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


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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    • "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.
    NeuroImage 07/2015; 122. DOI:10.1016/j.neuroimage.2015.07.051 · 6.36 Impact Factor
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    • "Rodent studies have demonstrated both structural and functional connections between amygdala and mPFC (McDonald et al., 1996; Quirk et al., 2003), and have shown that mPFC lesions (specifically of the infralimbic region; IL) result in impaired extinction retention, while leaving extinction learning intact (Milad & Quirk, 2002; Quirk et al., 2000). Similarly, in humans, recall of extinguished fear memories increases vmPFC reactivity in response to the CS+ (Milad et al., 2007; Phelps et al., 2004), and is positively associated with vmPFC thickness (Milad et al., 2005). Also, on a different emotion regulation task involving cognitive reappraisal of a negative event, the amygdala showed stronger coupling with the dlPFC, OFC, Subgenual ACC, and dmPFC, with the extent of such coupling being positively associated with post-reappraisal attenuation of negative affect (Banks et al., 2007; Ochsner et al., 2002; Urry et al., 2006). "
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    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.204 · 7.05 Impact Factor
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    • "To our knowledge there are no studies investigating a potential association between (the rate of) extinction learning (i.e., number of trials until complete extinction) and (the strength of) extinction memory. The prefrontal areas correlating with extinction learning performance in our study strongly overlap with areas that were previously found to correlate with extinction memory (Hartley et al. 2011; Milad et al. 2005). This is consistent with a positive relationship between extinction learning and extinction memory. "
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    ABSTRACT: The neural circuits underlying fear learning have been intensively investigated in pavlovian fear conditioning paradigms across species. These studies established a predominant role for the amygdala in fear acquisition, while the ventromedial prefrontal cortex (vmPFC) has been shown to be important in the extinction of conditioned fear. However, studies on morphological correlates of fear learning could not consistently confirm an association with these structures. The objective of the present study was to investigate if interindividual differences in morphology of the amygdala and the vmPFC are related to differences in fear acquisition and extinction learning in humans. We performed structural magnetic resonance imaging in 68 healthy participants who underwent a differential cued fear conditioning paradigm. Volumes of subcortical structures as well as cortical thickness were computed by the semi-automated segmentation software Freesurfer. Stronger acquisition of fear as indexed by skin conductance responses was associated with larger right amygdala volume, while the degree of extinction learning was positively correlated with cortical thickness of the right vmPFC. Both findings could be conceptually replicated in an independent sample of 53 subjects. The data complement our understanding of the role of human brain morphology in the mechanisms of the acquisition and extinction of conditioned fear.
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