A role for the human dorsal anterior cingulate cortex in fear expression.
ABSTRACT Rodent studies implicate the prelimbic (PL) region of the medial prefrontal cortex in the expression of conditioned fear. Human studies suggest that the dorsal anterior cingulate cortex (dACC) plays a role similar to PL in mediating or modulating fear responses. This study examined the role of dACC during fear conditioning in healthy humans with magnetic resonance imaging (MRI).
Novel analyses were conducted on data from two cohorts that had previously undergone scanning to study fear extinction. Structural and functional brain data were acquired with MRI; the functional MRI (fMRI) component employed an event-related design. Skin conductance response (SCR) was the index of conditioned responses.
We found that: 1) cortical thickness within dACC is positively correlated with SCR during conditioning; 2) dACC is activated by a conditioned fear stimulus; and 3) this activation is positively correlated with differential SCR. Moreover, the dACC region implicated in this research corresponds to the target of anterior cingulotomy, an ablative surgical treatment for patients with mood and anxiety disorders.
Convergent structural, functional, and lesion findings from separate groups of subjects suggest that dACC mediates or modulates fear expression in humans. Collectively, these data implicate this territory as a potential target for future anti-anxiety therapies.
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ABSTRACT: Background / Purpose: The present study uses a Pavlovian fear paradigm together with functional MRI (fMRI) and skin conductance response (SCR) to assess for sex differences in fear conditioning and extinction in trauma-exposed healthy controls (TE-HC) and PTSD groups. Main conclusion: Women with PTSD appeared to remember better previous extinction stimuli than men with PTSD, suggesting a potential new neuro-psychophysiological marker for sex differences in PTSD.68th Society of Biological Psychiatry Annual Meeting 2013; 05/2013
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ABSTRACT: Working memory (WM) capacity is associated with various emotional aspects, including states of depression and stress, reactions to emotional stimuli, and regulatory behaviors. We have previously investigated the effects of WM training (WMT) on cognitive functions and brain structures. However, the effects of WMT on emotional states and related neural mechanisms among healthy young adults remain unknown. In the present study, we investigated these effects in young adults who underwent WMT or received no intervention for 4 weeks. Before and after the intervention, subjects completed self-report questionnaires related to their emotional states and underwent scanning sessions in which brain activities related to negative emotions were measured. Compared with controls, subjects who underwent WMT showed reduced anger, fatigue, and depression. Furthermore, WMT reduced activity in the left posterior insula during tasks evoking negative emotion, which was related to anger. It also reduced activity in the left frontoparietal area. These findings show that WMT can reduce negative mood and provide new insight into the clinical applications of WMT, at least among subjects with preclinical-level conditions.Frontiers in Systems Neuroscience 10/2014; 8:200.
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ABSTRACT: The ventral prefrontal cortex is an integral part of the neural circuitry that is dysregulated in mood and anxiety disorders. However, the contribution of its distinct sub-regions to the regulation of negative emotion are poorly understood. Recently we implicated both the ventrolateral prefrontal cortex (vlPFC) and anterior orbitofrontal cortex (antOFC) in the regulation of conditioned fear and anxiety responses to a social stimulus, i.e., human intruder, in the marmoset monkey. In the present study we extend our investigations to determine the role of these two regions in regulating innate responses and coping strategies to a predator stimulus, i.e., a model snake. Both the vlPFC and antOFC lesioned groups exhibited enhanced anxiety-related responses to the snake in comparison to controls. Both groups also showed a reduction in active coping behavior. These results indicate that the vlPFC and antOFC contribute independently to the regulation of both innate fear and, as previously reported, conditioned fear, and highlight the importance of these regions in producing stimulus-appropriate coping responses. The finding that dysregulation in two distinct prefrontal regions produces the apparently similar behavioral phenotype of heightened negative emotion provides insight into the varied etiology that may underlie this symptom across a wide variety of neuropsychiatric conditions with implications for personalized treatment strategies.Frontiers in Systems Neuroscience 01/2014; 8:250.
