A commentary on Fear-conditioning mechanisms associated with trait vulnerability to anxiety in human

Dunsmoor, Joseph E.

LaBar, Kevin S.

Åhs, Fredrik

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Joseph Edward Dunsmoor

Fredrik eAhs

Kevin S LaBar

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Frontiers in Human Neuroscience

Neurocognitive mechanisms of fear conditioning and vulnerability to anxiety

Joseph E. Dunsmoor

Fredrik Åhs

Kevin S. LaBar

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Neurocognitive Mechanisms of Fear Conditioning and Vulnerability to Anxiety

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Dunsmoor, JE

Ahs, F

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Neurocognitive mechanisms of fear conditioning and vulnerability to anxiety.

HUMAN NEUROSCIENCE
Neurocognitive mechanisms of fear conditioning and 
vulnerability to anxiety
Joseph E. Dunsmoor, Fredrik Åhs and Kevin S. LaBar*
Department of Psychology and Neuroscience, Center for Cognitive Neuroscience, Duke University, Durham, NC, USA
*Correspondence: klabar@duke.edu
A commentary on
Fear-conditioning mechanisms associ-
ated with trait vulnerability to anxiety in 
humans
by Indovina, I., Robbins, T. W., Núñez-
Elizalde, A. O., Dunn, B. D., and Bishop, S. 
J. (2011). Neuron 69, 563–571.
Although anxiety disorders are the most 
common of psychiatric diseases with 28% 
life prevalence (Kessler et al., 2005), the 
etiology and neurobehavioral mechanisms 
underlying anxiety are not fully understood. 
Anxiety has commonly been separated into 
dimensions of state and trait anxiety (Freud, 
1924; Spielberger, 1966). State anxiety consti-
tutes the transitory negative emotions elic-
ited by a stressor whereas trait anxiety refers 
to the predisposition to react negatively to 
stressful situations. Twin studies suggest both 
genetic and environmental contributions to 
trait anxiety (Lau et al., 2006). In addition, 
investigations have begun to demonstrate the 
role of genetic factors in fear conditioning in 
humans (Hettema et al., 2003; Lonsdorf et al., 
2009), suggesting that genetic influences 
might determine how we learn from stressful 
experiences. The idea that fear conditioning 
provides an explanation for the acquisition 
of anxiety disorders has a long and storied 
history in psychological science (e.g., Pavlov, 
1927; Mineka and Zinbarg, 2006). In the clas-
sic view, the evolutionarily adaptive capacity 
to defensively respond to learned threats can 
lead to maladaptive behavior. For instance, 
an anxious individual may learn that a 
stimulus or situation is threatening, which 
may then lead to pathological reactions (e.g., 
phobias and post-traumatic stress disorder). 
Understanding how humans control learned 
fear can provide more effective clinical treat-
ments and has spurred numerous investiga-
tions into the brain mechanisms underlying 
fear regulation.
Illuminated by previous investigations 
on frontal-limbic involvement in fear reg-
ulation, a recent fMRI study in Neuron by 
Indovina et al. (2011) examined individual 
differences in trait anxiety on cued and con-
textual fear conditioning in psychologically 
healthy adults. The authors hypothesized 
that trait anxiety influences brain activity 
in response to learned threat, with implica-
tions toward understanding the neurocog-
nitive mechanisms underlying resilience to 
anxiety. During fMRI scanning, participants 
viewed images of three different rooms con-
taining an actor (conditioned stimulus, CS). 
In one room, the CS signaled the delivery 
of a 103-dB aversive scream (unconditioned 
stimulus, US) by raising his hands to his 
ears. In another room, the US was not sig-
naled by the CS. A third room contained no 
US presentations and was thus considered 
safe. The authors made predictions con-
cerning two brain regions: the amygdala 
and the ventral prefrontal cortex (vPFC).
The brain imaging results revealed a 
separation in cued versus contextual fear 
responses. The CS presented in the pre-
dictable room evoked phasic amygdala 
responses that correlated with trait anxi-
ety levels; subjects with high trait anxiety 
showed stronger amygdala responses to 
the CS in the predictable room versus the 
CS in the safe room. However, this finding 
is somewhat difficult to interpret because 
the authors did not include an explic-
itly unpaired or randomly paired control 
stimulus (i.e., CS−) within the different 
contexts, as is the standard methodology 
in neuroimaging studies of fear condition-
ing (Buchel and Dolan, 2000)1. Since the 
authors did not control for non-associative 
