Skip to main content
Book cover

Behavioral Neurobiology of PTSD pp 69–91Cite as

Integrating NIMH Research Domain Criteria (RDoC) into PTSD Research

Part of the Current Topics in Behavioral Neurosciences book series (CTBN,volume 38)

Abstract

Three and a half decades of research on posttraumatic stress disorder (PTSD) has produced substantial knowledge on the pathobiology of this frequent and debilitating disease. However, despite all research efforts, so far no drug that has specifically targeted PTSD core symptoms progressed to clinical use. Instead, although not overly efficient, serotonin re-uptake inhibitors continue to be considered the gold standard of PTSD pharmacotherapy. The psychotherapeutic treatment and symptom-oriented drug therapy options available for PTSD treatment today show some efficacy, although not in all PTSD patients, in particular not in a substantial percent of those suffering from the detrimental sequelae of repeated childhood trauma or in veterans with combat related PTSD. PTSD has this in common with other psychiatric disorders – in particular effective treatment for incapacitating conditions such as resistant major depression, chronic schizophrenia, and frequently relapsing obsessive-compulsive disorder as well as dementia has not yet been developed through modern neuropsychiatric research.

In response to this conundrum, the National Institute of Mental Health launched the Research Domain Criteria (RDoC) framework which aims to leave diagnosis-oriented psychiatric research behind and to move on to the use of research domains overarching the traditional diagnosis systems. To the best of our knowledge, the paper at hand is the first that has systematically assessed the utility of the RDoC system for PTSD research. Here, we review core findings in neurobiological PTSD research and match them to the RDoC research domains and units of analysis. Our synthesis reveals that several core findings in PTSD such as amygdala overactivity have been linked to all RDoC domains without further specification of their distinct role in the pathophysiological pathways associated with these domains. This circumstance indicates that the elucidation of the cellular and molecular processes ultimately decisive for regulation of psychic processes and for the expression of psychopathological symptoms is still grossly incomplete. All in all, we find the RDoC research domains to be useful but not sufficient for PTSD research. Hence, we suggest adding two novel domains, namely stress and emotional regulation and maintenance of consciousness. As both of these domains play a role in various if not in all psychiatric diseases, we judge them to be useful not only for PTSD research but also for psychiatric research in general.

Keywords

  • Emotion regulation
  • Neurobiology
  • PTSD
  • RDOC
  • Research
  • Stress

This is a preview of subscription content, access via your institution.

References

  1. Forresia B, Caffoa E, Battagliab M (2015) Gene environment interplays: why PTSD makes a good case for gene–environment interaction studies and how adding a developmental approach can help. In: Martin CR, Preedy VR, Patel VB (eds) Comprehensive guide to post-traumatic stress disorder. Springer, pp 1–3. doi:10.1007/978-3-319-08613-2_84-1. ISBN 978-3-319-08613-2

  2. McFall M, Saxon AJ, Thompson CE et al (2005) Improving the rates of quitting smoking for veterans with posttraumatic stress disorder. Am J Psychiatry 162:1311–1319. doi:10.1176/appi.ajp.162.7.1311

    CrossRef  PubMed  Google Scholar 

  3. Dorrington S, Zavos H, Ball H et al (2014) Trauma, post-traumatic stress disorder and psychiatric disorders in a middle-income setting: prevalence and comorbidity. Br J Psychiatry. bjp. bp. 113.141796

    Google Scholar 

  4. Ringdal GI, Ringdal K, Simkus A (2007) War-related distress among Kosovar Albanians. J Loss Trauma 13:59–71

    CrossRef  Google Scholar 

  5. Kessler RC (1995) Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52:1048. doi:10.1001/archpsyc.1995.03950240066012

    CrossRef  PubMed  CAS  Google Scholar 

  6. Hauffa R, Rief W, Brähler E et al (2011) Lifetime traumatic experiences and posttraumatic stress disorder in the German population: results of a representative population survey. J Nerv Ment Dis 199:934–939. doi:10.1097/NMD.0b013e3182392c0d

    CrossRef  PubMed  Google Scholar 

  7. de Vries G-J, Olff M (2009) The lifetime prevalence of traumatic events and posttraumatic stress disorder in the Netherlands. J Trauma Stress 22:259–267

    CrossRef  PubMed  Google Scholar 

  8. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5, 5th edn. American Psychiatric Association, Washington, DC

    CrossRef  Google Scholar 

  9. Pompili M, Sher L, Serafini G et al (2013) Posttraumatic stress disorder and suicide risk among veterans: a literature review. J Nerv Ment Dis 201:802–812. doi:10.1097/NMD.0b013e3182a21458

    CrossRef  PubMed  Google Scholar 

  10. Rodgers CS, Allard CB, Wansley P (2010) Post-traumatic stress disorder and quality of life in women. In: Handbook of disease burdens and quality of life measures. Springer, pp 3439–3456

    Google Scholar 

  11. Scott WJ (1990) PTSD in DSM-III: a case in the politics of diagnosis and disease. Soc Probl 37:294–310. doi:10.2307/800744

