Presence and acquired origin of reduced recall for fear extinction in PTSD: Results of a twin study

Abstract

Recall of fear extinction, which is thought to aid in recovery from a psychologically traumatic event, is hypothesized to be deficient in post-traumatic stress disorder (PTSD), but this has not yet been demonstrated in the laboratory, nor has its origin been investigated. To address these two issues, 14 pairs of monozygotic twins discordant for combat exposure, in 7 of which the combat-exposed twin had PTSD, underwent a two-day fear conditioning and extinction procedure. On Day 1, subjects viewed colored light conditioned stimuli, some of which were paired with mild electric shock, followed by extinction of the conditioned responses. On Day 2, recall of Day 1 extinction learning (i.e., extinction retention) was assessed. Skin conductance response (SCR) was the dependent measure. There were no group differences during acquisition or extinction learning. However, a significant PTSD Diagnosis (in the exposed twin) x combat Exposure interaction emerged during extinction recall, with the PTSD combat veterans having larger SCRs than their own co-twins, and than the non-PTSD combat veterans and their co-twins. These results indicate that retention of extinction of conditioned fear is deficient in PTSD. Furthermore, they support the conclusion that this deficit is acquired as a result of combat trauma leading to PTSD, rather than being a predisposing factor to developing PTSD upon the stress of combat.

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

“…Some design aspects are worth noting; in our experimental paradigm, extinction training was initiated within approximately 10 min after fear conditioning, which was done in order to allow comparison to previous studies (McLaughlin et al., 2015; Milad et al., 2005, 2005, 2007, 2008; van ‘t Wout et al., 2013). Prior research supports the presence of differences in extinction processes depending on their temporal relationship with fear conditioning (Myers, Ressler, & Davis, 2006).…”

“…The experimental protocol utilized a standardized 2‐day Pavlovian fear‐conditioning–extinction‐recall paradigm (Milad, Orr, Pitman, & Rauch, 2005; Milad et al., 2005, 2007, 2008; van ‘t Wout et al., 2013) using E‐Prime 2.0 software (Psychology Software Tools, Pittsburgh, PA). 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).…”