NEUROBIOLOGY OF POST-TRAUMATIC STRESS DISORDER
Keywords:
PTSD, HPA axis, brain, neuroinflammation, stress, fear
Abstract
Post-traumatic stress disorder (PTSD) is a psychiatric disorder which stems from exposure to severe trauma. It has a high comorbidity rate and increased mortality. This mini review is focused on presenting a concise state of the art overview of the neurobiology of PTSD. It starts with the explanation of the physiologic stress response followed by an elaboration of the function of specific systems in PTSD, including the autonomic nervous system, neuroendocrinology, inflammation, and neuroanatomy, and their role in the pathophysiology of PTSD. PTSD is prototype of disease influenced by gene environment interaction, thus every biological abnormality associated with PTSD can be vied either as a consequence or a risk factor for the emergence of the disease. The review is concluded by an elaboration of the contemporary therapeutic strategies for PTSD, including an overview of secondary prevention strategies which are currently investigated.
References
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3. Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron. 2007;56:19–32.
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.
5. Kornfield SL, Hantsoo L, Epperson CN. What does sex have to do with it? The role of sex as a biological variable in the development of posttraumatic stress disorder. Curr Psychiatry Rep. 2018;20:39.
6. Tovote P, Fadok JP, Lüthi A. Neuronal circuits for fear and anxiety. Nat Rev Neurosci. 2015 Jun;16(6):317-31.
7. Regier DA, Narrow WE, Clarke DE, Kraemer HC, Kuramoto SJ, et al. 2013 DSM-5 field trials in the United States and Canada, Part II: test-retest reliability of selected categorical diagnoses. Am J Psychiatry. 2013;170:59–70.
8. Abdallah CG, Southwick SM, Krystal JH. Neurobiology of posttraumatic stress disorder (PTSD): a path from novel pathophysiology to innovative therapeutics. Neurosci Lett. 2017;649:130–132.
9. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338(3):171–179.
10. Cannon WB. Organization for physiological homeostasis. Physiol Rev. 1929;9(3):399–431.
11. de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6(6):463–475.
12. Joels M, Sarabdjitsingh RA, Karst H. Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. Pharmacol Rev. 2012;64(4):901–938.
13. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, Milad MR, Liberzon I. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012;13:769–787.
14. Task Force of the European Society of Cardiology. Heart rate variability: Standards of measurement, physiological interpretation, and clinical use. European Heart Journal. 1996;17:354–381.
15. Berntson GG, Bigger JT, Eckberg DL, Grossman P, Kaufmann PG, Malik M, et al. Heart rate variability: Origins, methods, and interpretive caveats. Psychophysiology. 1997;34:623–648. doi: 10.1111/j.1469-8986.1997.tb02140.x.
16. Minassian A, Maihofer AX, Baker DG, Nievergelt CM, Geyer MA, Risbrough VB. Association of predeployment heart rate variability with risk of post deployment posttraumatic stress disorder in active-duty marines. JAMA Psychiatry. 2015;72(10):979–986. doi:10.1001/jamapsychiatry.2015.0922.
17. Shaikh al arab A, Guedon-Moreau L, Ducrocq F, Molenda S, Duhem S, Salleron J, et al. Temporal analysis of heart rate variability as a predictor of post traumatic stress disorder in road traffic accidents survivors. J Psychiatr Res. 2012;46:790–796.
18. Schneider M, Schwerdtfeger A. Autonomic dysfunction in posttraumatic stress disorder indexed by heart rate variability: a meta-analysis. Psychol Med. 2020 Sep;50(12):1937-1948.
19. Kubzansky LD, Koenen KC. Is posttraumatic stress disorder related to development of heart disease? An update. Cleve Clin J Med. 2009;76(Suppl 2):S60–S65.
20. Porges SW. The polyvagal theory: new insights into adaptive reactions of the autonomic nervous system. Cleve Clin J Med. 2009;76(Suppl 2):S86–S90.
21. Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994 Aug;90(2):878-83.
22. Kotecha D, New G, Flather MD, Eccleston D, Pepper J, Krum H. Five-minute heart rate variability can predict obstructive angiographic coronary disease. Heart. 2012;98:395–401.
23. Binici Z, Mouridsen MR, Køber L, Sajadieh A. Decreased nighttime heart rate variability is associated with increased stroke risk. Stroke. 2011;42:3196–3201.
24. Shah AJ, Lampert R, Goldberg J, Veledar E, Bremner JD, Vaccarino V. Posttraumatic stress disorder and impaired autonomic modulation in male twins. Biol Psychiatry. 2013 Jun 1;73(11):1103-10.
