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Untangling PTSD and TBI: Challenges and Strategies in Clinical Care and Research

  • Neurotrauma (D Sandsmark, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) can result from similar injuries and can result in similar symptoms, such as problems with sleep, concentration, memory, and mood. Although PTSD and persistent sequelae due to a TBI (PST) have generally been viewed as pragmatically confounded but conceptually separable entities, we examine emerging evidence emphasizing the breadth of overlap in both clinical presentation and underlying pathophysiology between PST and PTSD.

Recent Findings

New evidence underscores the poor specificity of symptoms to etiology and emphasizes the potential, after both physical brain injury and traumatic stress, for changes in each of the three interacting systems that coordinate the body’s response to the experience or expectation of major injury—the immune, endocrine, and neuromodulatory neurotransmitter systems.

Summary

A view of PTSD and PST sharing common pathophysiologic elements related to the CNS response to acute injury or threat carries important implications for research and clinical care.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. McMahon PJ, Hricik A, Yue JK, Puccio AM, Inoue T, Lingsma HF, et al. Symptomatology and functional outcome in mild traumatic brain injury: results from the prospective TRACK-TBI study. J Neurotrauma. 2014;31:26–33 Available from: http://online.liebertpub.com/doi/abs/10.1089/neu.2013.2984.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Figueroa XA, Wright JK. Ok, Doc... What do I really have? Posttraumatic stress disorder versus traumatic brain injury. J Spec Oper Med. 2015 [cited 2018 Jul 19];15:59–66. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26630096.

  3. Verfaellie M, Lafleche G, Spiro A, Bousquet K. Neuropsychological outcomes in OEF/OIF veterans with self-report of blast exposure: associations with mental health, but not MTBI. Neuropsychology. 2014;28:337–46 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24245929.

    Article  PubMed  Google Scholar 

  4. Stein MB, McAllister TW. Exploring the convergence of posttraumatic stress disorder and mild traumatic brain injury. Am J Psychiatry. 2009;166:768–76 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19448186.

    Article  PubMed  Google Scholar 

  5. Gilbert KS, Kark SM, Gehrman P, Bogdanova Y. Sleep disturbances, TBI and PTSD: implications for treatment and recovery. Clin Psychol Rev. Elsevier B.V.; 2015;40:195–212. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0272735815000884

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pagulayan KF, Hoffman JM, Temkin NR, Machamer JE, Dikmen SS. Functional limitations and depression after traumatic brain injury: examination of the temporal relationship. Arch Phys Med Rehabil. 2008;89:1887–92.

    Article  PubMed  Google Scholar 

  7. Corrigan JD, Selassie AW, Orman JA. The epidemiology of traumatic brain injury. J Head Trauma Rehabil. 2010;25:72–80 Available from: http://ovidsp.tx.ovid.com.libaccess.lib.mcmaster.ca/sp-3.17.0a/ovidweb.cgi?&S=BNAEFPJDCADDPMGANCJKJBMCBOBGAA00&Link+Set=S.sh.70%7C1%7Csl_10.

    Article  PubMed  Google Scholar 

  8. Frencham KAR, Fox AM, Maybery MT. Neuropsychological studies of mild traumatic brain injury: a meta-analytic review of research since 1995. J Clin Exp Neuropsychol. 2005;27:334–51.

    Article  PubMed  Google Scholar 

  9. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington D.C.; 2013.

  10. Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in US soldiers returning from Iraq. N Engl J Med. 2008;358:453–63 Available from: http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:New+engla+nd+journal#0.

    Article  CAS  PubMed  Google Scholar 

  11. Yurgil KA, Barkauskas DA, Vasterling JJ, Nievergelt CM, Larson GE, Schork NJ, et al. Association between traumatic brain injury and risk of posttraumatic stress disorder in active-duty marines. JAMA Psychiatry. 2014;71:149–57.

    Article  PubMed  CAS  Google Scholar 

  12. Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. Am J Epidemiol. 2008;167:1446–52.

    Article  PubMed  Google Scholar 

  13. Howlett JR, Stein MB. Post-traumatic stress disorder: relationship to traumatic brain injury and approach to treatment [Internet]. Transl. Res. Trauma. Brain Inj. 2016 [cited 2018 Jul 19]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26583182

  14. Brenner LA, Ivins BJ, Schwab K, Warden D, Nelson LA, Jaffee M, et al. Traumatic brain injury, posttraumatic stress disorder, and postconcussive symptom reporting among troops returning from iraq. J Head Trauma Rehabil. 2010;25:307–12 Available from: http://www.ncbi.nlm.nih.gov/pubmed/20042982.

    Article  PubMed  Google Scholar 

  15. Goodrich GL, Martinsen GL, Flyg HM, Kirby J, Garvert DW, Tyler CW. Visual function, traumatic brain injury, and posttraumatic stress disorder. J Rehabil Res Dev. 2014;51:547–58 Available from: https://www.rehab.research.va.gov/jour/2014/514/page547.html.

