Stress Response Modulation Underlying the Psychobiology of Resilience

Abstract

Purpose of Review

This review focuses on the relationship between resilience and the ability to effectively modulate the stress response. Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes—manifesting psychopathology in one individual, but having minimal effect, or even enhancing resilience, in another. We highlight aspects of stress response modulation related to early life development and epigenetics, selected neurobiological and neurochemical systems, and a number of emotional, cognitive, psychosocial, and behavioral factors important in resilience. We also briefly discuss interventions with potential to build and promote resilience.

Recent Findings

Throughout this review, we include evidence from recent preclinical and clinical studies relevant to the psychobiology of resilient stress response modulation.

Summary

Effective modulation of the stress response is an essential component of resilience and is dependent on a complex interplay of neurobiological and behavioral factors.

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Fig. 1

References

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

  1. 1.

    Garmezy N, Masten AS, Tellegen A. The study of stress and competence in children: a building block for developmental psychopathology. Child Dev. 1984;55(1):97–111.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Southwick SM, Charney DS. The science of resilience: implications for the prevention and treatment of depression. Science. 2012;338(6103):79–82.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Southwick, S.M., Pietrzak, R.H., Tsai, J., Krystal, J.H., Resilience: an update PTSD Research Quarterly 2015. 25(4).

  4. 4.

    Horn, S.R., D.S. Charney, and A. Feder, Understanding resilience: new approaches for preventing and treating PTSD. Exp Neurol, 2016. 284(Pt B): p. 119–132.

  5. 5.

    • McEwen BS. In pursuit of resilience: stress, epigenetics, and brain plasticity. Ann N Y Acad Sci. 2016;1373(1):56–64. https://doi.org/10.1111/nyas.13020. A current, comprehensive, and thoughtful review of the role of stress, genetics, and neuroplasticity in resilience.

    PubMed  Article  Google Scholar 

  6. 6.

    Wu G, et al. Understanding resilience. Front Behav Neurosci. 2013;7:10.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Rutter M. Resilience as a dynamic concept. Dev Psychopathol. 2012;24(2):335–44.

    PubMed  Article  Google Scholar 

  8. 8.

    Pietrzak RH, Southwick SM. Psychological resilience in OEF-OIF Veterans: application of a novel classification approach and examination of demographic and psychosocial correlates. J Affect Disord. 2011;133(3):560–8.

    PubMed  Article  Google Scholar 

  9. 9.

    Kim-Cohen J, Turkewitz R. Resilience and measured gene-environment interactions. Dev Psychopathol. 2012;24(4):1297–306.

    PubMed  Article  Google Scholar 

  10. 10.

    Southwick SM, Bonanno GA, Masten AS, Panter-Brick C, Yehuda R. Resilience definitions, theory, and challenges: interdisciplinary perspectives. Eur J Psychotraumatol. 2014;5:25338.

    Article  Google Scholar 

  11. 11.

    Masten AS. Ordinary magic: resilience processes in development. Am Psychol. 2001;56(3):227–38.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    • Masten AS. Global perspectives on resilience in children and youth. Child Dev. 2014;85(1):6–20. https://doi.org/10.1111/cdev.12205. A current and important review highlighting the global importance of building resilience and the interaction between development and resilience. This also highlights many factors ranging from global, regional, community, to cultural levels that influence resilience.

    PubMed  Article  Google Scholar 

  13. 13.

    Masten AS. Invited commentary: resilience and positive youth development frameworks in developmental science. J Youth Adolesc. 2014;43(6):1018–24.

    PubMed  Article  Google Scholar 

  14. 14.

    Cicchetti D. Annual research review: resilient functioning in maltreated children—past, present, and future perspectives. J Child Psychol Psychiatry. 2013;54(4):402–22.

    PubMed  Article  Google Scholar 

  15. 15.

    Anacker C, O’Donnell KJ, Meaney MJ. Early life adversity and the epigenetic programming of hypothalamic-pituitary-adrenal function. Dialogues Clin Neurosci. 2014;16(3):321–33.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Arnsten AF. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011;69(12):e89–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Frodl T, O'Keane V. How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans. Neurobiol Dis. 2013;52:24–37.

