Development of anxiety: the role of threat appraisal and fear learning.
ABSTRACT Anxious individuals exhibit threat biases at multiple levels of information processing. From a developmental perspective, abnormal safety learning in childhood may establish threat-related appraisal biases early, which may contribute to chronic disorders in adulthood. This review illustrates how the interface among attention, threat appraisal, and fear learning can generate novel insights for outcome prediction. This review summarizes data on amygdala function, as it relates to learning and attention, highlights the importance of examining threat appraisal, and introduces a novel imaging paradigm to investigate the neural correlates of threat appraisal and threat-sensitivity during extinction recall. This novel paradigm can be used to investigate key questions relevant to prognosis and treatment. Depression and Anxiety, 2011.© 2010 Wiley-Liss, Inc.
- Procedia - Social and Behavioral Sciences 07/2013; 84:1660-1665.
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ABSTRACT: The value of common polymorphisms in guiding clinical psychiatry is limited by the complex polygenic architecture of psychiatric disorders. Common polymorphisms have too small an effect on risk for psychiatric disorders as defined by clinical phenomenology to guide clinical practice. To identify polymorphic effects that are large and reliable enough to serve as biomarkers requires detailed analysis of a polymorphism's biology across levels of complexity from molecule to cell to circuit and behavior. Emphasis on behavioral domains rather than clinical diagnosis, as proposed in the Research Domain Criteria framework, facilitates the use of mouse models that recapitulate human polymorphisms because effects on equivalent phenotypes can be translated across species and integrated across levels of analysis. A knockin mouse model of a common polymorphism in the brain-derived neurotrophic factor gene (BDNF) provides examples of how such a vertically integrated translational approach can identify robust genotype-phenotype relationships that have relevance to psychiatric practice. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.Biological psychiatry. 01/2015;
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ABSTRACT: The value of common polymorphisms in guiding clinical psychiatry is limited by the complex polygenic architecture of psychiatric disorders. Common polymorphisms have too small an effect on risk for psychiatric disorders as defined by clinical phenomenology to guide clinical practice. To identify polymorphic effects that are large and reliable enough to serve as biomarkers requires detailed analysis of a polymorphism’s biology across levels of complexity from molecule to cell to circuit and behavior. Emphasis on behavioral domains rather than clinical diagnosis as proposed in the Research Domain Criteria (RDoC) framework facilitates the use of mouse models that recapitulate human polymorphisms because effects on equivalent phenotypes can be translated across species and integrated across levels of analysis. A knock-in mouse model of a common polymorphism in the brain-derived neurotrophic factor gene (BDNF) provides examples of how such a vertically integrated translational approach can identify robust genotype-phenotype relationships that have relevance to psychiatric practice.Biological Psychiatry. 01/2015;
DEPRESSION AND ANXIETY 0:1–13 (2010)
DEVELOPMENT OF ANXIETY: THE ROLE OF THREAT
APPRAISAL AND FEAR LEARNING
Jennifer C. Britton, Ph.D.,?Shmuel Lissek, Ph.D., Christian Grillon, Ph.D., Maxine A. Norcross, B.S.,
and Daniel S. Pine, M.D.
Anxious individuals exhibit threat biases at multiple levels of information
processing. From a developmental perspective, abnormal safety learning in
childhood may establish threat-related appraisal biases early, which may
contribute to chronic disorders in adulthood. This review illustrates how the
interface among attention, threat appraisal, and fear learning can generate
novel insights for outcome prediction. This review summarizes data on
amygdala function, as it relates to learning and attention, highlights the
importance of examining threat appraisal, and introduces a novel imaging
paradigm to investigate the neural correlates of threat appraisal and threat-
sensitivity during extinction recall. This novel paradigm can be used to
investigate key questions relevant to prognosis and treatment. Depression and
Anxiety 0:1–13, 2010.
rrrr2010 Wiley-Liss, Inc.
Key words: fear conditioning; generalization; attention; amygdala; ventro-
medial prefrontal cortex
Childhood anxiety disorders can be viewed as ‘‘gate-
way’’ conditions because they signal increased risk for
various mental illnesses. Indeed, childhood anxiety
disorders predict a 2- to 3-fold increased risk for adult
disorders, particularly anxiety disorders and major
depressive disorder (MDD).[1–4]Nevertheless, many
anxious children mature to become healthy adults, free
of psychopathology.As a result, there is a need to
understand the factors that distinguish between the
subgroups of anxious children that have relatively high
and low risk for adverse outcomes.
Long-term adverse outcomes may vary based on
patterns of information processing and associated
neural responses engaged when confronting threats
that signal impending danger. Specifically, anxious
individuals exhibit threat biases at multiple levels of
information processing, including aspects of attention
orienting, cognitive appraisal, and learning.[5,6]In
addition, neuroimaging studies conducted in separate
samples of children, adolescents, and adults implicate
similar brain regions in tasks measuring these anxiety-
related information processing biases.[7–10]This work
raises questions on the degree to which neural
responding to threats at one point in life predicts
outcome at later points in life. As such, neuroimaging
may eventually be used to identify subgroups of
anxious children most likely to develop chronic
Two earlier reviews set the stage for this review.
One review focused on integrating clinical and basic
perspectives on anxietyand the other focused on
using neuroscience to inform therapeutics.This
review focuses more narrowly on neurocognitive
influences on fear learning, a topic not addressed in
these past reviews. The goal here is to illustrate how a
narrow focus on the interface among attention, threat
appraisal, and fear learning can generate novel insights
for outcome prediction. This review proceeds in three
Published online in Wiley Online Library (wileyonlinelibrary.com).
Received for publication 16 April 2010; Revised 23 June 2010;
Accepted 29 June 2010
The authors disclose the following financial relationships within
the past 3 years: Contract grant sponsor: National Institutes of
Health and the National Institute of Mental Health.
?Correspondence to: Jennifer C. Britton, National Institute of
Mental Health, 9000 Rockville Pike, Building 15K, Bethesda, MD
20892. E-mail: firstname.lastname@example.org
Mood and Anxiety Disorders Program, National Institute of
Mental Health, Bethesda, Maryland
rrrr 2010 Wiley-Liss, Inc.
stages. The first section broadly summarizes data on
amygdala function as it relates to learning and
attention; the second section then focuses more
narrowly on a specific information-processing func-
tion, threat appraisal. The final section introduces a
novel imaging paradigm to investigate the neural
correlates of threat appraisal during extinction recall.
AND AMYGDALA PLASTICITY
CONDITIONING AND EXTINCTION
Considerable research on learning examines the
functioning of the amygdala, a brain region that
plays a key role in stimulus-reinforcement learning.
The amygdala is often examined through classical
fear conditioning and extinction procedures, both of
which can be considered instances of ‘‘fear learning.’’
In conditioning experiments, a neutral conditioned
stimulus (CS) acquires the ability to provoke fear
through stimulus-reinforcement learning, when the CS
is paired with an aversive unconditioned stimulus
(UCS). In animals, experimental manipulations show
that intact amygdala function is required for the
acquisition and expression of fear conditioning.[11,12]
Many such studies use simple fear conditioning
paradigms, where a single CS is paired with the
UCS, whereas translational work in humans typically
employs differential conditioning paradigms involving
two CSs. The CS1 is paired with the UCS and the
CS? is never paired with the UCS. Following
conditioning, fear responses can be attenuated through
the process of extinction, a second form of stimulus-
reinforcement learning. In this learning process, the
CS1 is repeatedly presented in the absence of the
UCS,whichleads to reduced
Although some initial research attributed extinction
to forgetting, more recent findings suggest that
extinction involves active learning of the CS1–no
threat association.[13,14]After extinction, the organism
learns to reclassify a CS1 that was earlier viewed as
threatening. Using such paradigms with shock as the
UCS, functional magnetic resonance imaging studies
(fMRI) in adults implicate the amygdala in fear
conditioning and extinction,[15,16]which is consistent
with animal work.
Research on fear conditioning and extinction has
long been considered relevant to anxiety disorders.
Anxiety disorder patients have exaggerated fear res-
ponses to simple cue conditioning.[17,18]Nevertheless,
psychophysiological research in both pediatric and
adult anxiety disorder patients demonstrates relatively
subtle perturbations in differential cue condition-
ing.[19,20]Moreover, contrary to initial predictions that
anxious individuals condition to a greater extent,
most research has failed to find enhanced levels of
differential conditioning; anxious individuals have
enhanced responding to conditioned safety cues,
possibly due to deficits in stimulus classification.
