogenesis.

Magnetic resonance spectroscopic imaging

(MRSI). A non-invasive research and diagnostic technique that is similar to MRI but uses a stronger field to detect regional body chemistry at the cellular level. It is also called 1H-nuclear magnetic resonance spectroscopic imaging and proton magnetic resonance spectroscopic imaging.

N-acetylaspartate

A putative marker of neuronal integrity thought to be present predominantly in neuronal cell bodies. It emits the largest signal in magnetic resonance spectroscopic imaging of the human brain.

Dorsal anterior cingulate cortex

(dACC). A cortical area that roughly corresponds to Brodmann area 24. It may also be called anterior the mid-cingulate cortex.

Voxel-based morphometry

An automated neuroimaging analytic technique that allows the investigation of focal differences in brain anatomy using the statistical approaches of statistical parametric mapping and smoothing applied to structural images.

Diffusion tensor imaging

A structural MRI-based technique that tracks the diffusion of water molecules within a closed space, usually a tube such as a neural axon. It is useful in revealing white matter fibre structure and providing information regarding regional brain connectivity.

Positron emission tomography

(PET). A functional neuroimaging technique that uses radioactive isotopes to quantify regional cerebral blood flow, glucose metabolism or receptor occupancy.

Functional MRI

(fMRI). A functional neuroimaging technique that uses a magnetic field and radio waves to measure the blood-oxygenation-level-dependent signal, which serves as an index of regional brain activation.

Phasic

Designating intermittent signalling, usually in response to a stimulus.

Dissociation

The splitting off of a mental process or group of mental processes from the main body of consciousness.

Tonic

Designating continuous, steady or baseline signalling.

Extrasynaptic

Located outside the synapse. Extrasynaptic receptors can be accessed by neuromodulatory factors derived from the periphery and circulating in the cerebrospinal fluid.

Heritable

Capable of being passed from one generation to the next via DNA.

Single-nucleotide polymorphism

(SNP). A variation in a DNA sequence in which a single nucleotide (A, C, G or T) at a specific locus differs between members of the same biological species or between paired chromosomes of an individual.

Neuromodulation

An alteration in the response of a neuron induced by a substance that would not, by itself, affect neuronal firing rate.

DNA methylation

The modification of a strand of DNA in which a methyl group is added to a cytosine molecule that stands directly before a guanine molecule in the same chain. It has the effect of reducing gene expression.

Allele

One or more alternative forms of a genetic locus or a gene.

Epigenesis

One or more mechanisms that regulate gene function without altering the underlying DNA sequence.

Face validity

The degree to which a model or a term appears to measure what it is supposed to measure.

Construct validity

The degree to which a model or a term corresponds to or reflects an underlying theory.

Glucocorticoid negative feedback

A negative-feedback phenomenon by which cortisol reduces its own release through inhibition of the hypothalamus–pituitary–adrenal cortical axis.

Brain-derived neurotrophic factor

(BDNF). A protein that is often released from a neuron, and that is involved in growth and the differentiation of new neurons and synapses.

TrkB

A membranous tyrosine kinase receptor that binds brain-derived neurotrophic factor and other neurotrophic factors (also known as neurotrophins).

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Pitman, R., Rasmusson, A., Koenen, K. et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 13, 769–787 (2012). https://doi.org/10.1038/nrn3339

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