A Role for the Human Dorsal Anterior Cingulate Cortex
in Fear Expression
Mohammed R. Milad, Gregory J. Quirk, Roger K. Pitman, Scott P. Orr, Bruce Fischl, and Scott L. Rauch
Background: Rodent studies implicate the prelimbic (PL) region of the medial prefrontal cortex in the expression of conditioned fear.
This study examined the role of dACC during fear conditioning in healthy humans with magnetic resonance imaging (MRI).
Methods: Novel analyses were conducted on data from two cohorts that had previously undergone scanning to study fear extinction.
conductance response (SCR) was the index of conditioned responses.
Results: We found that: 1) cortical thickness within dACC is positively correlated with SCR during conditioning; 2) dACC is activated by a
conditioned fear stimulus; and 3) this activation is positively correlated with differential SCR. Moreover, the dACC region implicated in this
research corresponds to the target of anterior cingulotomy, an ablative surgical treatment for patients with mood and anxiety disorders.
Conclusions: Convergent structural, functional, and lesion findings from separate groups of subjects suggest that dACC mediates or
modulates fear expression in humans. Collectively, these data implicate this territory as a potential target for future anti-anxiety therapies.
Key Words: Classical, conditioning, fear, galvanic skin response,
gyrus cinguli, magnetic resonance imaging, memory
prelimbic (PL) division of the medial prefrontal cortex (mPFC)
also plays a role in conditioned fear expression (7–10). For
example, microstimulation of PL increases conditioned freezing
(11), whereas inactivation of PL reduces it (12,13). The PL region
in rodents seems to be homologous with the dorsal anterior
cingulate cortex (dACC) in humans (14,15). The dACC in humans
and non-human primates projects to the basolateral amygdala
(BLA), similarly to PL in rodents. Moreover, because BLA seems
to be involved in mediating conditioned fear (16) and the dACC
projections to BLA are excitatory (17), it is plausible that dACC
might be involved in mediating or modulating fear expression
through excitation of the amygdala. Therefore, we investigated
whether the human dACC is implicated in conditioned fear.
Although several human neuroimaging studies have reported
incidental activation of the dACC during acquisition of fear
conditioning (4,18–21), the role of the dACC in the expression of
conditioned fear responses has not been well explored. To
address this, we first examined whether the size of the dACC, as
measured by cortical thickness, would be correlated with skin
conductance response (SCR) to a conditioned stimulus signaling
fear (CS?) during acquisition. Second, we examined whether
dACC would be activated during fear acquisition and whether
such activation would be correlated with the expression of
plethora of data across species highlight the role of the
amygdala in the acquisition and expression of learned
fear (1–6). Rodent studies, however, suggest that the
conditioned fear responses. We conducted novel analyses on
two separate cohorts of healthy humans that had been previously
scanned to study the neural circuits of fear extinction (22,23). We
predicted that, consistent with a role of dACC in the generation
of conditioned fear, the structure and function of the dACC
would be positively correlated with the SCR to conditioned
stimuli during fear acquisition.
Methods and Materials
Subjects were mentally healthy and ranged in age from 19 to
39. Fourteen subjects (8 men, 6 women) participated in the
structural magnetic resonance imaging (MRI) component. Thir-
teen different subjects (7 men, 6 women) participated in the fMRI
component. Written informed consent was obtained in accor-
dance with the requirements of the Partners Healthcare System
Human Research Committee.
Reported herein are novel analyses of the aforementioned
two separate cohorts that underwent a fear conditioning and
extinction protocol as part of previously reported studies (22–
24). Here we focus on the relationship between cortical thickness
and functional activation of the dACC and conditioned fear
expression during the acquisition (conditioning) phase. In brief,
participants underwent a differential fear conditioning paradigm
in which they viewed pictures of different rooms (contexts)
containing a variable colored light (cue). One color was paired
with a mild electric shock (unconditioned stimulus [US]) to their
fingers (CS?), whereas a different color was not (CS?). The US
delivery occurred immediately at CS? offset.
In the structural component, we used automated methods to
measure thickness across the entire cerebral cortex. Thickness at
each vertex (resolution unit) was correlated with SCR to the CS?
averaged across trials, and these correlations were mapped as
previously described (22). This method allows for an unbiased
search of correlates between SCR and cortical thickness.
