Impaired safety signal learning may be a biomarker of PTSD

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'.

Figure 1

Diagram of the trial design in the AX+/BX− human paradigm. CS=conditioned stimulus, US=unconditioned stimulus

Figure 2

Diagram of the AX+/BX− session in the human paradigm.

Figure 3

Mean Fear-Potentiated Startle on AX+, BX−, and AB trials across diagnostic groups from three studies. A. Fear-potentiated startle in Vietnam veterans with high symptoms of PTSD (n=13) and low symptoms of PTSD (n=14), and healthy age-matched controls (n=28). Figure adapted from (Jovanovic et al., 2009). B. Fear-potentiated startle in a traumatized civilian sample with PTSD (n=29) and without PTSD (n=61). Figure adapted from (Jovanovic et al., 2010b). C. Fear-potentiated startle in a traumatized civilian sample with comorbid PTSD and MDD (n=22), PTSD only (n=14), MDD only (n=17), and neither diagnosis (n=53). Figure adapted from (Jovanovic et al., 2010a). The Y-axis represents average percent startle potentiation for each trial type. This value was derived as follows: Percent Startle Potentiation = 100 x (startle magnitude during CS trials – NA startle)/(NA startle).

Figure 4

Representative cases of each lesion group are represented by both the MR images showing either edema resulting from cell death after neurotoxic damage for (A) and (B), or loss of tissue due to aspiration for (C). Damage was then plotted onto an infant brain atlas as seen on the right hand columns for (A, B, & C). Arrows indicate either unintended damage or unintended sparing. Abbreviations: A=amygdala; ERh=entorhinal cortex; H=hippocampus; PRh=perirhinal cortex; TE, temporal cortical area and TH/TF=cytoarchitectonic fields of the parahippocampal gyrus as defined by von Bonin and Bailey (1947); Orbital Frontal Cortex Areas 10, 11, 12, 13, 14, & 25 as defined by Broadmann (1909).