    PubMed  Article  Google Scholar 

  18. 18.

    Heim C, Shugart M, Craighead WE, Nemeroff CB. Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol. 2010;52(7):671–90.

    PubMed  Article  Google Scholar 

  19. 19.

    Lyons DM, et al. Developmental cascades linking stress inoculation, arousal regulation, and resilience. Front Behav Neurosci. 2009;3:32.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Moffitt TE, Arseneault L, Belsky D, Dickson N, Hancox RJ, Harrington H, et al. A gradient of childhood self-control predicts health, wealth, and public safety. Proc Natl Acad Sci U S A. 2011;108(7):2693–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Fergusson DM, Boden JM, Horwood LJ. Childhood self-control and adult outcomes: results from a 30-year longitudinal study. J Am Acad Child Adolesc Psychiatry. 2013;52(7):709–717.e1.

    PubMed  Article  Google Scholar 

  22. 22.

    Bowers ME, Yehuda R. Intergenerational transmission of stress in humans. Neuropsychopharmacology. 2016;41(1):232–44.

    PubMed  Article  Google Scholar 

  23. 23.

    •• Yehuda R, Daskalakis NP, Bierer LM, Bader HN, Klengel T, Holsboer F, et al. Holocaust exposure induced intergenerational effects on FKBP5 methylation. Biol Psychiatry. 2016;80(5):372–80. https://doi.org/10.1016/j.biopsych.2015.08.005. The first study to demonstrate the effects of intergenerational trauma on the FKBP5 myelination.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Yehuda R, Koenen KC, Galea S, Flory JD. The role of genes in defining a molecular biology of PTSD. Dis Markers. 2011;30(2–3):67–76.

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Toepfer P, Heim C, Entringer S, Binder E, Wadhwa P, Buss C. Oxytocin pathways in the intergenerational transmission of maternal early life stress. Neurosci Biobehav Rev. 2017;73:293–308.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79(1):16–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci. 2012;13(11):769–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Popoli M, Yan Z, McEwen B, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011;13(1):22–37.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Krystal JH, Neumeister A. Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience. Brain Res. 2009;1293:13–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Bremner JD, Krystal JH, Southwick SM, Charney DS. Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse. 1996;23(1):39–51.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    • Arnsten AF, Raskind MA, Taylor FB, Connor DF. The effects of stress exposure on prefrontal cortex: translating basic research into successful treatments for post-traumatic stress disorder. Neurobiol Stress. 2015;1:89–99. https://doi.org/10.1016/j.ynstr.2014.10.002. A comprehensive review of the deleterious effects of stress on the PFC including discussion of pharmacologic interventions to ameloriate or reverse these effects.

    PubMed  Article  Google Scholar 

  32. 32.

    Dienstbier RA. Arousal and physiological toughness: implications for mental and physical health. Psychol Rev. 1989;96(1):84–100.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Southwick SM, Bremner JD, Rasmusson A, Morgan CA III, Arnsten A, Charney DS. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;46(9):1192–204.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Wu G, Feder A, Wegener G, Bailey C, Saxena S, Charney D, et al. Central functions of neuropeptide Y in mood and anxiety disorders. Expert Opin Ther Targets. 2011;15(11):1317–31.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Sah R, Geracioti TD. Neuropeptide Y and posttraumatic stress disorder. Mol Psychiatry. 2013;18(6):646–55.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    • Schmeltzer SN, Herman JP, Sah R. Neuropeptide Y (NPY) and posttraumatic stress disorder (PTSD): a translational update. Experimental neurology. 2016;284(Pt B):196-210. Doi:https://doi.org/10.1016/j.expneurol.2016.06.020. A current review providing evidence from clinical to preclinical data regarding the role of NPY in PTSD and resilience.

  37. 37.

    Enman NM, Sabban EL, McGonigle P, van Bockstaele EJ. Targeting the neuropeptide Y system in stress-related psychiatric disorders. Neurobiol Stress. 2015;1:33–43.

