Contribution of Genetic and Neuroimaging Studies towards a Better Understanding of Post-Traumatic Stress Disorder

외상 후 스트레스 장애의 이해에 있어서 유전학 및 뇌영상 연구의 기여

  • Kim, Ji-Eun E. (Department of Psychiatry, Seoul National University College of Medicine) ;
  • Lyoo, In-Kyoon (Department of Psychiatry, Seoul National University College of Medicine) ;
  • Jun, Chan-Soo (Department of Psychiatry, Seoul National University College of Medicine) ;
  • Lee, Yu-Sang (Yong-In Mental Hospital)
  • 김지은 (서울대학교 의과대학 정신과학교실) ;
  • 류인균 (서울대학교 의과대학 정신과학교실) ;
  • 전찬수 (서울대학교 의과대학 정신과학교실) ;
  • 이유상 (용인정신병원)
  • Received : 2010.09.06
  • Accepted : 2010.10.04
  • Published : 2010.11.30

Abstract

Significant advances have been made in understanding the biological underpinnings of post-traumatic stress disorder(PTSD), particularly in the field of genetics and neuroimaging. Association studies in candidate genes related with hypothalamic-pituitary-adrenal axis, monoamines including serotonin, dopamine and noradrenaline, and proteins including FK506-binding protein 5 and brain-derived neurotrophic factor have provided important insights with regard to the vulnerability factors in PTSD. Genome-wide association studies and epigenetic studies may provide further information for the role of genes in the pathophysiology of PTSD. Hippocampus, medial prefrontal cortex, anterior cingulated cortex and amygdala have been considered as key structures that underlie PTSD pathophysiology. Future research that combines genetic and neuroimaging information may provide an opportunity for a more comprehensive understanding of PTSD.

Keywords

References

  1. Brewin CR, Andrews B, Valentine JD. Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 2000;68:748-766. https://doi.org/10.1037/0022-006X.68.5.748
  2. Sack WH, Clarke GN, Seeley J. Posttraumatic stress disorder across two generations of Cambodian refugees. J Am Acad Child Adolesc Psychiatry 1995;34:1160-1166. https://doi.org/10.1097/00004583-199509000-00013
  3. Yehuda R, Halligan SL, Bierer LM. Relationship of parental trauma exposure and PTSD to PTSD, depressive and anxiety disorders in offspring. J Psychiatr Res 2001; 35:261-270 https://doi.org/10.1016/S0022-3956(01)00032-2
  4. Stein MB, Jang KL, Taylor S, Vernon PA, Livesley WJ. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am J Psychiatry 2002;159:1675-1681. https://doi.org/10.1176/appi.ajp.159.10.1675
  5. Lyons MJ, Goldberg J, Eisen SA, True W, Tsuang MT, Meyer JM, et al. Do genes influence exposure to trauma? A twin study of combat. Am J Med Genet 1993;48:22-27 https://doi.org/10.1002/ajmg.1320480107
  6. Kendler KS, Heath A, Martin NG, Eaves LJ. Symptoms of anxiety and depression in a volunteer twin population. The etiologic role of genetic and environmental factors. Arch Gen Psychiatry 1986;43:213-221. https://doi.org/10.1001/archpsyc.1986.01800030023002
  7. Koenen KC, Nugent NR, Amstadter AB. Gene-environment interaction in posttraumatic stress disorder: review, strategy and new directions for future research. Eur Arch Psychiatry Clin Neurosci 2008;258:82-96. https://doi.org/10.1007/s00406-007-0787-2
  8. Amstadter AB, Nugent NR, Koenen KC. Genetics of PTSD: Fear Conditioning as a Model for Future Research. Psychiatr Ann 2009;39:358-367. https://doi.org/10.3928/00485713-20090526-01
  9. Smith MA, Davidson J, Ritchie JC, Kudler H, Lipper S, Chappell P, et al. The corticotropin-releasing hormone test in patients with posttraumatic stress disorder. Biol Psychiatry 1989;26:349-355. https://doi.org/10.1016/0006-3223(89)90050-4
  10. Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL Jr, Mason JW. Low urinary cortisol excretion in patients with posttraumatic stress disorder. J Nerv Ment Dis 1990;178:366-369. https://doi.org/10.1097/00005053-199006000-00004
  11. de Kloet CS, Vermetten E, Geuze E, Kavelaars A, Heijnen CJ, Westenberg HG. Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res 2006;40:550-567. https://doi.org/10.1016/j.jpsychires.2005.08.002
  12. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003;160:1554-1565. https://doi.org/10.1176/appi.ajp.160.9.1554
  13. Van Eekelen JA, Jiang W, De Kloet ER, Bohn MC. Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus. J Neurosci Res 1988;21:88-94. https://doi.org/10.1002/jnr.490210113
  14. Sarrieau A, Sharma S, Meaney MJ. Postnatal development and environmental regulation of hippocampal glucocorticoid and mineralocorticoid receptors. Brain Res 1988;471:158-162.
