389

Ann. N.Y. Acad. Sci. 985: 389-410 (2003). 2003 New York Academy of Sciences.
Neuroimaging Studies of Amygdala Function in
Anxiety Disorders
SCOTT L. RAUCH,
a,b
LISA M. SHIN,
a,b,c
AND CHRISTOPHER I. WRIGHT
a,d
a
Department of Psvchiatrv, Massachusetts General Hospital, Boston, Massachusetts
02129, USA
b
Department of Psvchiatrv Harvard Medical School, Boston, Massachusetts, USA
c
Department of Psvchologv, Tufts Universitv, Medford, Massachusetts, USA
d
Department of Neurologv, Brigham and Womens Hospital, Harvard Medical School,
Boston, Massachusetts, USA
ABSTRACT: Neuroimaging research has helped to advance neurobiological
models of anxiety disorders. The amygdala is known to play an important role
in normal fear conditioning and is implicated in the pathophysiology of anxiety
disorders. The amygdala may also be a target for the beneficial effects of cog-
nitive-behavioral and medication treatments for anxiety disorders. In the cur-
rent paper, we review neuroimaging research pertaining to the role of the
amygdala in anxiety disorders and their treatment. Moreover, we discuss the
development of new neuroimaging paradigms for measuring aspects of
amygdala function, as well as the function of related brain regions. We con-
clude that such tools hold great promise for facilitating progress in relevant ba-
sic neuroscience as well as clinical research domains.
KEYWORDS: functional magnetic resonance imaging; positron emission tomog-
raphy; posttraumatic stress disorder; phobias; obsessive-compulsive disorder;
panic disorder
INTRODUCTION
In recent years, neuroimaging research has helped to advance neurobiological
models oI psychiatric disorders. In this paper, we review neuroimaging research per-
taining to the role oI the amygdala in anxiety disorders and their treatment. SpeciIi-
cally, we Iirst describe the clinical characteristics oI selected anxiety disorders and
their treatment; next we explain how contemporary neuroimaging methods can be
used to test hypotheses about pathophysiology and treatment response, Iocusing on
recently developed cognitive activation probes Ior assessing Iunction in the amygda-
la and related brain areas; then we brieIly review the existing literature relevant to
neuroimaging oI the amygdala in anxiety disorders; and, Iinally, we conclude with a
Address Ior correspondence: Scott L. Rauch, M.D., Director, Psychiatric Neuroimaging
Research, Department oI Psychiatry, Massachusetts General HospitalEast, Building 149,
Room 9130, 13th Street, Charlestown, Massachusetts 02129. Voice: 617-724-9553; Iax: 617-
726-4078.
rauchpsych.mgh.harvard.edu
390 ANNALS NEW YORK ACADEMY OF SCIENCES
discussion oI the Iuture, including techniques currently in development Ior exploring
the role oI the amygdala in anxiety disorders. This paper necessarily extends previ-
ous reviews that we have written, together with our colleagues, on related topics.
14

ANXIETY DISORDERS AND THEIR TREATMENT
Clinical Characteristics of Anxiety Disorders
Anxiety and Iear are normal human emotional states that presumably serve an
adaptive Iunction. Anxiety disorders represent one category oI psychiatric
syndromes
5
that are characterized by maladaptive anxiety symptoms that cause dis-
tress and impair Iunction.
Posttraumatic Stress Disorder
In posttraumatic stress disorder (PTSD), one oI Iew psychiatric conditions Ior
which the etiology is deIined, individuals evolve a constellation oI symptoms in the
aItermath oI a severe emotionally traumatic event; the cardinal Ieatures oI PTSD in-
clude: reexperiencing phenomena (such as Ilashbacks, which can occur spontane-
ously or in response to reminders oI the traumatic event), avoidance (such as
avoiding situations that remind the individual oI the traumatic event), and hyper-
arousal (such as exaggerated startle response). Given the phenomenology oI PTSD,
the Iear-conditioning paradigm has been considered a valuable model Ior developing
hypotheses about the pathophysiology oI this disorder.