    PubMed  Article  Google Scholar 

  38. 38.

    Kautz M, Charney DS, Murrough JW. Neuropeptide Y, resilience, and PTSD therapeutics. Neurosci Lett. 2017;649:164–9.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Morgan CA 3rd, et al. Plasma neuropeptide-Y concentrations in humans exposed to military survival training. Biol Psychiatry. 2000;47(10):902–9.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Morgan CA 3rd, et al. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol Psychiatry. 2002;52(2):136–42.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Morgan CA 3rd, et al. Relationship among plasma cortisol, catecholamines, neuropeptide Y, and human performance during exposure to uncontrollable stress. Psychosom Med. 2001;63(3):412–22.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Rasmusson AM, Hauger RL, Morgan CA III, Bremner JD, Charney DS, Southwick SM. Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol Psychiatry. 2000;47(6):526–39.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Zhou Z, Zhu G, Hariri AR, Enoch MA, Scott D, Sinha R, et al. Genetic variation in human NPY expression affects stress response and emotion. Nature. 2008;452(7190):997–1001.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Pervanidou P, Chrousos GP. Neuroendocrinology of post-traumatic stress disorder. Prog Brain Res. 2010;182:149–60.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    • Galatzer-Levy IR, Ma S, Statnikov A, Yehuda R, Shalev AY. Utilization of machine learning for prediction of post-traumatic stress: a re-examination of cortisol in the prediction and pathways to non-remitting PTSD. Translational psychiatry. 2017;7(3):e0. doi:https://doi.org/10.1038/tp.2017.38. A review of novel, advanced computational methods to better inform neurobiological studies, in this case, the role of cortisol in PTSD.

  46. 46.

    Inslicht SS, Otte C, McCaslin SE, Apfel BA, Henn-Haase C, Metzler T, et al. Cortisol awakening response prospectively predicts peritraumatic and acute stress reactions in police officers. Biol Psychiatry. 2011;70(11):1055–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Galatzer-Levy IR, Steenkamp MM, Brown AD, Qian M, Inslicht S, Henn-Haase C, et al. Cortisol response to an experimental stress paradigm prospectively predicts long-term distress and resilience trajectories in response to active police service. J Psychiatr Res. 2014;56:36–42.

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Jones T, Moller MD. Implications of hypothalamic-pituitary-adrenal axis functioning in posttraumatic stress disorder. J Am Psychiatr Nurses Assoc. 2011;17(6):393–403.

    PubMed  Article  Google Scholar 

  49. 49.

    Morgan CA 3rd, 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. 2004;61(8):819–25.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Morgan CA 3rd, et al. Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation, and objective performance in humans exposed to underwater navigation stress. Biol Psychiatry. 2009;66(4):334–40.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Sripada RK, Welsh RC, Marx CE, Liberzon I. The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity. Hum Brain Mapp. 2014;35(7):3249–61.

    PubMed  Article  Google Scholar 

  52. 52.

    Sripada RK, Marx CE, King AP, Rajaram N, Garfinkel SN, Abelson JL, et al. DHEA enhances emotion regulation neurocircuits and modulates memory for emotional stimuli. Neuropsychopharmacology. 2013;38(9):1798–807.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry. 1999;156(4):646–9.

    CAS  PubMed  Google Scholar 

  54. 54.

    Southwick SM, Vythilingam M, Charney DS. The psychobiology of depression and resilience to stress: implications for prevention and treatment. Annu Rev Clin Psychol. 2005;1(1):255–91.

    PubMed  Article  Google Scholar 

  55. 55.

    Charney, D.S. and H.K. Manji, Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE, 2004. 2004(225): p. re5.

  56. 56.