  15. Hansson AC, Cintra A, Belluardo N, Sommer W, Bhatnagar M, Bader M, et al. Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat. Eur J Neurosci 2000;12:2918-2934. https://doi.org/10.1046/j.1460-9568.2000.00185.x
  16. McEwen BS, Gould EA, Sakai RR. The vulnerability of the hippocampus to protective and destructive effects of glucocorticoids in relation to stress. Br J Psychiatry Suppl 1992;(15):18-23.
  17. De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269-301. https://doi.org/10.1210/er.19.3.269
  18. Wong EY, Herbert J. Roles of mineralocorticoid and glucocorticoid receptors in the regulation of progenitor proliferation in the adult hippocampus. Eur J Neurosci 2005;22:785-792. https://doi.org/10.1111/j.1460-9568.2005.04277.x
  19. Liberzon I, Lopez JF, Flagel SB, Vazquez DM, Young EA. Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 1999; 11:11-17.
  20. Buemann B, Vohl MC, Chagnon M, Chagnon YC, Gagnon J, Perusse L, et al. Abdominal visceral fat is associated with a BclI restriction fragment length polymorphism at the glucocorticoid receptor gene locus. Obes Res 1997;5:186-192. https://doi.org/10.1002/j.1550-8528.1997.tb00292.x
  21. Dobson MG , Redfern CP, Unwin N, Weaver JU. The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. J Clin Endocrinol Metab 2001;86:2270-2774. https://doi.org/10.1210/jc.86.5.2270
  22. van Rossum EF, Koper JW, van den Beld AW, Uitterlinden AG, Arp P, Ester W, et al. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol(Oxf) 2003;59:585-592. https://doi.org/10.1046/j.1365-2265.2003.01888.x
  23. Bachmann AW, Sedgley TL, Jackson RV, Gibson JN, Young RM, Torpy DJ. Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology 2005;30:297-306. https://doi.org/10.1016/j.psyneuen.2004.08.006
  24. Vermeer H, Hendriks-Stegeman BI, van den Brink CE, van der Saag PT, van der Burg B, van Buul-Offers SC, et al. A novel specific bioassay for the determination of glucocorticoid bioavailability in human serum. Clin Endocrinol(Oxf) 2003;59:49-55. https://doi.org/10.1046/j.1365-2265.2003.01793.x
  25. Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 2000;141:4107-4113. https://doi.org/10.1210/en.141.11.4107
  26. Koenen KC, Saxe G, Purcell S, Smoller JW, Bartholomew D, Miller A, et al. Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children. Mol Psychiatry 2005;10:1058-1059. https://doi.org/10.1038/sj.mp.4001727
  27. Segman RH, Shefi N, Goltser-Dubner T, Friedman N, Kaminski N, Shalev AY. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol Psychiatry 2005;10:500-513, 425. https://doi.org/10.1038/sj.mp.4001636
  28. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008;299:1291-1305. https://doi.org/10.1001/jama.299.11.1291
  29. Steiner MA, Wotjak CT. Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res 2008;170:397-432. https://doi.org/10.1016/S0079-6123(08)00433-0
  30. Patel S, Roelke CT, Rademacher DJ, Cullinan WE, Hillard CJ. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary- adrenal axis. Endocrinology 2004;145:5431-5438. https://doi.org/10.1210/en.2004-0638
  31. Lu AT, Ogdie MN, Jarvelin MR, Moilanen IK, Loo SK, McCracken JT, et al. Association of the cannabinoid receptor gene(CNR1) with ADHD and post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 2008;147B:1488-1494. https://doi.org/10.1002/ajmg.b.30693
