Article

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

Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2005; 102(30):10706-11. DOI: 10.1073/pnas.0502441102
Source: PubMed

ABSTRACT

The ventromedial prefrontal cortex (vmPFC) has been implicated in fear extinction [Phelps, E. A., Delgado, M. R., Nearing, K. I. & Ledoux, J. E. (2004) Neuron 43, 897-905; Herry, C. & Garcia, R. (2003) Behav. Brain Res. 146, 89-96]. 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 vertex-based analysis across the entire cortical surface and a region-of-interest 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.

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    • "The neuroscience of punishment-driven learning has reached a different conclusion. Studies using classical fear conditioning consistently find that the vmPFC BOLD signal correlates with the updating of a learned fear response (Phelps et al., 2004;Milad et al., 2005b;Kalisch et al., 2006;Milad et al., 2007a;Delgado et al., 2008;Schiller et al., 2008;Milad and Quirk, 2012;Schiller et al., 2013). This finding repeats in tasks using various strategies for inhibiting the fear response to a stimulus that was previously paired with an aversive outcome (Schiller and Delgado, 2010). "
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    ABSTRACT: Decision-making studies have implicated the ventromedial prefrontal cortex (vmPFC) in tracking the value of rewards and punishments. At the same time, fear-learning studies have pointed to a role of the same area in updating previously learned cue–outcome associations. To disentangle these accounts, we used a reward reversal-learning paradigm in a functional magnetic resonance imaging study in 18 human participants. Participants first learned that one of two colored squares (color A) was associated with monetary reward, whereas the other (color B) was not, and then had to learn that these contingencies reversed. Consistent with value representation, activity of a dorsal region of vmPFC was positively correlated with reward magnitude. Conversely, a more ventral region of vmPFC responded more to color A than to color B after contingency reversal, compatible with a role of inhibiting the previously learned response that was no longer appropriate. Moreover, the response strength was correlated with subjects’ behavioral learning strength. Our findings provide direct evidence for the spatial dissociation of value representation and affective response inhibition in the vmPFC.
    Full-text · Article · Dec 2015
    • "Following previous research (Milad et al, 2005 "
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    ABSTRACT: Alterations in learning processes and the neural circuitry that supports fear conditioning and extinction represent mechanisms through which trauma exposure might influence risk for psychopathology. Few studies examine how trauma or neural structure relates to fear conditioning in children. Children (n=94) aged 6-18 years, 40.4% (n=38) with exposure to maltreatment (physical abuse, sexual abuse, or domestic violence), completed a fear conditioning paradigm utilizing blue and yellow bells as conditioned stimuli (CS+/CS-) and an aversive alarm noise as the unconditioned stimulus. Skin conductance responses (SCR) and self-reported fear were acquired. Magnetic resonance imaging data were acquired from 60 children. Children without maltreatment exposure exhibited strong differential conditioning to the CS+ versus CS-, based on SCR and self-reported fear. In contrast, maltreated children exhibited blunted SCR to the CS+ and failed to exhibit differential SCR to the CS+ versus CS- during early conditioning. Amygdala and hippocampal volume were reduced among children with maltreatment exposure and were negatively associated with SCR to the CS+ during early conditioning in the total sample, although these associations were negative only among non-maltreated children and were positive among maltreated children. The association of maltreatment with externalizing psychopathology was mediated by this perturbed pattern of fear conditioning. Child maltreatment is associated with failure to discriminate between threat and safety cues during fear conditioning in children. Poor threat-safety discrimination might reflect either enhanced fear generalization or a deficit in associative learning, which may in turn represent a central mechanism underlying the development of maltreatment-related externalizing psychopathology in children.Neuropsychopharmacology accepted article preview online, 18 December 2015. doi:10.1038/npp.2015.365.
    No preview · Article · Dec 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Our observation that synergistic actions among the hippocampus, the amygdala and the vmPFC safeguard the organism from fear renewal might be of relevance to understand trauma-induced anxiety conditions such as PTSD. Reduced vmPFC volumes have been observed in patients with PTSD (Hartley et al., 2011; Milad et al., 2005), which could be a risk factor (as well as a maintaining factor) in PTSD due to the role it plays in mediating effects of the hippocampus on the amygdala. Morphologic alterations in PTSD have also been found in the amygdala (Morey et al., 2012) and the hippocampus (Bremner et al., 1995), further pointing to the usefulness of circuit-level analysis to understand neural dysfunctions in this disorder. "
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    ABSTRACT: The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · NeuroImage
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