    Wolf EJ, Mitchell KS, Koenen KC, Miller MW. Combat exposure severity as a moderator of genetic and environmental liability to post-traumatic stress disorder. Psychol Med. 2014;44(7):1499–509.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    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(11):1291–305.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W, et al. Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry. 2008;65(2):190–200.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Schartner C, Ziegler C, Schiele MA, Kollert L, Weber H, Zwanzger P, et al. CRHR1 promoter hypomethylation: an epigenetic readout of panic disorder? Eur Neuropsychopharmacol. 2017;27(4):360–71.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    • Watkins LE, Han S, Harpaz-Rotem I, Mota NP, Southwick SM, Krystal JH, et al. FKBP5 polymorphisms, childhood abuse, and PTSD symptoms: results from the National Health and Resilience in Veterans Study. Psychoneuroendocrinology. 2016;69:98–105. https://doi.org/10.1016/j.psyneuen.2016.04.001. This reports on the interaction between FKBP5 and childhood abuse in the later onset of PTSD among a nationally representative sample of Veterans.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Paez-Pereda M, Hausch F, Holsboer F. Corticotropin releasing factor receptor antagonists for major depressive disorder. Expert Opin Investig Drugs. 2011;20(4):519–35.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Coric V, Feldman HH, Oren DA, Shekhar A, Pultz J, Dockens RC, et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress Anxiety. 2010;27(5):417–25.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Binneman B, et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry. 2008;165(5):617–20.

    PubMed  Article  Google Scholar 

  64. 64.

    Armbruster D, Mueller A, Strobel A, Lesch KP, Brocke B, Kirschbaum C. Children under stress—COMT genotype and stressful life events predict cortisol increase in an acute social stress paradigm. Int J Neuropsychopharmacol. 2012;15(9):1229–39.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Kolassa IT, Kolassa S, Ertl V, Papassotiropoulos A, de Quervain DJF. The risk of posttraumatic stress disorder after trauma depends on traumatic load and the catechol-o-methyltransferase Val(158)Met polymorphism. Biol Psychiatry. 2010;67(4):304–8.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    •• Johnson EC, Border R, Melroy-Greif WE, de Leeuw CA, Ehringer MA, Keller MC. No evidence that schizophrenia candidate genes are more associated with schizophrenia than noncandidate genes. Biol Psychiatry. 2017;82:702–8. https://doi.org/10.1016/j.biopsych.2017.06.033. This study evaluted the larged schizophrenia GWAS to date and found that many of the previously identified canidate genes are not well supported in genome-wide studies. These results highlight the caution that must be taken in interpreting results from canidate gene studies.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    McAllister AK. Spatially restricted actions of BDNF. Neuron. 2002;36(4):549–50.

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Taliaz D, Loya A, Gersner R, Haramati S, Chen A, Zangen A. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci. 2011;31(12):4475–83.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Castren E, Rantamaki T. The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev Neurobiol. 2010;70(5):289–97.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    • Park CH, Kim J, Namgung E, Lee DW, Kim GH, Kim M, et al. The BDNF Val66Met polymorphism affects the vulnerability of the brain structural network. Front Hum Neurosci. 2017;11:400. https://doi.org/10.3389/fnhum.2017.00400. This study reports on the role of BDNF Val66Met polymorphism in neuroplasticity and white matter stucture that may influence risk of psychopathology.

    PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 2008;59(3):399–412.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev. 2012;64(2):238–58.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci. 2012;35(1):24–35.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Frustaci A, Pozzi G, Gianfagna F, Manzoli L, Boccia S. Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits. Neuropsychobiology. 2008;58(3–4):163–70.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry. 2009;14(7):681–95.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Gatt JM, Nemeroff CB, Schofield PR, Paul RH, Clark CR, Gordon E, et al. Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression. Biol Psychiatry. 2010;68(9):818–24.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    • Averill LA, Purohit P, Averill CL, Boesl MA, Krystal JH, Abdallah CG. Glutamate dysregulation and glutamatergic therapeutics for PTSD: evidence from human studies. Neurosci Lett. 2017;649:147–55. https://doi.org/10.1016/j.neulet.2016.11.064. This review is among the first to consolidate and present the clinical evidence of glutamatergic dysregulation and related potential therapeutic targets in PTSD.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Harvey BH, Shahid M. Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: focus on pharmacology and preclinical translational models. Pharmacol Biochem Behav. 2012;100(4):775–800.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Schur RR, et al. Brain GABA levels across psychiatric disorders: a systematic literature review and meta-analysis of (1) H-MRS studies. Hum Brain Mapp. 2016;37(9):3337–52.