Phobias
Phobias are characterized by reliable exaggerated anxiety responses to innocuous
stimuli or situations. Such phobic responses include both the psychic experience oI
anxiety and peripheral maniIestations oI anxiety (such as changes in heart rate,
blood pressure, and respiration), as well as the tendency to avoid the Ieared object
or situation. Social phobia (also known as social anxiety disorder; SAD) entails pho-
bic responses to any oI a range oI diIIerent social situations (such responses may
range Irom more circumscribed abnormal perIormance anxiety, to anxiety about
more generalized exposure to social situations). SpeciIic phobias (SPs) entail phobic
responses to any oI various particular stimuli or situations (such as small animals,
heights, water, and enclosed spaces). Though there is some appeal to models based
on learned Iear Ior these disorders, like Ior PTSD, existing data about phobias do not
provide support Ior the hypothesis that these are typically learned phenomena. To the
contrary, current evidence suggests that there may be a strong Iamilial component to
such conditions, perhaps based on inherited aspects oI temperament.
6,7
Panic Disorder
Panic disorder (PD) is characterized by recurrent panic episodes, typically occur-
ring spontaneously, without overt precipitants. Panic attacks entail a rapid escalation
to extreme anxiety, accompanied by physical symptoms such as rapid breathing, pal-
pitations, sweating, and dizziness, as well as emotional and cognitive symptoms,
such as the Ieeling that something catastrophic is about to happen or that immediate
391 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
escape is necessary. Individuals with PD oIten develop avoidance oI places or situa-
tions where they believe panic attacks are more likely to occur (including where such
attacks have occurred in the past), or where escape may be diIIicult (such as crowded
or conIined places).
Obsessive-Compulsive Disorder
Obsessive-compulsive disorder (OCD) is characterized by intrusive, unwanted
thoughts (that is, obsessions) and ritualized, repetitive behaviors (that is, compul-
sions). In OCD, the obsessions are typically accompanied by anxiety that drives the
compulsions; the compulsions are perIormed to neutralize the obsessions and atten-
dant anxiety.
Given that patients with anxiety disorders either suIIer exaggerated Iear respons-
es to relatively innocuous stimuli (such as phobias) or spontaneous Iear responses in
the absence oI true threat (such as PD), contemporary models oI these conditions
have, to varying degrees, suggested dysIunction within the amygdala, or within neu-
ral systems (or circuits) involving the amygdala.
1reatment of Anxiety Disorders
Cognitive-behavioral treatments are relatively eIIective Ior treating the anxiety
disorders.
8
In particular, behavioral strategies typically entail some component oI
graded exposure to anxiety-provoking stimuli while helping the patient tolerate the
attendant discomIort, master the Ieared situation, and limit or prevent maladaptive
responses. Integrated or parallel cognitive strategies oIten entail replacing maladap-
tive cognitive structures (such as Ialse belieIs about potential catastrophic outcomes)
with more adaptive ones (such as supportive reality-based cognitions). Though the
neural substrates oI these treatment mechanisms remain poorly understood, current
theories are predicated on similarities between behavior therapy and extinction Iol-
lowing Iear conditioning. Hence, it has been suggested that cognitive-behavioral
treatments might involve 'top-down modulation oI amygdala activity.
Medications can also be eIIective Ior treating people with anxiety disorders.
8
Generally, benzodiazepines (such as clonazepam and alprazolam) provide rapid and
eIIective anxiolytic action. However, although the beneIicial eIIects oI antidepres-
sant agents (such as serotonergic reuptake inhibitors |SRIs|, tricyclic antidepressants
|TCAs|, and monoamine oxidase inhibitors |MAOIs|) are typically delayed by sev-
eral weeks, these oIten represent the treatments oI choice Ior providing both endur-
ing reduction oI the anxiety symptoms themselves, as well as the broader array oI
symptoms that constitute these syndromes.
