Perhaps the most well-replicated biological finding in post-traumatic stress disorder (PTSD) is higher autonomic (heart rate and skin conductance) and facial electromyography responding during internal, mental imagery of the traumatic event and upon exposure to external, trauma-related cues.
Higher heart rate responding to sudden loud tones in PTSD probably reflects an acquired sensitization of the nervous system.
Diminished volumes of the hippocampus and anterior cingulate cortex are the most frequently replicated neuroanatomic findings in patients with PTSD. These do not appear to be fully explained by comorbid conditions such as substance abuse and depression.
Some evidence exists to support both pre-existing vulnerability and neurotoxicity as origins of brain volume reductions in PTSD. On the basis of present data, it is going too far to say that stress damages the brain, but there is no doubt that it changes it.
Functional neuroimaging studies suggest that the amygdala and dorsal anterior cingulate cortex are hyper(re)active, whereas the ventral medial prefrontal cortex is hypo(re)active, in PTSD. These abnormalities are likely to underlie the attentional bias towards threat, impaired emotion regulation and persistence of fear memories in this disorder.
The classic model of stress based on chronic hyperactivity of the hypothalamus–pituitary–adrenal cortical axis does not characterize PTSD.
A number of neurotransmitters and neuroendocrinological factors interact to influence PTSD risk, symptom profiles and severity. These factors vary across individuals owing to genetic and epigenetic factors, as well as within individuals over time in response to environmental influences, including exposure to psychological trauma.
As with other mental disorders, genetic vulnerability to PTSD is likely to involve the sum of contributions from multiple alleles, each with small effects.
The full range of molecular genetic factors, which include genotype, methylation, histone deacetylation and gene expression, probably influence or accompany the development of PTSD. However, at this time, there are no definitive findings for any one gene or gene system in the aetiology of the disorder.
Animal models have identified important molecular pathways that are likely to contribute to the pathophysiology of PTSD and may constitute promising therapeutic targets.
Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.
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American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 3rd edn (American Psychiatric Association, 1980).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatric Press, 2000).
Dobbs, D. & Wilson, W. P. Observations on persistence of war neurosis. Dis. Nerv. Syst. 21, 686–691 (1960).
Orr, S. P., Metzger, L. J., Miller, M. W. & Kaloupek, D. G. in Assessing Psychological Trauma and PTSD: A Handbook for Practicioners 2nd edn (eds Wilson, J. P. & Keane, T. M.) 289–343 (Guilford Publications, 2004).
Metzger, L. J., Gilbertson, M. W. & Orr, S. P. in Neuropsychology of PTSD: Biological, Clinical, and Cognitive Perspectives (eds Vasterling, J. & Brewin, C.) 83–102 (Guilford Publications, 2005).
Pole, N. The psychophysiology of posttraumatic stress disorder: a meta-analysis. Psychol. Bull. 133, 725–746 (2007). A comprehensive review and meta-analysis of the most important psychophysiological research in PTSD as of that date.
Keane, T. M. et al. Utility of psychophysiological measurement in the diagnosis of posttraumatic stress disorder: results from a Department of Veterans Affairs Cooperative Study. J. Consult. Clin. Psychol. 66, 914–923 (1998).
Pitman, R. K., Orr, S. P., Forgue, D. F., de Jong, J. B. & Claiborn, J. M. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch. Gen. Psychiatry 44, 970–975 (1987). This study introduced a novel symptom provocation technique for PTSD that has come into widespread psychophysiologic, neuroimaging and other research use.
Blanchard, E. B. et al. Psychophysiology of posttraumatic stress disorder related to motor vehicle accidents: replication and extension. J. Consult Clin. Psychol. 64, 742–751 (1996).
Kleim, B., Wilhelm, F. H., Glucksman, E. & Ehlers, A. Sex differences in heart rate responses to script-driven imagery soon after trauma and risk of posttraumatic stress disorder. Psychosom. Med. 72, 917–924 (2010).
Orr, S. P. et al. Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch. Gen. Psychiatry 60, 283–288 (2003).
Shalev, A. Y. et al. Auditory startle response in trauma survivors with posttraumatic stress disorder: a prospective study. Am. J. Psychiatry 157, 255–261 (2000).
Pitman, R. K. et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatry 51, 189–192 (2002).
Griffin, M. G., Resick, P. A. & Galovski, T. E. Does physiologic response to loud tones change following cognitive-behavioral treatment for posttraumatic stress disorder? J. Trauma Stress. 25, 25–32 (2012).
Peri, T., Ben-Shakhar, G., Orr, S. P. & Shalev, A. Y. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol. Psychiatry 47, 512–519 (2000).
Blechert, J., Michael, T., Vriends, N., Margraf, J. & Wilhelm, F. H. Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behav. Res. Ther. 45, 2019–2033 (2007).
Lissek, S. & Grillon, C. in The Oxford Handbook of Traumatic Stress Disorders (eds Beck, J. G. & Sloan, D. M.) 175–190 (Oxford Univ. Press, 2012).
Wessa, M. & Flor, H. Failure of extinction of fear responses in posttraumatic stress disorder: evidence from second-order conditioning. Am. J. Psychiatry 164, 1684–1692 (2007).
Milad, M. R. et al. Presence and acquired origin of reduced recall for fear extinction in PTSD: results of a twin study. J. Psychiatr. Res. 42, 515–520 (2008).