    PubMed  Article  Google Scholar 

  80. 80.

    Faye, C., et al., Neurobiological mechanisms of stress resilience and implications for the aged population. Curr Neuropharmacol, 2017.

  81. 81.

    • Kelmendi B, Adams TG, Yarnell S, Southwick S, Abdallah CG, Krystal JH: PTSD from neurobiology to pharmacological treatments. Eur J Psychotraumatol 2016;7:31858. doi:10.3402/ejpt.v7.31858. A current review concisely describing both FDA-approved and investigational therapeutic options for PTSD and their related underlying neurobiological mechanisms.

  82. 82.

    Thomas E, Stein DJ. Novel pharmacological treatment strategies for posttraumatic stress disorder. Expert Rev Clin Pharmacol. 2017;10(2):167–77.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    • Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16(7):472–86. https://doi.org/10.1038/nrd.2017.16. A current review of the progress and current status in identifying novel glutamatergic-based treatment targets for antidepressant-resistant depression.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    • Krystal JH, Abdallah CG, Averill LA, Kelmendi B, Harpaz-Rotem I, Sanacora G, et al. Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Current psychiatry reports. 2017;19(10):74. https://doi.org/10.1007/s11920-017-0829-z. A current review highlighting the novel antidepressant ketamine’s positive effects on synaptic health in PTSD.

    PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Gorzalka BB, Hill MN. Integration of endocannabinoid signaling into the neural network regulating stress-induced activation of the hypothalamic-pituitary-adrenal axis. Curr Top Behav Neurosci. 2009;1:289–306.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Gorzalka BB, Hill MN, Hillard CJ. Regulation of endocannabinoid signaling by stress: implications for stress-related affective disorders. Neurosci Biobehav Rev. 2008;32(6):1152–60.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Lutz B, Marsicano G, Maldonado R, Hillard CJ. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015;16(12):705–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    • Lee TT, Hill MN, Lee FS. Developmental regulation of fear learning and anxiety behavior by endocannabinoids. Genes Brain Behav. 2016;15(1):108–24. https://doi.org/10.1111/gbb.12253. A current review discussing the role of endocannabinoids in fear response and anxious behavior through evidence from human and rodent studies.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Lee TT, Gorzalka BB. Timing is everything: evidence for a role of corticolimbic endocannabinoids in modulating hypothalamic-pituitary-adrenal axis activity across developmental periods. Neuroscience. 2012;204:17–30.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    • Akiki, T.J., C.L. Averill, and C.G. Abdallah, A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatry Rep, 2017. 19(11): p. 81. This timely review highlights findings of large-scale structural and functional network dysruptions in PTSD and proposes a novel network-based model of PTSD.

  91. 91.

    Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci. 2009;10(6):410–22.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology. 2008;33(1):56–72.

    PubMed  Article  Google Scholar 

  93. 93.

    Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 2010;35(1):169–91.

    PubMed  Article  Google Scholar 

  94. 94.

    Charney DS. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am J Psychiatry. 2004;161(2):195–216.

    PubMed  Article  Google Scholar 

  95. 95.

    • LeDoux JE. Coming to terms with fear. Proc Natl Acad Sci U S A. 2014;111(8):2871–8. https://doi.org/10.1073/pnas.1400335111. A current and comprehensive review of the neurobiological underpinnings of fear response and a discussion of recently proposed survival circuits and global organismic states.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Nikolova YS, Bogdan R, Brigidi BD, Hariri AR. Ventral striatum reactivity to reward and recent life stress interact to predict positive affect. Biol Psychiatry. 2012;72(2):157–63.

    PubMed  Article  Google Scholar 

  97. 97.

    Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ. Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatry. 1997;154(7):926–33.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Troy, A.S. and I.B. Mauss, Resilience in the face of stress: emotion regulation as a protective factor. , in Resilience and mental health: challenges across the lifespan, S.M. Southwick, Litz, B.T., Charney, D., & Friedman, M.J. , Editor. 2011, Cambridge University Press.

