Systematic Reviews
Copyright ©The Author(s) 2022.
World J Psychiatry. Jan 19, 2022; 12(1): 151-168
Published online Jan 19, 2022. doi: 10.5498/wjp.v12.i1.151
Table 1 Study Selection Phase 1: Keywords used for stepwise including (and thus excluding) items
CriterionInput for this criterionAutomatic keyword screening (Rayyan): Used keywords for includeIncludedThus excluded
15659Trauma; traumas; traumatic; traumatized; traumatised; posttraumatic; PTSD 5194465
25194Asymptomatic; bridging; delayed; dormant; emerge; emerges; emerging; increase; increases; increasing; interval; late; latency; latent; onset; progression; progressive; symptom-free 22872907
32287Adrenal; adrenalin; allostatic; ANS; autonomous; biochemical; biological; biology; biomarker; biomarkers; brain; cell; ceruleus; chemokine; coeruleus; cortex; cortisol; corticosteroids; corticosteroid; CT; cytokine; cytokines; DNA; epicortisol; epigenetic; epigenomic; epinephrine; frontal; genetic; hippocampus; hippocampal; HPA; hydrocortisone; hypothalamic; hypothalamus; imaging; immune; immunological; inflammation; LC; marker; markers; MRI; NE; nervous; neurobiological; neurobiology; neuroimaging; noradrenalin; norepinephrine; parasympathetic; PET; phenotype; phenotypical; pituitary; PNS; prefrontal; psychobiological; psychobiology; SNS; SPECT; stem; sympathetic7161571
4716Amnesia; amnesic; amnestic; cause; causal; dissociation; dissociative; factor; mechanism; mechanisms; predictor; protective; risk; sensitisation; sensitised; sensitization; sensitized; stage; staging; susceptibility; trigger; vulnerability455261
Table 2 Study Selection Phase 2: Manual title and abstract screening, inclusion and exclusion
CriterionInput for this criterionManual title and abstract screening: Record refers toInclusionExclusion
1438Trauma and PTSD308130
2308Delayed onset73235
373Neurobiology 6211
462Causal mechanisms or risk factors602
60Full-text articles assessed for eligibility60
Table 3 Overview of Human Studies
Population (n)
Assessment times
Admon et al[14], 2013Soldiers (33)Treating a fellow soldier with severe combat injuryPre-deployment and 18 mo later
Alway et al[30],2016TBI patients (85)Motor vehicle accidents (76.5%), other accidents, assaults6 mo, 1-, 2-, 3-, and 4-yr post-injury
Bryant et al[29], 2009Traumatic injury patients with no (708) or mild TBI (459)Transport accident, assault, fall, work injury, other injuryDuring hospital admission and at 3 mo post-injury
Bryant et al[28], 2013Road traffic accident survivors admitted to trauma hospital (1084)Transport accident, assault, fall, work injury, other injuryDuring hospital admission and at 3-, 12-, and 24 mos post-injury
Busso et al[21], 2014Adolescents exposed to bombing (78)Terrorist attack at the 2013 Boston marathon1 year prior to trauma (n = 44), 4-6 wk posttrauma (n = 78)
Cacciaglia et al[13], 2017Healthy rescue ambulance workers (18), non-exposed matched controls (18)Exposed group: vehicle accident (41%), traumatic loss of a loved one, domestic violence, childhood abuseCross-sectional; trauma occurred a mean of 7.41 yr ago
Chase et al[39], 2015Help-seeking veterans (16) and family members (10)Exposure to blast during employment to combat-intense settingsCross-sectional; > 7 yr after exposure
Do Prado et al[31], 2017Adolescents with childhood trauma (30), controls without history of early life stress (27)Sexual abuse, physical abuse, emotional abuse, physical neglect, emotional neglectCross-sectional; maltreatment ended > 12 mo ago
Gandubert et al[19], 2016Emergency room patients (123)Physical assault, sexual assault, serious accident, otherDuring the first week and at 1-, 4-, and 12 mos post-trauma
Gil et al[35], 2005Traumatic brain injury patients (120)Traffic accident< 1 week, 3 mo, and 6 mo later
Glenn et al[27], 2017Soldiers deployed to Afghanistan (852)Combat experience, difficult living and working environment4 wk before and 22 wk after deployment
Jung et al[47], 2019Community-dwelling women (nurses) (50020)Various self-reported on Brief Trauma QuestionnaireBiennial from enrollment
Monfort and Trehel[44], 201793-year-old veteran (1)WW II combat experiences65 years later
Roy et al[36], 2015Combat veterans without PTSD, depression, or post-concussive syndrome < 2 mo after return (81)Deployment to Iraq or Afghanistan > 3 mo< 2 mo after return, 3, 6, and 12 mo
Smid et al[26], 2015Deployed soldiers (693)4 mo deployment to Afghanistan2 mo prior to deployment and 1-, 6-, 12-, and 24 mo following deployment
Solomon and Mikulincer[42], 2006Combat veterans with combat stress reaction (CSR) (131) or without (83)1982 Lebanon War1, 2, 3, and 20 yr after the war
Solomon et al[41], 2017Ex-prisoners of war (101), combat controls (15)1973 Yom Kippur War18, 30, 35, 42 yr after the war
Stein et al[43], 2013Community-dwelling (25,018)Lifetime exposure to 27 traumatic eventsCross-sectional
Uddin et al[32], 2010PTSD-affected (23) and -unaffected individuals (77) from large sampleLifetime exposure to 19 traumatic eventsCross-sectional
Vaiva et al[20], 2005Hospitalized traumatology patients (78)Road traffic accident1 and 6 wk, 12 mo
Wang et al[33], 2015Blunt chest trauma patients (57)Motor vehicle accidents (61.4%), falls, other accidents1, 3, 6 mo
Waszczuk et al[46], 2020First responders (1490)Working at the World Trade Center site, New York following the 9/11, 2001 terrorist attacksMean = 7.75 monitoring visits per 1.49 yr, PTSD diagnosis at 12 yr