  32. Asan E. The catecholaminergic innervation of the rat amygdala. Adv Anat Embryol Cell Biol 1998;142:1-118.
  33. Galvez R, Mesches MH, McGaugh JL. Norepinephrine release in the amygdala in response to footshock stimulation. Neurobiol Learn Mem 1996;66:253-257. https://doi.org/10.1006/nlme.1996.0067
  34. Hatfield T, McGaugh JL. Norepinephrine infused into the basolateral amygdala posttraining enhances retention in a spatial water maze task. Neurobiol Learn Mem 1999;71:232-239. https://doi.org/10.1006/nlme.1998.3875
  35. Abercrombie ED, Jacobs BL. Microinjected clonidine inhibits noradrenergic neurons of the locus coeruleus in freely moving cats. Neurosci Lett 1987;76:203-208. https://doi.org/10.1016/0304-3940(87)90716-6
  36. Buffalari DM, Grace AA. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of alpha-2 and beta receptor activation. J Neurosci 2007;27:12358-12366. https://doi.org/10.1523/JNEUROSCI.2007-07.2007
  37. Mustapic M, Pivac N, Kozaric-Kovacic D, Dezeljin M, Cubells JF, Muck-Seler D. Dopamine beta-hydroxylase( DBH) activity and -1021C/T polymorphism of DBH gene in combat-related post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 2007;144B:1087-1089. https://doi.org/10.1002/ajmg.b.30526
  38. Tang YL, Li W, Mercer K, Bradley B, Gillespie CF, Bonsall R, et al. Genotype-controlled analysis of serum dopamine beta-hydroxylase activity in civilian posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2010.
  39. Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL. Morphine use after combat injury in Iraq and post-traumatic stress disorder. N Engl J Med 2010;362: 110-117. https://doi.org/10.1056/NEJMoa0903326
  40. Pitman RK, Delahanty DL. Conceptually driven pharmacologic approaches to acute trauma. CNS Spectr 2005; 10:99-106. https://doi.org/10.1017/S109285290001943X
  41. Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 2002;51:189-192. https://doi.org/10.1016/S0006-3223(01)01279-3
  42. Hurley EA. The moral costs of prophylactic propranolol. Am J Bioeth 2007;7:35-36.
  43. Muravieva EV, Alberini CM. Limited efficacy of propranolol on the reconsolidation of fear memories. Learn Mem 2010;17:306-313. https://doi.org/10.1101/lm.1794710
  44. Sharp S, Thomas C, Rosenberg L, Rosenberg M, Meyer W 3rd. Propranolol does not reduce risk for acute stress disorder in pediatric burn trauma. J Trauma 2010; 68:193-197. https://doi.org/10.1097/TA.0b013e3181a8b326
  45. Lappalainen J, Kranzler HR, Malison R, Price LH, Van Dyck C, Rosenheck RA, et al. A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States. Arch Gen Psychiatry 2002;59:825-831. https://doi.org/10.1001/archpsyc.59.9.825
  46. Sah R, Ekhator NN, Strawn JR, Sallee FR, Baker DG , Horn PS, et al. Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder. Biol Psychiatry 2009;66:705-707. https://doi.org/10.1016/j.biopsych.2009.04.037
  47. Morgan CA 3rd, Rasmusson AM, Wang S, Hoyt G, Hauger RL, Hazlett G . Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol Psychiatry 2002;52:136-142. https://doi.org/10.1016/S0006-3223(02)01319-7
  48. Rainnie DG . Serotonergic modulation of neurotransmission in the rat basolateral amygdala. J Neurophysiol 1999;82:69-85. https://doi.org/10.1152/jn.1999.82.1.69
  49. Graeff FG , Viana MB, Mora PO. Opposed regulation by dorsal raphe nucleus 5-HT pathways of two types of fear in the elevated T-maze. Pharmacol Biochem Behav 1996;53:171-177. https://doi.org/10.1016/0091-3057(95)02012-8
  50. Kalia M. Neurobiological basis of depression: an update. Metabolism 2005;54:24-27.
  51. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386-389. https://doi.org/10.1126/science.1083968
  52. Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nothen MM, et al. Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 2004;12:377-382. https://doi.org/10.1038/sj.ejhg.5201149
  53. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274:1527-1531. https://doi.org/10.1126/science.274.5292.1527
  54. Lee HJ, Lee MS, Kang RH, Kim H, Kim SD, Kee BS, et al. Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder. Depress Anxiety 2005;21:135-139. https://doi.org/10.1002/da.20064
  55. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002;297:400-403. https://doi.org/10.1126/science.1071829
  56. Gallinat J, Strohle A, Lang UE, Bajbouj M, Kalus P, Montag C, et al. Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety. Neuroimage 2005;26:123-131. https://doi.org/10.1016/j.neuroimage.2005.01.001
  57. Schinka JA, Busch RM, Robichaux-Keene N. A meta- analysis of the association between the serotonin transporter gene polymorphism(5-HTTLPR) and trait anxiety. Mol Psychiatry 2004;9:197-202. https://doi.org/10.1038/sj.mp.4001405
  58. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005; 62:529-535. https://doi.org/10.1001/archpsyc.62.5.529
  59. Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, et al. Interaction between the serotonin transporter gene(5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA 2009;301:2462-2471. https://doi.org/10.1001/jama.2009.878
  60. Kuzelova H, Ptacek R, Macek M. The serotonin transporter gene(5-HTT) variant and psychiatric disorders: review of current literature. Neuro Endocrinol Lett 2010; 31:4-10.