    Article  PubMed  Google Scholar 

  16. Callahan ML, Storzbach D. Sensory sensitivity and posttraumatic stress disorder in blast exposed veterans with mild traumatic brain injury. Appl Neuropsychol. 2018;9095:1–9.

    Google Scholar 

  17. Ragsdale KA, Neer SM, Beidel DC, Frueh BC, Stout JW. Posttraumatic stress disorder in OEF/OIF veterans with and without traumatic brain injury. J Anxiety Disord. Elsevier Ltd; 2013;27:420–6. Available from: doi:https://doi.org/10.1016/j.janxdis.2013.04.003

    Article  PubMed  Google Scholar 

  18. King PR, Donnelly KT, Warner G, Wade M, Pigeon WR. The natural history of sleep disturbance among OEF/OIF veterans with TBI and PTSD and the role of proxy variables in its measurement. J Psychosom Res [Internet]. Elsevier; 2017;96:60–6. Available from: doi:https://doi.org/10.1016/j.jpsychores.2017.03.012

    Article  PubMed  Google Scholar 

  19. Perez-Garcia G, De Gasperi R, Gama Sosa MA, Perez GM, Otero-Pagan A, Tschiffely A, et al. PTSD-Related Behavioral Traits in a Rat Model of Blast-Induced mTBI Are Reversed by the mGluR2/3 Receptor Antagonist BCI-838. Eneuro [Internet]. 2018;5:ENEURO.0357–17.2018. Available from: http://eneuro.sfn.org/lookup/doi/10.1523/ENEURO.0357-17.2018

  20. •• Perez-Garcia G, Gama Sosa MA, De Gasperi R, Lashof-Sullivan M, Maudlin-Jeronimo E, Stone JR, et al. Chronic post-traumatic stress disorder-related traits in a rat model of low-level blast exposure. Behav Brain Res [Internet]. Elsevier B.V.; 2018;340:117–25. Available from: doi:https://doi.org/10.1016/j.bbr.2016.09.061. In this rat model of repetitive low-level blast under anesthesia, exposed rats displayed a pattern of increased anxiety-like behavior, enhanced pre-pulse inhibition, and alterations in novel object exploration when assessed at 7–9 months post-blast.

    Article  PubMed  Google Scholar 

  21. •• Zuckerman A, Ram O, Ifergane G, Matar MA, Kaplan Z, Hoffman JR, et al. The role of endogenous and exogenous corticosterone on behavioral and cognitive responses to low-pressure blast wave exposure. J Neurotrauma [Internet]. 2018;neu.2018.5672. Available from: http://www.liebertpub.com/doi/10.1089/neu.2018.5672 This study characterizes both cognitive and anxiety-like effects of blast-exposure in unanesthetized rats, finding heterogeneous patterns of what are termed ‘mTBI’-like and ‘PTSD’-like patterns of persistent effects.

  22. Schneider BL, Ghoddoussi F, Charlton JL, Kohler RJ, Galloway MP, Perrine SA, et al. Increased cortical gamma-aminobutyric acid precedes incomplete extinction of conditioned fear and increased hippocampal excitatory tone in a mouse model of mild traumatic brain injury. J Neurotrauma. 2016;33:1614–24 Available from: http://online.liebertpub.com/doi/10.1089/neu.2015.4190.

    Article  PubMed  Google Scholar 

  23. Kamnaksh A, Kovesdi E, Kwon S-K, Wingo D, Ahmed F, Grunberg NE, et al. Factors affecting blast traumatic brain injury. J Neurotrauma. 2011;28:2145–53 Available from: http://www.liebertonline.com/doi/abs/10.1089/neu.2011.1983.

    Article  PubMed  Google Scholar 

  24. Kwon SKC, Kovesdi E, Gyorgy AB, Wingo D, Kamnaksh A, Walker J, et al. Stress and traumatic brain injury: a behavioral, proteomics, and histological study. Front Neurol 2011;MAR:1–14.

  25. Klemenhagen KC, O’Brien SP, Brody DL. Repetitive concussive traumatic brain injury interacts with post-injury foot shock stress to worsen social and depression-like behavior in mice. PLoS One. 2013;8:1–15.

    Article  CAS  Google Scholar 

  26. Ojo JO, Greenberg MB, Leary P, Mouzon B, Bachmeier C, Mullan M, et al. Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury. Front Behav Neurosci [Internet]. 2014;8. Available from: http://journal.frontiersin.org/article/10.3389/fnbeh.2014.00213/abstract

  27. Garfinkel SN, Liberzon I. Neurobiology of PTSD: a review of neuroimaging findings. Psychiatr Ann. 2009;39:370–81 Available from: http://www.healio.com/doiresolver?doi=10.3928/00485713-20090527-01.