It is important to emphasize that the proIile oI response to these various treat-
ments is not uniIorm across (or within) these disorders. Eor instance, cognitive-be-
havioral methods are regarded as the best treatment Ior SPs, with little compelling
evidence oI beneIits Irom pharmacotherapy. Eurther, whereas PD and SAD have
been shown to respond to a range oI antidepressant medications (that is, SRIs, TCAs,
and MAOIs), OCD appears to be selectively responsive to SRIs (over MAOIs or
TCAs that are not speciIically SRIs).
In summary, although cognitive-behavioral therapies and pharmacotherapies are
eIIective in the treatment oI anxiety disorders, the precise site(s) where these inter-
ventions have their beneIicial eIIects in the brain remains unclear. The amygdala is
392 ANNALS NEW YORK ACADEMY OF SCIENCES
implicated as one possible site oI action Ior these treatments. Cognitive-behavioral
therapy may inIluence top-down modulation oI amygdala responses, similar to that
seen in extinction Iollowing Iear conditioning. Benzodiazepines are known to have
their eIIects via the GABAergic system; GABAergic cells are known to be present
in high concentration within the amygdala. Similarly, antidepressant medications are
known to inIluence monoaminergic transmission, and monoaminergic neurons are
known to ramiIy diIIusely through the brain, and particularly densely upon limbic
structures such as the amygdala.
9
NEUROIMAGING TECHNIQUES
Functional Aeuroimaging 1echniques and Paradigms
Various experimental paradigms have been employed in conjunction with Iunc-
tional neuroimaging modalities in eIIorts to delineate the pathophysiology oI psychi-
atric disorders. In the literature reviewed below, imaging methods include positron
emission tomography (PET) with tracers that measure blood Ilow (such as oxygen-
15-labeled carbon dioxide) or glucose metabolism (that is, Iluorine-18-labeled Iluo-
rodeoxyglucose |EDG|), single photon emission tomography (SPECT) with tracers
that measure correlates oI blood Ilow (such as technetium-99-labeled hexamethyl
propylene amine oxime |TcHMPAO|), and Iunctional magnetic resonance imaging
(IMRI) to measure blood oxygenation level dependent (BOLD) signal changes. Each
oI these techniques yields maps that reIlect regional brain activity.
Such brain activity proIiles are sensitive to the state oI the subject at the time oI
tracer distribution or image acquisition. Hence, Iunctional imaging paradigms can be
categorized based upon the type oI state manipulations employed by the investiga-
tors, and the principal statistical comparisons applied. In neutral state paradigms,
subjects are studied during a nominal 'resting state, or while perIorming a non-spe-
ciIic continuous task. Thus, hypotheses regarding between-group diIIerences in re-
gional brain activity are tested, without particular attention to momentary state
variables. In svmptom provocation paradigms, subjects are scanned during a symp-
tomatic state (aIter having their symptoms intentionally induced) as well as during
control conditions. Within-group comparisons can be made to test hypotheses re-
garding the mediating anatomy oI the symptomatic state; group-by-condition inter-
actions can be sought to distinguish responses in patient vs. control groups.
Behavioral and/or pharmacologic challenges can be used to induce symptoms. In
some cases, when symptomatic states occur spontaneously, experiments are de-
signed to capture these events without the need Ior provocation or induction per se.
In cognitive activation paradigms, subjects are studied while perIorming specially
designed cognitive/behavioral tasks. This approach is intended to increase sensitiv-
ity by employing tasks that speciIically activate brain systems oI interest. Again,
group-by-condition interactions are sought to test the Iunctional responsivity or in-
tegrity oI speciIic brain systems in patients vs. control subjects. Any oI these three
paradigm types can also be employed in the context oI a longitudinal design; most
notably, in treatment studies, subjects are scanned in the context oI a treatment pro-
tocol. In pre/post-treatment studies, subjects are scanned both beIore and aIter a trial.
Then, within-group comparisons are made to test hypotheses regarding changes in
393 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
brain activity proIiles associated with symptomatic improvement. Alternatively, cor-
relation analyses can be perIormed to identiIy pretreatment brain activity character-
istics that predict subsequent treatment response.
