Systematic Reviews
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Psychiatry. Jan 19, 2022; 12(1): 151-168
Published online Jan 19, 2022. doi: 10.5498/wjp.v12.i1.151
Neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder: A scoping review
Geert E Smid, Jonna Lind, Jens Peter Bonde
Geert E Smid, ARQ Centrum'45, ARQ National Psychotrauma Centre, Diemen 1112XE, Netherlands
Geert E Smid, Department of Humanist Chaplaincy Studies, University of Humanistic Studies, Utrecht 3512 HD, Netherlands
Jonna Lind, ARQ Centre of Excellence on War, Persecution and Violence, ARQ National Psychotrauma Centre, Diemen 1112XE, Netherlands
Jens Peter Bonde, Department of Occupational and Environmental Medicine, Frederiksberg and Bispebjerg Hospital, Copenhagen 2400, Denmark
Jens Peter Bonde, Department of Public Health, University of Copenhagen, Copenhagen 1014, Denmark
Author contributions: Smid G wrote the first draft of the manuscript; Smid G and Lind J searched and selected the literature; Smid G and Bonde JP conceived the study; all authors contributed to the manuscript revision and read and approved the submitted version.
Supported by the Danish Working Environment Research Fund from Arbejdsmiljøforskningsfonden (to Bonde JP).
Conflict-of-interest statement: The authors report no conflicts of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA Scoping Review Checklist, and the manuscript was prepared and revised according to the PRISMA Scoping Review Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Geert E Smid, MD, PhD, Professor, ARQ Centrum'45, ARQ National Psychotrauma Centre, Nienoord 5, Diemen 1112XE, Netherlands.
Received: March 30, 2021
Peer-review started: March 30, 2021
First decision: July 15, 2021
Revised: July 30, 2021
Accepted: November 25, 2021
Article in press: November 25, 2021
Published online: January 19, 2022

The capacity of posttraumatic stress disorder (PTSD) to occur with delayed onset has been documented in several systematic reviews and meta-analyses. Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms.


To obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.


A scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed, which included 38 studies in the qualitative synthesis.


Neurobiological mechanisms underlying PTSD symptoms, onset, and course involve several interconnected systems. Neural mechanisms involve the neurocircuitry of fear, comprising several structures, such as the hippocampus, amygdala, and prefrontal cortex, that are amenable to time-dependent increases in activity through sensitization and kindling. Neural network models explain generalization of the fear response. Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses, both of which may be involved in sensitization to stress. Neuroinflammatory mechanisms are characterized by immune activation, which is sometimes due to the effects of traumatic brain injury. Finally, neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities, and these may be particularly relevant in cases of long-delayed PTSD.


Thus, delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.

Keywords: Posttraumatic stress disorder, Delayed expression, Sensitization, Neurobiology, Neuroendocrine, Neuroinflammatory

Core Tip: Multiple neurobiological mechanisms underlying delayed expression of posttraumatic stress disorder contribute to sensitization, kindling, and generalization leading to increasing symptoms, through epigenetic, neuroinflammatory, neuroendocrine, and neural interactions.