    Article  Google Scholar 

  28. Fehily B, Fitzgerald M. Repeated mild traumatic brain injury: potential mechanisms of damage. Cell Transplant [Internet]. 2016;5. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medp&AN=27502467 http://mcgill.on.worldcat.org/atoztitles/link?sid=OVID:medline&id=pmid:27502467&id=doi:10.3727%2F096368916X692807&issn=0963-6897&isbn=&volume=&issue=&spage=&pages=&date=

  29. McAllister TW. Neurobiological consequences of traumatic brain injury. Dialogues Clin Neurosci. 2011;13:287–300.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Matzinger P. Tolerance, danger, and the extended family. Annu Rev lmmunol. 1994;12:991–1045 Available from: https://www.annualreviews.org/doi/pdf/10.1146/annurev.iy.12.040194.005015.

    Article  CAS  Google Scholar 

  31. Skaper SD, Facci L, Zusso M, Giusti P. An inflammation-centric view of neurological disease: beyond the neuron. Front Cell Neurosci. 2018;12:1–26 Available from: http://journal.frontiersin.org/article/10.3389/fncel.2018.00072/full.

    Article  CAS  Google Scholar 

  32. Simon DW, McGeachy MJ, Baylr H, Clark RSB, Loane DJ, Kochanek PM. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol. 2017;13:171–91.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Jassam YN, Izzy S, Whalen M, McGavern DB, El Khoury J. Neuroimmunology of traumatic brain injury: time for a paradigm shift. Neuron [Internet]. Elsevier Inc.; 2017;95:1246–65. Available from: doi:https://doi.org/10.1016/j.neuron.2017.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Deslauriers J, Powell SB, Risbrough VB. Immune signaling mechanisms of PTSD risk and symptom development: insights from animal models. Curr Opin Behav Sci [Internet]. Elsevier Ltd; 2017;14:123–32. Available from: doi:https://doi.org/10.1016/j.cobeha.2017.01.005

    Article  PubMed  PubMed Central  Google Scholar 

  35. Olff M, van Zuiden M. Neuroendocrine and neuroimmune markers in PTSD: pre-, peri- and post-trauma glucocorticoid and inflammatory dysregulation. Curr Opin Psychol [Internet]. Elsevier Ltd; 2017;14:132–7. Available from: doi:https://doi.org/10.1016/j.copsyc.2017.01.001

    Article  PubMed  Google Scholar 

  36. Cho HJ, Sajja VSSS, VandeVord PJ, Lee YW. Blast induces oxidative stress, inflammation, neuronal loss and subsequent short-term memory impairment in rats. Neuroscience [Internet]. IBRO; 2013;253:9–20. Available from: doi:https://doi.org/10.1016/j.neuroscience.2013.08.037

    Article  CAS  PubMed  Google Scholar 

  37. Lagraoui M, Latoche JR, Cartwright NG, Sukumar G, Dalgard CL, Schaefer BC. Controlled cortical impact and craniotomy induce strikingly similar profiles of inflammatory gene expression, but with distinct kinetics. Front Neurol 2012;OCT:1–14.

  38. Tagge CA, Fisher AM, Minaeva OV, Gaudreau-Balderrama A, Moncaster JA, Zhang XL, et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain. 2018;141:422–58.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Corps KN, Roth TL, McGavern DB. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol. 2015;72:355–62.

    Article  PubMed  PubMed Central  Google Scholar 

  40. •• Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002–12 This systematic meta-analysis and meta-regression incorporates 20 studies identifies evidence for increased IL-6, IL-1β, TNFα, and interferon-γ in PTSD, and finds evidence for comorbid MDD, pharmacotherapy, assay used, and circadian factors as sources of variance across studies.

    Article  PubMed  Google Scholar 

  41. Lisieski MJ, Eagle AL, Conti AC, Liberzon I, Perrine SA. Single-prolonged stress: a review of two decades of progress in a rodent model of post-traumatic stress disorder. Front Psychiatry. 2018;9:1–22.

    Article  Google Scholar 

  42. Barnum CJ, Pace TWW, Hu F, Neigh GN, Tansey MG. Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS challenge. J Neuroinflammation. 2012;9:1–15.

    Article  Google Scholar 

  43. •• Levkovitz Y, Fenchel D, Kaplan Z, Zohar J, Cohen H. Early post-stressor intervention with minocycline, a second-generation tetracycline, attenuates post-traumatic stress response in an animal model of PTSD. Eur Neuropsychopharmacol [Internet]. Elsevier; 2015;25:124–32. Available from: https://doi.org/10.1016/j.euroneuro.2014.11.012. This study provided support for the potential clinical relevance of pharmacologic modulation of post-stressor inflammatory responses in preventing PTSD-like symptoms after a psychological stressor.

