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  • Review Article
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Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits

Nature Reviews Neurology volume 18, pages 273–288 (2022)Cite this article

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Abstract

Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder, characterized by re-experiencing, avoidance, negative emotions and thoughts, and hyperarousal in the months and years following exposure to severe trauma. PTSD has a prevalence of approximately 6–8% in the general population, although this can increase to 25% among groups who have experienced severe psychological trauma, such as combat veterans, refugees and victims of assault. The risk of developing PTSD in the aftermath of severe trauma is determined by multiple factors, including genetics — at least 30–40% of the risk of PTSD is heritable — and past history, for example, prior adult and childhood trauma. Many of the primary symptoms of PTSD, including hyperarousal and sleep dysregulation, are increasingly understood through translational neuroscience. In addition, a large amount of evidence suggests that PTSD can be viewed, at least in part, as a disorder that involves dysregulation of normal fear processes. The neural circuitry underlying fear and threat-related behaviour and learning in mammals, including the amygdala–hippocampus–medial prefrontal cortex circuit, is among the most well-understood in behavioural neuroscience. Furthermore, the study of threat-responding and its underlying circuitry has led to rapid progress in understanding learning and memory processes. By combining molecular–genetic approaches with a translational, mechanistic knowledge of fear circuitry, transformational advances in the conceptual framework, diagnosis and treatment of PTSD are possible. In this Review, we describe the clinical features and current treatments for PTSD, examine the neurobiology of symptom domains, highlight genomic advances and discuss translational approaches to understanding mechanisms and identifying new treatments and interventions for this devastating syndrome.

Key points

  • Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric disorder, characterized by re-experiencing, avoidance, negative emotions and thoughts, and hyperarousal.

  • PTSD is frequently comorbid with neurological conditions such as traumatic brain injury, post-traumatic epilepsy and chronic headaches.

  • PTSD has a prevalence of approximately 6–8% in the general population and up to 25% among individuals who have experienced severe trauma.

  • Many of the neural circuit mechanisms that underlie the PTSD symptoms of fear-related and threat-related behaviour, hyperarousal and sleep dysregulation are becoming increasingly clear.

  • Key brain regions involved in PTSD include the amygdala–hippocampus–prefrontal cortex circuit, which is among the most well-understood networks in behavioural neuroscience.

  • Combining molecular–genetic approaches with a mechanistic knowledge of fear circuitry will enable transformational advances in the conceptual framework, diagnosis and treatment of PTSD.

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Fig. 1: Schematic diagram of neural circuitry involved in fear conditioning and post-traumatic stress disorder.
Fig. 2: Neurophysiological findings commonly seen in individuals with PTSD.
Fig. 3: Schematic diagram of circuits and neurotransmitters regulating fear and threat responses.

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Acknowledgements

This work was supported by NIH awards P50-MH115874 (to W.C./K.J.R.), R01-MH108665 (to K.J.R.), R01-MH063266 (to W.C.), R01-MH123993 (to V.Y.B.), and the Frazier Institute at McLean Hospital (to K.J.R.). I.R. was partially supported by (R01-MH120400).

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  1. SPARED Center, Department of Psychiatry, McLean Hospital, Harvard Medical School, Boston, MA, USA

    Kerry. J. Ressler, Sabina Berretta, Vadim Y. Bolshakov, Isabelle M. Rosso, Edward G. Meloni, Scott L. Rauch & William A. Carlezon Jr

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  1. Kerry. J. Ressler
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  2. Sabina Berretta
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  3. Vadim Y. Bolshakov
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  4. Isabelle M. Rosso
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  5. Edward G. Meloni
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The authors contributed equally to all aspects of the article.

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Correspondence to Kerry. J. Ressler.

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Competing interests

K.J.R. has received consulting income from Alkermes, Bionomics, Bioxcel and Jazz Pharmaceuticals, and is on scientific advisory boards for the Army STARRS Project, Janssen, the National Center for PTSD, Sage Therapeutics and Verily. He has also received sponsored research support from Brainsway and Takeda. He also serves on the Boards of ACNP and Biological Psychiatry. W.C. has received consulting income from Psy Therapeutics and has a sponsored research agreement with Cerevel Therapeutics. He is the editor-in-chief for Neuropsychopharmacology and serves on the board of ACNP. None of this work is directly related to the work presented here. S.L.R. receives compensation as a Board member of Community Psychiatry and for his role as Secretary of SOBP. He also serves on the Boards of ADAA and NNDC. He has received royalties from Oxford University Press and APPI.

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Nature Reviews Neurology thanks Matthew Girgenti, Soraya Seedat and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Hyperarousal

A core feature of post-traumatic stress disorder (PTSD) that includes irritability, panic and disruptions in sleep and cognitive function.

Startle response

A reflex that occurs rapidly and unconsciously in response to an external stimulus such as a noise burst.

Hypervigilance

A core feature of post-traumatic stress disorder (PTSD) characterized by a heightened state of active threat assessment.

Cre-recombinase-dependent expression

A method of inducing alterations in gene expression involving the ability of the enzyme Cre-recombinase to induce site-specific recombination of genetic material.

Engram

A theoretical representation of a neural unit of memory storage.

Orbicularis muscle

A muscle located in the eyelid, activity of which is often an end point in human fear conditioning research.

Endophenotypes

Secondary phenotypes that reliably co-occur as a sub-feature of a broader primary phenotype.

Co-regulated

Two or more biological processes that are modulated (activated, suppressed) in parallel by a common upstream factor.

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Ressler, K.J., Berretta, S., Bolshakov, V.Y. et al. Post-traumatic stress disorder: clinical and translational neuroscience from cells to circuits. Nat Rev Neurol 18, 273–288 (2022). https://doi.org/10.1038/s41582-022-00635-8

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