Elsevier

Biological Psychiatry

Volume 62, Issue 5, 1 September 2007, Pages 446-454
Biological Psychiatry

Original Article
Recall of Fear Extinction in Humans Activates the Ventromedial Prefrontal Cortex and Hippocampus in Concert

https://doi.org/10.1016/j.biopsych.2006.10.011Get rights and content

Background

Extinction of conditioned fear is thought to form a new safety memory that is expressed in the context in which the extinction learning took place. Rodent studies implicate the ventromedial prefrontal cortex (vmPFC) and hippocampus in extinction recall and its modulation by context, respectively. The aim of the present study is to investigate the mediating anatomy of extinction recall in healthy humans.

Methods

We used event-related functional magnetic resonance imaging (fMRI) and a 2-day fear conditioning and extinction protocol with skin conductance response as the index of conditioned responses.

Results

During extinction recall, we found significant activations in vmPFC and hippocampus in response to the extinguished versus an unextinguished stimulus. Activation in these brain regions was positively correlated with the magnitude of extinction memory. Functional connectivity analysis revealed significant positive correlation between vmPFC and hippocampal activation during extinction recall.

Conclusions

These results support the involvement of the human hippocampus as well as vmPFC in the recall of extinction memory. Furthermore, this provides a paradigm for future investigations of fronto-temporal function during extinction recall in psychiatric disorders such as posttraumatic stress disorder.

Section snippets

Subjects

A total of 17 psychiatrically healthy subjects (9 men and 8 women, mean age 25 years old, range 19–39) were recruited from the local community. Written informed consent was obtained in accordance with the requirements of the Partners Healthcare System Human Research Committee. Data from three subjects were excluded owing to technical problems, resulting in a final sample size of 14.

Fear Conditioning, Extinction, and Testing Procedures

The stimuli and experimental protocol used in the present study were similar to those used in a previous

Statistical Significance, ROIs

The statistical significance threshold for the contrasts described was p < 10−4 for the peak voxel, accompanied by at least four adjacent voxels with p < 10−3. These calculations incorporated small volume correction on the basis of the volumes of a priori ROIs, viz. vmPFC, hippocampus, and amygdala. A separate Bonferroni correction based on whole brain volume was used to set a significance threshold of p < 10−6 for loci outside the a priori areas (Kennedy et al. 1998). Table 1 lists all brain

Discussion

We observed vmPFC activation to an extinguished CS+ relative to an unextinguished CS+ during extinction recall. This was accompanied by hippocampal activation. Activations in both of these brain regions were positively correlated with an index of extinction memory recall. In addition, activations in these two brain regions during extinction recall were positively correlated with one another. We also observed vmPFC activation during the late stage of extinction learning. Furthermore, we

References (49)

  • D. Barrett et al.

    Metabolic mapping of mouse brain activity after extinction of a conditioned emotional response

    J Neurosci

    (2003)
  • M.E. Bouton

    Context and behavioral processes in extinction

    Learn Mem

    (2004)
  • J.D. Bremner

    Brain imaging in anxiety disorders

    Expert Rev Neurother

    (2004)
  • J.D. Bremner et al.

    Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression

    Am J Psychiatry

    (2004)
  • D.S. Charney

    Discovering the neural basis of human social anxiety: A diagnostic and therapeutic imperative

    Am J Psychiatry

    (2004)
  • K.A. Corcoran et al.

    Hippocampal inactivation disrupts the acquisition and contextual encoding of fear extinction

    J Neurosci

    (2005)
  • K.A. Corcoran et al.

    Hippocampal inactivation disrupts contextual retrieval of fear memory after extinction

    J Neurosci

    (2001)
  • A.M. Dale

    Optimal experimental design for event-related fMRI

    Hum Brain Mapp

    (1999)
  • M. Farinelli et al.

    Hippocampal train stimulation modulates recall of fear extinction independently of prefrontal cortex synaptic plasticity and lesions

    Learn Mem

    (2006)
  • M.W. Gilbertson et al.

    Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma

    Nat Neurosci

    (2002)
  • J.A. Gottfried et al.

    Human orbitofrontal cortex mediates extinction learning while accessing conditioned representations of value

    Nat Neurosci

    (2004)
  • D.J. Heeger et al.

    What does fMRI tell us about neuronal activity?

    Nat Rev Neurosci

    (2002)
  • C. Herry et al.

    Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice

    J Neurosci

    (2002)
  • C. Herry et al.

    Extinction of auditory fear conditioning requires MAPK/ERK activation in the basolateral amygdala

    Eur J Neurosci

    (2006)
  • Cited by (928)

    View all citing articles on Scopus
    View full text