    Article  CAS  PubMed  Google Scholar 

  44. • Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm D-H. Effects of systemic administration of ibuprofen on stress response in a rat model of post-traumatic stress disorder. Korean J Physiol Pharmacol. 2016;20:357. Available from: https://synapse.koreamed.org/DOIx.php?id=https://doi.org/10.4196/kjpp.2016.20.4.357 Similar to Levkovitz et al , but using a different immune modulator in a different PTSD model, this study found an effect of the anti-inflammatory drug ibuprofen on both inflammatory biomarkers, serum corticosterone, and anxiety-like behavior after the single prolonged stress paradigm, 366.

    Article  CAS  Google Scholar 

  45. Wang M, Duan F, Wu J, Min Q, Huang Q, Luo M, et al. Effect of cyclooxygenase-2 inhibition on the development of post-traumatic stress disorder in rats. Mol Med Rep. 2018;17:4925–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Wohleb ES, McKim DB, Shea DT, Powell ND, Tarr AJ, Sheridan JF, et al. Re-establishment of anxiety in stress-sensitized mice is caused by monocyte trafficking from the spleen to the brain. Biol Psychiatry [Internet]. Elsevier; 2014;75:970–81. Available from: https://doi.org/10.1016/j.biopsych.2013.11.029

    Article  CAS  PubMed  Google Scholar 

  47. •• McKim DB, Patterson JM, Wohleb ES, Jarrett BL, Reader BF, Godbout JP, et al. Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol Psychiatry [Internet]. Elsevier; 2016;79:803–13. Available from: https://doi.org/10.1016/j.biopsych.2015.07.010. Building on previous work demonstrating the role of splenic release of monocytes in the reemergence of anxiety symptoms upon encountering a new stressor, this work identifies peripheral release of noradrenaline as a required link in eliciting this monocyte release, and the currently clinically-utilized pharmacotherapy propranolol as effective in interrupting this this process.

    Article  CAS  PubMed  Google Scholar 

  48. Reader BF, Jarrett BL, McKim DB, Wohleb ES, Godbout JP, Sheridan JF. Peripheral and central effects of repeated social defeat stress: monocyte trafficking, microglial activation, and anxiety. Neuroscience [internet]. IBRO; 2015;289:429–42. Available from: https://doi.org/10.1016/j.neuroscience.2015.01.001

    Article  CAS  PubMed  Google Scholar 

  49. Morris MC, Compas BE, Garber J. Relations among posttraumatic stress disorder, comorbid major depression, and HPA function: a systematic review and meta-analysis. Clin Psychol rev [Internet]. Elsevier Ltd; 2012;32:301–15. Available from: https://doi.org/10.1016/j.cpr.2012.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  50. Matić G, Milutinović DV, Nestorov J, Elaković I, Jovanović SM, Perišić T, et al. Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD. Prog Neuro-Psychopharmacology Biol Psychiatry. 2013;43:238–45.

    Article  CAS  Google Scholar 

  51. Tanriverdi F, Schneider HJ, Aimaretti G, Masel BE, Casanueva FF, Kelestimur F. Pituitary dysfunction after traumatic brain injury: a clinical and pathophysiological approach. Endocr Rev. 2015;36:305–42.

    Article  CAS  PubMed  Google Scholar 

  52. Daskalakis NP, Provost AC, Hunter RG, Guffanti G. Noncoding RNAs: stress, glucocorticoids, and posttraumatic stress disorder. Biol Psychiatry [Internet]. Elsevier Inc; 2018;83:849–65. Available from: https://doi.org/10.1016/j.biopsych.2018.01.009

    Article  CAS  PubMed  Google Scholar 

  53. Dick A, Provencal N. Central neuroepigenetic regulation of the hypothalamic–pituitary–adrenal axis. Prog Mol Biol Transl Sci. 2018;158:105–27.

    Article  PubMed  CAS  Google Scholar 

  54. Tan CL, Alavi SA, Baldeweg SE, Belli A, Carson A, Feeney C, et al. The screening and management of pituitary dysfunction following traumatic brain injury in adults: British Neurotrauma Group guidance. J Neurol Neurosurg Psychiatry. 2017;88:971–81.

    Article  PubMed  Google Scholar 

  55. Michopoulos V, Norrholm SD, Jovanovic T. Diagnostic biomarkers for posttraumatic stress disorder: promising horizons from translational neuroscience research. Biol Psychiatry [Internet]. Elsevier; 2015 [cited 2015 Sep 16];78:344–53. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006322315000657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Michopoulos V, Vester A, Neigh G. Posttraumatic stress disorder: a metabolic disorder in disguise? Exp Neurol [Internet]. Elsevier B.V.; 2016;284:220–9. Available from: http://www.sciencedirect.com/science/article/pii/S0014488616301546

    Article  PubMed  PubMed Central  Google Scholar 

  57. Rasmusson AM, Pineles SL. Neurotransmitter, peptide, and steroid hormone abnormalities in PTSD: biological endophenotypes relevant to treatment. Curr Psychiatry Rep Curr Psychiatry Rep. 2018;20.