Metzger, L. J., Pitman, R. K., Miller, G. A., Paige, S. R. & Orr, S. P. Intensity dependence of auditory P2 in monozygotic twins discordant for Vietnam combat: associations with posttraumatic stress disorder. J. Rehabil. Res. Dev. 45, 437–449 (2008).
Grillon, C. & Morgan, C. A. Fear-potentiated startle conditioning to explicit and contextual cues in Gulf War veterans with posttraumatic stress disorder. J. Abnorm. Psychol. 108, 134–142 (1999).
Griffin, M. G. A prospective assessment of auditory startle alterations in rape and physical assault survivors. J. Trauma. Stress 21, 91–99 (2008).
Buhlmann, U. et al. Physiologic responses to loud tones in individuals with obsessive-compulsive disorder. Psychosom. Med. 69, 166–172 (2007).
Guthrie, R. M. & Bryant, R. A. Auditory startle response in firefighters before and after trauma exposure. Am. J. Psychiatry 162, 283–290 (2005).
Guthrie, R. M. & Bryant, R. A. Extinction learning before trauma and subsequent posttraumatic stress. Psychosom. Med. 68, 307–311 (2006).
Orr, S. P. et al. Predicting post-trauma stress symptoms from pre-trauma psychophysiologic reactivity, personality traits and measures of psychopathology. Biol. Mood Anxiety Disord. 2, 8 (2012).
O'Donnell, M. L., Creamer, M., Elliott, P. & Bryant, R. Tonic and phasic heart rate as predictors of posttraumatic stress disorder. Psychosom. Med. 69, 256–261 (2007).
Suendermann, O., Ehlers, A., Boellinghaus, I., Gamer, M. & Glucksman, E. Early heart rate responses to standardized trauma-related pictures predict posttraumatic stress disorder: a prospective study. Psychosom. Med. 72, 301–308 (2010).
Shalev, A. Y. et al. A prospective study of heart rate response following trauma and the subsequent development of posttraumatic stress disorder. Arch. Gen. Psychiatry 55, 553–559 (1998).
Kobayashi, I., Boarts, J. M. & Delahanty, D. L. Polysomnographically measured sleep abnormalities in PTSD: a meta-analytic review. Psychophysiology 44, 660–669 (2007).
Sapolsky, R. M., Uno, H., Rebert, C. S. & Finch, C. E. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J. Neurosci. 10, 2897–2902 (1990).
Bremner, J. D. et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am. J. Psychiatry 152, 973–981 (1995).
Gurvits, T. V. et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol. Psychiatry 40, 1091–1099 (1996).
Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G. & McClarty, B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol. Med. 27, 951–959 (1997).
Kitayama, N., Vaccarino, V., Kutner, M., Weiss, P. & Bremner, J. D. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J. Affect. Disord. 88, 79–86 (2005).
Wang, Z. et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch. Gen. Psychiatry 67, 296–303 (2010). This was the first study in humans to use high-resolution sMRI to determine more specific volume diminutions within selected hippocampal subfields and to delineate those regions specific to PTSD versus ageing effects.
Smith, M. E. Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 15, 798–807 (2005).
Karl, A. et al. A meta-analysis of structural brain abnormalities in PTSD. Neurosci. Biobehav. Rev. 30, 1004–1031 (2006).
Woon, F. & Hedges, D. W. Gender does not moderate hippocampal volume deficits in adults with posttraumatic stress disorder: a meta-analysis. Hippocampus 21, 243–252 (2011).
Gilbertson, M. W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nature Neurosci. 5, 1242–1247 (2002). This study used data from monozygotic twins discordant for combat exposure and PTSD to suggest that smaller hippocampal volume in PTSD represents a pre-existing vulnerability factor.
Bonne, O. et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am. J. Psychiatry 158, 1248–1251 (2001).
Fennema-Notestine, C. Stein, M. B., Kennedy, C. M., Archibald, S. L. & Jernigan, T. L. Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder. Biol. Psychiatry 52, 1089–1101 (2002).
De Bellis, M. D., Hall, J., Boring, A. M., Frustaci, K. & Moritz, G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol. Psychiatry 50, 305–309 (2001).
Emdad, R. et al. Morphometric and psychometric comparisons between non-substance-abusing patients with posttraumatic stress disorder and normal controls. Psychother. Psychosom. 75, 122–132 (2006).
Bonne, O. et al. Reduced posterior hippocampal volume in posttraumatic stress disorder. J. Clin. Psychiatry 69, 1087–1091 (2008).
Schuff, N. et al. Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder. Psychiatry Res. 162, 147–157 (2008).
Karl, A. & Werner, A. The use of proton magnetic resonance spectroscopy in PTSD research — meta-analyses of findings and methodological review. Neurosci. Biobehav. Rev. 34, 7–22 (2010).
Myslobodsky, M. S. et al. Changes of brain anatomy in patients with posttraumatic stress disorder: a pilot magnetic resonance imaging study. Psychiatry Res. 58, 259–264 (1995).
Bremner, J. D. Hypotheses and controversies related to effects of stress on the hippocampus: an argument for stress-induced damage to the hippocampus in patients with posttraumatic stress disorder. Hippocampus 11, 75–81 (2001).
Vermetten, E., Vythilingam, M., Southwick, S. M., Charney, D. S. & Bremner, J. D. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol. Psychiatry 54, 693–702 (2003).
Woon, F. L., Sood, S. & Hedges, D. W. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 1181–1188 (2010).
Kasai, K. et al. Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol. Psychiatry 63, 550–556 (2008).