  61. Inglis FM, Moghaddam B. Dopaminergic innervation of the amygdala is highly responsive to stress. J Neurochem 1999;72:1088-1094.
  62. Puglisi-Allegra S, Cabib S. Psychopharmacology of dopamine: the contribution of comparative studies in inbred strains of mice. Prog Neurobiol 1997;51:637-661. https://doi.org/10.1016/S0301-0082(97)00008-7
  63. Yehuda R, Southwick S, Giller EL, Ma X, Mason JW. Urinary catecholamine excretion and severity of PTSD symptoms in Vietnam combat veterans. J Nerv Ment Dis 1992;180:321-325. https://doi.org/10.1097/00005053-199205000-00006
  64. Comings DE, Muhleman D, Gysin R. Dopamine D2 receptor( DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Biol Psychiatry 1996;40:368-372. https://doi.org/10.1016/0006-3223(95)00519-6
  65. Gelernter J, Southwick S, Goodson S, Morgan A, Nagy L, Charney DS. No association between D2 dopamine receptor(DRD2) "A" system alleles, or DRD2 haplotypes, and posttraumatic stress disorder. Biol Psychiatry 1999;45:620-625. https://doi.org/10.1016/S0006-3223(98)00087-0
  66. Broekman BF, Olff M, Boer F. The genetic background to PTSD. Neurosci Biobehav Rev 2007;31:348-362. https://doi.org/10.1016/j.neubiorev.2006.10.001
  67. Young RM, Lawford BR, Noble EP, Kann B, Wilkie A, Ritchie T, et al. Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol Alcohol 2002; 37:451-456. https://doi.org/10.1093/alcalc/37.5.451
  68. Voisey J, Swagell CD, Hughes IP, Morris CP, van Daal A, Noble EP, et al. The DRD2 gene 957C>T polymorphism is associated with posttraumatic stress disorder in war veterans. Depress Anxiety 2009;26:28-33. https://doi.org/10.1002/da.20517
  69. Bailey JN, Goenjian AK, Noble EP, Walling DP, Ritchie T, Goenjian HA. PTSD and dopaminergic genes, DRD2 and DAT, in multigenerational families exposed to the Spitak earthquake. Psychiatry Res 2010;178:507-510. https://doi.org/10.1016/j.psychres.2010.04.043
  70. Segman RH, Cooper-Kazaz R, Macciardi F, Goltser T, Halfon Y, Dobroborski T, et al. Association between the dopamine transporter gene and posttraumatic stress disorder. Mol Psychiatry 2002;7:903-907. https://doi.org/10.1038/sj.mp.4001085
  71. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 1995; 374:450-453. https://doi.org/10.1038/374450a0
  72. Martinowich K, Manji H, Lu B. New insights into BDNF function in depression and anxiety. Nat Neurosci 2007;10:1089-1093. https://doi.org/10.1038/nn1971
  73. Yamada K, Mizuno M, Nabeshima T. Role for brainderived neurotrophic factor in learning and memory. Life Sci 2002;70:735-744. https://doi.org/10.1016/S0024-3205(01)01461-8
  74. Rasmusson AM, Shi L, Duman R. Downregulation of BDNF mRNA in the hippocampal dentate gyrus after reexposure to cues previously associated with footshock. Neuropsychopharmacology 2002;27:133-142. https://doi.org/10.1016/S0893-133X(02)00286-5
  75. Dell'osso L, Carmassi C, Del Debbio A, Dell'osso MC, Bianchi C, da Pozzo E, et al. Brain-derived neurotrophic factor plasma levels in patients suffering from posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:899-902. https://doi.org/10.1016/j.pnpbp.2009.04.018
  76. Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, et al. Brain derived neurotrophic factor(BDNF) gene variants and Alzheimer's disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet 2006;141B:387-393. https://doi.org/10.1002/ajmg.b.30332
  77. Lee HJ, Kang RH, Lim SW, Paik JW, Choi MJ, Lee MS. No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and post-traumatic stress disorder. Stress and Health 2006;22:115-119. https://doi.org/10.1002/smi.1085
  78. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004;24:10099-10102. https://doi.org/10.1523/JNEUROSCI.2680-04.2004
  79. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006;311:864-868. https://doi.org/10.1126/science.1120972
  80. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007;131:391-404. https://doi.org/10.1016/j.cell.2007.09.018
  81. Feder A, Nestler EJ, Charney DS. Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 2009;10:446-457. https://doi.org/10.1038/nrn2649
  82. Tang WY, Ho SM. Epigenetic reprogramming and imprinting in origins of disease. Rev Endocr Metab Disord 2007;8:173-182. https://doi.org/10.1007/s11154-007-9042-4
  83. Uddin M, Aiello AE, Wildman DE, Koenen KC , Pawelec G , de Los Santos R, et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci U S A 2010;107:9470-9475. https://doi.org/10.1073/pnas.0910794107
  84. Franklin TB, Russig H, Weiss IC, Graff J, Linder N, Michalon A, et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 2010;68:408-415. https://doi.org/10.1016/j.biopsych.2010.05.036