  58. Shorter E, Fink M. Endocrine psychiatry: solving the riddle of melancholia. New York: Oxford University Press; 2010.

    Google Scholar 

  59. Sachar EJ, Finkelstein J, Hellman L. Growth hormone responses in depressive illness: I. response to insulin tolerance test. Arch Gen Psychiatry. 1971;25:263–9.

    Article  Google Scholar 

  60. Prange AJ, Lara PP, Wilson IC, Alltop LB, Breese GR. Effects of thyrotropin-releasing hormone in depression. Lancet (London, England). 1972 [cited 2018 Sep 2];2:999–1002. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4116985

    Article  Google Scholar 

  61. Asnis GM, Sachar EJ, Halbreich U, Nathan RS, Ostrow L, Soloman M, et al. Endocrine responses to thyrotropin-releasing hormone in major depressive disorders. Psychiatry Res. 1981 [cited 2018 Sep 2];5:205–15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6117098

    Article  CAS  PubMed  Google Scholar 

  62. 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;29:389–404.

    Article  CAS  PubMed  Google Scholar 

  63. Wang S. Traumatic stress and thyroid function. Child Abus Negl. 2006;30:585–8.

    Article  Google Scholar 

  64. de Kloet CS, Vermetten E, Heijnen CJ, Geuze E, Lentjes EGWM, Westenberg HGM. Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder. Psychoneuroendocrinology. 2007;32:215–26.

    Article  PubMed  CAS  Google Scholar 

  65. Morris P, Hopwood M, Maguire K, Norman T, Schweitzer I. Blunted growth hormone response to clonidine in post-traumatic stress disorder. Psychoneuroendocrinology. 2004;29:269–78.

    Article  CAS  PubMed  Google Scholar 

  66. Van Liempt S, Vermetten E, Lentjes E, Arends J, Westenberg H. Decreased nocturnal growth hormone secretion and sleep fragmentation in combat-related posttraumatic stress disorder; potential predictors of impaired memory consolidation. Psychoneuroendocrinology [Internet]. Elsevier Ltd; 2011;36:1361–9. Available from: https://doi.org/10.1016/j.psyneuen.2011.03.009

    Article  CAS  PubMed  Google Scholar 

  67. Olff M, Güzelcan Y, de Vries GJ, Assies J, Gersons BPR. HPA- and HPT-axis alterations in chronic posttraumatic stress disorder. Psychoneuroendocrinology. 2006;31:1220–30.

    Article  CAS  PubMed  Google Scholar 

  68. Reist C, Kauffmann CD, Chicz-Demet a CCC, Demet EM. REM latency, dexamethasone suppression test, and thyroid releasing hormone stimulation test in posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19:433–43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7624494.

    Article  CAS  PubMed  Google Scholar 

  69. Olff M, de Vries GJ, Güzelcan Y, Assies J, Gersons BPR. Changes in cortisol and DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology. 2007;32:619–26.

    Article  CAS  PubMed  Google Scholar 

  70. Rauch SAM, King AP, Liberzon I, Sripada RK. Changes in salivary cortisol during psychotherapy for posttraumatic stress disorder: a pilot study in 30 veterans. J Clin Psychiatry. 2017;78:599–603.

    Article  PubMed  Google Scholar 

  71. Khoury N, Marvar PJ, Gillespie CF, Wingo A, Schqartz A, Bradley B, et al. The renin-angiotensin pathway in PTSD: ACE inhibgitor and ARB medications are associated with fewer traumatic stress symptoms. J Clin Psychiatry. 2012;73:849–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. • Nylocks KM, Michopoulos V, Rothbaum AO, Almli L, Gillespie CF, Wingo A, et al. An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms. Am J Med Genet Part B Neuropsychiatr Genet. 2015;168:307–15 Available from: http://doi.wiley.com/10.1002/ajmg.b.32313. This cross-sectional observational study provides further support for an effect of renin-angiotensin signaling and pharmacologic modulation on PTSD diagnosis and symptom burden, while also providing evidence for a genetic basis to heterogeneity in the impact of pharmacologic modulators on symptoms.

    Article  CAS  Google Scholar 

  73. Benvenga S, Campenní A, Ruggeri RM, Trimarchi F. Clinical review 113: Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab. 2000;85:1353–61.

    Article  CAS  PubMed  Google Scholar 

  74. Wilkinson CW, Pagulayan KF, Petrie EC, Mayer CL, Colasurdo EA, Shofer JB, et al. High prevalence of chronic pituitary and target-organ hormone abnormalities after blast-related mild traumatic brain injury. Front Neurol. 2012 [cited 2015 Aug 12];3:11. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3273706&tool=pmcentrez&rendertype=abstract.