The inconsistent findings from physiology research
could reflect the failure to account for possible
information processing perturbations occurring when
patients learn about danger and safety. These perturba-
tions could prevent patients from recognizing safety
signals or inhibiting fear responses when safety cues are
Although these physiological data provide modest
evidence for an association between fear learning and
clinical anxiety, much stronger evidence emerges from
research on exposure therapy, which relies on princi-
ples of extinction. Patients treated with exposure
therapy are taught to acquire stimulus-safety learning
through threat exposure, where the patient learns to
reduce fear reactions over time. In the case of anxiety
disorders, excessive fears manifest in safe contexts, and
exposure therapy teaches patients to react appropri-
ately in these contexts. When recalled in the extinction
context, the amount of fear elicited by exposure is
expected to reflect the competition between the
original fear memory and the extinction memory. If
the extinction memory is successfully recalled as part of
the therapy, then the fear reaction should diminish.
Fully effective treatment allows these instances of
extinction learning to produce clinical benefit when
skills learned during exposure generalize to other
situations. Thus, fear reactions also should diminish
to a range of other real-world stimuli resembling the
original feared object. Moreover, fear learning interacts
with other psychological processes and associated brain
regions. Through these interactions, attention control
and orienting, appraisal of fear states, conceptualized
by elaborations of classifications, and the ability to
discriminate threat/safety in situations when this
differentiation is difficult shapes fear learning. Figure 1
presents a schematic of these processes and associated
ATTENTION AND THE AMYGDALA
Attention is the process whereby capacity-limited
neurocognitive resources are allocated based on the
relative salience of environmental cues.[23,24]This
process of attention allocation may influence stimu-
lus-response learning, partially through effects on the
amygdala. Amygdala–attention interactions involve
both bottom-up and top-down mechanisms,[12,24,25]
and both mechanisms may influence fear learning. For
bottom-up processes, the amygdala can respond very
rapidly to threat-related stimuli, thereby changing the
focus of attention and facilitating stimulus-response
learning about a salient stimulus and other stimuli that
predict its occurrence.[12,26]For top-down processes
instantiated in the prefrontal cortex (PFC), the
representation of task-related goals influences amygda-
la engagement, which, in turn, influences stimulus–
response learning. For example, when attention is
allocated to a demanding cognitive task, task-related
2 Britton et al.
Depression and Anxiety
goals can reduce the amygdala response to task-
irrelevant emotionally salient cues.Such an effect
of attention on the amygdala also would be expected to
account for well-known effects of top–down attention
on stimulus–response learning.
Clinical expressions of anxiety are known to involve
perturbed attention allocation in potentially dangerous
situations, where attentional capture in response to
threat may be strengthened and regulation may be
diminished. Threatening displays from conspecifics,
such as an angry facial display from a stranger, or other
innately dangerous stimuli, such as snakes or cues of
suffocation, evoke threat responses, even in the absence
of prior exposure or learning with these stimuli.[28,29]
Threat-related attention biases are seen in the anxiety
disorders, even when threats (e.g. angry faces) are
presented too rapidly to be labeled.These perturba-
tions in attention are thought to influence risk for
anxiety by shaping physiologic and neural responding
during learning. Although based on available data, it is
reasonable to suggest that attention shapes risk for
anxiety through effects on the amygdala and fear
physiology of fear learning in anxiety disorders. As
a result, virtually no data directly consider the impact
of attention on between-group differences in fear
learning through effects on brain circuitry. Some
research does investigate the interactions between
attention and fear learning in healthy adults,[31–34]
setting the stage for future work in patients.
As with behavioral research on attention, most
imaging research on amygdala function in anxiety
disorders relies on paradigms that expose participants
to various facial expressions in the absence of any
learning-related manipulation. This research consis-
tently finds enhanced amygdala responding to threa-
tening faces in a range of adult and pediatric anxiety
disorders.[7–9,26]For example, anxious children exhib-
ited greater amygdala activation to overt fearful faces,
and amygdala activation correlated positively with trait
responses to emotional stimuli in anxiety often are
viewed as reflecting perturbed conditioning-related
processes, few research studies directly evaluate this
possibility.[36–38]Nevertheless, other imaging work
does focus on the relationships among clinical anxiety,
attention, and amygdala function. Two studies com-
pared anxiety disorder patients and healthy subjects
exposed to rapidly presented, difficult to detect, threat
cues. Both studies found evidence of amygdala
hyperactivation in anxiety disorder patients.[8,26]Other
studies compared amygdala responding when patients
and healthy subjects are required to view threat cues in
a series of alternating attention states, such as during
passive viewing, incidental threat processing, and
cognitive tasks that directly focus attention on threat
content.In healthy individuals, amygdala activation
is suppressed under cognitive tasks which require high
levels of effort,[24,27,39]
and this attention effect
moderates between-group differences in amygdala
activation.[7,40]To fully integrate basic and clinical
approaches of attention and amygdala function, work is
needed to extend such findings to research on
conditioning and extinction.
studies examine the
Research on amygdala plasticity also informs brain
imaging. Molecular research on amygdala function
delineates factors that support stimulus-reinforcement
learning, as reflected in conditioning and extinction.
Such learning requires engagement of particular
molecular signaling cascades previously shown to
support cellular plasticity.[41,42]High levels of plasticity
exhibited by the amygdala are thought to enable
plasticity often is quantified through invasive techni-
ques, it also may manifest in the temporal dynamics
of amygdala functioning, as assessed through neuro-
imaging. For example, amygdala activation rapidly
Figure 1. Influences on fear learning. As illustrated in the
highlighted box, fear learning primarily involves the amygdala
and the ventromedial prefrontal cortex (vmPFC). Through
repeated pairing of the conditioned stimulus (CS1) and
unconditioned stimulus (UCS), the neural representation of
the CS1 is activated in tandem with the amygdala response to
the UCS. Following learning, the CS1 alone excites the
amygdala and its projections to brain regions mediating the
autonomic (e.g. heart-rate, respiration, and sweating response),
endocrine (cortisol response), and behavioral (e.g. freezing,
flight/fight response) constituents of the fear response. When
the CS1 is presented in the absence of the UCS during
extinction, the vmPFC is proposed to inhibit this amygdala
activation. Although fear learning principally involves the
amygdala and vmPFC, attention, appraisal, and safety/threat
discrimination processes and associated brain regions interact
with fear learning to influence the fear response. The ventro-
lateral prefrontal cortex (vlPFC) and anterior cingulate cortex
(ACC) influence the control of attention orienting and resource
allocation. The dorsomedial prefrontal cortex (dmPFC) and
dorsolateral prefrontal cortex (dlPFC) elaborate the learned
classification via threat appraisal and emotion regulation
processes. The hippocampus provides context and fear general-
ization information. Together, these processes and the under-
lying brain network influence fear response.
3 Review: Development, Anxiety, and Fear Learning
Depression and Anxiety
habituates during fear conditioning[44,45]and face
viewing,[46,47]possibly reflecting cellular aspects of
amygdala plasticity. Moreover, the amygdala response
also resets eventually,[48,49]which may represent an
adaptive, plasticity-related aspect of amygdala function
that maintains vigilance for subsequent threats or other
salient cues. Thus, habituation failures or, alternatively,
sensitization in the amygdala response may contribute
to heightened anxiety.[50,51]
As with other work linking anxiety to amygdala
responding, research on novelty demonstrates different
amygdala response patterns in behaviorally inhibited
and noninhibited individuals.[52,53]These temperamen-
tal differences may reflect difficulties in resolving
ambiguity in novel stimuli. As such, increased vigilance
to novelty may reflect a failure to adapt, which, in turn,
may arise from perturbed amygdala plasticity. Evidence
of thesebetween-group differences in
plasticity demonstrates the importance of using brain
imaging to examine the interface between clinical
anxiety and either conditioning or extinction.
DEFINING THREAT APPRAISAL
The term ‘‘appraisal’’ refers to the process of stimulus
classification, based on goal relevance for the organ-
ism.[5,54]The term ‘‘threat appraisal’’ refers to such
classification when it is based on danger or a stimulus’
capacity for harming the organism. To create such
classifications, stimuli must be evaluated based both on
their emotional valence and their goal relevance.