    CrossRef  Google Scholar 

  12. Berger W, Mendlowicz MV, Marques-Portella C et al (2009) Pharmacologic alternatives to antidepressants in posttraumatic stress disorder: a systematic review. Prog Neuro-Psychopharmacol Biol Psychiatry 33:169–180. doi:10.1016/j.pnpbp.2008.12.004

    CrossRef  CAS  Google Scholar 

  13. Yehuda R, Bierer LM, Sarapas C et al (2009) Cortisol metabolic predictors of response to psychotherapy for symptoms of PTSD in survivors of the World Trade Center attacks on September 11, 2001. Psychoneuroendocrinology 34:1304–1313. doi:10.1016/j.psyneuen.2009.03.018

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  14. Cusack K, Jonas DE, Forneris CA et al (2016) Psychological treatments for adults with posttraumatic stress disorder: a systematic review and meta-analysis. Clin Psychol Rev 43:128–141. doi:10.1016/j.cpr.2015.10.003

    CrossRef  PubMed  Google Scholar 

  15. Almli LM, Stevens JS, Smith AK et al (2015) A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces. Am J Med Genet B Neuropsychiatr Genet 168:327–336. doi:10.1002/ajmg.b.32315

    CrossRef  CAS  Google Scholar 

  16. Klengel T, Mehta D, Anacker C et al (2013) Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 16:33–41. doi:10.1038/nn.3275

    CrossRef  PubMed  CAS  Google Scholar 

  17. Bam M, Yang X, Zumbrun EE et al (2016) Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation. Sci Rep 6:31209. doi:10.1038/srep31209

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  18. Schmidt U, Herrmann L, Hagl K et al (2013) Therapeutic action of fluoxetine is associated with a reduction in prefrontal cortical miR-1971 expression levels in a mouse model of posttraumatic stress disorder. Front Psychiatry 4:66. doi:10.3389/fpsyt.2013.00066

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  19. Schmidt U, Keck ME, Buell DR (2015) miRNAs and other non-coding RNAs in posttraumatic stress disorder: a systematic review of clinical and animal studies. J Psychiatr Res 65:1–8. doi:10.1016/j.jpsychires.2015.03.014

    CrossRef  PubMed  Google Scholar 

  20. Freedman R, Leonard S, Olincy A et al (2001) Evidence for the multigenic inheritance of schizophrenia. Am J Med Genet 105:794–800

    CrossRef  CAS  PubMed  Google Scholar 

  21. Martins-de-Souza D (2013) Biomarkers for psychiatric disorders: where are we standing. Markers 35:1–2

    CrossRef  Google Scholar 

  22. Pinsonneault J, Sadée W (2003) Pharmacogenomics of multigenic diseases: sex-specific differences in disease and treatment outcome. AAPS Pharm Sci 5:49–61

    CrossRef  Google Scholar 

  23. Pitman RK, Rasmusson AM, Koenen KC et al (2012) Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 13:769–787. doi:10.1038/nrn3339

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  24. Schmidt U, Kaltwasser SF, Wotjak CT (2013) Biomarkers in posttraumatic stress disorder: overview and implications for future research. Dis Markers 35:43–54. doi:10.1155/2013/835876

    CrossRef  PubMed  PubMed Central  Google Scholar 

  25. Vermetten E, Bremner JD (2002) Circuits and systems in stress. II. Applications to neurobiology and treatment in posttraumatic stress disorder. Depress Anxiety 16(1):14–38

    CrossRef  PubMed  Google Scholar 

  26. Vermetten E, Bremner JD (2002) Circuits and systems in stress. I. Preclinical studies. Depress Anxiety 15(3):126–147

    CrossRef  PubMed  Google Scholar 

  27. Hayes JP, Hayes SM, Mikedis AM (2012) Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol Mood Anxiety Disord 2:9. doi:10.1186/2045-5380-2-9

    CrossRef  PubMed  PubMed Central  Google Scholar 

  28. Bremner JD, Randall P, Vermetten E et al (1997) Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse – a preliminary report. Biol Psychiatry 41:23–32. doi:10.1016/S0006-3223(96)00162-X

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  29. Vermetten E, Vythilingam M, Southwick SM et al (2003) Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry 54:693–702. doi:10.1016/S0006-3223(03)00634-6

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  30. Acheson DT, Gresack JE, Risbrough VB (2012) Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology 62(2):674–685

    CrossRef  CAS  PubMed  Google Scholar 

  31. Crochemore C, Lu J, Wu Y et al (2005) Direct targeting of hippocampal neurons for apoptosis by glucocorticoids is reversible by mineralocorticoid receptor activation. Mol Psychiatry 10:790–798. doi:10.1038/sj.mp.4001679

    CrossRef  PubMed  CAS  Google Scholar 

  32. Klaassens ER, Giltay EJ, Cuijpers P et al (2012) Adulthood trauma and HPA-axis functioning in healthy subjects and PTSD patients: a meta-analysis. Psychoneuroendocrinology 37:317–331. doi:10.1016/j.psyneuen.2011.07.003