  85. Yehuda R, Bierer LM. Transgenerational transmission of cortisol and PTSD risk. Prog Brain Res 2008;167: 121-135.
  86. Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet 2001;2:91-99.
  87. Cornelis MC, Nugent NR, Amstadter AB, Koenen KC. Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Curr Psychiatry Rep 2010;12:313-326. https://doi.org/10.1007/s11920-010-0126-6
  88. Koenen KC, De Vivo I, Rich-Edwards J, Smoller JW, Wright RJ, Purcell SM. Protocol for investigating genetic determinants of posttraumatic stress disorder in women from the Nurses' Health Study II. BMC Psychiatry 2009;9:29. https://doi.org/10.1186/1471-244X-9-29
  89. Foy MR, Stanton ME, Levine S, Thompson RF. Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol 1987;48:138-149. https://doi.org/10.1016/S0163-1047(87)90664-9
  90. Sapolsky RM. Glucocorticoid toxicity in the hippocampus: temporal aspects of neuronal vulnerability. Brain Res 1985;359:300-305. https://doi.org/10.1016/0006-8993(85)91440-4
  91. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 1995;152:973-981. https://doi.org/10.1176/ajp.152.7.973
  92. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 1990;10:2897-2902.
  93. Yehuda R, Kahana B, Binder-Brynes K, Southwick SM, Mason JW, Giller EL. Low urinary cortisol excretion in Holocaust survivors with posttraumatic stress disorder. Am J Psychiatry 1995;152:982-986. https://doi.org/10.1176/ajp.152.7.982
  94. Bonne O, Vythilingam M, Inagaki M, Wood S, Neumeister A, Nugent AC, et al. Reduced posterior hippocampal volume in posttraumatic stress disorder. J Clin Psychiatry 2008;69:1087-1091. https://doi.org/10.4088/JCP.v69n0707
  95. Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C, et al. Magnetic resonance imaging- based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse--a preliminary report. Biol Psychiatry 1997;41:23-32. https://doi.org/10.1016/S0006-3223(96)00162-X
  96. Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Nazeer A, 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 2003;160:924-932. https://doi.org/10.1176/appi.ajp.160.5.924
  97. Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996;40:1091-1099. https://doi.org/10.1016/S0006-3223(96)00229-6
  98. Hedges DW, Allen S, Tate DF, Thatcher GW, Miller MJ, Rice SA, et al. Reduced hippocampal volume in alcohol and substance naïve Vietnam combat veterans with posttraumatic stress disorder. Cogn Behav Neurol 2003;16:219-224. https://doi.org/10.1097/00146965-200312000-00003
  99. Li L, Chen S, Liu J, Zhang J, He Z, Lin X. Magnetic resonance imaging and magnetic resonance spectroscopy study of deficits in hippocampal structure in fire victims with recent-onset posttraumatic stress disorder. Can J Psychiatry 2006;51:431-437. https://doi.org/10.1177/070674370605100704
  100. Villarreal G , Hamilton DA, Petropoulos H, Driscoll I, Rowland LM, Griego JA, et al. Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder. Biol Psychiatry 2002;52:119-125. https://doi.org/10.1016/S0006-3223(02)01359-8
  101. Fennema-Notestine C, Stein MB, Kennedy CM, Archibald SL, Jernigan TL. Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder. Biol Psychiatry 2002;52:1089-1101. https://doi.org/10.1016/S0006-3223(02)01413-0
  102. Freeman T, Kimbrell T, Booe L, Myers M, Cardwell D, Lindquist DM, et al. Evidence of resilience: neuroimaging in former prisoners of war. Psychiatry Res 2006;146:59-64. https://doi.org/10.1016/j.pscychresns.2005.07.007
  103. Golier JA, Yehuda R, De Santi S, Segal S, Dolan S, de Leon MJ. Absence of hippocampal volume differences in survivors of the Nazi Holocaust with and without posttraumatic stress disorder. Psychiatry Res 2005;139:53-64. https://doi.org/10.1016/j.pscychresns.2005.02.007
  104. Jatzko A, Rothenhofer S, Schmitt A, Gaser C, Demirakca T, Weber-Fahr W, et al. Hippocampal volume in chronic posttraumatic stress disorder(PTSD): MRI study using two different evaluation methods. J Affect Disord 2006;94:121-126. https://doi.org/10.1016/j.jad.2006.03.010