  75. Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M. Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry. 1993 [cited 2015 Sep 15];50:294–305. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8466391

    Article  CAS  Google Scholar 

  76. Hendrickson RC, Raskind MA. Noradrenergic dysregulation in the pathophysiology of PTSD. Exp Neurol [Internet]. Elsevier B.V.; 2016 [cited 2016 Jun 2];284:181–95. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27222130

    Article  CAS  PubMed  Google Scholar 

  77. Mcdonald BC, Flashman LA, Saykin AJ. Executive dysfunction following traumatic brain injury: neural substrates and treatment strategies. NeuroRehabilitation. 2002;17:333–44.

    Article  PubMed  Google Scholar 

  78. Kobori N, Clifton GL, Dash PK. Enhanced catecholamine synthesis in the prefrontal cortex after traumatic brain injury: implications for prefrontal dysfunction. J Neurotrauma. 2006;23:1094–102.

    Article  PubMed  Google Scholar 

  79. Surmeier DJ. Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet Neurol. 2007;6:933–8.

    Article  CAS  PubMed  Google Scholar 

  80. Raskind MA, Peskind ER, Holmes C, Goldstein DS. Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer’s disease. Biol Psychiatry [Internet]. 1999 [cited 2015 Aug 12];46:756–65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10494443

    Article  CAS  PubMed  Google Scholar 

  81. Szot P. Compensatory changes in the noradrenergic nervous system in the locus ceruleus and hippocampus of postmortem subjects with Alzheimer’s disease and dementia with Lewy bodies. J Neurosci. 2006;26:467–78 Available from: http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.4265-05.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI : substrates of dementia? Nat Rev Neurol [Internet]. Nat Publ Group; 2013;9:211–21. Available from: https://doi.org/10.1038/nrneurol.2013.29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bracha HS, Garcia-Rill E, Mrak RE, Skinner R. Postmortem locus coeruleus neuron count in three American veterans with probable or possible war-related PTSD. J Neuropsychiatry Clin Neurosci. 2005;17:503–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Geracioti TD, Baker DG, Ekhator NN, West SA, Hill KK, Bruce A. B, et al. CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry [Internet]. 2001 [cited 2015 Sep 15];158:1227–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11481155

    Article  Google Scholar 

  85. Southwick SM, Krystal JH, Morgan CA, Johnson D, Nagy LM, Nicolaou A, et al. Abnormal noradrenergic function in posttraumatic stress disorder. Arch Gen Psychiatry [Internet]. 1993 [cited 2015 Sep 12];50:266–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8466387

    Article  CAS  PubMed  Google Scholar 

  86. Hendrickson RC, Raskind MA, Millard SP, Sikkema C, Terry GE, Pagulayan KF, et al. Evidence for altered brain reactivity to norepinephrine in veterans with a history of traumatic stress. Neurobiol Stress. 2018;8:103–11.

    Article  PubMed  PubMed Central  Google Scholar 

  87. 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 [Internet]. 1992 [cited 2015 Aug 24];180:321–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1583475

  88. Lemieux AM, Coe CL. Abuse-related postraumatic stress disorder: evidence for chronic neuroendocrine activation in women. 1995;57:105–15.

  89. De Bellis MD, Baum AS, Birmaher B, Keshavan MS, Eccard CH, Boring AM, et al. A.E. Bennett Research Award. Developmental traumatology. Part I: biological stress systems. Biol Psychiatry [Internet]. 1999 [cited 2015 Sep 16];45:1259–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10349032

  90. Glover DA, Powers MB, Bergman L, Smits JAJ, Telch MJ, Stuber M. Urinary dopamine and turn bias in traumatized women with and without PTSD symptoms. Behav Brain Res. 2003;144:137–41.

    Article  CAS  PubMed  Google Scholar 

  91. Hamner MB, Diamond BI. Elevated plasma dopamine in posttraumatic stress disorder: a preliminary report. Biol Psychiatry. 1993;33:304–6.

    Article  CAS  PubMed  Google Scholar 

  92. Geracioti TD, West SA, Baker DG, Hill KK, Ekhator NN, Wortman MD, et al. Low CSF concentration of a dopamine metabolite in tobacco smokers. Am J Psychiatry. 1999;156:130–2.