    CrossRef  PubMed  CAS  Google Scholar 

  33. Naughton M, Dinan TG, Scott LV (2014) Corticotropin-releasing hormone and the hypothalamic-pituitary-adrenal axis in psychiatric disease. Handb Clin Neurol 124:69–91. doi:10.1016/B978-0-444-59602-4.00005-8

    CrossRef  PubMed  Google Scholar 

  34. Zaba M, Kirmeier T, Ionescu IA et al (2015) Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients. Psychoneuroendocrinology 55:102–115. doi:10.1016/j.psyneuen.2015.02.005

    CrossRef  PubMed  CAS  Google Scholar 

  35. Fries GR, Gassen NC, Schmidt U, Rein T (2015) The FKBP51-glucocorticoid receptor balance in stress-related mental disorders. Curr Mol Pharmacol 9:126–140

    CrossRef  CAS  PubMed  Google Scholar 

  36. Binder EB (2009) The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 34:S186–S195

    CrossRef  CAS  PubMed  Google Scholar 

  37. van Zuiden M, Kavelaars A, Geuze E et al (2013) Predicting PTSD: pre-existing vulnerabilities in glucocorticoid-signaling and implications for preventive interventions. Brain Behav Immun 30:12–21

    CrossRef  CAS  PubMed  Google Scholar 

  38. Binder EB, Bradley RG, Liu W et al (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299:1291–1305

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bachmann AW, Sedgley TL, Jackson RV et al (2005) Glucocorticoid receptor polymorphisms and post-traumatic stress disorder. Psychoneuroendocrinology 30:297–306. doi:10.1016/j.psyneuen.2004.08.006

    CrossRef  PubMed  CAS  Google Scholar 

  40. Touma C, Gassen NC, Herrmann L et al (2011) FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior. Biol Psychiatry 70:928–936. doi:10.1016/j.biopsych.2011.07.023

    CrossRef  PubMed  CAS  Google Scholar 

  41. Schmidt U, Buell DR, Ionescu IA et al (2015) A role for synapsin in FKBP51 modulation of stress responsiveness: convergent evidence from animal and human studies. Psychoneuroendocrinology 52:43–58. doi:10.1016/j.psyneuen.2014.11.005

    CrossRef  PubMed  CAS  Google Scholar 

  42. Golub Y, Kaltwasser SF, Mauch CP et al (2011) Reduced hippocampus volume in the mouse model of posttraumatic stress disorder. J Psychiatr Res 45:650–659. doi:10.1016/j.jpsychires.2010.10.014

    CrossRef  PubMed  Google Scholar 

  43. Morris MC, Rao U (2013) Psychobiology of PTSD in the acute aftermath of trauma: integrating research on coping, HPA function and sympathetic nervous system activity. Asian J Psychiatry 6:3–21. doi:10.1016/j.ajp.2012.07.012

    CrossRef  Google Scholar 

  44. Blanchard EB, Kolb LC, Prins A et al (1991) Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with posttraumatic stress disorder. J Nerv Ment Dis 179:371–373

    CrossRef  CAS  PubMed  Google Scholar 

  45. Geracioti TD, Baker DG, Ekhator NN et al (2001) CSF norepinephrine concentrations in posttraumatic stress disorder. Am J Psychiatry 158:1227–1230. doi:10.1176/appi.ajp.158.8.1227

    CrossRef  PubMed  Google Scholar 

  46. Yehuda R, Southwick S, Giller EL et al (1992) Urinary catecholamine excretion and severity of PTSD symptoms in Vietnam combat veterans. J Nerv Ment Dis 180:321–325

    CrossRef  CAS  PubMed  Google Scholar 

  47. Giustino TF, Fitzgerald PJ, Maren S (2016) Revisiting propranolol and PTSD: memory erasure or extinction enhancement? Neurobiol Learn Mem 130:26–33

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hendrickson RC, Raskind MA (2016) Noradrenergic dysregulation in the pathophysiology of PTSD. Exp Neurol. doi: 10.1016/j.expneurol.2016.05.014

  49. Bandelow B, Baldwin D, Abelli M et al (2016) Biological markers for anxiety disorders, OCD and PTSD: a consensus statement. Part II. Neurochemistry, neurophysiology and neurocognition. World J Biol Psychiatry 1–53. doi: 10.1080/15622975.2016.1190867

  50. Koch SBJ, van Zuiden M, Nawijn L et al (2016) Intranasal oxytocin normalizes amygdala functional connectivity in posttraumatic stress disorder. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 41:2041–2051. doi:10.1038/npp.2016.1

    CrossRef  CAS  Google Scholar 

  51. Schmeltzer SN, Herman JP, Sah R (2016) Neuropeptide Y (NPY) and posttraumatic stress disorder (PTSD): a translational update. Exp Neurol. doi: 10.1016/j.expneurol.2016.06.020