  99. 99.

    Gross JJ, Thompson RA. Emotion regulation: conceptual foundations. In: Gross JJ, editor. Handbook of Emotion Regulation. New York: Guilford Press; 2007. p. 3–24.

    Google Scholar 

  100. 100.

    Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9(5):242–9.

    PubMed  Article  Google Scholar 

  101. 101.

    • Dore BP, Boccagno C, Burr D, Hubbard A, Long K, Weber J, et al. Finding positive meaning in negative experiences engages ventral striatal and ventromedial prefrontal regions associated with reward valuation. J Cogn Neurosci. 2017;29(2):235–44. https://doi.org/10.1162/jocn_a_01041. An MRI study highlighting the role of the ventral striatum and PFC in positive cognitive reappraisal and the relationship between reappraisal and reward circuitry.

    PubMed  Article  Google Scholar 

  102. 102.

    Buhle JT, Silvers JA, Wager TD, Lopez R, Onyemekwu C, Kober H, et al. Cognitive reappraisal of emotion: a meta-analysis of human neuroimaging studies. Cereb Cortex. 2014;24(11):2981–90.

    PubMed  Article  Google Scholar 

  103. 103.

    • Reeck C, Ames DR, Ochsner KN. The social regulation of emotion: an integrative, cross-disciplinary model. Trends Cogn Sci. 2016;20(1):47–63. https://doi.org/10.1016/j.tics.2015.09.003. This provides a unique perspective on the social aspects underlying much of emotion regulation.

    PubMed  Article  Google Scholar 

  104. 104.

    Vrticka P, Vuilleumier P. Neuroscience of human social interactions and adult attachment style. Front Hum Neurosci. 2012;6:212.

    PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    • Kuzmanovic B, Jefferson A, Vogeley K. The role of the neural reward circuitry in self-referential optimistic belief updates. NeuroImage. 2016;133:151–62. https://doi.org/10.1016/j.neuroimage.2016.02.014. An MRI study highlighting the role of the PFC and ventral striatum in optimistic judgements.

    PubMed  Article  Google Scholar 

  106. 106.

    Speer ME, Bhanji JP, Delgado MR. Savoring the past: positive memories evoke value representations in the striatum. Neuron. 2014;84(4):847–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Carver CS, Scheier MF, Segerstrom SC. Optimism. Clin Psychol Rev. 2010;30(7):879–89.

    PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Bonanno GA, Burton CL. Regulatory flexibility: an individual differences perspective on coping and emotion regulation. Perspect Psychol Sci. 2013;8(6):591–612.

    PubMed  Article  Google Scholar 

  109. 109.

    • Tang YY, Holzel BK, Posner MI. The neuroscience of mindfulness meditation. Nat Rev Neurosci. 2015;16(4):213–25. https://doi.org/10.1038/nrn3916. A current and comprehensive review providing good discussion of the neuroscience of mindfulness.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Thompson RW, Arnkoff DB, Glass CR. Conceptualizing mindfulness and acceptance as components of psychological resilience to trauma. Trauma Violence Abuse. 2011;12(4):220–35.

    PubMed  Article  Google Scholar 

  111. 111.

    Olff M, Koch SBJ, Nawijn L, Frijling JL, van Zuiden M, Veltman DJ. Social support, oxytocin, and PTSD. Eur J Psychotraumatol. 2014;5:26513.

    PubMed  Article  Google Scholar 

  112. 112.

    Olff M. Bonding after trauma: on the role of social support and the oxytocin system in traumatic stress. Eur J Psychotraumatol. 2012;3:18597.

    Article  Google Scholar 

  113. 113.

    Norris FH, Sherrieb K, Galea S. Prevalence and consequences of disaster-related illness and injury from Hurricane Ike. Rehabil Psychol. 2010;55(3):221–30.

    PubMed  Article  Google Scholar 

  114. 114.

