Thickness of ventromedial prefrontal cortex in
humans is correlated with extinction memory
Mohammed R. Milad*, Brian T. Quinn†, Roger K. Pitman*, Scott P. Orr*‡, Bruce Fischl†, and Scott L. Rauch*§
*Department of Psychiatry and†Nuclear Magnetic Resonance Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
and‡Research Service, Veterans Affairs Medical Center, Manchester, NH 03104
Edited by Marcus E. Raichle, Washington University School of Medicine, St. Louis, MO, and approved June 3, 2005 (received for review March 24, 2005)
The ventromedial prefrontal cortex (vmPFC) has been implicated in
fear extinction [Phelps, E. A., Delgado, M. R., Nearing, K. I. &
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.
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 associ-
ated 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
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 genet-
ically 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 once-
neutral 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 condi-
tioned 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 extinction
memory is recalled when the CS is later presented.
xtinction of conditioned fear is of substantial basic and
clinical neuroscientific interest. To describe posttraumatic
Convergent data from the animal literature implicate the
ventral medial prefrontal cortex (vmPFC) in the recall and
expression of extinction memory (5, 9). Lesion and pharmaco-
logical manipulation studies show that the vmPFC is critical for
extinction recall after a delay (10, 11). Activity in single neurons
recorded from the infralimbic (IL) region of the vmPFC (12),
mPFC-evoked potentials (13), and vmPFC metabolism (14) are
all inversely correlated with fear expression during extinction
recall. Furthermore, microstimulation of IL neurons reduces
conditioned freezing in rats that have been conditioned but not
extinguished, simulating a postextinction state (12, 15). Thus, in
rodents, the vmPFC appears to inhibit conditioned fear re-
sponses and mediate extinction recall.
Human neuroimaging studies of fear conditioning have tra-
ditionally focused on acquisition (16). However, two recent
functional MRI studies investigated the neural circuitry of fear
extinction. Gottfried and Dolan (17) showed increased activa-
tion in the vmPFC, including medial orbitofrontal cortex
(mOFC), during extinction of aversive olfactory conditioning.
Phelps et al. (18) found that response in vmPFC during day 2
extinction recall significantly correlated with the success of
extinction training on day 1, as measured by skin conductance
response (SCR), consistent with a role for the vmPFC in the
retention of extinction learning. Extinction of eye-blink condi-
tioning has also been shown to activate the mPFC (19). In
addition, several imaging studies have shown that during differ-
ential conditioning, mPFC activity increases to the CS? (a
stimulus that is not paired with the shock), consistent with the
role of the mPFC in signaling safety (20, 21). Thus, human
(v)mPFC regions appear to play a role similar to that in rodents.
Could the size of the vmPFC explain why some people have
better control of their fear and, therefore, perhaps are more
resilient to emotional trauma? Preliminary data from animals
show that superior extinction memory performance is associated
with larger IL.¶Furthermore, morphometric studies in humans
have shown reduced mPFC volume in PTSD relative to non-
PTSD patients (23). The goal of the present study was to
investigate whether individual differences in fear extinction
relate to the size of the vmPFC in healthy humans. Therefore, we
examined the relationship between brain morphometry and the
results of a 2-day differential conditioning experiment during
which SCRs were measured. The psychophysiological experi-
ment we performed was originally designed to investigate the
effect of context manipulations on extinction retention (24). In
the present study, an automated method (25) was used to
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: vmPFC, ventromedial prefrontal cortex; CS, conditioned stimulus; US, un-
conditioned stimulus; SCR, skin conductance response; mOFC, medial orbitofrontal cortex;
PTSD, posttraumatic stress disorder; IL, infralimbic; ROI, region of interest; rACC, rostral
anterior cingulate cortex; SC, subcallosal cortex; dACC, dorsal anterior cingulate cortex;
CXs, visual contexts.
§To whom correspondence should be addressed at: Department of Psychiatry, 149 13th
Street, CNY 2618, Charlestown, MA 02129. E-mail: email@example.com.
¶Cintron, B. & Quirk, G. J. (2004) Soc. Neurosci. Abstr. 328, 13.
© 2005 by The National Academy of Sciences of the USA
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vol. 102 ?
related cues, PTSD patients show a relative failure of activa-
tion in the mPFC (37, 38, 53, 54, 55). These neuroimaging
studies support the hypothesis that dysfunctional mPFC activ-
ity may underlie the exaggerated fear responses commonly
observed in PTSD. It is also important to note that PTSD
patients have been shown to be deficient in behavioral extinc-
tion (6). A recent morphometric study found reduced vmPFC
volume in persons with PTSD compared with trauma-exposed
persons without PTSD (34). Decreased PFC cortical volumes
have also been observed in panic disorder (56) and obsessive–
compulsive disorder (27).
Recall of extinction learning is also likely to be germane to
the success of behavioral therapies, which are theoretically
extinction-based. Thus, future studies should investigate
whether measures of cortical thickness within the vmPFC
predict therapeutic response to behavioral therapies for anx-
We thank Dr. Gregory J. Quirk for helpful comments on the manuscript
and Michelle Wedig for technical assistance. The work was supported in
part by a grant from the National Institute of Mental Health (to S.L.R.)
and the Massachusetts General Hospital Tosteson Fellowship (to
M.R.M.). In addition, support for this research was provided in part by
the National Center for Research Resources, the National Institute for
Biomedical Imaging and Bioengineering, and the Mental Illness and
Neuroscience Discovery Institute (to B.F.).
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