Research on threat appraisal is complex, due to the
fact that appraisal is indexed by multiple measures.
Research indexing appraisal in rodents and nonhuman
primates typically relies on motor and associated
physiological responses.[55,56]Such work finds threat-
related responding to exhibit complex associations with
threat intensity. In some situations, a group of
measures each show coherent, linear relationships to
threat intensity, but in other situations they show
discordant, nonlinear relationships. For example, high
levels of arousal are associated with both approach–
attack and freezing behaviors, representing high and
low levels of motor activity, respectively.Although
arousal levels may be high in response to threat, the
behavioral reaction may depend on additional factors.
For example, imminent and direct threats can elicit
ambiguous threats can elicit freezing as opposed to
behavioral avoidance (i.e. flight). Thus, different
threats produce distinct forms of motor physiology
output, complicating attempts to precisely quantify
threat appraisals. Given the complex nature of apprai-
sal, multiple measures are needed to precisely quantify
learning-related mammalian appraisal biases.
In humans, as in rodents and nonhuman primates,
threat appraisal can be indexed by physiologic arousal
whereas anticipated or
and defensive/avoidance behaviors, though humans
also use language to classify stimuli. In fact, anxiety
disorders are defined by subjective reports of inappro-
priately experienced fear and avoidance, which can be
considered one form of threat appraisal bias. Patients
with anxiety disorders and individuals scoring high on
anxiety scales classify some stimuli as dangerous that
healthy individuals classify as safe.[59–62]As such, verbal
reports of an individual’s internally experienced fear
reflect aspects of threat appraisal that are particularly
relevant to clinical work. For research with humans,
this investigation involves asking research participants
to rate their fear, which might engage different
neurocognitive processes than when naturally encoun-
tering threats. As such, the act of appraisal itself might
complicate research on fear by influencing the physiol-
ogy of threat processing. In some threatening situa-
tions, verbal reports positively correlate with motor
and physiologic response patterns,[63,64]but in other
situations they either do not correlate or even show
opposite patterns of correlation.[65,66]This discordance
further emphasizes the need in research on appraisal to
acquire data using multiple measures and the need to
understand how appraisal may change learning. Thus,
biased threat appraisals in anxiety disorders can
manifest as correlated patterns in verbal, motor, and
physiological measures or as a particularly aberrant
response pattern in any one of these measures.
THREAT APPRAISAL IN CLINICAL ANXIETY
Anxiety disorder patients have biased appraisals of
threats, as reflected in exaggerated physiological
arousal, avoidance, and reports of fear. Such biases
consistently manifest in patients, as discussed in an
earlier review.This earlier review focuses on biased
appraisals of innately feared dangers in the absence of
prior exposures, which are capable of evoking fear and
associated threat responses. These dangers include cues
of suffocation or threatening social displays, which
evoke enhanced fear responses, specifically in separa-
tion anxiety disorder and social anxiety disorder,
respectively.In fact, exaggerated fear of innately
feared threats may represent the strongest correlate of
anxiety disorders in laboratory-based research.This
review does not focus on responses to innately feared
threats but rather focuses on appraisal biases that
manifest during fear learning, the process where a
neutral stimulus acquires a threat value through its
pairing with an aversive experience. Moreover, this
review focuses on the role of learning as a shared
feature across anxiety disorders and does not focus on
individual anxiety disorders. This approach follows
from the fact that studies of conditioning and exposure
therapy implicate learning-related biases in many
Studies of fear conditioning and extinction learning
draw parallels with studies of emotion regulation.
Emotion regulation work focuses on the process of
4 Britton et al.
Depression and Anxiety
reappraisal and its influence on the amygdala. In
reappraisal, a subject first attempts to monitor or
‘‘appraise’’ their emotional reaction to a stimulus, and
then they attempt to change or ‘‘reappraise’’ this
reaction. For example, individuals might be asked to
reinterpret or distance themselves from initial reactions
to a threat, a process which dampens amygdala
responding and negative affect in healthy individuals.
Both appraisal and reappraisal shape perceptions of
emotional significance through the medial PFC.[69–71]
Not only do patients with anxiety disorders exhibit
biased initial appraisals of threats, but they also show a
reduced capacity to alter these initial appraisals,[5,72,73]
which may be reflected in aberrant PFC engage-
a key regulator of amygdala engage-
ment.[69,75–77]Of note, as with other research on
appraisal biases, work on reappraisal in anxiety
primarily focuses on responding to intrinsic as opposed
to learned, newly acquired fears. Nevertheless, the
work on emotion regulation does inform research on
fear learning. In fact, one study showed that both
emotion regulation and extinction activated the medial
PFC/subgenual ACC.Studies of conditioning, such
as appraisal, might model neural and psychological
factors related to amygdala engagement during the
initial stages of threat encounters. Conversely, studies
of extinction, such as reappraisal, might model PFC
regulation of this initial amygdala engagement, as
it facilitates attempts to reclassify the stimulus as
APPRAISAL, CONDITIONING, AND
Earlier work on conditioning supports the impor-
tance of studying how appraisal biases are learned.
Earlier, anxiety disorders had been thought to result
from enhanced conditioning; however, a more recent
perspective suggests that patients with anxiety dis-
orders show difficulty distinguishing threat from
safety when studied with conditioning and extinction
paradigms.[18,60]The available data in this area also
suggest that appraisal biases in anxiety disorders can
manifest as perturbed fear generalization gradients.
Fear generalization is a natural process where the
‘‘threat’’ value of a feared stimulus is transferred to
stimuli resembling the feared stimulus.To study fear
generalization in more detail, Lissek et al. developed a
paradigm that involved two procedures: fear condition-
ing and a generalization test.During differential fear
conditioning, a small and large circle served as the CS?
and the CS1. During the generalization test, circles of
varying size between the CS? and the CS1 were
shown to the participant. Following conditioning, the
CS1 was a clear, unambiguous threat cue, but the
meaning of each stimulus resembling the CS1 was
ambiguous. As is important for studies of appraisal,
data from multiple measures were recorded, including
eyeblink startle, motor response times, and perceived
risk. In healthy subjects, each measure showed signs of
varying in tandem with features of the CS, consistent
with the presence of a generalization gradient. This
gradient fell along the continuum between the CS1
and CS?, the two extreme stimuli. For startle and risk
perception data, the greatest responses occurred to the
CS1 and decreased along a curvilinear pattern as the
CS became more like the CS?. Brain regions are also
expected to show graded responses to stimuli that
resemble each other.[80,81]
Adults with panic disorder exhibited signs of an
appraisal bias on this task, when compared to healthy
subjects.In healthy adults, subjective fear ratings
and psychophysiology data indicated the ability to
discriminate ‘‘safety’’ cues that were quite similar in
appearance to the CS1. Interestingly, on multiple
measures, the fear responses to a clear, unambiguous
CS1 and CS? differed from each other, both in
patients and healthy adults with no evidence of
between-group differences in conditioning. This result
suggests that adults with panic disorder and healthy
subjects appraise some forms of overt threat as similarly
dangerous. However, for more ambiguous threats, a
threat appraisal bias did manifest in panic disorder
patients through the process of overgeneralization or
deficient discrimination. Although groups similarly
appraised the unambiguous CS1 threat, patients
appraised an ambiguous CS threat as more dangerous
than did the healthy adults, with parallel between-
group differences in physiology and subjective ratings.
In essence, the ‘‘threat’’ value of the CS1, acquired
through learning, had been more extensively trans-
ferred to stimuli resembling the CS1 in patients than
healthy subjects.Thus, some appraisal biases in a
range of anxiety disorders may reflect a compromised
capacity for learning the boundaries separating safe and
threatening stimuli and inhibiting fear responses in safe
EXTINCTION AND CLASSIFICATION
Extinction is another learning process where bound-
aries among threats are necessary. However, although
generalization gradients reflect boundaries along a
stimulus-feature gradient,extinction reflects bound-
aries along a temporal and contextual gradient. In
extinction, a time-related reclassification must occur;
stimuli that are currently dangerous must be distin-
guished from those that were previously dangerous.