  52. Block SR, Liberzon I (2016) Attentional processes in posttraumatic stress disorder and the associated changes in neural functioning. Exp Neurol doi: 10.1016/j.expneurol.2016.05.009

  53. Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuro-Psychopharmacol Biol Psychiatry 29(8):1201–1213

    CrossRef  CAS  Google Scholar 

  54. Litz BT, Orsillo SM, Kaloupek D, Weathers F (2000) Emotional processing in posttraumatic stress disorder. J Abnorm Psychol 109:26

    CrossRef  CAS  PubMed  Google Scholar 

  55. Phan KL, Britton JC, Taylor SF et al (2006) Corticolimbic blood flow during Nontraumatic emotional processing in posttraumatic stress disorder. Arch Gen Psychiatry 63:184. doi:10.1001/archpsyc.63.2.184

    CrossRef  PubMed  Google Scholar 

  56. Schuitevoerder S, Rosen JW, Twamley EW et al (2013) A meta-analysis of cognitive functioning in older adults with PTSD. J Anxiety Disord 27:550–558. doi:10.1016/j.janxdis.2013.01.001

    CrossRef  PubMed  Google Scholar 

  57. Vasterling JJ, Duke LM, Brailey K et al (2002) Attention, learning, and memory performances and intellectual resources in Vietnam veterans: PTSD and no disorder comparisons. Neuropsychology 16:5–14. doi:10.1037//0894-4105.16.1.5

    CrossRef  PubMed  Google Scholar 

  58. Fleeson W, Furr RM, Arnold EM (2010) An agenda for symptom-based research. Behav Brain Sci 33:157. doi:10.1017/S0140525X10000750

    CrossRef  PubMed  Google Scholar 

  59. Schmidt U (2015) A plea for symptom-based research in psychiatry. Eur J Psychotraumatol. doi: 10.3402/ejpt.v6.27660

  60. Sharpe M, Walker J (2009) Symptoms: a new approach. Psychiatry 8:146–148. doi:10.1016/j.mppsy.2009.03.016

    CrossRef  Google Scholar 

  61. Insel T, Cuthbert B, Garvey M et al (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167:748–751. doi:10.1176/appi.ajp.2010.09091379

    CrossRef  PubMed  Google Scholar 

  62. World Health Organization (1992) The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. World Health Organization, Geneva

    Google Scholar 

  63. Wildes JE, Marcus MD (2015) Application of the research domain criteria (RDoC) framework to eating disorders: emerging concepts and research. Curr Psychiatry Rep. doi: 10.1007/s11920-015-0572-2

  64. Cuthbert BN (2014) The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology: forum – the research domain criteria project. World Psychiatry 13:28–35. doi:10.1002/wps.20087

    CrossRef  PubMed  PubMed Central  Google Scholar 

  65. Unoka Z, Richman MJ (2016) Neuropsychological deficits in BPD patients and the moderator effects of co-occurring mental disorders: a meta-analysis. Clin Psychol Rev 44:1–12

    CrossRef  PubMed  Google Scholar 

  66. Morris SE, Cuthbert BN (2012) Research domain criteria: cognitive systems, neural circuits, and dimensions of behavior. Dialogues Clin Neurosci 14:29–37

    PubMed  PubMed Central  Google Scholar 

  67. Woody ML, Gibb BE (2015) Integrating NIMH research domain criteria (RDoC) into depression research. Curr Opin Psychol 4:6–12. doi:10.1016/j.copsyc.2015.01.004

    CrossRef  PubMed  PubMed Central  Google Scholar 

  68. Hamm AO, Richter J, Pané-Farré C et al (2016) Panic disorder with agoraphobia from a behavioral neuroscience perspective: applying the research principles formulated by the research domain criteria (RDoC) initiative: panic disorder with agoraphobia. Psychophysiology 53:312–322. doi:10.1111/psyp.12553

    CrossRef  PubMed  Google Scholar 

  69. Morris SE, Vaidyanathan U, Cuthbert BN (2016) Changing the diagnostic concept of schizophrenia: the NIMH research domain criteria initiative. In: Li M, Spaulding WD (eds) The neuropsychopathology of schizophrenia. Springer International Publishing, Cham, pp 225–252

    Google Scholar 

  70. Badcock JC, Hugdahl K (2014) A synthesis of evidence on inhibitory control and auditory hallucinations based on the research domain criteria (RDoC) framework. Front Hum Neurosci 8:180

    CrossRef  PubMed  PubMed Central  Google Scholar 

  71. Tanofsky-Kraff M, Engel S, Yanovski JA et al (2013) Pediatric disinhibited eating: toward a research domain criteria framework. Int J Eat Disord 46:451–455. doi:10.1002/eat.22101

    CrossRef  PubMed  Google Scholar 

  72. Gur RC, Gur RE (2016) Social cognition as an RDoC domain. Am J Med Genet B Neuropsychiatr Genet 171:132–141. doi:10.1002/ajmg.b.32394