    Silverman MN, Deuster PA. Biological mechanisms underlying the role of physical fitness in health and resilience. Interface Focus. 2014;4(5):20140040.

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Greenwood BN, Fleshner M. Exercise, stress resistance, and central serotonergic systems. Exerc Sport Sci Rev. 2011;39(3):140–9.

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Leppin AL, Bora PR, Tilburt JC, Gionfriddo MR, Zeballos-Palacios C, Dulohery MM, et al. The efficacy of resiliency training programs: a systematic review and meta-analysis of randomized trials. PLoS One. 2014;9(10):e111420.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Horowitz JL, Garber J. The prevention of depressive symptoms in children and adolescents: a meta-analytic review. J Consult Clin Psychol. 2006;74(3):401–15.

    PubMed  Article  Google Scholar 

  118. 118.

    McKay-Jackson C. A critical approach to social emotional learning instruction through community-based service learning. J Transform Educ. 2014;12(3):292–312.

    Article  Google Scholar 

  119. 119.

    Durlak JA, Weissberg RP, Dymnicki AB, Taylor RD, Schellinger KB. The impact of enhancing students’ social and emotional learning: a meta-analysis of school-based universal interventions. Child Dev. 2011;82(1):405–32.

    PubMed  Article  Google Scholar 

  120. 120.

    Badura-Brack AS, Naim R, Ryan TJ, Levy O, Abend R, Khanna MM, et al. Effect of attention training on attention bias variability and PTSD symptoms: randomized controlled trials in Israeli and U.S. Combat Veterans. Am J Psychiatry. 2015;172(12):1233–41.

    PubMed  Article  Google Scholar 

  121. 121.

    Naim R, Abend R, Wald I, Eldar S, Levi O, Fruchter E, et al. Threat-related attention bias variability and posttraumatic stress. Am J Psychiatry. 2015;172(12):1242–50.

    PubMed  Article  Google Scholar 

  122. 122.

    Paulus MP, Aupperle R. Finding the balance between safety and threat may hold the key to success when treating PTSD. Am J Psychiatry. 2015;172(12):1173–5.

    PubMed  Article  Google Scholar 

  123. 123.

    Jha AP, Stanley EA, Kiyonaga A, Wong L, Gelfand L. Examining the protective effects of mindfulness training on working memory capacity and affective experience. Emotion. 2010;10(1):54–64.

    PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Muller-Engelmann M, et al. Mindfulness-based stress reduction (MBSR) as a standalone intervention for posttraumatic stress disorder after mixed traumatic events: a mixed-methods feasibility study. Front Psychol. 2017;8:1407.

    PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Hopwood TL, Schutte NS. A meta-analytic investigation of the impact of mindfulness-based interventions on post traumatic stress. Clin Psychol Rev. 2017;57:12–20.

    PubMed  Article  Google Scholar 

  126. 126.

    Hilton L, Maher AR, Colaiaco B, Apaydin E, Sorbero ME, Booth M, et al. Meditation for posttraumatic stress: systematic review and meta-analysis. Psychol Trauma. 2017;9(4):453–60.

    PubMed  Article  Google Scholar 

  127. 127.

    Denny BT, Ochsner KN. Behavioral effects of longitudinal training in cognitive reappraisal. Emotion (Washington, D.C.). 2014;14(2):425–33.

    Article  Google Scholar 

  128. 128.

    Cutuli D. Cognitive reappraisal and expressive suppression strategies role in the emotion regulation: an overview on their modulatory effects and neural correlates. Front Syst Neurosci. 2014;8:175.

    PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Moyal N, Henik A, Anholt GE. Cognitive strategies to regulate emotions—current evidence and future directions. Front Psychol. 2013;4:1019.

    Google Scholar 

  130. 130.

    •• Bagot RC, et al. Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles. Biological Psychiatry. 2017;81(4):285–95. This paper investigates the ability of ketamine (and imipramine) to alter transcriptional mechanisms of vulnerability and resilience to stress, which has significant impliations for these drugs as novel treatment targets in stress-related psychopathology. Specifically, they found both drugs were able to reverse transcriptionally-based vulnerabilities and enhance resilience.