This process requires reappraising the emotional value
of a previously feared stimulus. Thus, extinction, the
process of learning a new stimulus-safety association, is
linked to the process of emotion regulation of
Considerable work in the rodent examines neural
mediators of extinction learning, and this research
provides a strong foundation for examining neural
correlates of anxiety disorders. Lasting extinction
of conditioned fear in the rodent requires intact
5Review: Development, Anxiety, and Fear Learning
Depression and Anxiety
functioning of neurons connecting the infralimbic
cortex to the intercalated cells of the amygdala.[76,83,84]
Similar findings have been generated in humans. In an
fMRI study, ventromedial PFC (vmPFC) and amygdala
activation have been detected in extinction learn-
ing.[16,85]In addition, during a reversal learning task
in healthy adults, the amygdala tracked the fear signal,
whereas the vmPFC tracked the safety signal.
Finally, individual differences in extinction learning
and the underlying neural circuitry influence the
emergence of anxiety. The methionine (Met) allele
variant of the brain-derived neurotrophic factor Val66-
Met single nucleotide polymorphism is associated with
anxiety and impairs extinction learning in both rodents
and humans. Less vmPFC activation and greater
amygdala activation during extinction were detected
in human carriers of the Met allele,and this effect of
the Met allele on fear circuitry function may manifest
uniquely in anxious and healthy individuals.
In both rodent and human studies, the infralimbic
cortex (IL)/or vmPFC involvement seems particularly
important for the process of extinction recall, which
differs in subtle ways from extinction learning. In
extinction learning, the organism demonstrates the
capacity to acutely lower responses to the CS1, shortly
after the CS1 has been presented multiple times in the
absence of the UCS. Extinction recall refers to the
process whereby the organism retains this ability over
time. During extinction recall, the organism is reexposed
to the previously extinguished CS1 after a considerable
delay following extinction learning. Although IL lesions
do not disrupt the learning of extinction contingencies,
they do prevent consolidation of this learning. Rodents
with IL lesions not only show normal conditioning and
extinction but also show an exaggerated return of fear on
retesting one day after extinction training.Neuro-
imaging studies of extinction recall among adults
demonstrate the clinical relevance of such findings.
Here, vmPFC structure and function is linked to fear-
related behavior during extinction recall, based on
physiological[85,90]and clinical indices.
LEARNING AND DEVELOPMENT
Development constrains the neural pathways that
support various types of learning, including fear
learning.In other words, the ability of an organism
to learn about safety and danger varies across develop-
ment, such that immature organisms rely on different
brain structures and show unique learning-related
changes, relative to mature organisms. Although no
neuroimaging study examines the interactions between
human development and fear learning, the early
appearance of individual differences in fear responses
suggests these interactions exist. In rodents, diverse
experiences occurring at key stages in development can
produce similar changes in underlying neural circuitry
and associated behaviors engaged by threats. For
example, pups either separated from their mothers
during critical development periods or reared by
mothers with impaired licking/grooming abilities have
high stress reactivity, suggesting that developmental
experiences can alter the threat response.[92,93]On the
other hand, similar experiences occurring at different
developmental stages can produce unique behaviors.
For example, amygdala lesions in childhood monkeys
increase fear responses to conspecifics, whereas this
fear is reduced with adult lesions.Finally, behaviors
acquired at different stages of development can be
mediated by distinct circuits. Studies of language and
motor learning suggest that different neural pathways
support skill acquisition at different stages in life.In
humans, developmental trajectories of facial expression
recognition suggest that sensitivity to discrimination is
refined with age.[96,97]At least in some contexts,
children may exhibit greater amygdala activation to
neutral faces, relative to fearful faces.These data
may suggest that neutral faces are deemed more
ambiguous until discrimination and appraisal proces-
sing mature. In fact, amygdala activation to fearful
faces is greater in adolescents compared to adults.[98,99]
In addition, at least in rodents, hippocampal contribu-
tions to fear learning seem to mature later than
amygdala contributions.As such, the ability to
discriminate among a group of complex threat-related
stimuli occurs later, in tandem with maturation in the
hippocampus, than the ability to discriminate from
overtly safe and dangerous stimuli.Therefore, it is
likely that the developmental stage influences the
capacity for fear learning, and these interactions are
mediated by neural circuitry changes. This develop-
mental work on fear learning can inform therapeutics,
because different strategies may be most efficient when
attempting to alter behaviors in two individuals that are
mediated by unique ontogeny.
Fear and safety learning may interact with develop-
ment in several important ways, and this interaction,
in turn, may predict the outcome of pediatric anxiety.
Although the ability of the amygdala to generate
conditioned fear responses likely emerges early,[102,103]
cortical regions reach maturity later in develop-
ment.Moreover, the neural circuitry underlying
fear conditioning and extinction may change with age
as the vmPFC and the connectivity among the
amygdala, hippocampus, and vmPFC matures.[98,105,106]
In addition, developmental changes in brain structure
and function may enable increased cognitive appraisals
and classification of complex threats.[107–110]Within the
context of conditioning experiments, the capacity to
discriminate ‘‘threat’’ from ‘‘safety’’ may also mature
with development, such that failures to increase this
discrimination capacity in childhood may contribute to
persistent anxiety disorders.
Epidemiological data suggest that data on the
physiological correlates of extinction are needed in
pediatric anxiety. The prevalence of anxiety is high in
childhood and adolescence;however, most of these
disorders remit by adulthood.Interestingly, during
6 Britton et al.
Depression and Anxiety
this same developmental transition, newly onset anxiety
disorders also become increasingly rare.[1,2]This trajec-
tory suggests that the failure to overcome pediatric
anxiety accounts for a significant proportion of anxiety
in adults. Adult anxiety may reflect a failure to
extinguish childhood fear reactions, expressed in in-
appropriate contexts. As such, deficient extinction may
predict persistence of anxiety disorders into adulthood.
DEVELOPING A NOVEL
This final section reviews factors that inform the
development of imaging paradigms for assessing neural
correlates of extinction recall. Such efforts face
technical hurdles, including complications related to
UCS selection, methods for quantifying generalization
gradients, and procedures for constraining the effects
of attention on neural circuitry function. This section
delineates a range of approaches for addressing these
hurdles and then presents one illustrative paradigm.
The proposed paradigm is provided as only one
option because additional paradigms will posses other
advantages.However, the delineation of specific
procedures and their associated justification provides
a useful guide for considering alternative approaches.
Finally, research questions are posed to illustrate how
novel imaging paradigms might extend our basic under-
standing of conditioning and extinction to generate
relatively clear specific hypotheses concerning extinction
recall. This future work will shape research on pediatric
anxiety disorder outcome and treatment.
Attempts to examine fear learning are shaped by the
nature of the UCS. Levels of conditioning are
influenced by UCS potency, with a strong, novel, and
evolutionarily relevant UCS generating strong con-
This UCS selection also heavily
shapes attempts to study extinction.Extinction
tends to occur quickly in studies of physiological
responding among humans.As a result, studies that
employ a relatively weak UCS will posses limited
ability to examine individual differences in extinction.
For these reasons, the use of a relatively potent UCS
carries clear advantages.
In conditioning research on adult anxiety disorders,
electric shock represents the UCS that generates the
most consistent findings. For example, fear learning
paradigms employing a shock UCS generate relatively
robust increases in sustained fear, as reflected in
physiological reactions to the experimental context.
Such measures of sustained fear correlate with clinical
measures of anxiety and are reduced by treatment with
clinically effective medications.Moreover, the over-
generalization of conditioned fear in panic disorder
patients emerged in a shock UCS paradigm.[60,82]
However, shock is not the only viable UCS. Lissek
et al. compared the subjective response to various UCSs
in research with adults and showed no differences in the
anxiety provoked by white noise, tone, alarm, and
screams (Fig. 2). In some circumstances, more robust
between-group differences may emerge in research on
anxiety disorders that relies on relatively mild as
opposed to more aversive threat-related stimuli.
However, in other circumstances, studies using a mild
UCS will be insensitive to relevant between-group
differences. For example, subsequent work substituted
airpuffs to the throat, a mildly aversive UCS, for
shock.[118,119]This milder UCS failed to generate
sustained elevations in fear in paradigms previously
generating consistent clinically relevant findings.
Obvious ethical questions emerge concerning the use
of shock UCS research in pediatric anxiety disorders.