The functional component used blood oxygen level-depen-
dent (BOLD) signal to measure brain activation. The main effect
of stimulus type was first assessed via a CS? versus CS? contrast
across trials. To examine the relationship between activation in
the dACC and fear expression, we conducted a voxel-wise
Resonance Center (BF), Massachusetts General Hospital and Harvard
Department of Psychiatry (GJQ), University of Puerto Rico School of
ment of Veterans Affairs Medical Center, Manchester, New Hampshire.
Address reprint requests to Mohammed R. Milad, Ph.D., Department of
Psychiatry, Massachusetts General Hospital, Bldg 149, 13th Street, 2nd
Floor, Charlestown, MA 02129; E-mail: email@example.com.
Received February 22, 2007; revised April 17, 2007; accepted April 24, 2007.
BIOL PSYCHIATRY 2007;62:1191–1194
© 2007 Society of Biological Psychiatry
correlational analysis with differential SCR (CS? ? CS?). For
further methodological details, see Supplement 1.
All subjects showed significant increases in SCR to the CS?
relative to the CS?, indicating successful differential condition-
ing (23,24). We observed a significant positive correlation be-
tween thickness in the dACC region (peak vertex: r ? .70, p ?
.005 [Talairach coordinates ?3, 23, 18) and SCR to the CS?
(Figures 1A and 1B). We did not observe a significant correlation
that satisfied our statistical threshold (p ? .01, two-tailed, uncor-
rected) between dACC thickness and SCR to the CS? (r ? .58,
p ? .03) or differential SCR (CS? ? CS?) (r ? .57, p ? .03).
In the BOLD signal analyses, we observed a significant main
effect of stimulus type across conditioning trials. Specifically,
dACC activation was significantly higher in response to the CS?
relative to the CS? (p ? .001, peak at x ? 1, y ? 21, z ? 27,
Figure 1C). Voxel-wise correlational analysis revealed a signifi-
cant correlation between differential SCR and dACC activation
(r ? .84, p ? .001, x ? 3, y ? 33, z ? 21, Figure 1D). We also
examined whether dACC increased its activity to the presentation
of the CS? or the US, as a control; but we did not find a
significant effect for either. Nevertheless, we conducted further
across the medial cortical surface showing the location of the significant correlation between dACC thickness and fear conditioning (red circle). Threshold is
set at p ? .01 (dark red) to p ? .001 (bright yellow). (B) Regression plot for the correlation between the dACC and skin conductance response to the
conductance response (CS? ? CS?). (E) A typical anterior cingulotomy lesion, as visualized from parasagittal perspective via a conventional clinical
T1-weighted magnetic resonance imaging (MRI) (red circle). (F) Reduction of symptom severity in obsessive-compulsive disorder (OCD) symptoms after
cingulotomy. Post-surgery mean follow-up time was 36 months with an SD of 32 months. YBOCS, Yale-Brown Obsessive Compulsive Scale score. *p ? .05.
Error bars represent SEM. (Data from Dougherty et al. ).
1192 BIOL PSYCHIATRY 2007;62:1191–1194
M. R. Milad et al.
analyses to examine the association between dACC response to
the CS?, the US, and the corresponding SCRs. With a CS? versus
pre-CS? contrast, we found a significant correlation between
SCR to the CS? and dACC activation (r ? .70, p ? .003, x ? ?1,
y ? 30, z ? 10). We also found a significant correlation between
the unconditioned response (UCR) to the shock and dACC
activation during its delivery (r ? .69, p ? .004, x ? 3, y ? 20,
z ? 24). Because the shock was delivered immediately after the
offset of the CS (i.e., during fixation), here the contrast was UCR
during fixation versus fixation alone.
To investigate whether dACC was activated as part of an
orienting response to any stimulus, we examined whether SCR
induced by presentation of the context alone (i.e., before shock)
correlated with dACC activity. Here SCR was calculated as peak
skin conductance level during context presentation—skin con-
ductance level during the preceding 2 sec. The average SCR to
the context was .14 ? .09 SD (square root ?S, ranging from ?.03
to .26). Novel contrast images for context versus fixation were
created for each subject and correlated with SCR to the context
on a voxel-wise basis. No significant correlations were observed.