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Price RB. From mice to men: can ketamine enhance resilience to stress? Biol Psychiatry. 2016;79(9):e57–9.

    PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Amat J, Dolzani SD, Tilden S, Christianson JP, Kubala KH, Bartholomay K, et al. Previous ketamine produces an enduring blockade of neurochemical and behavioral effects of uncontrollable stress. J Neurosci. 2016;36(1):153–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    •• Brachman RA, et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry. 2016;79(9):776–86. This paper provides pre-clinical evidence that ketamine can induce resilience to stress and may be a useful preventative measure protecting against stress-related psychopathology.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Hillard CJ. Stress regulates endocannabinoid-CB1 receptor signaling. Semin Immunol. 2014;26(5):380–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    • Lutz B, et al. The endocannabinoid system in guarding against fear, anxiety and stress. Nature Reviews Neuroscience. 2015;16:705. This review provides a nice summary of the role of endocannabinoid system signaling and modulation in stress response, including fear reactions and stress coping.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Milaniak I, Cecil CAM, Barker ED, Relton CL, Gaunt TR, McArdle W, et al. Variation in DNA methylation of the oxytocin receptor gene predicts children’s resilience to prenatal stress. Dev Psychopathol. 2017;29(5):1663–74.

    PubMed  Article  Google Scholar 

  137. 137.

    Sippel LM, Han S, Watkins LE, Harpaz-Rotem I, Southwick SM, Krystal JH, et al. Oxytocin receptor gene polymorphisms, attachment, and PTSD: results from the National Health and Resilience in Veterans Study. J Psychiatr Res. 2017;94:139–47.

    PubMed  Article  Google Scholar 

  138. 138.

    Tollenaar MS, Molendijk ML, Penninx BWJH, Milaneschi Y, Antypa N. The association of childhood maltreatment with depression and anxiety is not moderated by the oxytocin receptor gene. Eur Arch Psychiatry Clin Neurosci. 2017;267:517–26.

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Cornum R, Matthews MD, Seligman ME. Comprehensive soldier fitness: building resilience in a challenging institutional context. Am Psychol. 2011;66(1):4–9.

    PubMed  Article  Google Scholar 

  140. 140.

    Fravell M, Nasser K, Cornum R. The soldier fitness tracker: global delivery of comprehensive soldier fitness. Am Psychol. 2011;66(1):73–6.

    PubMed  Article  Google Scholar 

  141. 141.

    Rasing SPA, Creemers DHM, Janssens JMAM, Scholte RHJ. Depression and anxiety prevention based on cognitive behavioral therapy for at-risk adolescents: a meta-analytic review. Front Psychol. 2017;8:1066.

    PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Andersen, J., et al., Highly realistic scenario based training simulates the psychophysiology of real world use of force encounters: implications for improved police officer performance. Vol. 5. 2016. 1–13.

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Acknowledgements

The authors acknowledge the support from the US Department of Veterans Affairs through its support for the National Center for PTSD. We also recognize the National Center for Advancing Translational Science for its support of the Yale Center for Clinical Investigation (UL1RR024139). In addition, the authors acknowledge the support from the US Department of Veterans Affairs VISN 1 Research Office (Career Development Award, LAA), Brain and Behavior Research Foundation (LAA, CGA, BK), and the Robert E. Leet and Clara Guthrie Patterson Mentored Clinical Research Trust (LAA).

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Correspondence to Lynnette A. Averill.

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Lynnette A. Averill, Christopher L. Averill, Benjamin Kelmendi, and Steven M. Southwick declare no conflict of interest.

Chadi G. Abdallah has received personal fees from Janssen and Genentech, both outside the submitted work.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

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Averill, L.A., Averill, C.L., Kelmendi, B. et al. Stress Response Modulation Underlying the Psychobiology of Resilience. Curr Psychiatry Rep 20, 27 (2018). https://doi.org/10.1007/s11920-018-0887-x

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Keywords

  • Resilience
  • Stress
  • Trauma
  • Neurobiology
  • Intervention