One could argue that shock UCS represents a minimal
Figure 2. Unconditioned stimulus selection. Thirty-five adults (mean age527.9) rated similar anxiety levels following a 95dB, 3sec
exposure to white noise, 2Hz tone, alarm, and a scream (all P4.3). Mean and standard deviations are displayed.
7Review: Development, Anxiety, and Fear Learning
Depression and Anxiety
risk procedure, given that shock yields less pain than
that associated with venupuncture and the shock level
is determined by the subject to be only mildly aversive,
not painful. On the other hand, given the vulnerable
state of anxious children, it is important to consider an
alternative UCS. Aversive airpuffs, loud sounds, and
aversive pictures have been used in fear conditioning
and fear-potentiated startle research as alternatives to
shock.[17,20,119–121]Considerable research, including
research on temperament, clinical anxiety, and amyg-
dala response, demonstrates meaningful associations
between pediatric anxiety and response to aversive
airpuffs.[122,123]However, the magnitude of rated fear
generated is low, raising questions on the suitability of
this probe for conditioning research.
The suitability of a novel UCS involving an aversive
photograph of a fearful woman, coupled with a loud
shrieking scream, has been evaluated. This novel UCS
extended other research on conditioning and imitation,
showing that observing extreme fear in a conspecific
serves as a potent UCS in both humans and other
mammals.Moreover, the subjective and physiologic
responses to this novel UCS fall between that
associated with shock UCS and milder UCSs, such as
loud sounds or aversive pictures, presented in isola-
tion.Finally, this UCS was subsequently used
successfully in a conditioning study of pediatric anxiety
disorders.As a result, this ‘‘screaming lady’’ UCS
represents a reasonable alternative to an aversive shock
UCS and mild auditory or tactile UCSs (e.g. loud
sounds, airpuffs). In addition, this UCS is well suited
for an imaging study on extinction recall.
The ‘‘screaming lady’’ paradigm possesses other
advantages associated with its utility for testing
fear-related generalization gradients. Following con-
ditioning using circles of two different sizes (CS1 and
CS?), Lissek et al. had presented circles with varying
diameters to contrast generalization gradients in
healthy adults and adults with panic disorder.Using
a similar approach, the screaming lady paradigm allows
the examination of such gradients in pediatric anxiety
disorders. Specifically, in the screaming lady paradigm,
photographs of two ladies are used in conditioning.
One lady serves as the CS1 and the other as the
CS?.Through morphing software, a continuum of
stimuli can be generated by mixing perceptual features
of these CS1 and CS? stimuli to study generalization
gradients in fear response to these stimuli. Figure 3
illustrates the two types of stimuli used to assess
generalization gradients following conditioning, circles
of two different sizes and two different women with
neutral facial expressions. Figure 4 illustrates proce-
dures for examining generalization gradients during
threat appraisal in research on pediatric anxiety
disorders. In this illustration, differential conditioning
to the two neutral photographs occurs and is followed
by extinction. At a later period, subjects are exposed to
both the CS1 and CS?, during which time they
attempt to recall various aspects of each stimulus.
Subjects also are exposed to stimuli varying along
a continuum of similarity between the features of the
CS1 and CS?. Thus, the ‘‘screaming lady’’ paradigm
can be used to examine generalization gradients during
extinction recall in pediatric anxiety disorders.
ATTENTION AND APPRAISAL
The ‘‘screaming lady’’ paradigm generates reason-
able, relatively stable between-group differences in
reported fear to the conditioned faces.Moreover,
these between-group differences can be quantified
Figure 3. Morph images used for generalization. Several types of stimuli may be used to assess generalization gradients. (A) Circles.
The circles at the extremes are the images used in the fear conditioning procedure. Circles of varying size created a continuum of stimuli
between these two extremes.(B) Faces. The faces at the extremes are the pure images of the light-haired and dark-haired women
with neutral facial expressions used in the fear conditioning procedure. The light-haired woman is morphed into the dark-haired woman
using 10% increments, providing a continuum of similarity between the two women. The continuum of circles or faces can be used to
assess fear generalization gradients following conditioning.
8Britton et al.
Depression and Anxiety
using generalization gradients and have meaningfully
informed research on adult anxiety disorders.The
culmination of ideas sets the stage for an imaging study
of extinction recall in pediatric anxiety disorders using
the ‘‘screaming lady’’ paradigm. Work reviewed above
suggests the feasibility of using such an approach to
examine aspects of extinction recall. Research on
extinction is clinically relevant, given that exposure
therapy relies on procedures from extinction to generate
clinically meaningful benefits for both pediatric and
adult patients. Moreover, prior basic science work, also
reviewed above, generates relatively specific hypotheses
concerning the role of a relatively specific neural circuit
in individual differences. Finally, from the developmen-
tal perspective, extinction emerges as a particularly
relevant process. Pediatric anxiety is extremely common
and the typical outcome of such anxiety is remission,
possibly reflecting instances of successful extinction. As
a result, adult anxiety disorders can be conceptualized as
failures to extinguish pediatric fears, a view that directly
informs outcome prediction.
From this perspective, we developed an appropriate
imaging paradigm of extinction recall. This paradigm
possesses three essential features: fear learning, atten-
tion modulation, and fear generalization. First, in
terms of fear learning, fear conditioning and immediate
extinction would be conducted in the psychophysiolo-
gical laboratory, using similar procedures employed by
Lau et al.
Second, at a later date, research
participants would undergo fMRI to study how the
neural correlates of extinction recall are modulated by
attention. During scanning, subjects would attempt to
recall their experience with extinction under different
attention states. This approach would effectively model
brain circuits engaged during extinction recall, a
However, such an approach to imaging between-group
differences also should incorporate understandings
of attention as it influences amygdala engagement.
As reviewed above, attention powerfully influences
amygdala engagement in research among healthy
and anxious children and adults. Most importantly,
Figure 4. Threat appraisal paradigm. On Day 1, participants undergo fear acquisition and extinction procedures using the ‘‘screaming
lady’’ paradigm in the psychophysiology laboratory using similar methods as Lau et al.Two women with neutral facial expressions are
shown. One woman (CS1) is paired with a screaming lady (UCS), whereas the other woman (CS?) never gets paired with the UCS.
Approximately 2 weeks later, participants return and undergo extinction recall in the magnetic resonance imaging (MRI) scanner.
Participants are shown a continuum of neutral face stimuli that vary between the CS? to CS1 while attending to their emotional state.
A generalization gradient in brain activation in the ventromedial prefrontal cortex is expected. CS, conditioned stimulus; UCS,
unconditioned stimulus; vmPFC, ventromedial prefrontal cortex.
9 Review: Development, Anxiety, and Fear Learning
Depression and Anxiety
between-group differences in pediatric anxiety disor-
ders are gated by attention. In particular, the most
consistent between-group differences in the amygdala
and ventral PFC emerge during fear appraisals when
subjects focus attention on their internal reaction to a
fearful stimulus.[7,40]Therefore, this extinction recall
imaging paradigm assessed amygdala and vPFC activity
in an emotionally relevant attention state, i.e. focusing
on internal fear, as well as in two additional attention
states, where subjects are asked to recall the CS1–UCS
association and to rate a physical feature of the
Combining these two aspects of this novel approach,
amygdala and prefrontal cortical function can be
contrasted as part of a fear learning process in anxious
and healthy youth in varying attention states and, in
particular, during threat appraisals. This investigation
can be accomplished through a paradigm where
subjects view blocks of images and are instructed to
make a yes/no judgments according to three instruc-
tions: (1) Are you afraid? (Threat appraisal); (2) Did she
scream? (Explicit memory); and (3) Is her hair jet
black? (Perceptual discrimination). Finally, this para-
digm generates data on fear generalization in the
context of extinction recall. Specifically, in each block,
morphed images that form a continuum of similarity
between the CS1 and CS? are randomly presented.