Kitayama, N., Quinn, S. & Bremner, J. D. Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder. J. Affect. Disord. 90, 171–174 (2006).
Carrion, V. G., Weems, C. F., Richert, K., Hoffman, B. C. & Reiss, A. L. Decreased prefrontal cortical volume associated with increased bedtime cortisol in traumatized youth. Biol. Psychiatry 68, 491–493 (2010).
Kim, S. J. et al. Asymmetrically altered integrity of cingulum bundle in posttraumatic stress disorder. Neuropsychobiology 54, 120–125 (2006).
Sekiguchi, A. et al. Brain structural changes as vulnerability factors and acquired signs of post-earthquake stress. Mol. Psychiatry 22 May 2012 (doi:10.1038/mp.2012.51).
Morrow, B. A., Elsworth, J. D., Rasmusson, A. M. & Roth, R. H. The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat. Neuroscience 92, 553–564 (1999).
Herry, C. et al. Neuronal circuits of fear extinction. Eur. J. Neurosci. 31, 599–612 (2010).
Milad, M. R. & Quirk, G. J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).
Liberzon, I. et al. Brain activation in PTSD in response to trauma-related stimuli. Biol. Psychiatry 45, 817–826 (1999).
Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).
Bremner, J. D. et al. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol. Med. 35, 791–806 (2005).
Shin, L. M. et al. Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: a PET investigation. Am. J. Psychiatry 156, 575–584 (1999).
Gold, A. L. et al. Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder. Psychol. Med. 41, 2563–2572 (2011).
Felmingham, K. et al. Neural responses to masked fear faces: sex differences and trauma exposure in posttraumatic stress disorder. J. Abnorm. Psychol. 119, 241–247 (2010).
Shin, L. M. et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch. Gen. Psychiatry 61, 168–176 (2004).
Felmingham, K. et al. Changes in anterior cingulate and amygdala after cognitive behavior therapy of posttraumatic stress disorder. Psychol. Sci. 18, 127–129 (2007). This article used fMRI to reveal functional brain changes in response to cognitive behavioural therapy in PTSD.
Milad, M. R. et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol. Psychiatry 66, 1075–1082 (2009).
Shin, L. M. et al. An fMRI study of anterior cingulate function in posttraumatic stress disorder. Biol. Psychiatry 50, 932–942 (2001).
Rougemont-Bucking, A. et al. Altered processing of contextual information during fear extinction in PTSD: an fMRI study. CNS Neurosci. Ther. 17, 227–236 (2011).
Bryant, R. A. et al. Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study. Biol. Psychiatry 58, 111–118 (2005).
Pannu, H. J., Labar, K. S., Petty, C. M., McCarthy, G. & Morey, R. A. Alterations in the neural circuitry for emotion and attention associated with posttraumatic stress symptomatology. Psychiatry Res. 172, 7–15 (2009).
Fonzo, G. A. et al. Exaggerated and disconnected insular–amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol. Psychiatry 68, 433–441 (2010).
Shin, L. M. et al. Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Arch. Gen. Psychiatry 66, 1099–1107 (2009).
Shin, L. M. et al. Exaggerated activation of dorsal anterior cingulate cortex during cognitive interference: a monozygotic twin study of posttraumatic stress disorder. Am. J. Psychiatry 168, 979–985 (2011).
Bremner, J. D. et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder. Am. J. Psychiatry 160, 924–932 (2003).
Shin, L. M. & Liberzon, I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191 (2010).
Simmons, A. N. et al. Functional activation and neural networks in women with posttraumatic stress disorder related to intimate partner violence. Biol. Psychiatry 64, 681–690 (2008).
Strigo, I. A. et al. Neural correlates of altered pain response in women with posttraumatic stress disorder from intimate partner violence. Biol. Psychiatry 68, 442–450 (2010).
Aupperle, R. L. et al. Dorsolateral prefrontal cortex activation during emotional anticipation and neuropsychological performance in posttraumatic stress disorder. Arch. Gen. Psychiatry 69, 360–371 (2012). This paper linked functional brain activation patterns with neuropsychological test performance in PTSD.
Hayes, J. P., Hayes, S. M. & Mikedis, A. M. Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol. Mood Anxiety Disord. 2, 9 (2012).
Elzinga, B. M. & Bremner, J. D. Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)? J. Affect. Disord. 70, 1–17 (2002).
Rauch, S. L., Shin, L. M. & Phelps, E. A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol. Psychiatry 60, 376–382 (2006).
Pitman, R. K. Combat effects on mental health: the more things change, the more they remain the same. Arch. Gen. Psychiatry 63, 127–128 (2006).
Geuze, E. et al. Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol. Psychiatry 13, 74–83 (2008).
Murrough, J. W. et al. Reduced amygdala serotonin transporter binding in posttraumatic stress disorder. Biol. Psychiatry 70, 1033–1038 (2011).
Liberzon, I. et al. Altered central mu-opioid receptor binding after psychological trauma. Biol. Psychiatry 61, 1030–1038 (2007).
Murrough, J. W. et al. The effect of early trauma exposure on serotonin type 1B receptor expression revealed by reduced selective radioligand binding. Arch. Gen. Psychiatry 68, 892–900 (2011).
Southwick, S. M. et al. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol. Psychiatry 46, 1192–1204 (1999).
Pitman, R. K. Post-traumatic stress disorder, hormones, and memory. Biol. Psychiatry 26, 221–223 (1989).