We found that dACC thickness was positively correlated with
conditioned fear responses to the CS?, as indexed by SCR. In a
separate cohort of subjects, dACC functional activation increased
to the CS? relative to the CS? during fear conditioning, and
dACC activity was positively correlated with differential SCR. The
convergence of structural and functional correlates of condi-
tioned fear responding in the dACC reported herein is remark-
able, considering that these two data sets were obtained from
separate cohorts. Although the presentation of the CS? and the
US did not induce significant activation in the dACC, the SCRs
induced by these two stimuli were positively correlated with the
variance in dACC activation during these two conditions. This
suggests that the dACC might be involved in the expression of
fear responses in general. In a finding consistent with this view,
Vogt et al. (25) suggested that fear is associated with activation
specifically in this region of the ACC. Indeed, rodent studies
support the involvement of a homologous region, the prelimbic
cortex, in the expression of conditioned fear (7,8,11,13).
An alternate interpretation of the present data is that the
correlations observed between dACC and SCR might reflect a
role of the dACC in detecting salience (i.e., the importance of the
stimulus being presented). The data presented herein cannot rule
out this possibility. However, presentation of the CS? and the US
were also arousing, especially during the early conditioning
trials. Yet, we did not observe a significant dACC response to
either the CS? or US, which argues against this possibility. Also,
SCR induced after the presentation of the context was not
correlated with dACC activity. Nonetheless, further studies are
needed to more fully delineate the involvement of the dACC in
A role for the dACC in the generation of autonomic responses
has been previously reported (26). Electrical stimulation of the
dACC induces SCRs (27), whereas lesions of this brain region
attenuate SCRs (28). Previous neuroimaging studies have re-
ported positive correlations between activation in sub-regions of
the ACC (including dACC) and changes in autonomic responses
including SCR during high arousal states (reviewed in 29).
Non-specific SCRs have been found to be positively correlated
with dACC activation during aversive fear conditioning (21).
These studies suggest a link between dACC and SCR in general.
Other neuroimaging studies, however, have failed to find corre-
lations between resting state or spontaneous fluctuations of SCR
and dACC activation (30–32). Furthermore, frontal lesions in
humans, including dACC lesions, do not affect resting or orient-
ing SCRs (33). In the present study, the absence of a significant
correlation between dACC activation and SCR to the context
alone indicates that dACC activation is not associated with
changes in SCR under all circumstances.
The location of the dACC region that we found to be
correlated with fear expression approximates the target of ante-
rior cingulotomy (34,35), an ablative neurosurgical treatment for
patients with treatment-refractory mood and anxiety disorders
(see Figure 1E). Up to 40% of patients with severe obsessive
compulsive disorder (OCD) who had previously failed to re-
spond to medications and behavioral therapy show marked
improvement in OCD symptoms after cingulotomy (Figure 1F)
(36). Patients receiving brief intra-operative electrical stimulation
of the dACC report feelings of intense fear, whereas ablation of
this brain region significantly reduces anxiety symptoms (37).
The data obtained herein further suggest that the dACC could be
a potential target for future anti-anxiety therapies. Whereas
enhancement of function within ventromedial PFC has been
proposed as a means for suppressing amygdala responses and
facilitating extinction recall (3,23,38–41), neutralizing dACC
function might be an effective complementary strategy for ame-
The work was supported by a grant from the National Institute
of Mental Health (1R21MH072156-1) to SLR.
Dr. Rauch receives occasional honoraria or consulting fees
from Cyberonics, Novartis, and Neurogen; he has also received
funding for research at Massachusetts General Hospital from
Cephalon and Medtronic; finally, past fellows in his research
division have received funding from Pfizer. None of the remain-
ing co-authors have any financial disclosures to report.
We thank Dr. Jennifer Britton for assistance with data
analysis and Dr. Kevin Corcoran for helpful comments on the
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