  105. Schuff N, Neylan TC, Lenoci MA, Du AT, Weiss DS, Marmar CR, et al. Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder. Biol Psychiatry 2001;50:952-959. https://doi.org/10.1016/S0006-3223(01)01245-8
  106. Yehuda R, Golier JA, Tischler L, Harvey PD, Newmark R, Yang RK, et al. Hippocampal volume in aging combat veterans with and without post-traumatic stress disorder: relation to risk and resilience factors. J Psychiatr Res 2007;41:435-445. https://doi.org/10.1016/j.jpsychires.2005.12.002
  107. Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD. Magnetic resonance imaging(MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 2005;88:79-86. https://doi.org/10.1016/j.jad.2005.05.014
  108. Bonne O, Brandes D, Gilboa A, Gomori JM, Shenton ME, Pitman RK, et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry 2001;158:1248-1251. https://doi.org/10.1176/appi.ajp.158.8.1248
  109. De Bellis MD, Hall J, Boring AM, Frustaci K, Moritz G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol Psychiatry 2001;50:305-309. https://doi.org/10.1016/S0006-3223(01)01105-2
  110. Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP, et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002;5:1242-1247. https://doi.org/10.1038/nn958
  111. Bremner JD, Vermetten E. Neuroanatomical changes associated with pharmacotherapy in posttraumatic stress disorder. Ann N Y Acad Sci 2004;1032:154-157. https://doi.org/10.1196/annals.1314.012
  112. Wang Z, Neylan TC, Mueller SG , Lenoci M, Truran D, Marmar CR, et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch Gen Psychiatry 2010;67:296-303. https://doi.org/10.1001/archgenpsychiatry.2009.205
  113. Shin LM, Whalen PJ, Pitman RK, Bush G , Macklin ML, Lasko NB, et al. An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol Psychiatry 2001;50:932-942. https://doi.org/10.1016/S0006-3223(01)01215-X
  114. Yamasue H, Kasai K, Iwanami A, Ohtani T, Yamada H, Abe O, et al. Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism. Proc Natl Acad Sci U S A 2003;100:9039-9043. https://doi.org/10.1073/pnas.1530467100
  115. Corbo V, Clement MH, Armony JL, Pruessner JC, Brunet A. Size versus shape differences: contrasting voxelbased and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder. Biol Psychiatry 2005;58:119-124. https://doi.org/10.1016/j.biopsych.2005.02.032
  116. Kasai K, Yamasue H, Gilbertson MW, Shenton ME, Rauch SL, Pitman RK. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry 2008;63:550-556. https://doi.org/10.1016/j.biopsych.2007.06.022
  117. Vyas A, Bernal S, Chattarji S. Effects of chronic stress on dendritic arborization in the central and extended amygdala. Brain Res 2003;965:290-294. https://doi.org/10.1016/S0006-8993(02)04162-8
  118. Hoerst M, Weber-Fahr W, Tunc-Skarka N, Ruf M, Bohus M, Schmahl C, et al. Metabolic alterations in the amygdala in borderline personality disorder: a proton magnetic resonance spectroscopy study. Biol Psychiatry 2010;67:399-405. https://doi.org/10.1016/j.biopsych.2009.09.030
  119. Kryger R, Wilce PA. The effects of alcoholism on the human basolateral amygdala. Neuroscience 2010;167:361-371. https://doi.org/10.1016/j.neuroscience.2010.01.061
  120. Kleinhans NM, Richards T, Weaver K, Johnson LC, Greenson J, Dawson G , et al. Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders. Neuropsychologia 2010;48:3665-3670. https://doi.org/10.1016/j.neuropsychologia.2010.07.022
  121. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR, et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatry 1996;53:380-387. https://doi.org/10.1001/archpsyc.1996.01830050014003
  122. Pavlisa G, Papa J, Pavic L, Pavlisa G. Bilateral MR volumetry of the amygdala in chronic PTSD patients. Coll Antropol 2006;30:565-568.
