Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder: A scoping review

Table 1 Study Selection Phase 1: Keywords used for stepwise including (and thus excluding) items

Criterion	Input for this criterion	Automatic keyword screening (Rayyan): Used keywords for include	Included	Thus excluded
1	5659	Trauma; traumas; traumatic; traumatized; traumatised; posttraumatic; PTSD	5194	465
2	5194	Asymptomatic; bridging; delayed; dormant; emerge; emerges; emerging; increase; increases; increasing; interval; late; latency; latent; onset; progression; progressive; symptom-free	2287	2907
3	2287	Adrenal; 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; sympathetic	716	1571
4	716	Amnesia; amnesic; amnestic; cause; causal; dissociation; dissociative; factor; mechanism; mechanisms; predictor; protective; risk; sensitisation; sensitised; sensitization; sensitized; stage; staging; susceptibility; trigger; vulnerability	455	261
	455	Deduplication	438	17

ANS: Autonomous nervous system; CT: Computed tomography; HPA: Hypothalamic-pituitary axis; LC: Locus coeruleus; MRI: Magnetic resonance imaging; NE: Norepinephrine; PET: Positron emission tomography; PNS: Parasympathetic nervous system; SNS: Sympathetic nervous system; SPECT: Single photon emission computed tomography; PTSD: Posttraumatic stress disorder.

Table 2 Study Selection Phase 2: Manual title and abstract screening, inclusion and exclusion

Criterion	Input for this criterion	Manual title and abstract screening: Record refers to	Inclusion	Exclusion
1	438	Trauma and PTSD	308	130
2	308	Delayed onset	73	235
3	73	Neurobiology	62	11
4	62	Causal mechanisms or risk factors	60	2
	60	Full-text articles assessed for eligibility	60

PTSD: Posttraumatic stress disorder.

Table 3 Overview of Human Studies

Ref.	Population (n)	Trauma/stressor	Assessment times
Admon et al[14], 2013	Soldiers (33)	Treating a fellow soldier with severe combat injury	Pre-deployment and 18 mo later
Alway et al[30],2016	TBI patients (85)	Motor vehicle accidents (76.5%), other accidents, assaults	6 mo, 1-, 2-, 3-, and 4-yr post-injury
Bryant et al[29], 2009	Traumatic injury patients with no (708) or mild TBI (459)	Transport accident, assault, fall, work injury, other injury	During hospital admission and at 3 mo post-injury
Bryant et al[28], 2013	Road traffic accident survivors admitted to trauma hospital (1084)	Transport accident, assault, fall, work injury, other injury	During hospital admission and at 3-, 12-, and 24 mos post-injury
Busso et al[21], 2014	Adolescents exposed to bombing (78)	Terrorist attack at the 2013 Boston marathon	1 year prior to trauma (n = 44), 4-6 wk posttrauma (n = 78)
Cacciaglia et al[13], 2017	Healthy rescue ambulance workers (18), non-exposed matched controls (18)	Exposed group: vehicle accident (41%), traumatic loss of a loved one, domestic violence, childhood abuse	Cross-sectional; trauma occurred a mean of 7.41 yr ago
Chase et al[39], 2015	Help-seeking veterans (16) and family members (10)	Exposure to blast during employment to combat-intense settings	Cross-sectional; > 7 yr after exposure
Do Prado et al[31], 2017	Adolescents with childhood trauma (30), controls without history of early life stress (27)	Sexual abuse, physical abuse, emotional abuse, physical neglect, emotional neglect	Cross-sectional; maltreatment ended > 12 mo ago
Gandubert et al[19], 2016	Emergency room patients (123)	Physical assault, sexual assault, serious accident, other	During the first week and at 1-, 4-, and 12 mos post-trauma
Gil et al[35], 2005	Traumatic brain injury patients (120)	Traffic accident	< 1 week, 3 mo, and 6 mo later
Glenn et al[27], 2017	Soldiers deployed to Afghanistan (852)	Combat experience, difficult living and working environment	4 wk before and 22 wk after deployment
Jung et al[47], 2019	Community-dwelling women (nurses) (50020)	Various self-reported on Brief Trauma Questionnaire	Biennial from enrollment
Monfort and Trehel[44], 2017	93-year-old veteran (1)	WW II combat experiences	65 years later
Roy et al[36], 2015	Combat 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], 2015	Deployed soldiers (693)	4 mo deployment to Afghanistan	2 mo prior to deployment and 1-, 6-, 12-, and 24 mo following deployment
Solomon and Mikulincer[42], 2006	Combat veterans with combat stress reaction (CSR) (131) or without (83)	1982 Lebanon War	1, 2, 3, and 20 yr after the war
Solomon et al[41], 2017	Ex-prisoners of war (101), combat controls (15)	1973 Yom Kippur War	18, 30, 35, 42 yr after the war
Stein et al[43], 2013	Community-dwelling (25,018)	Lifetime exposure to 27 traumatic events	Cross-sectional
Uddin et al[32], 2010	PTSD-affected (23) and -unaffected individuals (77) from large sample	Lifetime exposure to 19 traumatic events	Cross-sectional
Vaiva et al[20], 2005	Hospitalized traumatology patients (78)	Road traffic accident	1 and 6 wk, 12 mo
Wang et al[33], 2015	Blunt chest trauma patients (57)	Motor vehicle accidents (61.4%), falls, other accidents	1, 3, 6 mo
Waszczuk et al[46], 2020	First responders (1490)	Working at the World Trade Center site, New York following the 9/11, 2001 terrorist attacks	Mean = 7.75 monitoring visits per 1.49 yr, PTSD diagnosis at 12 yr