    CrossRef  Google Scholar 

  73. Bauer MR, Ruef AM, Pineles SL et al (2013) Psychophysiological assessment of PTSD: a potential research domain criteria construct. Psychol Assess 25:1037–1043. doi:10.1037/a0033432

    CrossRef  PubMed  Google Scholar 

  74. Montalvo-Ortiz JL, Gelernter J, Hudziak J, Kaufman J (2016) RDoC and translational perspectives on the genetics of trauma-related psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 171:81–91. doi:10.1002/ajmg.b.32395

    CrossRef  CAS  Google Scholar 

  75. Young G (2014) PTSD, endophenotypes, the RDoC, and the DSM-5. Psychol Inj Law 7:75–91. doi:10.1007/s12207-014-9187-x

    CrossRef  Google Scholar 

  76. Morey RA, Dunsmoor JE, Haswell CC, Brown VM, Vora A, Weiner J, Stjepanovic D, Wagner HR, Brancu M, Marx CE, Naylor JC (2015) Fear learning circuitry is biased toward generalization of fear associations in posttraumatic stress disorder. Transl Psychiatry 5(12):e700

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35:24–35. doi:10.1016/j.tins.2011.06.007

    CrossRef  PubMed  CAS  Google Scholar 

  78. Acheson DT, Geyer MA, Baker DG, Nievergelt CM, Yurgil K, Risbrough VB, Team MI (2015) Conditioned fear and extinction learning performance and its association with psychiatric symptoms in active duty marines. Psychoneuroendocrinology 51:495–505

    CrossRef  CAS  PubMed  Google Scholar 

  79. Graham BM, Milad MR (2011) The study of fear extinction: implications for anxiety disorders. Am J Psychiatry 168:1255–1265. doi:10.1176/appi.ajp.2011.11040557

    CrossRef  PubMed  PubMed Central  Google Scholar 

  80. LeDoux J (2007) The amygdala. Curr Biol CB 17:R868–R874. doi:10.1016/j.cub.2007.08.005

    CrossRef  PubMed  CAS  Google Scholar 

  81. Quirk GJ, Mueller D (2008) Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 33:56–72. doi:10.1038/sj.npp.1301555

    CrossRef  PubMed  Google Scholar 

  82. Liberzon I, Abelson JL (2016) Context processing and the neurobiology of post-traumatic stress disorder. Neuron 92(1):14–30

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zuj DV, Palmer MA, Lommen MJJ, Felmingham KL (2016) The centrality of fear extinction in linking risk factors to PTSD: a narrative review. Neurosci Biobehav Rev 69:15–35. doi:10.1016/j.neubiorev.2016.07.014

    CrossRef  PubMed  Google Scholar 

  84. Middlemas DS, Bylund DB (2015) Brain-derived neurotrophic factor. In: Stolerman IP, Price LH (eds) Encyclopedia of psychopharmacology. Springer, Heidelberg, pp 310–313

    Google Scholar 

  85. Felmingham KL, Dobson-Stone C, Schofield PR et al (2013) The brain-derived neurotrophic factor Val66Met polymorphism predicts response to exposure therapy in posttraumatic stress disorder. Biol Psychiatry 73:1059–1063. doi:10.1016/j.biopsych.2012.10.033

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  86. Byrne SP, Rapee RM, Richardson R et al (2015) D-cycloserine enhances generalization of fear extinction in children: research article: DCS enhances fear extinction in children. Depress Anxiety 32:408–414. doi:10.1002/da.22356

    CrossRef  PubMed  CAS  Google Scholar 

  87. Sartori SB, Maurer V, Murphy C et al (2016) Combined neuropeptide S and D-cycloserine augmentation prevents the return of fear in extinction-impaired rodents: advantage of dual versus single drug approaches. Int J Neuropsychopharmacol Off Sci J Coll Int Neuropsychopharmacol CINP. doi: 10.1093/ijnp/pyv128

  88. de Kleine RA, Smits JAJ, Hendriks G-J, et al (2015) Extinction learning as a moderator of d-cycloserine efficacy for enhancing exposure therapy in posttraumatic stress disorder. J Anxiety Disord 34:63–67. doi:10.1016/j.janxdis.2015.06.005

    CrossRef  PubMed  Google Scholar 

  89. Difede J, Cukor J, Wyka K et al (2014) D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 39:1052–1058. doi:10.1038/npp.2013.317

    CrossRef  CAS  Google Scholar 

  90. Scheeringa MS, Weems CF (2014) Randomized placebo-controlled D-cycloserine with cognitive behavior therapy for pediatric posttraumatic stress. J Child Adolesc Psychopharmacol 24:69–77. doi:10.1089/cap.2013.0106

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  91. Singewald N, Schmuckermair C, Whittle N et al (2015) Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol Ther 149:150–190. doi:10.1016/j.pharmthera.2014.12.004

    CrossRef  PubMed  CAS  Google Scholar 

  92. Acheson D, Feifel D, de Wilde S, Mckinney R, Lohr J, Risbrough V (2013) The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. Psychopharmacology 229(1):199–208