phasic responses (e.g., sensitization) within 
the three contexts, it is not clear whether 
activity to the CS in the different rooms is 
a consequence of stronger acquisition per se, 
or heightened reactivity in general (Lissek 
et al., 2005). The relationship between trait 
anxiety and amygdala activity has previ-
ously been demonstrated during extinc-
tion in healthy adults, such that sustained 
amygdala responses during extinction are 
correlated with trait anxiety scores (Barrett 
and Armony, 2009; Sehlmeyer et al., 2010). 
However, these investigations did not find 
an association between amygdala activa-
tion and trait anxiety during fear acquisi-
tion. This raises a concern that the amygdala 
findings of Indovina et al. (2011) may not 
replicate when non-associative control pro-
cedures are in place.
In contrast to the results for the amy-
gdala, Indovina et al. (2011) found that 
the predictive CS evoked increased pha-
sic activity in the vPFC that was inversely 
related with trait anxiety; subjects with low 
trait anxiety showed stronger vPFC activity 
to the CS in the predictable room versus 
the unpredictable room. Low trait anxious 
subjects also showed greater sustained 
vPFC activity throughout the fear-related 
unpredictable context relative to high trait 
anxious individuals. The authors concluded 
that activation in the vPFC demonstrates 
a role for this region in the automatic 
regulation of fear prior to fear extinction. 
As increased vPFC activity was observed 
primarily in low trait anxious individuals 
and was inversely correlated with SCRs, 
this region may provide a marker of resil-
ience to anxiety disorders. While this is a 
1Indovina et al. (2011) only report difference scores in amygdala activity, which leaves out important informa-
tion regarding the magnitude of brain responses to the CS in the predictable and safe room. For instance, it is not 
possible to determine from difference scores if high and low trait anxious individuals showed similarly strong 
amygdala responses to the aversive CS in the predictable room, but only high trait-anxious individuals expressed 
lower amygdala responses to the CS in the safe room. It appears that there is little difference in amygdala activity 
to the CS in the predictable and safe rooms among low anxious subjects – only high trait anxious subjects show 
a differential response. A lack of differential amygdala activity to the CS in the predictable and unpredictable 
room among the low trait anxious subjects could indicate a lack of specificity (if amygdala activity is high in 
both contexts) or an overall lack of reactivity (if amygdala activity is low in both contexts). Reporting separate 
estimates of brain activity across all conditions would help to resolve this issue.
Frontiers in Human Neuroscience www.frontiersin.org April 2011 | Volume 5 | Article 35 | 1
General Commentary
published: 04 April 2011
doi: 10.3389/fnhum.2011.00035
question that remains to be answered is 
whether the same genetic factors that con-
tribute to individual differences in fear 
conditioning also contribute to trait anxi-
ety, and whether the putative brain func-
tions delineated by Indovina et al. (2011) 
could serve as an intermediate phenotype 
for these factors.
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vPFC activity as a marker of automatic fear 
regulation. Yet, this activity occurs prior to 
extinction and it is therefore appropriate to 
regard the predictable cue and unpredict-
able context as fear-relevant. To be charac-
teristic of maladaptive responding, activity 
should be assessed during generalization 
testing (Dunsmoor et al., 2011), reversal 
(Schiller et al., 2008), or extinction learn-
ing/recall, as demonstrated by Milad et al. 
(2009) for individuals with PTSD relative to 
trauma-exposed control subjects. Indovina 
et al. (2011) appear to make the argument 
that the automatic regulation of fear is 
adaptive even in situations in which the US 
is still expected. In fact, with the threat of the 
US still present, an over-regulation of fear 
responses can be detrimental to low-anx-
ious participants if they are not prepared 
to defensively respond to the US when it 
inevitably occurs (Domjan, 2005).Thus, the 
vPFC signal may in fact be maladaptive to 
low-anxious individuals. Still another alter-
native interpretation is that the vPFC signal 
relates to the predictive value of features 
in the environment that signal the US. In 
the predictable room, the CS was the most 
reliable predictor of the US whereas in the 
unpredictable room, the context itself was 