Rasmusson, A. M. et al. Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD. Biol. Psychiatry 47, 526–539 (2000).
Perry, B. D., Giller, E. L. Jr & Southwick, S. M. Altered platelet α2-adrenergic binding sites in posttraumatic stress disorder. Am. J. Psychiatry 144, 1511–1512 (1987).
Maes, M. et al. Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression. Neuropsychopharmacology 20, 188–197 (1999).
Blanchard, E. B., Kolb, L. C., Prins, A., Gates, S. & McCoy, G. C. Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with posttraumatic stress disorder. J. Nerv. Ment. Dis. 179, 371–373 (1991).
Southwick, S. M. et al. Abnormal noradrenergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 50, 266–274 (1993).
Mellman, T. A., Kumar, A., Kulick-Bell, R., Kumar, M. & Nolan, B. Nocturnal/daytime urine noradrenergic measures and sleep in combat-related PTSD. Biol. Psychiatry 38, 174–179 (1995).
Liberzon, I., Abelson, J. L., Flagel, S. B., Raz, J. & Young, E. A. Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study. Neuropsychopharmacology 21, 40–50 (1999).
Bremner, J. D. et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 246–254 (1997).
Taylor, F. B. et al. Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder. Biol. Psychiatry 59, 577–581 (2006).
Raskind, M. A. et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol. Psychiatry 61, 928–934 (2007).
Vaiva, G. et al. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol. Psychiatry 54, 947–949 (2003).
Stein, M. B., Kerridge, C., Dimsdale, J. E. & Hoyt, D. B. Pharmacotherapy to prevent PTSD: results from a randomized controlled proof-of-concept trial in physically injured patients. J. Trauma Stress. 20, 923–932 (2007).
Hoge, E. A. et al. Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery. CNS Neurosci. Ther. 18, 21–27 (2012).
Southwick, S. M. et al. Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 749–758 (1997).
Baumann, M. H., Mash, D. C. & Staley, J. K. The serotonin agonist m-chlorophenylpiperazine (mCPP) binds to serotonin transporter sites in human brain. Neuroreport 6, 2150–2152 (1995).
Murphy, D. L., Lesch, K. P., Aulakh, C. S. & Pigott, T. A. Serotonin-selective arylpiperazines with neuroendocrine, behavioral, temperature, and cardiovascular effects in humans. Pharmacol. Rev. 43, 527–552 (1991).
Kennett, G. A. et al. Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function. Neuropharmacology 33, 1581–1588 (1994).
Britton, K. T., Akwa, Y., Spina, M. G. & Koob, G. F. Neuropeptide Y blocks anxiogenic-like behavioral action of corticotropin-releasing factor in an operant conflict test and elevated plus maze. Peptides 21, 37–44 (2000).
Zhou, Z. et al. Genetic variation in human NPY expression affects stress response and emotion. Nature 452, 997–1001 (2008).
Morgan, C. A. et al. Neuropeptide-Y, cortisol, and subjective distress in humans exposed to acute stress: replication and extension of previous report. Biol. Psychiatry 52, 136–142 (2002).
Sah, R. et al. Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder. Biol. Psychiatry 66, 705–707 (2009).
Yehuda, R., Brand, S. & Yang, R. K. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol. Psychiatry 59, 660–663 (2006).
Dunn, A. J. & Berridge, C. W. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res. Brain Res. Rev. 15, 71–100 (1990).
Baker, D. G. et al. Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder. Am. J. Psychiatry 162, 992–994 (2005).
de Kloet, C. S. et al. Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder. Prog. Brain Res. 167, 287–291 (2008).
Geracioti, T. D. Jr et al. Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder. Psychoneuroendocrinology 33, 416–424 (2008).
Yehuda, R. et al. Low urinary cortisol excretion in patients with posttraumatic stress disorder. J. Nerv. Ment. Dis. 178, 366–369 (1990).
Yehuda, R. Post-traumatic stress disorder. N. Engl. J. Med. 346, 108–114 (2002). This article reviewed a highly influential body of research involving hyper-responsiveness of glucocorticoid receptors, enhanced negative feedback of the hypothalamus–pituitary–adrenal cortical axis and lower circulating cortisol levels in PTSD.
Yehuda, R., Boisoneau, D., Lowy, M. T. & Giller, E. L. Jr. Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch. Gen. Psychiatry 52, 583–593 (1995).
Yehuda, R., Lowy, M. T., Southwick, S. M., Shaffer, D. & Giller, E. L. Jr. Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder. Am. J. Psychiatry 148, 499–504 (1991).
Yehuda, R. Status of glucocorticoid alterations in post-traumatic stress disorder. Ann. NY Acad. Sci. 1179, 56–69 (2009).
Mehta, D. et al. Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: evidence from endocrine and gene expression studies. Arch. Gen. Psychiatry 68, 901–910 (2011).
Young, E. A. & Breslau, N. Cortisol and catecholamines in posttraumatic stress disorder: an epidemiologic community study. Arch. Gen. Psychiatry 61, 394–401 (2004).
Young, E. A. & Breslau, N. Saliva cortisol in posttraumatic stress disorder: a community epidemiologic study. Biol. Psychiatry 56, 205–209 (2004).
Rasmusson, A. M. et al. Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder. Biol. Psychiatry 50, 965–977 (2001).
Schelling, G. et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol. Psychiatry 55, 627–633 (2004).