    CrossRef  CAS  PubMed  PubMed Central  Google Scholar 

  93. Acheson DT, Risbrough VB (2015) Oxytocin enhancement of fear extinction: a new target for facilitating exposure-based treatments? Biol Psychiatry 78(3):154

    CrossRef  CAS  PubMed  Google Scholar 

  94. Risbrough VB, Glenn DE, Baker DG (2016) On the road to translation for PTSD treatment: theoretical and practical considerations of the use of human models of conditioned fear for drug development. Transl Neuropsychopharmacol 28:173–196

    CAS  Google Scholar 

  95. Vervliet B, Craske MG, Hermans D (2013) Fear extinction and relapse: state of the art. Annu Rev Clin Psychol 9:215–248

    CrossRef  PubMed  Google Scholar 

  96. Nawijn L, van Zuiden M, Frijling JL et al (2015) Reward functioning in PTSD: a systematic review exploring the mechanisms underlying anhedonia. Neurosci Biobehav Rev 51:189–204. doi:10.1016/j.neubiorev.2015.01.019

    CrossRef  PubMed  Google Scholar 

  97. Kashdan TB, Elhai JD, Frueh BC (2006) Anhedonia and emotional numbing in combat veterans with PTSD. Behav Res Ther 44:457–467. doi:10.1016/j.brat.2005.03.001

    CrossRef  PubMed  Google Scholar 

  98. Gable SL, Reis HT, Elliot AJ (2003) Evidence for bivariate systems: an empirical test of appetition and aversion across domains. J Res Personal 37:349–372. doi:10.1016/S0092-6566(02)00580-9

    CrossRef  Google Scholar 

  99. Sharf R, Sarhan M, DiLeone RJ (2010) Role of orexin/hypocretin in dependence and addiction. Brain Res 1314:130–138. doi:10.1016/j.brainres.2009.08.028

    CrossRef  PubMed  CAS  Google Scholar 

  100. Hoexter MQ, Fadel G, Felício AC et al (2012) Higher striatal dopamine transporter density in PTSD: an in vivo SPECT study with [99mTc]TRODAT-1. Psychopharmacology 224:337–345. doi:10.1007/s00213-012-2755-4

    CrossRef  PubMed  CAS  Google Scholar 

  101. Blum K, Giordano J, Oscar-Berman M et al (2012) Diagnosis and healing in veterans suspected of suffering from post-traumatic stress disorder (PTSD) using reward Gene testing and reward circuitry natural dopaminergic activation. J Genet Syndr Gene Ther 3:1000116. doi:10.4172/2157-7412.1000116

    CrossRef  PubMed  PubMed Central  Google Scholar 

  102. Heller AS, Johnstone T, Light SN et al (2013) Relationships between changes in sustained Fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment. Am J Psychiatry 170:197–206. doi:10.1176/appi.ajp.2012.12010014

    CrossRef  PubMed  PubMed Central  Google Scholar 

  103. Nawijn L, van Zuiden M, Koch SBJ et al (2016) Intranasal oxytocin enhances neural processing of monetary reward and loss in post-traumatic stress disorder and traumatized controls. Psychoneuroendocrinology 66:228–237. doi:10.1016/j.psyneuen.2016.01.020

    CrossRef  PubMed  CAS  Google Scholar 

  104. Koch SBJ, van Zuiden M, Nawijn L et al (2014) Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes. Psychoneuroendocrinology 40:242–256. doi:10.1016/j.psyneuen.2013.11.018

    CrossRef  PubMed  CAS  Google Scholar 

  105. Hayes JP, VanElzakker MB, Shin LM (2012) Emotion and cognition interactions in PTSD: a review of neurocognitive and neuroimaging studies. Front Integr Neurosci. doi: 10.3389/fnint.2012.00089

  106. Campanella C, Bremner JD (2016) Neuroimaging of PTSD. In: Bremner JD (ed) Posttraumatic stress disorder: from neurobiology to treatment. Wiley, Hoboken, p. 291

    CrossRef  Google Scholar 

  107. Schweizer S, Dalgleish T (2016) The impact of affective contexts on working memory capacity in healthy populations and in individuals with PTSD. Emotion 16:16–23. doi:10.1037/emo0000072

    CrossRef  PubMed  Google Scholar 

  108. Golier JA, Yehuda R, Lupien SJ et al (2002) Memory performance in holocaust survivors with posttraumatic stress disorder. Am J Psychiatry 159:1682–1688. doi:10.1176/appi.ajp.159.10.1682

    CrossRef  PubMed  Google Scholar 

  109. Paunovi N, Lundh LG, Ost LG (2002) Attentional and memory bias for emotional information in crime victims with acute posttraumatic stress disorder (PTSD). J Anxiety Disord 16:675–692

    CrossRef  CAS  PubMed  Google Scholar 

  110. Wagner AD, Stebbins GT, Masciari F et al (1998) Neuropsychological dissociation between recognition familiarity and perceptual priming in visual long-term memory. Cortex 34:493–511

