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: 9.81). 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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    • "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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    ABSTRACT: Early experiences critically shape the structure and function of the brain. Perturbations in typical/species-expected early experiences are known to have profound neural effects, especially in regions important for emotional responding. Parental care is one species-expected stimulus that plays a fundamental role in the development of emotion neurocircuitry. Emerging evidence across species suggests that phasic variation in parental presence during the sensitive period of childhood affects the recruitment of emotional networks on a moment-to-moment basis. Also, it appears that increasing independence from caregivers cues the termination of the sensitive period for environmental input into emotion network development. In this review, we examine how early parental care, the central nervous system, and behaviour come together to form a 'neuro-environmental loop', contributing to the formation of stable emotion regulation circuits. To achieve this end, we focus on the interaction of parental care and the developing amygdala-medial prefrontal cortex (mPFC) network-which is at the core of human emotional functioning. Using this model, we discuss how individual or group variations in parental-independence, across chronic and brief timescales, might contribute to neural and emotional phenotypes that have implications for long-term mental health.Neuropsychopharmacology accepted article preview online, 21 July 2015. doi:10.1038/npp.2015.204.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.204 · 7.83 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.
    Brain Structure and Function 02/2015; DOI:10.1007/s00429-015-1013-z · 4.57 Impact Factor
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    • "This idea is consistent with other studies that show that the vmPFC plays a protective role when cognitive appraisals are specifically engaged to regulate emotion (Eippert et al., 2007; Wager et al., 2008). Milad et al. (Milad et al., 2005) Fig. 6. Brain regions activated during rectal distension preceded by uncertain versus certain anticipation. "
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    ABSTRACT: The human brain responds both before and during the application of aversive stimuli. Anticipation allows the organism to prepare its nociceptive system to respond adequately to the subsequent stimulus. The context in which an uncomfortable stimulus is experienced may also influence neural processing. Uncertainty of occurrence, timing and intensity of an aversive event may lead to increased anticipatory anxiety, fear, physiological arousal and sensory perception. We aimed to identify, in healthy volunteers, the effects of uncertainty in the anticipation of uncomfortable rectal distension, and the impact of the autonomic nervous system (ANS) activity and anxiety-related psychological variables on neural mechanisms of anticipation of rectal distension using fMRI. Barostat-controlled uncomfortable rectal distensions were preceded by cued uncertain or certain anticipation in 15 healthy volunteers in a fMRI protocol at 3T. Electrocardiographic data were concurrently registered by MR scanner. The low frequency (LF)-component of the heart rate variability (HRV) time-series was extracted and inserted as a regressor in the fMRI model ('LF-HRV model'). The impact of ANS activity was analyzed by comparing the fMRI signal in the 'standard model' and in the 'LF-HRV model' across the different anticipation and distension conditions. The scores of the psychological questionnaires and the rating of perceived anticipatory anxiety were included as covariates in the fMRI data analysis. Our experiments led to the following key findings: 1) the subgenual anterior cingulate cortex (sgACC) is the only activation site that relates to uncertainty in healthy volunteers and is directly correlated to individual questionnaire score for pain-related anxiety; 2) uncertain anticipation of rectal distension involved several relevant brain regions, namely activation of sgACC and medial prefrontal cortex and deactivation of amygdala, insula, thalamus, secondary somatosensory cortex, supplementary motor area and cerebellum; 3) most of the brain activity during anticipation, but not distension, is associated with activity of the central autonomic network. This approach could be applied to study the ANS impact on brain activity in various pathological conditions, namely in patients with chronic digestive conditions characterized by visceral discomfort and ANS imbalance such as irritable bowel syndrome or inflammatory bowel diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
    NeuroImage 12/2014; 107. DOI:10.1016/j.neuroimage.2014.11.043 · 6.36 Impact Factor
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