Zohar, J. et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur. Neuropsychopharmacol. 21, 796–809 (2011).
de Quervain, D. J. Glucocorticoid-induced inhibition of memory retrieval: implications for posttraumatic stress disorder. Ann. NY Acad. Sci. 1071, 216–220 (2006).
McIntyre, C. K. & Roozendaal, B. in Neural Plasticity and Memory: From Genes to Brain Imaging (ed. Bermúdez-Rattoni, F.) 265–284 (CRC, 2007).
Sandi, C. Glucocorticoids act on glutamatergic pathways to affect memory processes. Trends Neurosci. 34, 165–176 (2011).
Hou, Y. T., Lin, H. K. & Penning, T. M. Dexamethasone regulation of the rat 3α-hydroxysteroid/dihydrodiol dehydrogenase gene. Mol. Pharmacol. 53, 459–466 (1998).
Rasmusson, A. M., Picciotto, M. R. & Krishnan-Sarin, S. Smoking as a complex but critical covariate in neurobiological studies of posttraumatic stress disorders: a review. J. Psychopharmacol. 20, 693–707 (2006).
Yehuda, R. et al. 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 (2009).
Rasmusson, A. M., Vythilingam, M. & Morgan, C. A. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr. 8, 651–657 (2003).
Chalbot, S. & Morfin, R. Dehydroepiandrosterone metabolites and their interactions in humans. Drug Metabol. Drug Interact. 22, 1–23 (2006).
Balazs, Z., Schweizer, R. A., Frey, F. J., Rohner-Jeanrenaud, F. & Odermatt, A. DHEA induces 11β–HSD2 by acting on CCAAT/enhancer-binding proteins. J. Am. Soc. Nephrol. 19, 92–101 (2008).
Spivak, B. et al. Elevated circulatory level of GABAA — antagonistic neurosteroids in patients with combat-related post-traumatic stress disorder. Psychol. Med. 30, 1227–1231 (2000).
Sondergaard, H. P., Hansson, L. O. & Theorell, T. Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: findings from a longitudinal study of refugees in Sweden. Psychother. Psychosom. 71, 298–303 (2002).
Rasmusson, A. M. et al. An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology 29, 1546–1557 (2004).
Gill, J., Vythilingam, M. & Page, G. G. Low cortisol, high DHEA, and high levels of stimulated TNFα, and IL-6 in women with PTSD. J. Trauma Stress 21, 530–539 (2008).
Morgan, C. A. 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 61, 819–825 (2004).
Morgan, C. A., Rasmusson, A., Pietrzak, R. H., Coric, V. & Southwick, S. M. Relationships among plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate, cortisol, symptoms of dissociation, and objective performance in humans exposed to underwater navigation stress. Biol. Psychiatry 66, 334–340 (2009).
Yehuda, R., Brand, S. R., Golier, J. A. & Yang, R. K. Clinical correlates of DHEA associated with post-traumatic stress disorder. Acta Psychiatr. Scand. 114, 187–193 (2006).
Rasmusson, A. M. et al. Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder. Biol. Psychiatry 60, 704–713 (2006). This article reported deficits in the synthesis of GABAergic neuroactive steroids in PTSD, suggesting a mechanism that may confer resistance to SSRI treatment and contribute to comorbidities, such as depression and chronic pain.
Genazzani, A. D. et al. Long-term low-dose dehydroepiandrosterone oral supplementation in early and late postmenopausal women modulates endocrine parameters and synthesis of neuroactive steroids. Fertil. Steril. 80, 1495–1501 (2003).
Schmidt, P. J. et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch. Gen. Psychiatry 62, 154–162 (2005).
Semyanov, A., Walker, M. C., Kullmann, D. M. & Silver, R. A. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269 (2004).
Pinna, G., Dong, E., Matsumoto, K., Costa, E. & Guidotti, A. In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc. Natl Acad. Sci. USA 100, 2035–2040 (2003).
True, W. R. et al. A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch. Gen. Psychiatry 50, 257–264 (1993).
Stein, M. B., Jang, K. L., Taylor, S., Vernon, P. A. & Livesley, W. J. Genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms: a twin study. Am. J. Psychiatry 159, 1675–1681 (2002).
Sartor, C. E. et al. Common genetic and environmental contributions to post-traumatic stress disorder and alcohol dependence in young women. Psychol. Med. 41, 1497–1505 (2011).
Lyons, M. J. et al. Do genes influence exposure to trauma? A twin study of combat. Am. J. Med. Genet. 48, 22–27 (1993).
Jang, K. L., Stein, M. B., Taylor, S., Asmundson, G. J. & Livesley, W. J. Exposure to traumatic events and experiences: aetiological relationships with personality function. Psychiatry Res. 120, 61–69 (2003).
Cornelis, M. C., Nugent, N. R., Amstadter, A. B. & Koenen, K. C. Genetics of post-traumatic stress disorder: review and recommendations for genome-wide association studies. Curr. Psychiatry Rep. 12, 313–326 (2010).
Sartor, C. E. et al. Common heritable contributions to low-risk trauma, high-risk trauma, posttraumatic stress disorder, and major depression. Arch. Gen. Psychiatry 69, 293–299 (2012).
Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009).
Ressler, K. J. et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470, 492–497 (2011).
Chang, S. C. et al. No association between ADCYAP1R1 and post-traumatic stress disorder in two independent samples. Mol. Psychiatry 17, 239–241 (2012).
Segman, R. H. et al. Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. Mol. Psychiatry 10, 500–513 (2005).