  123. Lindauer RJ, Vlieger EJ, Jalink M, Olff M, Carlier IV, Majoie CB, et al. Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder. Biol Psychiatry 2004;56:356-363. https://doi.org/10.1016/j.biopsych.2004.05.021
  124. Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A. A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev 2006;30:1004-1031. https://doi.org/10.1016/j.neubiorev.2006.03.004
  125. Woon FL, Hedges DW. Amygdala volume in adults with posttraumatic stress disorder: a meta-analysis. J Neuropsychiatry Clin Neurosci 2009;21:5-12. https://doi.org/10.1176/appi.neuropsych.21.1.5
  126. Phelps EA, Delgado MR, Nearing KI, LeDoux JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 2004;43:897-905. https://doi.org/10.1016/j.neuron.2004.08.042
  127. Milad MR, Quinn BT, Pitman RK, Orr SP, Fischl B, Rauch SL. Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory. Proc Natl Acad Sci U S A 2005;102:10706-10711. https://doi.org/10.1073/pnas.0502441102
  128. Geuze E, Westenberg HG , Heinecke A, de Kloet CS, Goebel R, Vermetten E. Thinner prefrontal cortex in veterans with posttraumatic stress disorder. Neuroimage 2008;41:675-681. https://doi.org/10.1016/j.neuroimage.2008.03.007
  129. Woodward SH, Schaer M, Kaloupek DG , Cediel L, Eliez S. Smaller global and regional cortical volume in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 2009;66:1373-1382. https://doi.org/10.1001/archgenpsychiatry.2009.160
  130. Mollica RF, Lyoo IK, Chernoff MC, Bui HX, Lavelle J, Yoon SJ, et al. Brain structural abnormalities and mental health sequelae in South Vietnamese ex-political detainees who survived traumatic head injury and torture. Arch Gen Psychiatry 2009;66:1221-1232. https://doi.org/10.1001/archgenpsychiatry.2009.127
  131. Liberzon I, Martis B. Neuroimaging studies of emotional responses in PTSD. Ann N Y Acad Sci 2006;1071:87-109. https://doi.org/10.1196/annals.1364.009
  132. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al. A positron emission tomographic study of symptom provocation in PTSD. Ann N Y Acad Sci 1997;821:521-523. https://doi.org/10.1111/j.1749-6632.1997.tb48320.x
  133. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, et al. Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry 1999;45:817-826. https://doi.org/10.1016/S0006-3223(98)00246-7
  134. Hendler T, Rotshtein P, Yeshurun Y, Weizmann T, Kahn I, Ben-Bashat D, et al. Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context. Neuroimage 2003;19:587-600. https://doi.org/10.1016/S1053-8119(03)00141-1
  135. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatry 1999;156:1787-1795.
  136. Bremner JD, Staib LH, Kaloupek D, Southwick SM, Soufer R, Charney DS. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol Psychiatry 1999;45:806-816. https://doi.org/10.1016/S0006-3223(98)00297-2
  137. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse- related PTSD: A PET investigation. Am J Psychiatry 1999;156:575-584.
  138. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, 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 2004;61:168-176. https://doi.org/10.1001/archpsyc.61.2.168
  139. Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, Neufeld RW, et al. Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation. Am J Psychiatry 2001;158:1920-1922. https://doi.org/10.1176/appi.ajp.158.11.1920
  140. Lindauer RJ, Booij J, Habraken JB, Uylings HB, Olff M, Carlier IV, et al. Cerebral blood flow changes during script-driven imagery in police officers with posttraumatic stress disorder. Biol Psychiatry 2004;56:853-861. https://doi.org/10.1016/j.biopsych.2004.08.003
  141. Kim SJ, Lyoo IK, Lee YS, Kim J, Sim ME, Bae SJ, et al. Decreased cerebral blood flow of thalamus in PTSD patients as a strategy to reduce re-experience symptoms. Acta Psychiatr Scand 2007;116:145-153. https://doi.org/10.1111/j.1600-0447.2006.00952.x
  142. Davis M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci 1992;15:353-375. https://doi.org/10.1146/annurev.ne.15.030192.002033
  143. Liberzon I, Britton JC, Phan KL. Neural correlates of traumatic recall in posttraumatic stress disorder. Stress 2003;6:151-156. https://doi.org/10.1080/1025389031000136242