    Article  PubMed  Google Scholar 

  93. Strawn JR, Pyne-Geithman GJ, Ekhator NN, Horn PS, Uhde TW, Shutter LA, et al. Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology [Internet]. Elsevier Ltd; 2010;35:1001–7. Available from: https://doi.org/10.1016/j.psyneuen.2010.01.001

    Article  CAS  PubMed  Google Scholar 

  94. Geracioti TD, Jefferson-Wilson L, Strawn JR, Baker DG, Dashevsky BA, Horn PS, et al. Effect of traumatic imagery on cerebrospinal fluid dopamine and serotonin metabolites in posttraumatic stress disorder. J Psychiatr Res [Internet]. Elsevier Ltd; 2013;47:995–8. Available from: https://doi.org/10.1016/j.jpsychires.2013.01.023

    Article  PubMed  Google Scholar 

  95. Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378:507–17 Available from: http://www.nejm.org/doi/10.1056/NEJMoa1507598.

    Article  CAS  PubMed  Google Scholar 

  96. Ressler KJ. Alpha-adrenergic receptors in PTSD — failure or time for precision medicine? Ed N Engl J Med. 2018;3786:575–6 Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMe1716724.

    Article  Google Scholar 

  97. • Raskind MA, Millard SP, Petrie EC, Peterson K, Williams T, Hoff DJ, et al. Higher pretreatment blood pressure is associated with greater PTSD symptom reduction in soldiers treated with prazosin. Biol Psychiatry [Internet]. Elsevier; 2016;80:736–42. Available from: https://doi.org/10.1016/j.biopsych.2016.03.2108. This post hoc analysis of an RCT of prazosin for PTSD found that baseline measures of a putative biomarker of the α 1 noradrenaline receptor upregulation ‘predicted’ which participants showed a clinically significant response to prazosin, consistent with heterogeneity in the response to pharmacotherapy for PTSD being related to heterogeneity in the underlying pathophysiology.

    Article  CAS  PubMed  Google Scholar 

  98. The Management of Posttraumatic Stress Disorder Work Group. Va/dod clinical practice guideline for the management of posttraumatic stress disorder and acute stress disorder. 2017;Version 3. Available from: https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf

  99. Villarreal G, Hamner MB, Cañive JM, Robert S, Calais LA, Durklaski V, et al. Efficacy of quetiapine monotherapy in posttraumatic stress disorder: a randomized, placebo-controlled trial. Am J Psychiatry. 2016;173:1205–12 Available from: http://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2016.15070967.

    Article  PubMed  Google Scholar 

  100. Byers MG, Allison KM, Wendel CS, Lee JK. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans. J Clin Psychopharmacol. 2010;30:225–9 Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00004714-201006000-00002.

    Article  PubMed  Google Scholar 

  101. Carey P, Suliman S, Ganesan K, Seedat S, Stein DJ. Olanzapine monotherapy in posttraumatic stress disorder: efficacy in a randomized, double-blind, placebo-controlled study. Hum Psychopharmacol Clin Exp. 2002;27:386–91.

    Article  CAS  Google Scholar 

  102. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry. 2002;159:1777–9.

    Article  PubMed  Google Scholar 

  103. McAllister TW, Flashman LA, Sparling MB, Saykin AJ. Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment -- a review. Brain Inj. 2004;18:331–50.

    Article  PubMed  Google Scholar 

  104. Jenkins PO, Mehta MA, Sharp DJ. Catecholamines and cognition after traumatic brain injury. Brain. 2016;139:2345–71.

    Article  PubMed  PubMed Central  Google Scholar 

  105. McIntosh TK, Yu T, Gennarelli TA. Alterations in regional brain catecholamine concentrations after experimental brain injury in the rat. J Neurochem [Internet]. 1994 [cited 2018 Aug 19];63:1426–33. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7931293

    Article  Google Scholar 

  106. Prasad MR, Ramaiah C, McIntosh TK, Dempsey RJ, Hipkens S, Yurek D. Regional levels of lactate and norepinephrine after experimental brain injury. J Neurochem. 1994 [cited 2018 Aug 19];63:1086–94. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8051549

  107. Levin BE, Pan S, Dunn-Meynell A. Chronic alterations in rat brain α-adrenoceptors following traumatic brain injury. Restor Neurol Neurosci. 1994 [cited 2016 Feb 4];7:5–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21551766

  108. Kobori N, Hu B, Dash PK. Altered adrenergic receptor signaling following traumatic brain injury contributes to working memory dysfunction. Neuroscience [Internet]. 2011 [cited 2015 Sep 17];172:293–302. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3010433&tool=pmcentrez&rendertype=abstract.

  109. Massucci JL, Kline AE, Ma X, Zafonte RD, Dixon CE. Time dependent alterations in dopamine tissue levels and metabolism after experimental traumatic brain injury in rats. Neurosci Lett. 2004;372:127–31.

    Article  CAS  PubMed  Google Scholar 

  110. Schindler AG, Meabon JS, Pagulayan KF, Hendrickson RC, Meeker KD, Cline M, et al. Blast–related disinhibition and risk seeking in mice and combat veterans: potential role for dysfunctional phasic dopamine release. Neurobiol Dis. 2017;106:23–34.