Zieker, J. et al. Differential gene expression in peripheral blood of patients suffering from post-traumatic stress disorder. Mol. Psychiatry 12, 116–118 (2007).
Yehuda, R. et al. Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol. Psychiatry 66, 708–711 (2009).
Uddin, M. et al. Gene expression and methylation signatures of MAN2C1 are associated with PTSD. Dis. Markers 30, 111–121 (2011).
Kilpatrick, D. G. et al. The serotonin transporter genotype and social support and moderation of posttraumatic stress disorder and depression in hurricane-exposed adults. Am. J. Psychiatry 164, 1693–1699 (2007). This was the first study to document a genotype by environment interaction in risk of PTSD. The data suggested that the low expression variant of the serotonin transporter gene increases risk of PTSD under conditions of high stress and low social support but not under low stress conditions.
Binder, E. B. et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299, 1291–1305 (2008).
Uddin, M. et al. Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc. Natl Acad. Sci. USA 107, 9470–9475 (2010). This study provided evidence of a biological model of PTSD aetiology in which an externally experienced traumatic event induces downstream alterations in immune function by reducing methylation levels of immune-related genes.
Smith, A. K. et al. Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 156B, 700–708 (2011).
Xie, P. et al. Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch. Gen. Psychiatry 66, 1201–1209 (2009).
Xie, P., Kranzler, H. R., Farrer, L. & Gelernter, J. Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 159B, 644–652 (2012).
Koenen, K. C. et al. Modification of the association between serotonin transporter genotype and risk of posttraumatic stress disorder in adults by county-level social environment. Am. J. Epidemiol. 169, 704–711 (2009).
Philibert, R. A. et al. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 543–549 (2008).
Koenen, K. C. et al. SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depress. Anxiety 28, 639–647 (2011).
Trollope, A. F. et al. Stress, epigenetic control of gene expression and memory formation. Exp. Neurol. 233, 3–11 (2012).
El-Sayed, A. M., Halossim, M. R., Galea, S. & Koenen, K. C. Epigenetic modifications associated with suicide and common mood and anxiety disorders: a systematic review of the literature. Biol. Mood Anxiety Disord. 2, 10 (2012).
Pitman, R. K., Orr, S. P. & Shalev, A. Y. Once bitten, twice shy: beyond the conditioning model of PTSD. Biol. Psychiatry 33, 145–146 (1993).
Adamec, R. E. & Shallow, T. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol. Behav. 54, 101–109 (1993). An early and influential study of the PredEx animal model for PTSD.
Zoladz, P. R., Conrad, C. D., Fleshner, M. & Diamond, D. M. Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder. Stress 11, 259–281 (2008).
Cohen, H., Zohar, J. & Matar, M. The relevance of differential response to trauma in an animal model of posttraumatic stress disorder. Biol. Psychiatry 53, 463–473 (2003).
Mesches, M. H., Fleshner, M., Heman, K. L., Rose, G. M. & Diamond, D. M. Exposing rats to a predator blocks primed burst potentiation in the hippocampus in vitro. J. Neurosci. 19, RC18 (1999).
Liberzon, I., Lopez, J. F., Flagel, S. B., Vazquez, D. M. & Young, E. A. Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J. Neuroendocrinol. 11, 11–17 (1999). This study demonstrated the construct validity of the SPS animal model of PTSD.
Kohda, K. et al. Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model. Neuroscience 148, 22–33 (2007).
Servatius, R. J., Ottenweller, J. E., Bergen, M. T., Soldan, S. & Natelson, B. H. Persistent stress-induced sensitization of adrenocortical and startle responses. Physiol Behav. 56, 945–954 (1994).
Pynoos, R. S., Ritzmann, R. F., Steinberg, A. M., Goenjian, A. & Prisecaru, I. A behavioral animal model of posttraumatic stress disorder featuring repeated exposure to situational reminders. Biol. Psychiatry 39, 129–134 (1996).
Rau, V. & Fanselow, M. S. Exposure to a stressor produces a long lasting enhancement of fear learning in rats. Stress 12, 125–133 (2009).
Li, X., Han, F., Liu, D. & Shi, Y. Changes of Bax, Bcl-2 and apoptosis in hippocampus in the rat model of post-traumatic stress disorder. Neurol. Res. 32, 579–586 (2010).
Kozlovsky, N., Matar, M. A., Kaplan, Z., Zohar, J. & Cohen, H. A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder. Eur. Neuropsychopharmacol. 19, 759–771 (2009).
Zhe, D., Fang, H. & Yuxiu, S. Expressions of hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in the single-prolonged stress-rats. Acta Histochem. Cytochem. 41, 89–95 (2008).
Adamec, R., Muir, C., Grimes, M. & Pearcey, K. Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress. Behav. Brain Res. 179, 192–207 (2007).
Adamec, R., Fougere, D. & Risbrough, V. CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD. Int. J. Neuropsychopharmacol. 13, 747–757 (2010).
Cohen, H., Matar, M. A., Buskila, D., Kaplan, Z. & Zohar, J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol. Psychiatry 64, 708–717 (2008).
Kaouane, N. et al. Glucocorticoids can induce PTSD-like memory impairments in mice. Science 335, 1510–1513 (2012).
Knox, D., Perrine, S. A., George, S. A., Galloway, M. P. & Liberzon, I. Single prolonged stress decreases glutamate, glutamine, and creatine concentrations in the rat medial prefrontal cortex. Neurosci. Lett. 480, 16–20 (2010).