Table 4 Overview of animal studies
Animals (n)
Assessment times
Anxiety and delayed effects
Neurobiological observation methods
Ardi et al[15], 2014Rats: naïve (12), swim (12), swim + reminder (R) (12), UWT (12), UWT + R (12)Rats were given daily 1-minute swim trials for 5 days. On day 6, ‘swim’ rats had an additional swim trial, and ‘UWT’ rats were swimming and then held underwater for 30 s using a net. On day 7, rats from the ‘reminder’ groups were exposed to 30 s of swimmingFollowing the ‘reminder’, rats were tested after 30 min.; ‘swim’ and ‘UWT’ rats were tested on day 7Undergoing UWT results in reduced exploration in the open field even 24 h after the trauma compared to ‘swim’ and ‘naïve’ groups. Exposure to the reminder resulted in significantly enhanced anxiety behaviorelectrophysiological recordings of hippocampal dentate gyrus GABA-ergic local circuit activity: paired-pulse inhibition (reflecting feedback inhibition), frequency-dependent inhibition (reflecting feed-forward inhibition), long-term potentiation; biochemical analysis: amygdala extracellular-signal-regulated kinase activity
Justice et al[45], 2015Mice: wild type controls (43) and PTSD-group (65), Alzheimer’s Disease model controls (76) and PTSD-group (145)Mice in the PTSD group were immobilized for 2h on boards with tape in a brightly lit area. For the reminder, the procedure was repeated during 15 min.2–3 mo and 6–12 moAnimals displayed elevated anxiety and slightly elevated startle amplitudesresting and peak plasma corticosteroid levels, cerebrospinal fluid beta-amyloid levels
Serova et al[25], 2019Rats: 1 wk following stress (57), 2 wk following stress (42), controls (56)Rats were immobilized for 2 h on a board by taping the limbs and restricting motion of the head, then subjected to forced swim for 20 min.1 or 2 wk following stressAt 1 week, 17.5%, and at 2 wk, 57.1% of animals displayed severe anxietyGene expression in the mediobasal hypothalamus and locus coeruleus (LC), immunohistochemistry
Wilson et al[34], 2013Rats: PTSD-group (10), controls (10)PTSD group rats were secured in plexiglas cylinders and placed in a cage with a cat for one hour on days 1 and 11 of a 31-day stress regimen, and their cage cohort was changed dailyday 0, day 12, day 31The PTSD group displayed significantly higher anxiety than the control group, and significantly diminished growthrate over the 31-day stress periodGrowth, plasma (corticosterone), adrenal glands (weight, oxidative stress), and hippocampus, amygdala, and pre-frontal cortex (oxidative stress and inflammatory markers: interleukin-1β, NALP3-inflammosome, glyceraldehyde 3-phosphate dehydrogenase)
Table 5 Overview of review studies
Study types
Review focus
Admon et al[11], 2013HumanReviews predisposing and acquired neural abnormalities that can be discerned based on PTSD neuroimaging studies that include genetic, environmental, twin, and prospective data
Belda et al[22], 2015AnimalReviews sensitization: A phenomenon whereby exposure to a particular stimulus triggers a state of hyperresponsiveness
Kim et al[18], 2019Human, animalReviews influences of chronic exposure to stress on the immune system, resulting in increased proinflammatory cytokine levels. Focuses on changes in the amygdala, hippocampus, PFC, and insula, that are particularly influenced by excess cytokines
McFarlane[17], 2000HumanFocuses on people who develop PTSD de novo, i.e., without preexisting disorder at the time of the traumatic event that may have acted as a risk factor to the onset of PTSD
McFarlane[23], 2010HumanExamines the issue of the timing of the onset of PTSD following exposure to traumatic events
McFarlane et al[16], 2002HumanReviews the knowledge from neural networks to model a framework for exploring the relationship between neurobiology, cognition, and behavior in PTSD
McFarlane et al[40], 2017HumanArgues that major advances in the biological treatments of PTSD depend on a more sophisticated classification of PTSD that acknowledges the heterogeneity of this condition
Michopoulos et al[24], 2015HumanReviews putative PTSD biomarkers with specific emphasis on the interaction between neurobiological influences on disease risk and symptom progression
Smid et al[38], 2003HumanReviews risk factors for delayed PTSD, including combat trauma, stressful events after the trauma and previous emotional problems
Soreq[37], 2010Human, animalReviews effects that are often reported yr after prophylactic treatment with cholinesterase inhibitors for protection under threat of chemical warfare, e.g., during the Gulf War, and their similarity to symptoms of PTSD
Wilker and Kolassa[10], 2013Human, animalReviews genetic risk factors in PTSD etiology from the perspective of a psychobiological model, which proposes that intrusive memories, the core PTSD symptom, result from the formation of an associative neural fear network, which stores sensory-perceptual representations of traumatic memories
Zovkic et al[12], 2013Human, animalDiscusses epigenetic regulation of PTSD in human studies and in animal models and ways in which these models can be expanded. Reviews the literature that directly addresses the involvement of epigenetics in PTSD and puts it into the broader context of epigenetics in stress and fear learning