Morphed images are used in this paradigm to precisely
characterize threat sensitivity, as reflected in levels of
behavioral and neural discrimination among similar
Several hypotheses emerge from this novel neuroi-
maging paradigm that incorporates fear learning,
attention modulation, and fear generalization princi-
ples. First, as noted earlier, anxiety disorders in
childhood predict anxiety disorders and major depres-
sion in adulthood. However, not all children and
adolescents with an anxiety disorder will have long-
term adverse outcomes. Activation of the vmPFC, a
region involved in emotion regulation and extinction
processes, during threat appraisal may reflect the
ability to discriminate threat and safety. Perturbations
found in vmPFC activation and fear overgeneralization
during threat appraisal may identify groups that are
likely to develop chronic disorders. Reduced vmPFC
activation is expected to be associated with poor long-
term outcomes, because perturbations in vmPFC
activation are expected to lead anxious youth to
appraise ambiguous stimuli as dangerous (i.e. extinc-
tion deficit and fear overgeneralization), and thereby,
contribute to the development of anxiety disorders. In
addition, from a developmental perspective, deviations
from the normal maturation trajectory of vmPFC
function and threat safety classification ability may
allow the identification of sensitive periods for clinical
activation and associated deficits in safety learning
may predict clinical outcome. Exposure therapy draws
on principles of extinction. With repeated exposures to
a feared stimulus, the fear reaction is expected to
decrease; however, threat safety discrimination ability
must be intact. Greater vmPFC activation during
threat appraisal, indicative of better discrimination
capability, may be associated with greater symptom
improvement during exposure therapy. In addition,
pharmacologic manipulations of glutamatergic system
via the N-methyl-D-aspartic acid (NMDA) receptor
(e.g. D-cycloserine, DCS) may facilitate extinction.
Giving DCS before exposure therapy enhances fear
reduction in social phobiaand acrophobia.
These treatments may have the ability to alter fear
learning by facilitating the ability to disambiguate
threats. Assessing vmPFC activation during extinction
recall may help identify individuals who would show
greater benefits from pharmacological manipulation of
extinction. For example, pharmacological treatment
may be best suited for individuals with less vmPFC
activation. In summary, research that investigates the
boundaries separating threat- and safety-related stimuli
may carry major therapeutic implications.
This review summarizes the manner in which
attention impacts fear learning through appraisal biases
in anxiety disorders. From a developmental perspec-
tive, abnormal fear safety learning in childhood may
establish threat-related appraisal biases early. These
appraisal biases may, in turn, contribute to the
Individuals with anxiety disorders tend to classify
ambiguous stimuli as threatening more so than healthy
individuals. Therefore, the boundary separating threat
and safety may be blurred in patients with anxiety.
appraisal, and fear generalization, a novel imaging
paradigm was developed to investigate the neural
correlates of threat appraisal and threat-sensitivity to
ambiguous stimuli during extinction recall. This
paradigm can be used to investigate key questions
relevant to prognosis and treatment.
in part by the Intramural Research Program of the
National Institutes of Health and the National Institute
of Mental Health (J.C.B., S.L., C.G., M.A.N., D.S.P.).
An earlier version of this work has been presented at the
Anxiety Disorders Association of American annual
conference in March 2010.
This research was supported
1. Beesdo K, Bittner A, Pine DS, et al. Incidence of social anxiety
disorder and the consistent risk for secondary depression in the
first three decades of life. Arch Gen Psychiatry 2007;64:903–912.
10 Britton et al.
Depression and Anxiety
2. Pine DS, Cohen P, Gurley D, et al. The risk for early-adulthood
anxiety and depressive disorders in adolescents with anxiety and
depressive disorders. Arch Gen Psychiatry 1998;55:56–64.
3. Gregory AM, Caspi A, Moffitt TE, et al. Juvenile mental health
histories of adults with anxiety disorders. Am J Psychiatry 2007;
4. Stein MB, Fuetsch M, Muller N, et al. Social anxiety disorder
and the risk of depression: a prospective community study of
adolescents and young adults. Arch Gen Psychiatry 2001;58:
5. Pine DS. Research review: a neuroscience framework for
pediatric anxiety disorders. J Child Psychol Psychiatry 2007;48:
6. Pine DS, Helfinstein SM, Bar-Haim Y. Challenges in developing
novel treatments for childhood disorders: lessons from research
on anxiety. Neuropsychopharmacology 2009;34:213–228.
7. McClure EB, Monk CS, Nelson EE, et al. Abnormal attention
modulation of fear circuit function in pediatric generalized
anxiety disorder. Arch Gen Psychiatry 2007;64:97–106.
8. Rauch SL, Whalen PJ, Shin LM, et al. Exaggerated amygdala
response to masked facial stimuli in posttraumatic stress disorder:
a functional MRI study. Biol Psychiatry 2000;47:769–776.
9. Stein MB, Goldin PR, Sareen J, et al. Increased amygdala
activation to angry and contemptuous faces in generalized social
phobia. Arch Gen Psychiatry 2002;59:1027–1034.
10. Monk CS, Nelson EE, McClure EB, et al. Ventrolateral
prefrontal cortex activation and attentional bias in response to
angry faces in adolescents with generalized anxiety disorder. Am J
11. Fanselow MS, LeDoux JE. Why we think plasticity underlying
Pavlovian fear conditioning occurs in the basolateral amygdala.
12. LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci
13. Bouton ME. Context, ambiguity, and unlearning: sources of
relapse after behavioral extinction. Biol Psychiatry 2002;52:
14. Bouton ME. Context and behavioral processes in extinction.
Learn Mem 2004;11:485–494.
15. LaBar KS, Gatenby JC, Gore JC, et al. Human amygdala
activation during conditioned fear acquisition and extinction: a
mixed-trial fMRI study. Neuron 1998;20:937–945.
16. Phelps EA, Delgado MR, Nearing KI, et al. Extinction learning
in humans: role of the amygdala and vmPFC. Neuron 2004;43:
17. Craske MG, Waters AM, Lindsey Bergman R, et al. Is aversive
learning a marker of risk for anxiety disorders in children? Behav
Res Ther 2008;46:954–967.
18. Grillon C, Morgan 3rd CA. Fear-potentiated startle conditioning
to explicit and contextual cues in Gulf War veterans with
posttraumatic stress disorder. J Abnorm Psychol 1999;108:134–142.
19. Lissek S, Powers AS, McClure EB, et al. Classical fear
conditioning in the anxiety disorders: a meta-analysis. Behav
Res Ther 2005;43:1391–1424.
20. Lau JY, Lissek S, Nelson EE, et al. Fear conditioning in
adolescents with anxiety disorders: results from a novel experi-
mental paradigm. J Am Acad Child Adolesc Psychiatry 2008;47:
21. Orr SP, Metzger LJ, Lasko NB, et al. De novo conditioning in
trauma-exposed individuals with and without posttraumatic
stress disorder. J Abnorm Psychol 2000;109:290–298.
22. Davis M, Falls WA, Gewirtz J. Neural systems involved in fear
inhibition: extinction and conditioned inhibition. Contemporary
issues in modeling psychopathology 2000;113–142.
23. Desimone R. Visual attention mediated by biased competition in
extrastriate visual cortex. Philos Trans R Soc Lond B Biol Sci
24. Pessoa L, Ungerleider LG. Neuroimaging studies of attention
and the processing of emotion-laden stimuli. Prog Brain Res
25. Davis M, Whalen PJ. The amygdala: vigilance and emotion. Mol
26. Monk CS, Telzer EH, Mogg K, et al. Amygdala and ventrolateral
prefrontal cortex activation to masked angry faces in children and
adolescents with generalized anxiety disorder. Arch Gen Psy-
27. Pessoa L, McKenna M, Gutierrez E, et al. Neural processing of
emotional faces requires attention. Proc Natl Acad Sci USA
28. Marks IM. Fears P, Rituals P. Anxiety and Their Disorders. New
York: Oxford University Press; 1987.
29. Klein DF. False suffocation alarms, spontaneous panics, and
related conditions. An integrative hypothesis. Arch Gen Psy-
30. Bar-Haim Y, Lamy D, Pergamin L, et al. Threat-related
attentional bias in anxious and nonanxious individuals: a meta-
analytic study. Psychol Bull 2007;133:1–24.
31. Delgado MR, Nearing KI, Ledoux JE, et al. Neural circuitry
underlying the regulation of conditioned fear and its relation to
extinction. Neuron 2008;59:829–838.
32. Critchley HD, Mathias CJ, Dolan RJ. Fear conditioning in
humans: the influence of awareness and autonomic arousal on
functional neuroanatomy. Neuron 2002;33:653–663.
33. Knight DC, Waters NS, Bandettini PA. Neural substrates
of explicit and implicit fear memory. Neuroimage 2009;45:
34. Pischek-Simpson LK, Boschen MJ, Neumann DL, et al. The
development of an attentional bias for angry faces following
Pavlovian fear conditioning. Behav Res Ther 2009;47:322–330.