    CrossRef  CAS  PubMed  Google Scholar 

  111. Ehlers A, Michael T, Chen YP, Payne E, Shan S (2006) Enhanced perceptual priming for neutral stimuli in a traumatic context: a pathway to intrusive memories? Memory 14(3):316–328

    CrossRef  PubMed  Google Scholar 

  112. Vukojevic V, Kolassa I-T, Fastenrath M et al (2014) Epigenetic modification of the glucocorticoid receptor Gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors. J Neurosci 34:10274–10284. doi:10.1523/JNEUROSCI.1526-14.2014

    CrossRef  PubMed  CAS  Google Scholar 

  113. Kwapis JL, Wood MA (2014) Epigenetic mechanisms in fear conditioning: implications for treating post-traumatic stress disorder. Trends Neurosci 37:706–720. doi:10.1016/j.tins.2014.08.005

    CrossRef  PubMed  PubMed Central  CAS  Google Scholar 

  114. Minassian A, Maihofer AX, Baker DG, Nievergelt CM, Geyer MA, Risbrough VB (2015) Association of predeployment heart rate variability with risk of postdeployment posttraumatic stress disorder in active-duty marines. JAMA Psychiat 72(10):979–986

    CrossRef  Google Scholar 

  115. Zoladz PR, Diamond DM (2013) Current status on behavioral and biological markers of PTSD: a search for clarity in a conflicting literature. Neurosci Biobehav Rev 37:860–895. doi:10.1016/j.neubiorev.2013.03.024

    CrossRef  PubMed  Google Scholar 

  116. de Quervain DJ-F, Kolassa I-T, Ertl V et al (2007) A deletion variant of the alpha2b-adrenoceptor is related to emotional memory in Europeans and Africans. Nat Neurosci 10:1137–1139. doi:10.1038/nn1945

    CrossRef  PubMed  CAS  Google Scholar 

  117. Liberzon I, King AP, Ressler KJ et al (2014) Interaction of the ADRB2 Gene polymorphism with childhood trauma in predicting adult symptoms of posttraumatic stress disorder. JAMA Psychiat 71:1174. doi:10.1001/jamapsychiatry.2014.999

    CrossRef  CAS  Google Scholar 

  118. De Berardis D, Marini S, Serroni N et al (2015) Targeting the noradrenergic system in posttraumatic stress disorder: a systematic review and meta-analysis of prazosin trials. Curr Drug Targets 16:1094–1106

    CrossRef  CAS  PubMed  Google Scholar 

  119. Bangasser DA, Wiersielis KR, Khantsis S (2016) Sex differences in the locus coeruleus-norepinephrine system and its regulation by stress. Brain Res 1641:177–188. doi:10.1016/j.brainres.2015.11.021

    CrossRef  PubMed  CAS  Google Scholar 

  120. Sara SJ, Bouret S (2012) Orienting and reorienting: the locus coeruleus mediates cognition through arousal. Neuron 76:130–141. doi:10.1016/j.neuron.2012.09.011

    CrossRef  PubMed  CAS  Google Scholar 

  121. Bangasser DA, Valentino RJ (2014) Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front Neuroendocrinol 35:303–319. doi:10.1016/j.yfrne.2014.03.008

    CrossRef  PubMed  PubMed Central  Google Scholar 

  122. del Río-Casanova L, González A, Páramo M et al (2016) Emotion regulation strategies in trauma-related disorders: pathways linking neurobiology and clinical manifestations. Rev Neurosci. doi: 10.1515/revneuro-2015-0045

  123. Gross JJ (1998) The emerging field of emotion regulation: an integrative review. Rev Gen Psychol 2:271–299. doi:10.1037/1089-2680.2.3.271

    CrossRef  Google Scholar 

  124. Laddis A (2015) The pathogenesis and treatment of emotion dysregulation in borderline personality disorder. ScientificWorldJournal 2015:179276. doi:10.1155/2015/179276

    CrossRef  PubMed  PubMed Central  Google Scholar 

  125. Seligowski AV, Lee DJ, Bardeen JR, Orcutt HK (2015) Emotion regulation and posttraumatic stress symptoms: a meta-analysis. Cogn Behav Ther 44:87–102. doi:10.1080/16506073.2014.980753

    CrossRef  PubMed  Google Scholar 

  126. Vermetten E, Spiegel D (2014) Trauma and dissociation: implications for borderline personality disorder. Curr Psychiatry Rep 16:434. doi:10.1007/s11920-013-0434-8

    CrossRef  PubMed  Google Scholar 

  127. Ford JD, Courtois CA (2014) Complex PTSD, affect dysregulation, and borderline personality disorder. Borderline Personal Disord Emot Dysregulation 1:9. doi:10.1186/2051-6673-1-9