the most reliable predictor. Notably, across 
these two conditions, low-anxious partici-
pants engaged the vPFC region. Rather than 
reflecting emotion regulation, the vPFC 
may signal a more abstract representation of 
motivational value and/or salience in low-
anxious participants, consistent with mod-
els of this region in reinforcement learning 
(Rolls, 1996; Rangel et al., 2008). According 
to this view, the lack of vPFC activation in 
the high-anxious individuals may be mala-
daptive but for a different reason.
While the results from Indovina et al. 
(2011) provide potentially novel insights 
into the relationship between psychologi-
cal factors and fear conditioning, it will be 
important to determine whether the find-
ings extend to individuals with clinical anxi-
ety disorders. Further research is needed to 
address whether a vulnerability to develop 
an anxiety disorder in high trait-anxious 
individuals is characterized by enhanced 
conditionability to cue (Orr et al., 2000) or 
context (Grillon, 2002), overgeneralization 
of fear to safety cues (Grillon and Morgan, 
1999), deficits in extinction recall (Milad 
et al., 2009), or some combination thereof 
(see Lissek et al., 2005). Another  intriguing 
 potentially exciting possibility, it would also 
be important to know whether engagement 
of this region across subjects or trials results 
in down-regulation of amygdala fear signals 
or self-reported regulation attempts.
The vPFC region of interest (ROI) is 
not an area commonly implicated in the 
inhibition of conditioned fear. As noted by 
Indovina et al. (2011), hypotheses regard-
ing the role of the vPFC in their study 
were in contrast to the classic view held 
in the rodent and human fear condition-
ing literature, which regards the medial 
PFC as primarily involved in reducing fear 
responses through interconnections with 
the amygdala and hippocampus during 
extinction learning and recall of extinction 
memories (Milad and Quirk, 2002; Ehrlich 
et al., 2009).The vPFC ROI was defined on 
the basis of a prior investigation of placebo-
induced brain activity during anticipation 
of pain, where it was described as the orbit-
ofrontal cortex (OFC; Wager et al., 2004). 
The description of this area as “vPFC” 
throughout Indovina et al. (2011) is vague 
(activation appears to encompass portions 
of the vmPFC, vlPFC, and OFC), so it will 
be important to delineate the relative con-
tribution of this area with other PFC regions 
involved in aspects of emotion regulation. 
The vPFC region appears to bridge two 
areas that have been implicated in prior 
studies of emotion regulation: a lateral 
PFC region involved in voluntary regulation 
attempts and a medial PFC region involved 
in outcome-based/non-instructed forms 
of regulation (Ochsner and Gross, 2008; 
Etkin et al., 2011).For instance, the ante-
rior ventrolateral PFC – a region close to 
the vPFC region of Indovina et al. (2011) – 
has been implicated in voluntary cognitive 
reappraisal via down-regulation of amy-
gdala responses (Winecoff et al., 2010) and 
subsequent memory for reappraised emo-
tional stimuli via hippocampal interactions 
(Hayes et al., 2010). Moreover, Delgado 
et al. (2008) showed a link between the dor-
solateral PFC and vmPFC during instructed 
down-regulation of conditioned fear. Since 
Indovina et al. (2011) did not report a 
whole-brain analysis, it will be important 
in future studies to determine the unique 
contribution of this vPFC region relative to 
these other areas.
Finally, it is important to consider the 
possible alternatives to the adaptive role 
of this vPFC signal. The authors interpret 
Frontiers in Human Neuroscience www.frontiersin.org April 2011 | Volume 5 | Article 35 | 2
Dunsmoor et al. Conditioning and vulnerability to anxiety
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Received: 17 March 2011; accepted: 21 March 2011; pub-
lished online: 04 April 2011.
Citation: Dunsmoor JE, Åhs F and LaBar KS (2011) 
Neurocognitive mechanisms of fear conditioning and 
vulnerability to anxiety. Front. Hum. Neurosci. 5:35. doi: 
10.3389/fnhum.2011.00035
Copyright © 2011 Dunsmoor, Åhs and LaBar. This is an 
open-access article subject to a non-exclusive license between 
the authors and Frontiers Media SA, which permits use, 
distribution and reproduction in other forums, provided the 
original authors and source are credited and other Frontiers 
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Neurocognitive Mechanisms of Fear Conditioning and Vulnerability to Anxiety

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