Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory

Abstract

Here, we test the hypothesis that the cortical thickness of vmPFC regions is associated with how well healthy humans retain their extinction memory a day after having been conditioned and then extinguished. Fourteen participants underwent a 2-day fear conditioning and extinction protocol. The conditioned stimuli (CSs) were pictures of virtual lights, and the unconditioned stimulus (US) was an electric shock. On day 1, participants received 5 CS؉US pairings (conditioning), followed by 10 CS trials with no US (extinction). On day 2, the CS was presented alone to test for extinction memory. Skin conductance response (SCR) was the behavioral index of conditioning and extinction. Participants underwent MRI scans to obtain structural images, from which cortical thickness was measured. We performed a vertexbased analysis across the entire cortical surface and a region-ofinterest analysis of a priori hypothesized territories to measure cortical thickness and map correlations between this measure and SCR. We found significant, direct correlation between thickness of the vmPFC, specifically medial orbitofrontal cortex, and extinction retention. That is, thicker medial orbitofrontal cortex was associated with lower SCR to the conditioned stimulus during extinction recall (i.e., greater extinction memory). These results suggest that the size of the vmPFC might explain individual differences in the ability to modulate fear among humans.cortical thickness ͉ fear conditioning ͉ orbitofrontal cortex E xtinction of conditioned fear is of substantial basic and clinical neuroscientific interest. To describe posttraumatic stress disorder (PTSD), the Diagnostic and Statistical Manual of Mental Disorders (1) gives the example of a woman who is raped in an elevator and subsequently comes to fear all elevators. Recovery from PTSD entails, among other things, learning not to fear situations associated with the traumatic event (i.e., to extinguish conditioned fear responses) (2). It has been reported that 2 weeks after a rape, 92% of victims met symptom criteria for PTSD, but 3 months later only 47% did (3). Such individual differences in recovery from PTSD are likely related to genetically influenced individual differences in fear extinction and its retention (4). It is quite possible that these differences are mediated by variance in regional brain structures.Under a Pavlovian (classical) conditioning model, a onceneutral conditioned stimulus (CS) (e.g., a light) is paired with an aversive unconditioned stimulus (US) (e.g., a shock). After a few pairings, the CS comes to elicit various manifestations of a fear conditioned response, including freezing in rodents (5) and increased skin conductance in humans (6). When the CS is then repeatedly presented in the absence of the shock, the conditioned response is extinguished. There is substantial evidence indicating that fear extinction results in the formation of a new memory that coexists with, but opposes, the initial conditioning memory (7,8). Under favorable circumstances, the extinctio...

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). …”

“…Skin conductance reactivity (SCR) for each trial was calculated by subtracting mean skin conductance level during the 3 s before CS onset (i.e., context alone was being presented) from the highest skin conductance level during the 6 s CS duration to reflect changes beyond any change produced by the presentation of context (McLaughlin et al., 2015; Milad et al., 2005, 2005, 2007; Orr et al., 2000; van ‘t Wout et al., 2013). SCR data were normalized using log transformation.…”

“…Animal models and human studies of PTSD have highlighted aberrations in neural circuitry including hyperactivity in the amygdala and dorsal anterior cingulate cortex, regions that promote fear responses, alongside hypoactivity in the ventromedial prefrontal cortex (vmPFC), a region that is thought to suppress fear responses (Milad & Quirk, 2012; Quirk, Garcia, & González‐Lima, 2006; VanElzakker et al., 2014). 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).…”