    CrossRef  Google Scholar 

  128. Cohen Kadosh K, Luo Q, de Burca C et al (2016) Using real-time fMRI to influence effective connectivity in the developing emotion regulation network. NeuroImage 125:616–626. doi:10.1016/j.neuroimage.2015.09.070

    CrossRef  PubMed  PubMed Central  Google Scholar 

  129. Jerud AB, Pruitt LD, Zoellner LA, Feeny NC (2016) The effects of prolonged exposure and sertraline on emotion regulation in individuals with posttraumatic stress disorder. Behav Res Ther 77:62–67. doi:10.1016/j.brat.2015.12.002

    CrossRef  PubMed  Google Scholar 

  130. Fernandez KC, Jazaieri H, Gross JJ (2016) Emotion regulation: a transdiagnostic perspective on a new RDoC domain. Cogn Ther Res 40:426–440. doi:10.1007/s10608-016-9772-2

    CrossRef  Google Scholar 

  131. Holmes E, Brown R, Mansell W et al (2005) Are there two qualitatively distinct forms of dissociation? A review and some clinical implications. Clin Psychol Rev 25:1–23. doi:10.1016/j.cpr.2004.08.006

    CrossRef  PubMed  Google Scholar 

  132. Ginzburg K, Koopman C, Butler LD et al (2006) Evidence for a dissociative subtype of post-traumatic stress disorder among help-seeking childhood sexual abuse survivors. J Trauma Dissociation 7:7–27

    CrossRef  PubMed  Google Scholar 

  133. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders: DSM-IV-TR, 4th edn. American Psychiatric Association, Washington, DC. Text revision

    Google Scholar 

  134. Lanius RA, Brand B, Vermetten E et al (2012) The dissociative subtype of posttraumatic stress disorder: rationale, clinical and neurobiological evidence, and implications. Depress Anxiety 29:701–708. doi:10.1002/da.21889

    CrossRef  PubMed  Google Scholar 

  135. Perez DL, Dworetzky BA, Dickerson BC et al (2015) An integrative Neurocircuit perspective on psychogenic Nonepileptic seizures and functional movement disorders: neural functional unawareness. Clin EEG Neurosci 46:4–15. doi:10.1177/1550059414555905

    CrossRef  PubMed  Google Scholar 

  136. Pape W, Wöller W (2015) Low dose naltrexone in the treatment of dissociative symptoms. Nervenarzt 86:346–351. doi:10.1007/s00115-014-4015-9

    CrossRef  PubMed  CAS  Google Scholar 

  137. Goldstein LH, Mellers JDC, Landau S et al (2015) COgnitive behavioural therapy vs standardised medical care for adults with dissociative non-epileptic seizures (CODES): a multicentre randomised controlled trial protocol. BMC Neurol 15:98. doi:10.1186/s12883-015-0350-0

    CrossRef  PubMed  PubMed Central  Google Scholar 

  138. Lanius RA, Vermetten E, Loewenstein RJ et al (2010) Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatry 167:640–647. doi:10.1176/appi.ajp.2009.09081168

    CrossRef  PubMed  PubMed Central  Google Scholar 

  139. Felmingham K, Kemp AH, Williams L et al (2008) Dissociative responses to conscious and non-conscious fear impact underlying brain function in post-traumatic stress disorder. Psychol Med 38:1771–1780. doi:10.1017/S0033291708002742

    CrossRef  PubMed  CAS  Google Scholar 

  140. Vermetten E, Lanius RA (2012) Biological and clinical framework for posttraumatic stress disorder. Handb Clin Neurol 106:291–342

    CrossRef  PubMed  Google Scholar 

  141. Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, Hobfoll SE, Koenen KC, Neylan TC, Hyman SE (2015) Posttraumatic stress disorder. Nat Rev Primer. doi: 10.1038/nrdp.2015.57

Download references

Author information

Authors and Affiliations

  1. Trauma Outpatient Unit and RG Molecular Psychotraumatology, Clinical Department, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, Munich, 80804, Germany

    Ulrike Schmidt

  2. Department Psychiatry, Leiden University Medical Center Utrecht, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands

    Eric Vermetten

  3. Arq Psychotruama Research Group, Diemen, The Netherlands

    Eric Vermetten

Authors
  1. Ulrike Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric Vermetten
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric Vermetten .

Editor information

Editors and Affiliations

  1. Department Psychiatry, Leiden University Medical Center, Leiden, The Netherlands

    MD Eric Vermetten

  2. Department of Psychiatry, UC San Diego School of Medicine, San Diego, California, USA

    MD Dewleen G. Baker

  3. Department of Psychiatry, University of California San Diego, La Jolla, California, USA

    Prof. Dr. Victoria B. Risbrough

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Schmidt, U., Vermetten, E. (2017). Integrating NIMH Research Domain Criteria (RDoC) into PTSD Research. In: Vermetten, E., Baker, D., Risbrough, V. (eds) Behavioral Neurobiology of PTSD. Current Topics in Behavioral Neurosciences, vol 38. Springer, Cham. https://doi.org/10.1007/7854_2017_1

Download citation