Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder

Abstract

Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.

Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

“…Participants were presented with photographs of two different rooms, one serving as the fear acquisition context (CX+; picture of an office) and one as the fear extinction context (CX−; picture of a bookcase) in which two conditioned stimuli (CS+; red and blue light) and one never‐to‐be conditioned stimulus (CS−; yellow light) were presented. Two CS+ were included to allow comparison of results to previous studies on PTSD (Milad et al., 2009) and the effects of tDCS during fear extinction in healthy volunteers (van ‘t Wout et al., 2013), and lay the foundation for future sham‐controlled studies. For this same reason, we followed prior studies in the timing of habituation, conditioning, and extinction to occur on Day 1, and extinction recall on Day 2 approximately 24 hr later (McLaughlin et al., 2015; Milad et al., 2005, 2005, 2007, 2008; van ‘t Wout et al., 2013).…”

“…More specifically, vmPFC engagement during extinction learning predicts extinction success and is associated with “top‐down” modulation of amygdala‐driven fear expression (Do‐Monte, Manzano‐Nieves, Quiñones‐Laracuente, Ramos‐Medina, & Quirk, 2015; Lebrón, Milad, & Quirk, 2004; Milad et al., 2005, 2007; Phelps, Delgado, Nearing, & LeDoux, 2004; Quirk, Likhtik, Pelletier, & Paré, 2003; Rosenkranz, Moore, & Grace, 2003). Results from studies with PTSD patients revealed deficits in extinction recall (Milad et al., 2008), reduced vmPFC volume, and activation during fear extinction compared to controls (Bremner et al., 2005; Milad et al., 2009; Rauch et al., 2003; Rougemont‐Bücking et al., 2011; Shin, Rauch, & Pitman, 2006). Therefore, facilitating endogenous vmPFC activity using brain stimulation techniques, in the context of extinction learning, may be one method to improve fear extinction and retention (i.e., recall of safety memories; Milad & Quirk, 2002; Milad, Vidal‐Gonzalez, & Quirk, 2004) in those suffering from PTSD.…”

“…We conducted this pilot study to test the following hypotheses: (1) whether active tDCS during extinction learning compared to sham stimulation would augment late extinction learning, and (2) whether the effects of tDCS during extinction learning vs. during extinction consolidation, that is, immediately after extinction learning, on early extinction recall tested 24 hr later would differ. This idea of stimulating immediately after extinction learning, during consolidation, was based on reports that PTSD is associated with impairments in extinction recall (Garfinkel et al., 2014; Milad et al., 2008, 2009; Norrholm et al., 2011), even though extinction can be acquired. Therefore, testing the effects of tDCS during consolidation of fear extinction provides a first step to examining various possibly important time points in which noninvasive brain stimulation could be used to enhance components of extinction learning and memory (Marin & Milad, 2015).…”

Gradients of Fear Potentiated Startle During Generalization, Extinction, and Extinction Recall—and Their Relations With Worry

“…Several mechanisms have been proposed to explain how aberrant fear learning could contribute to anxiety, such that anxious compared to non-anxious individuals display: (a) easier conditionability ; (b) failure to inhibit fear to safety signals (Davis, Falls, & Gewirtz, 2000); (c) overgeneralization of fear to stimuli that are perceptually similar to a threat (Lissek et al, 2008;Lissek et al, 2009); and (d) deficient fear extinction Peri, Shakhar, Orr, & Shalev, 2000) and/or deficient recall of extinction memories (Milad et al, 2008;Milad et al, 2009). The theory of overgeneralization of fear is particularly interesting since different patterns (i.e., gradients) of fear response may be thought of as individual differences within the fear learning process that contribute to why some individuals develop and maintain anxiety disorders while others do not.…”

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex

“…For example, inactivation of the basal amygdala completely blocks acquisition of extinction (Herry et al, 2008) and c-fos induction in the basal amygdala is strongly reduced in animal models of impaired extinction learning (Muigg et al, 2008). Likewise higher amygdala activation during extinction learning has been described in a recent human imaging study investigating PTSD patients (Milad et al, 2009). In our case, stress lead to a significant raise of basal amygdala activation independently of the behavior during extinction (i.e.…”