35. Thomas KM, Drevets WC, Dahl RE, et al. Amygdala response
to fearful faces in anxious and depressed children. Arch Gen
36. Milad MR, Pitman RK, Ellis CB, et al. Neurobiological basis of
failure to recall extinction memory in posttraumatic stress
disorder. Biol Psychiatry 2009;66:1075–1082.
37. Bremner JD, Vermetten E, Schmahl C, et al. Positron emission
tomographic imaging of neural correlates of a fear acquisition
and extinction paradigm in women with childhood sexual-abuse-
related post-traumatic stress disorder. Psychol Med 2005;35:
38. Schneider F, Weiss U, Kessler C, et al. Subcortical correlates of
differential classical conditioning of aversive emotional reactions
in social phobia. Biol Psychiatry 1999;45:863–871.
39. Bishop SJ, Duncan J, Lawrence AD. State anxiety modulation of
the amygdala response to unattended threat-related stimuli.
J Neurosci 2004;24:10364–10368.
40. Beesdo K, Lau JY, Guyer AE, et al. Common and distinct
amygdala-function perturbations in depressed versus anxious
adolescents. Arch Gen Psychiatry 2009;66:275–285.
41. Li G, Nair SS, Quirk GJ. A biologically realistic network model
of acquisition and extinction of conditioned fear associations in
lateral amygdala neurons. J Neurophysiol 2009;101:1629–1646.
42. Rogan MT, Staubli UV, LeDoux JE. Fear conditioning induces
associative long-term potentiation in the amygdala. Nature 1997;
43. Thompson JV, Sullivan RM, Wilson DA. Developmental
emergence of fear learning corresponds with changes in
amygdala synaptic plasticity. Brain Res 2008;1200:58–65.
11 Review: Development, Anxiety, and Fear Learning
Depression and Anxiety
44. Davis FC, Johnstone T, Mazzulla EC, et al. Regional response
differences across the human amygdaloid complex during social
conditioning. Cereb Cortex 2010;20:612–621.
45. Straube T, Weiss T, Mentzel HJ, et al. Time course of amygdala
activation during aversive conditioning depends on attention.
46. Wright CI, Fischer H, Whalen PJ, et al. Differential prefrontal
cortex and amygdala habituation to repeatedly presented emo-
tional stimuli. Neuroreport 2001;12:379–383.
47. Breiter HC, Etcoff NL, Whalen PJ, et al. Response and
habituation of the human amygdala during visual processing of
facial expression. Neuron 1996;17:875–887.
48. Britton JC, Shin LM, Barrett LF, et al. Amygdala and fusiform
gyrus temporal dynamics: responses to negative facial expres-
sions. BMC Neurosci 2008;9:44.
49. Williams LM, Brown KJ, Das P, et al. The dynamics of cortico-
amygdala and autonomic activity over the experimental time course
of fear perception. Brain Res Cogn Brain Res 2004;21:114–123.
50. Protopopescu X, Pan H, Tuescher O, et al. Differential time
courses and specificity of amygdala activity in posttraumatic
stress disorder subjects and normal control subjects. Biol
51. Hare TA, Tottenham N, Galvan A, et al. Biological substrates of
emotional reactivity and regulation in adolescence during an
emotional go-nogo task. Biol Psychiatry 2008;63:927–934.
52. Schwartz CE, Wright CI, Shin LM, et al. Inhibited and
uninhibited infants ‘‘grown up’’: adult amygdalar response to
novelty. Science 2003;300:1952–1953.
53. Blackford JU, Avery SN, Shelton RC, et al. Amygdala temporal
dynamics: temperamental differences in the timing of amygdala
response to familiar and novel faces. BMC Neurosci 2009;10:145.
54. Scherer KR. Appraisal considered as a process of multilevel
sequential checking. In: Scherer KR, Schorr A, Johnstone T,
editors. Appraisal Processes in Emotion: Theory, Methods,
Research. New York: Oxford University Press; 2001:92–120.
55. LeDoux J. The emotional brain, fear, and the amygdala. Cell
Mol Neurobiol 2003;23:727–738.
56. Kalin NH. Studying non-human primates: a gateway to under-
standing anxiety disorders. Psychopharmacol Bull 2004;38:8–13.
57. Blanchard DC, Hynd AL, Minke KA, et al. Human defensive
behaviors to threat scenarios show parallels to fear- and anxiety-
related defense patterns of non-human mammals. Neurosci
Biobehav Rev 2001;25:761–770.
58. Bolles RC, Fanselow MS. A perceptual-defense-recuperative
model of fear and pain. Behav Brain Sci 1980;3:291–323.
59. Grillon C. Associative learning deficits increase symptoms of
anxiety in humans. Biol Psychiatry 2002;51:851–858.
60. Lissek S, Rabin SJ, McDowell DJ, et al. Impaired discriminative
fear-conditioning resulting from elevated fear responding to
learned safety cues among individuals with panic disorder. Behav
Res Ther 2009;47:111–118.
61. Rapee RM, Heimberg RG. A cognitive-behavioral model of
anxiety in social phobia. Behav Res Ther 1997;35:741–756.
62. Muris P, Luermans J, Merckelbach H, et al. ‘‘Danger is lurking
everywhere’’ the relation between anxiety and threat perception
abnormalities in normal children. J Behav Ther Exp Psychiatry
63. Dawson ME, Schell AM. Information processing and human
autonomic classical conditioning. In: Ackles PK, Jennings JR,
Coles MGH, editors. Advances in Psychophysiology. Greenwich,
CT: JAI Press; 1985;89–165.
64. Pitman RK, Orr SP, Forgue DF, et al. Psychophysiologic
assessment of posttraumatic stress disorder imagery in Vietnam
combat veterans. Arch Gen Psychiatry 1987;44:970–975.
65. Cuthbert BN, Lang PJ, Strauss C, et al. The psychophysiology of
anxiety disorder: fear memory imagery. Psychophysiology 2003;
66. Ohman A, Soares JJ. Emotional conditioning to masked stimuli:
expectancies for aversive outcomes following nonrecognized
fear-relevant stimuli. J Exp Psychol Gen 1998;127:69–82.
67. Ohman A, Mineka S. Fears, phobias, and preparedness: toward
an evolved module of fear and fear learning. Psychol Rev 2001;
68. Quirk GJ, Mueller D. Neural mechanisms of extinction learning
and retrieval. Neuropsychopharmacology 2008;33:56–72.
69. Ochsner KN, Bunge SA, Gross JJ, et al. Rethinking feelings: an
FMRI study of the cognitive regulation of emotion. J Cogn
70. Amodio DM, Frith CD. Meeting of minds: the medial frontal
cortex and social cognition. Nat Rev Neurosci 2006;7:268–277.
71. Schmitz TW, Johnson SC. Self-appraisal decisions evoke
dissociated dorsal-ventral aMPFC networks. Neuroimage 2006;
72. Carthy T, Horesh N, Apter A, et al. Emotional reactivity
and cognitive regulation in anxious children. Behav Res Ther
73. Goldin PR, Manber T, Hakimi S, et al. Neural bases of social
anxiety disorder: emotional reactivity and cognitive regulation
during social and physical threat. Arch Gen Psychiatry 2009;66:
74. Shin LM, Orr SP, Carson MA, et al. Regional cerebral blood
flow in the amygdala and medial prefrontal cortex during
traumatic imagery in male and female Vietnam veterans with
PTSD. Arch Gen Psychiatry 2004;61:168–176.
75. Phan KL, Fitzgerald DA, Nathan PJ, et al. Neural substrates for
voluntary suppression of negative affect: a functional magnetic
resonance imaging study. Biol Psychiatry 2005;57:210–219.
76. Quirk GJ, Likhtik E, Pelletier JG, et al. Stimulation of medial
prefrontal cortex decreases the responsiveness of central amyg-
dala output neurons. J Neurosci 2003;23:8800–8807.
77. Urry HL, van Reekum CM, Johnstone T, et al. Amygdala and
ventromedial prefrontal cortex are inversely coupled during regula-
tion of negative affect and predict the diurnal pattern of cortisol
secretion among older adults. J Neurosci 2006;26:4415–4425.
