Elsevier

Neuropharmacology

Volume 62, Issue 2, February 2012, Pages 695-704
Neuropharmacology

Invited review
Impaired safety signal learning may be a biomarker of PTSD

https://doi.org/10.1016/j.neuropharm.2011.02.023Get rights and content

Abstract

A dysregulated fear response is one of the hallmark clinical presentations of patients suffering from posttraumatic stress disorder (PTSD). These patients show over-generalization of fear and in tandem an inability to inhibit fear responses in the presence of safety. Here, we summarize our recent findings using a conditional discrimination paradigm, which assesses safety signal processing (AX+/BX−) in combat and civilian PTSD populations. Overall, PTSD subjects demonstrate a lack of safety signal learning and an inability to modulate the fear responses with safety cues. We then review studies of the neurobiology of fear expression and inhibition in humans and non-humans, in order to provide a background for preliminary studies using reverse translation procedures in which the same AX+/BX− paradigm was used in rhesus macaques.

This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

Highlights

► Fear-potentiated startle is a highly useful translational measure of fear in PTSD. ► Conditional discrimination (AX+/BX−) assesses fear expression and inhibition of fear. ► Impaired fear inhibition is observed in combat and civilian trauma-related PTSD. ► Impaired fear inhibition is specific to PTSD rather than comorbid depression. ► Reverse translation of AX+/BX− can give insight into neurobiology of fear inhibition.

Section snippets

Clinical phenomenology of fear inhibition to safety signals

Excessive fear and anxiety, along with an inability to overcome these emotions, are some of the defining characteristics of many anxiety disorders, such as phobias, panic disorder and posttraumatic stress disorder (PTSD). Several theorists (Amstedler et al., 2009, Friedman, 2010, Keane et al., 1985) have proposed that fear conditioning processes are involved in the etiology and maintenance of PTSD. According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV; APA,

Reverse translation of fear inhibition to safety signals

Fear conditioning offers a unique framework for translational studies, given that it can be modeled in animal experiments. Animal models of fear conditioning and fear inhibition provide useful tools for the study of these phenomena; therefore, it is essential to translate these models to human research. Moreover, the use of similar methods across different species allows for reverse translation, whereby a clinical phenomenon can be explored more rigorously in animal models. Because AX+/BX−

General discussion and future directions

Taken together, the clinical and animal model literature suggests several discreet but interconnected areas of the brain wherein a healthy fear response becomes uncontrollable. Furthermore, a reverse translational approach promises to shed further light on the complicated interaction between areas such as the amygdala, which appear to be important for fear learning, and that of other areas such as the hippocampus and prefrontal cortices, which may be important for regulating learned fears.

Acknowledgements

The work described in this review has been supported by funding from the National Institutes of Mental Health, including the following grants: Kirschstein National Research Service Award Individual Fellowship 1F32 MH070129-01A2 (TJ), R37 MH47840 (MD), HD35471 and MH-58846 (JB) as well as grant MH086947 (JB and MD).

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