Harvey, B. H., Oosthuizen, F., Brand, L., Wegener, G. & Stein, D. J. Stress-restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology (Berl.) 175, 494–502 (2004).
Yamamoto, S. et al. Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder. J. Psychiatr. Res. 44, 1069–1074 (2010).
Yamamoto, S. et al. Effects of single prolonged stress and d-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology 33, 2108–2116 (2008).
Blundell, J. & Adamec, R. The NMDA receptor antagonist CPP blocks the effects of predator stress on pCREB in brain regions involved in fearful and anxious behavior. Brain Res. 1136, 59–76 (2007).
Adamec, R., Holmes, A. & Blundell, J. Vulnerability to lasting anxiogenic effects of brief exposure to predator stimuli: sex, serotonin and other factors-relevance to PTSD. Neurosci. Biobehav. Rev. 32, 1287–1292 (2008).
Harvey, B. H., Brand, L., Jeeva, Z. & Stein, D. J. Cortical/hippocampal monoamines, HPA-axis changes and aversive behavior following stress and restress in an animal model of post-traumatic stress disorder. Physiol. Behav. 87, 881–890 (2006).
Kesner, Y. et al. WFS1 gene as a putative biomarker for development of post-traumatic syndrome in an animal model. Mol. Psychiatry 14, 86–94 (2009).
Luo, F. F., Han, F. & Shi, Y. X. Changes in 5-HT1A receptor in the dorsal raphe nucleus in a rat model of post-traumatic stress disorder. Mol. Med. Report. 4, 843–847 (2011).
Harvey, B. H., Naciti, C., Brand, L. & Stein, D. J. Endocrine, cognitive and hippocampal/cortical 5HT1A/2A receptor changes evoked by a time-dependent sensitisation (TDS) stress model in rats. Brain Res. 983, 97–107 (2003).
Wang, H. T., Han, F. & Shi, Y. X. Activity of the 5-HT1A receptor is involved in the alteration of glucocorticoid receptor in hippocampus and corticotropin-releasing factor in hypothalamus in SPS rats. Int. J. Mol. Med. 24, 227–231 (2009).
Harada, K., Yamaji, T. & Matsuoka, N. Activation of the serotonin 5-HT2C receptor is involved in the enhanced anxiety in rats after single-prolonged stress. Pharmacol. Biochem. Behav. 89, 11–16 (2008).
Olson, V. G. et al. The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder. Biol. Psychiatry 70, 441–448 (2011).
Takei, S. et al. Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder. J. Psychiatr. Res. 45, 460–468 (2011).
Kozlovsky, N. et al. Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int. J. Neuropsychopharmacol. 10, 741–758 (2007).
Roth, T. L., Zoladz, P. R., Sweatt, J. D. & Diamond, D. M. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. J. Psychiatr. Res. 45, 919–926 (2011).
Pitman, R. K. & Orr, S. P. in Posttraumatic Stress Disorder in Litigation: Guidelines for Forensic Assessment (ed. Simon, R. I.) 207–223 (American Psychiatric Press, 2003).
Yehuda, R., McFarlane, A. C. & Shalev, A. Y. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol. Psychiatry 44, 1305–1313 (1998).
Delahanty, D. L., Raimonde, A. J. & Spoonster, E. Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol. Psychiatry 48. 940–947 (2000).
Brunet, A. et al. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42, 503–506 (2008).
Brunet, A. et al. Trauma reactivation under the influence of propranolol decreases posttraumatic stress symptoms and disorder: 3 open-label trials. J. Clin. Psychopharmacol. 31, 547–550 (2011).
Schiller, D. et al. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature 463, 49–53 (2010).
Milad, M. R. et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol. Psychiatry 62, 446–454 (2007).
Milad, M. R. et al. A role for the human dorsal anterior cingulate cortex in fear expression. Biol. Psychiatry 62, 1191–1194 (2007).
Goldstein, L. E., Rasmusson, A. M., Bunney, B. S. & Roth, R. H. Role of the amygdala in the coordination of behavioral, neuroendocrine, and prefrontal cortical monoamine responses to psychological stress in the rat. J. Neurosci. 16, 4787–4798 (1996).
Arnsten, A. F. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Rev. Neurosci. 10, 410–422 (2009).
Rosenkranz, J. A. & Grace, A. A. Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J. Neurosci. 22, 324–337 (2002).
Chhatwal, J. P., Myers, K. M., Ressler, K. J. & Davis, M. Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction. J. Neurosci. 25, 502–506 (2005).
Heldt, S. A. & Ressler, K. J. Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear. Eur. J. Neurosci. 26, 3631–3644 (2007).
Rosenkranz, J. A. & Grace, A. A. Dopamine attenuates prefrontal cortical suppression of sensory inputs to the basolateral amygdala of rats. J. Neurosci. 21, 4090–4103 (2001).
Braga, M. F., Aroniadou-Anderjaska, V., Manion, S. T., Hough, C. J. & Li, H. Stress impairs α1A adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala. Neuropsychopharmacology 29, 45–58 (2004).
Buffalari, D. M. & Grace, A. A. Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of α-2 and β receptor activation. J. Neurosci. 27, 12358–12366 (2007).
The authors declare no competing financial interests.
- Skin conductance
A measure of sweat activity recorded from two adjacent fingers and/or the thenar and hypothenar eminences of the palm of the hand. It is thought to be primarily under sympathetic nervous system influence.