78. Pavlov IP. Conditioned Reflexes. New York: Oxford University
79. Lissek S, Biggs AL, Rabin SJ, et al. Generalization of conditioned
fear-potentiated startle in humans: experimental validation and
clinical relevance. Behav Res Ther 2008;46:678–687.
80. Rosen JB, Donley MP. Animal studies of amygdala function in
fear and uncertainty: relevance to human research. Biol Psychol
81. Zald DH. The human amygdala and the emotional evaluation of
sensory stimuli. Brain Res Brain Res Rev 2003;41:88–123.
82. Lissek S, Rabin S, Heller RE, et al. Overgeneralization of
conditioned fear as a pathogenic marker of panic disorder. Am J
83. Burgos-Robles A, Vidal-Gonzalez I, Santini E, et al. Consolidation
of fear extinction requires NMDA receptor-dependent bursting in
the ventromedial prefrontal cortex. Neuron 2007;53:871–880.
84. Pare D, Quirk GJ, Ledoux JE. New vistas on amygdala networks
in conditioned fear. J Neurophysiol 2004;92:1–9.
85. Milad MR, Wright CI, Orr SP, et al. Recall of fear extinction in
humans activates the ventromedial prefrontal cortex and
hippocampus in concert. Biol Psychiatry 2007;62:446–454.
86. Schiller D, Levy I, Niv Y, et al. From fear to safety and back:
reversal of fear in the human brain. J Neurosci 2008;28:
12Britton et al.
Depression and Anxiety
87. Soliman F, Glatt CE, Bath KG, et al. A genetic variant BDNF
polymorphism alters extinction learning in both mouse and
human. Science 2010;327:863–866.
88. Lau JY, Goldman D, Buzas B, et al. BDNF gene polymorphism
responses to emotional faces in anxious and depressed adoles-
cents. Neuroimage 2009.
89. Milad MR, Quirk GJ. Neurons in medial prefrontal cortex signal
memory for fear extinction. Nature 2002;420:70–74.
90. Milad MR, Quinn BT, Pitman RK, et al. Thickness of
ventromedial prefrontal cortex in humans is correlated with
extinction memory. Proc Natl Acad Sci USA 2005;102:
91. Gross C, Hen R. The developmental origins of anxiety. Nat Rev
92. Caldji C, Tannenbaum B, Sharma S, et al. Maternal care during
infancy regulates the development of neural systems mediating
the expression of fearfulness in the rat. Proc Natl Acad Sci USA
93. Meaney MJ. Maternal care, gene expression, and the transmis-
sion of individual differences in stress reactivity across genera-
tions. Annu Rev Neurosci 2001;24:1161–1192.
94. Prather MD, Lavenex P, Mauldin-Jourdain ML, et al. Increased
social fear and decreased fear of objects in monkeys with neonatal
amygdala lesions. Neuroscience 2001;106:653–658.
95. Bloch C, Kaiser A, Kuenzli E, et al. The age of second language
acquisition determines the variability in activation elicited by
narration in three languages in Broca’s and Wernicke’s area.
96. Thomas KM, Drevets WC, Whalen PJ, et al. Amygdala response
to facial expressions in children and adults. Biol Psychiatry 2001;
97. Thomas LA, De Bellis MD, Graham R, et al. Development of
emotional facial recognition in late childhood and adolescence.
Dev Sci 2007;10:547–558.
98. Guyer AE, Monk CS, McClure-Tone EB, et al. A developmental
examination of amygdala response to facial expressions. J Cogn
99. Monk CS, McClure EB, Nelson EE, et al. Adolescent
immaturity in attention-related brain engagement to emotional
facial expressions. Neuroimage 2003;20:420–428.
100. Rudy JW. Contextual conditioning and auditory cue condition-
ing dissociate during development. Behav Neurosci 1993;107:
101. Sluzenski J, Newcombe NS, Kovacs SL. Binding, relational
memory, and recall of naturalistic events: a developmental
perspective. J Exp Psychol Learn Mem Cogn 2006;32:89–100.
102. Bachevalier J. Neural bases of memory development: insights
from neuropsychological studies in primates. In: Nelson CA,
Luciana M, editors. Handbook of Developmental Cognitive
Neuroscience. Cambridge, MA: MIT Press; 2001;365–380.
103. Hunt PS. A further investigation of the developmental
emergence of fear-potentiated startle in rats. Dev Psychobiol
104. Gogtay N, Thompson PM. Mapping gray matter development:
implications for typical development and vulnerability to
psychopathology. Brain Cogn 2010;72:6–15.
105. Kim JH, Hamlin AS, Richardson R. Fear extinction across
development: the involvement of the medial prefrontal cortex as
assessed by temporary inactivation and immunohistochemistry.
J Neurosci 2009;29:10802–10808.
106. Kim JH, Richardson R. New findings on extinction of
conditioned fear early in development: theoretical and clinical
implications. Biol Psychiatry 67:297–303.
107. Storsve AB, Richardson R. A developmental dissociation in
compound summation following extinction. Neurobiol Learn
108. Davis GE, Compas BE. Cognitive appraisal of major and daily
stressful events during adolescence: a multidimensional scaling
analysis. J Youth Adolesc 1986;15:377–388.
109. Hasan N, Power TG. Children’s appraisal of major life events.
Am J Orthopsychiatry 2004;74:26–32.
110. Stattin H. Developmental trends in the appraisal of anxiety-
provoking situations. J Pers 1984;52:46–57.
111. Pine DS. Pathophysiology of childhood anxiety disorders. Biol
112. Dunsmoor JE, Mitroff SR, LaBar KS. Generalization of
conditioned fear along a dimension of increasing fear intensity.
Learn Mem 2009;16:460–469.
113. Ohman A. Face the beast and fear the face: animal and social
fears as prototypes for evolutionary analyses of emotion.
114. Ohman A, Eriksson A, Olofsson C. One-trial learning and
superior resistance to extinction of autonomic responses condi-
tioned to potentially phobic stimuli. J Comp Physiol Psychol
115. Grillon C, Baas JP, Lissek S, et al. Anxious responses to
predictable and unpredictable aversive events. Behav Neurosci
116. Grillon C, Baas JM, Pine DS, et al. The benzodiazepine
alprazolam dissociates contextual fear from cued fear in humans
as assessed by fear-potentiated startle. Biol Psychiatry 2006;60:
117. Lissek S, Pine DS, Grillon C. The strong situation: a potential
impediment to studying the psychobiology and pharmacology
of anxiety disorders. Biol Psychol 2006;72:265–270.
118. Grillon C, Dierker L, Merikangas KR. Fear-potentiated startle
in adolescent offspring of parents with anxiety disorders. Biol
119. Grillon C, Merikangas KR, Dierker L, et al. Startle potentiation
by threat of aversive stimuli and darkness in adolescents: a
multi-site study. Int J Psychophysiol 1999;32:63–73.
120. Neumann DL, Waters AM, Westbury HR, et al. The use of an
unpleasant sound unconditional stimulus in an aversive
conditioning procedure with 8- to 11-year-old children. Biol
121. Liberman LC, Lipp OV, Spence SH, et al. Evidence for
retarded extinction of aversive learning in anxious children.
Behav Res Ther 2006;44:1491–1502.
122. Monk CS, Grillon C, Baas JM, et al. A neuroimaging method
for the study of threat in adolescents. Dev Psychobiol 2003;43:
123. Reeb-Sutherland BC, Helfinstein SM, Degnan KA, et al. Startle
response in behaviorally inhibited adolescents with a lifetime
occurrence of anxiety disorders. J Am Acad Child Adolesc
124. Lissek S, Baas JM, Pine DS, et al. Unpublished work 2005.
125. Lau JY, Nelson EE, Angold A, et al. Unpublished data 2009.
126. Ledgerwood L, Richardson R, Cranney J. Effects of D-cycloserine
on extinction of conditioned freezing. Behav Neurosci 2003;
127. Hofmann SG, Meuret AE, Smits JA, et al. Augmentation of
exposure therapy with D-cycloserine for social anxiety disorder.
Arch Gen Psychiatry 2006;63:298–304.
128. Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive
enhancers as adjuncts to psychotherapy: use of D-cycloserine in
phobic individuals to facilitate extinction of fear. Arch Gen
13 Review: Development, Anxiety, and Fear Learning
Depression and Anxiety