Table 4 Overview of animal studies

Ref.	Animals (n)	Trauma/stressor	Assessment times	Anxiety and delayed effects	Neurobiological observation methods
Ardi et al[15], 2014	Rats: 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 swimming	Following the ‘reminder’, rats were tested after 30 min.; ‘swim’ and ‘UWT’ rats were tested on day 7	Undergoing 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 behavior	electrophysiological 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], 2015	Mice: 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 mo	Animals displayed elevated anxiety and slightly elevated startle amplitudes	resting and peak plasma corticosteroid levels, cerebrospinal fluid beta-amyloid levels
Serova et al[25], 2019	Rats: 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 stress	At 1 week, 17.5%, and at 2 wk, 57.1% of animals displayed severe anxiety	Gene expression in the mediobasal hypothalamus and locus coeruleus (LC), immunohistochemistry
Wilson et al[34], 2013	Rats: 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 daily	day 0, day 12, day 31	The PTSD group displayed significantly higher anxiety than the control group, and significantly diminished growthrate over the 31-day stress period	Growth, 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)

UWT: Underwater trauma; GABA: Gamma aminobutyric acid; NALP3: NACHT, LRR and PYD domains-containing protein 3 (also: nucleotide-binding domain, leucine-rich repeat family pyrin domain containing 3); PTSD: Posttraumatic stress disorder.

Table 5 Overview of review studies

Ref.	Study types	Review focus
Admon et al[11], 2013	Human	Reviews 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], 2015	Animal	Reviews sensitization: A phenomenon whereby exposure to a particular stimulus triggers a state of hyperresponsiveness
Kim et al[18], 2019	Human, animal	Reviews 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], 2000	Human	Focuses 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], 2010	Human	Examines the issue of the timing of the onset of PTSD following exposure to traumatic events
McFarlane et al[16], 2002	Human	Reviews the knowledge from neural networks to model a framework for exploring the relationship between neurobiology, cognition, and behavior in PTSD
McFarlane et al[40], 2017	Human	Argues 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], 2015	Human	Reviews putative PTSD biomarkers with specific emphasis on the interaction between neurobiological influences on disease risk and symptom progression
Smid et al[38], 2003	Human	Reviews risk factors for delayed PTSD, including combat trauma, stressful events after the trauma and previous emotional problems
Soreq[37], 2010	Human, animal	Reviews 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], 2013	Human, animal	Reviews 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], 2013	Human, animal	Discusses 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

PTSD: Posttraumatic stress disorder; PFC: Prefrontal cortex.