25. van Zuiden M, Kavelaars A, Geuze E, Olff M, Heijnen CJ. Predicting PTSD: pre-existing vulnerabilities in glucocorticoid-signaling and implications for preventive interventions. Brain Behav Immun. 2013 May;30:12-21.
26. Florido A, Velasco ER, Monari S, Cano M, Cardoner N, Sandi C, et al. Glucocorticoid-based pharmacotherapies preventing PTSD. Neuropharmacology. 2023 Feb 15;224:109344.
27. Yehuda R, Halligan SL, Golier JA, Grossman R, Bierer LM. Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder. Psychoneuroendocrinology. 2004 Apr;29(3):389-404.
28. Yehuda R, Golier JA, Yang RK, Tischler L. Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biol Psychiatry. 2004 Jun 1;55(11):1110-6.
29. Vermeer H, Hendriks-Stegeman BI, van der Burg B, van Buul-Offers SC, Jansen M. Glucocorticoid-induced increase in lymphocytic FKBP51 messenger ribonucleic acid expression: a potential marker for glucocorticoid sensitivity, potency, and bioavailability. J Clin Endocrinol Metab. 2003;88:277-284.
30. Galatzer-Levy IR, Andero R, Sawamura T, Jovanovic T, Papini S, Ressler KJ, et al. A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder. Neuropharmacology. 2017 Apr;116:188-195.
31. Girgenti MJ, Wang J, Ji D, Cruz DA; Traumatic Stress Brain Research Group; Stein MB, Gelernter J, Young KA, Huber BR, Williamson DE, Friedman MJ, Krystal JH, Zhao H, Duman RS. Transcriptomic organization of the human brain in post-traumatic stress disorder. Nat Neurosci. 2021 Jan;24(1):24-33.
32. Ressler KJ, Berretta S, Bolshakov VY, Rosso IM, Meloni EG, Rauch SL, et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol. 2022 May;18(5):273-288.
33. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature. 2011 Feb 24;470(7335):492-7.
34. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry. 1997 May;154(5):624-9.
35. Yehuda R, Teicher MH, Trestman RL, Levengood RA, Siever LJ. Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry. 1996 Jul 15;40(2):79-88.
36. Yehuda R, Bierer LM, Sarapas C, Makotkine I, Andrew R, Seckl JR. Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001. Psychoneuroendocrinology. 2009 Oct;34(9):1304-13.
37. Sumner JA, Nishimi KM, Koenen KC, Roberts AL, Kubzansky LD. Posttraumatic stress disorder and inflammation: untangling issues of bidirectionality. Biol Psychiatry. 2020;87:885–97.
38. Sumner JA, Chen Q, Roberts AL, Winning A, Rimm EB, Gilsanz P, et al. Crosssectional and longitudinal associations of chronic posttraumatic stress disorder with inflammatory and endothelial function markers in women. Biol Psychiatry. 2017;82:875–84.
39. Sumner JA, Chen Q, Roberts AL, Winning A, Rimm EB, Gilsanz P, et al. Posttraumatic stress disorder onset and inflammatory and endothelial function biomarkers in women. Brain Behav Immun. 2018;69:203–9.
40. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71:423–31.
41. Miller MW, Maniates H, Wolf EJ, Logue MW, Schichman SA, Stone A, Milberg W, McGlinchey R. CRP polymorphisms and DNA methylation of the AIM2 gene influence associations between trauma exposure, PTSD, and C-reactive protein. Brain Behav Immun. 2018 Jan;67:194-202.
42. Wohleb ES, Powell ND, Godbout JP, Sheridan JF. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci. 2013;33:13820–33.
43. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D, et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA. 2003;100:1920–5.
44. Elkhatib SK, Case AJ. Autonomic regulation of T-lymphocytes: Implications in cardiovascular disease. Pharm Res. 2019;146:104293.
45. Tracey KJ. Reflex control of immunity. Nat Rev Immunol. 2009;9:418–28.
46. Hori H, Kim Y. Inflammation and post-traumatic stress disorder. Psychiatry Clin Neurosci. 2019;73:143–53.
47. 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.
48. Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci USA. 2012;109:5995–5999.
49. Fenster RJ, Lebois LAM, Ressler KJ, Suh J. Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man. Nat Rev Neurosci. 2018;19:535–551.
50. Jovanovic T, Ressler KJ. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am J Psychiatry. 2010;167:648–662.
51. Garfinkel SN, Abelson JL, King AP, Sripada RK, Wang X, Gaines LM, Liberzon I. Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal. J Neurosci. 2014;34:13435–13443.
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2025/07/18
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