    Article  CAS  PubMed  Google Scholar 

  111. Luauté J, Plantier D, Wiart L, Tell L. Care management of the agitation or aggressiveness crisis in patients with TBI. Systematic review of the literature and practice recommendations. Ann Phys Rehabil Med. 2016;59:58–67.

    Article  PubMed  Google Scholar 

  112. McAllister TW, Zafonte R, Jain S, Flashman LA, George MS, Grant GA, et al. Randomized placebo-controlled trial of methylphenidate or Galantamine for persistent emotional and cognitive symptoms associated with PTSD and/or traumatic brain injury. Neuropsychopharmacology [Internet]. Nature Publishing Group; 2016;41:1191–8. Available from: https://doi.org/10.1038/npp.2015.282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Dunn-Meynell AA, Hassanain M, Levin BE. Norepinephrine and traumatic brain injury: a possible role in post-traumatic edema. Brain Res. 1998;800:245–52.

    Article  CAS  PubMed  Google Scholar 

  114. Stover JF, Sakowitz OW, Schöning B, Rupprecht S, Kroppenstedt SN, Thomale UW, et al. Norepinephrine infusion increases interleukin-6 in plasma and cerebrospinal fluid of brain-injured rats. Med Sci Monit [Internet]. 2003 [cited 2018 Aug 19];9:BR382–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14523327.

  115. Stibick DL, Feeney DM. Enduring vulnerability to transient reinstatement of hemiplegia by prazosin after traumatic brain injury. J Neurotrauma. 2001;18:303–12 Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11284550.

    Article  CAS  PubMed  Google Scholar 

  116. Ruff RL, Ruff SS, Wang X-F, Ruff, Robert L.; Ruff, Suzanne S.; Wang X-F. Improving sleep: initial headache treatment in OIF/OEF veterans with blast-induced mild traumatic brain injury. J Rehabil Res Dev [Internet]. 2009 [cited 2013 May 27];46:1071–84. Available from: http://www.rehab.research.va.gov/jour/09/46/9/Ruff.html

    Article  PubMed  Google Scholar 

  117. Ruff RL, Riechers RG, Wang X-F, Piero T, Ruff SS. For veterans with mild traumatic brain injury, improved posttraumatic stress disorder severity and sleep correlated with symptomatic improvement. J Rehabil Res Dev [Internet]. 2012 [cited 2015 Jul 31];49:1305–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23408213

    Article  PubMed  Google Scholar 

  118. McAllister TW, McDonald BC, Flashman LA, Ferrell RB, Tosteson TD, Yanofsky NN, et al. Alpha-2 adrenergic challenge with guanfacine one month after mild traumatic brain injury: altered working memory and BOLD response. Int J Psychophysiol [Internet]. Elsevier B.V.; 2011;82:107–14. Available from: https://doi.org/10.1016/j.ijpsycho.2011.06.022

    Article  PubMed  PubMed Central  Google Scholar 

  119. Cicerone KD, Kalmar K. Persistent postconcussion syndrome: the structure of subjective complaints after mild traumatic brain injury. J Head Trauma Rehabil LWW. 1995;10:1–17.

    Article  Google Scholar 

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Funding

This work was supported by the Department of Veterans Affairs (VA) Northwest Network MIRECC (RCH, KAP); VA Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment (RCH); Career Development Award IK2CX001774 from the United States Department of Veterans Affairs, Clinical Science Research and Development Service (RCH); and Career Development Award 5IK2BX003258 from the United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Service (AGS). The funding sources had no input in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

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Authors and Affiliations

  1. VISN 20 Northwest Network Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, 1660 S. Columbian Way, S116 MIRECC, Seattle, WA, 98108, USA

    Rebecca C. Hendrickson & Kathleen F. Pagulayan

  2. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356560 Room BB1644, Seattle, WA, 98195-6560, USA

    Rebecca C. Hendrickson, Abigail G. Schindler & Kathleen F. Pagulayan

  3. Geriatric Research, Education and Clinical Center (GRECC), VA Puget Sound Health Care System, 1660 S. Columbian Way, S116 MIRECC, Seattle, WA, 98108, USA

    Abigail G. Schindler

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  1. Rebecca C. Hendrickson
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  3. Kathleen F. Pagulayan
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Correspondence to Rebecca C. Hendrickson.

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Kathleen F. Pagulayan, Rebecca C. Hendrickson and Abigail G. Schindler report grants from VA Research and Development, during the conduct of the study.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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The views expressed are those of the authors and do not reflect the official policy of the Department of Veterans Affairs or the US Government.

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Hendrickson, R.C., Schindler, A.G. & Pagulayan, K.F. Untangling PTSD and TBI: Challenges and Strategies in Clinical Care and Research. Curr Neurol Neurosci Rep 18, 106 (2018). https://doi.org/10.1007/s11910-018-0908-5

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