  144. Armony JL, Corbo V, Clement MH, Brunet A. Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am J Psychiatry 2005;162:1961-1963. https://doi.org/10.1176/appi.ajp.162.10.1961
  145. Bryant RA, Kemp AH, Felmingham KL, Liddell B, Olivieri G, Peduto A, et al. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: an fMRI study. Hum Brain Mapp 2008;29:517-523. https://doi.org/10.1002/hbm.20415
  146. Bush G , Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 2000;4:215-222. https://doi.org/10.1016/S1364-6613(00)01483-2
  147. Shin LM, Kosslyn SM, McNally RJ, Alpert NM, Thompson WL, Rauch SL, et al. Visual imagery and perception in posttraumatic stress disorder. A positron emission tomographic investigation. Arch Gen Psychiatry 1997;54:233-241. https://doi.org/10.1001/archpsyc.1997.01830150057010
  148. Kim MJ, Chey J, Chung A, Bae S, Khang H, Ham B, et al. Diminished rostral anterior cingulate activity in response to threat-related events in posttraumatic stress disorder. J Psychiatr Res 2008;42:268-277. https://doi.org/10.1016/j.jpsychires.2007.02.003
  149. Hsu CC, Chong MY, Yang P, Yen CF. Posttraumatic stress disorder among adolescent earthquake victims in Taiwan. J Am Acad Child Adolesc Psychiatry 2002;41:875-881. https://doi.org/10.1097/00004583-200207000-00022
  150. Bremner JD, Vermetten E, Vythilingam M, Afzal N, Schmahl C, Elzinga B, et al. Neural correlates of the classic color and emotional stroop in women with abuserelated posttraumatic stress disorder. Biol Psychiatry 2004;55:612-620. https://doi.org/10.1016/j.biopsych.2003.10.001
  151. Kim MJ, Lyoo IK, Kim SJ, Sim M, Kim N, Choi N, et al. Disrupted white matter tract integrity of anterior cingulate in trauma survivors. Neuroreport 2005;16:1049-1053. https://doi.org/10.1097/00001756-200507130-00004
  152. Kim SJ, Jeong DU, Sim ME, Bae SC, Chung A, Kim MJ, et al. Asymmetrically altered integrity of cingulum bundle in posttraumatic stress disorder. Neuropsychobiology 2006;54:120-125. https://doi.org/10.1159/000098262
  153. Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Staib LH, et al. Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry 2003;53:879-889. https://doi.org/10.1016/S0006-3223(02)01891-7
  154. Shin LM, Shin PS, Heckers S, Krangel TS, Macklin ML, Orr SP, et al. Hippocampal function in posttraumatic stress disorder. Hippocampus 2004;14:292-300. https://doi.org/10.1002/hipo.10183
  155. Werner NS, Meindl T, Engel RR, Rosner R, Riedel M, Reiser M, et al. Hippocampal function during associative learning in patients with posttraumatic stress disorder. J Psychiatr Res 2009;43:309-318. https://doi.org/10.1016/j.jpsychires.2008.03.011
  156. Ham BJ, Chey J, Yoon SJ, Sung Y, Jeong DU, Ju Kim S, et al. Decreased N-acetyl-aspartate levels in anterior cingulate and hippocampus in subjects with posttraumatic stress disorder: a proton magnetic resonance spectroscopy study. Eur J Neurosci 2007;25:324-329. https://doi.org/10.1111/j.1460-9568.2006.05253.x
  157. Stein MB, Simmons AN, Feinstein JS, Paulus MP. Increased amygdala and insula activation during emotion processing in anxiety-prone subjects. Am J Psychiatry 2007;164:318-327. https://doi.org/10.1176/appi.ajp.164.2.318
  158. Paulus MP, Stein MB. An insular view of anxiety. Biol Psychiatry 2006;60:383-387. https://doi.org/10.1016/j.biopsych.2006.03.042
  159. Fonzo GA, Simmons AN, Thorp SR, Norman SB, Paulus MP, Stein MB. 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 2010;68:433-441. https://doi.org/10.1016/j.biopsych.2010.04.028
  160. Simmons A, Strigo I, Matthews SC, Paulus MP, Stein MB. Anticipation of aversive visual stimuli is associated with increased insula activation in anxiety-prone subjects. Biol Psychiatry 2006;60:402-409. https://doi.org/10.1016/j.biopsych.2006.04.038
  161. Hopper JW, Frewen PA, van der Kolk BA, Lanius RA. Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery. J Trauma Stress 2007;20:713-725. https://doi.org/10.1002/jts.20284
  162. Koenigs M, Grafman J. Posttraumatic stress disorder: the role of medial prefrontal cortex and amygdala. Neuroscientist 2009;15:540-548. https://doi.org/10.1177/1073858409333072
  163. Gilboa A, Shalev AY, Laor L, Lester H, Louzoun Y, Chisin R, et al. Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biol Psychiatry 2004;55:263-272. https://doi.org/10.1016/j.biopsych.2003.08.004