- Event-related potentials
(ERPs). Electrical potentials that are generated in the brain as a consequence of the synchronized activation of neuronal networks by external stimuli. These evoked potentials are recorded at the scalp and consist of precisely timed sequences of waves or 'components'.
A procedure by which a conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, resulting in diminution of the conditioned response.
An electroencephalographic event-related potential response that is positive and reaches its maximum deflection approximately 300ms after a stimulus is presented. It is thought to reflect the amount of attentional resources allocated to the stimulus.
- Fear conditioning
An experimental paradigm that teaches an animal or human to associate a previously neutral conditioned stimulus (CS; for example, a light or a tone) with an aversive unconditioned stimulus (for example, an electric shock), the latter of which produces an aversive unconditioned response. Eventually, because of the association, the CS alone comes to elicit a fear response.
- Extinction retention
Memory that a conditioned stimulus has been previously extinguished, expressed as a continuing reduction of the conditioned response. It is also called extinction recall.
- Fear-potentiated startle
An increased electromyographic responsiveness to a startling stimulus that occurs when an animal or human is afraid.
An electroencephalographic event-related potential response that is positive and reaches its maximum deflection approximately 200ms after a stimulus is presented. It is thought to reflect 'tuning' of a mechanism that regulates the amount of sensory input to the cortex.
- Conditioned fear
Fear that is elicited by a conditioned stimulus (or cue) following fear conditioning. Typical measures include freezing in rodents, skin conductance in humans and potentiated startle in both.
- Corrugator EMG
A measure of electromyographic activity associated with contraction of the corrugator supercilii muscle, which draws the inner brow inward and downward during negatively valenced emotion.
- Structural MRI
(sMRI). A non-invasive diagnostic and research procedure that uses a magnetic field and radio waves to create detailed sectional images of the internal structure of the body, including the brain.
- Ventromedial prefrontal cortex
(vmPFC). A region within the medial wall of prefrontal cortex that roughly corresponds to Brodmann area 10. Some studies treat portions of adjacent Brodmann areas as part of the vmPFC.
A sector of the cornu ammonis subfield of the hippocampus and a major target of glucocorticoids.
- Dentate gyrus
A subfield of the hippocampus that contains adult neural stem cells and is an important site of neurogenesis.
- Magnetic resonance spectroscopic imaging
(MRSI). A non-invasive research and diagnostic technique that is similar to MRI but uses a stronger field to detect regional body chemistry at the cellular level. It is also called 1H-nuclear magnetic resonance spectroscopic imaging and proton magnetic resonance spectroscopic imaging.
A putative marker of neuronal integrity thought to be present predominantly in neuronal cell bodies. It emits the largest signal in magnetic resonance spectroscopic imaging of the human brain.
- Dorsal anterior cingulate cortex
(dACC). A cortical area that roughly corresponds to Brodmann area 24. It may also be called anterior the mid-cingulate cortex.
- Voxel-based morphometry
An automated neuroimaging analytic technique that allows the investigation of focal differences in brain anatomy using the statistical approaches of statistical parametric mapping and smoothing applied to structural images.
- Diffusion tensor imaging
A structural MRI-based technique that tracks the diffusion of water molecules within a closed space, usually a tube such as a neural axon. It is useful in revealing white matter fibre structure and providing information regarding regional brain connectivity.
- Positron emission tomography
(PET). A functional neuroimaging technique that uses radioactive isotopes to quantify regional cerebral blood flow, glucose metabolism or receptor occupancy.
- Functional MRI
(fMRI). A functional neuroimaging technique that uses a magnetic field and radio waves to measure the blood-oxygenation-level-dependent signal, which serves as an index of regional brain activation.
Designating intermittent signalling, usually in response to a stimulus.
The splitting off of a mental process or group of mental processes from the main body of consciousness.
Designating continuous, steady or baseline signalling.
Located outside the synapse. Extrasynaptic receptors can be accessed by neuromodulatory factors derived from the periphery and circulating in the cerebrospinal fluid.
Capable of being passed from one generation to the next via DNA.
- Single-nucleotide polymorphism
(SNP). A variation in a DNA sequence in which a single nucleotide (A, C, G or T) at a specific locus differs between members of the same biological species or between paired chromosomes of an individual.
An alteration in the response of a neuron induced by a substance that would not, by itself, affect neuronal firing rate.
- DNA methylation
The modification of a strand of DNA in which a methyl group is added to a cytosine molecule that stands directly before a guanine molecule in the same chain. It has the effect of reducing gene expression.
One or more alternative forms of a genetic locus or a gene.
One or more mechanisms that regulate gene function without altering the underlying DNA sequence.
- Face validity
The degree to which a model or a term appears to measure what it is supposed to measure.
- Construct validity
The degree to which a model or a term corresponds to or reflects an underlying theory.
- Glucocorticoid negative feedback
A negative-feedback phenomenon by which cortisol reduces its own release through inhibition of the hypothalamus–pituitary–adrenal cortical axis.
- Brain-derived neurotrophic factor
(BDNF). A protein that is often released from a neuron, and that is involved in growth and the differentiation of new neurons and synapses.
A membranous tyrosine kinase receptor that binds brain-derived neurotrophic factor and other neurotrophic factors (also known as neurotrophins).
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Pitman, R., Rasmusson, A., Koenen, K. et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 13, 769–787 (2012). https://doi.org/10.1038/nrn3339
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