Complementary Aeuroimaging 1echniques: Structure and Chemistry
Though the Iocus oI this paper is on Iunctional neuroimaging, there are also neu-
roimaging methods that enable investigators to measure structural and neurochemi-
cal characteristics oI the human brain. Eor instance, morphometric magnetic
resonance imaging (mMRI) involves automated or semi-automated segmentation oI
brain structures oI interest, enabling investigators to calculate volume or Ieatures oI
shape. Evolving methods in this Iield include strategies Ior parcellating cortical ter-
ritories, measuring cortical thickness, and subdividing subcortical nuclei. Imaging
studies oI neurochemistry have employed PET and SPECT methods in conjunction
with radiolabeled high-aIIinity ligands. In this way, regional receptor number and or
aIIinity can be characterized in vivo (that is, receptor characterization studies). Other
approaches include the use oI magnetic resonance spectroscopy (MRS) to measure
the regional relative concentration oI select 'MRS visible compounds. Eor instance,
MRS can be used to measure the compound N-acetyl aspartate (NAA), which is a
purported marker oI healthy neuronal density.
These various neuroimaging techniques should be viewed as complementary. In
instances where results Irom multiple studies converge, more cohesive and compel-
ling models oI pathophysiology have emerged.
Recently Developed Cognitive Activation Probes
Cognitive Activation Probes of Amvgdala Function
These probes have chieIly involved paradigms oI three types: (1) viewing Iace
stimuli; (2) viewing emotionally valenced stimuli; and (3) classical Iear condition-
ing. An initial series oI Iunctional imaging studies showed that passive viewing oI
human Iace stimuli produces reliable amygdala activation
10,11
and that amygdala
responses appear to be greatest to IearIul Iaces as opposed to neutral, happy, or angry
Iaces.
12
Hence, such paradigms represent tools Ior potentially assessing amygdala
responsivity to a particular class oI socially relevant threat-related stimuli. Interest-
ingly, whereas overtly presented Iace stimuli recruit a broad array oI other brain ar-
eas in addition to the amygdala and substantia inominata (such as Irontal cortical
territories), when Iace stimuli are instead presented beneath the level oI conscious
awareness (such as by using a backward masking technique) isolated amygdala ac-
tivation is observed.
13
Consequently, such masked-Iaces paradigms provide a poten-
tial tool Ior exploring amygdala responsivity relatively dissociated Irom the top-
down inIluences oI Irontal cortex. Eurthermore, a series oI studies have shown that
repeated presentation oI Iace stimuli can be used to demonstrate habituation oI
amygdala responses.
14,15
Such paradigms provide a potential tool Ior characterizing
habituation proIiles within the amygdala. OI note, these studies, together with the
large extant literature on neuroimaging and Iace stimuli, indicate that humans exhib-
it diIIerential responses within the right and leIt amygdala; the right amygdala ap-
pears to show a more temporally dynamic pattern oI response, whereas the leIt
394 ANNALS NEW YORK ACADEMY OF SCIENCES
amygdala appears to exhibit a more temporally stable response with a more robust
diIIerence in response based on the emotional valence oI the stimuli.
There are several potentially conIounding Ieatures oI cognitive activation para-
digms that utilize standardized sets oI Iace stimuli. Eor instance, it has been shown
that the relation between the race oI the subjects and the race oI the Iaces used as
stimuli can produce a substantial source oI variance.
16
Although the use oI stimulus
sets that include Iaces Irom a broad range oI races may mitigate this problem to some
extent, this still represents a source oI variance that is diIIicult to quantiIy or control.
Consequently, we have explored the use oI schematic, rather than actual human, Iace
stimuli as a Iunctional imaging probe oI amygdala response, because such schematic
Iace stimuli do not represent any particular race. Initial Iunctional imaging Iindings
indicate that schematic Iaces can produce reliable and robust activation within the
amygdala.
17
These may provide a potential tool Ior measuring amygdala responsiv-
ity while obviating the conIounds oI race that are intrinsic to paradigms that employ
actual human Iace stimuli.
Other paradigms that involve viewing pictures have indicated robust and reliable
amygdala activation in response to emotionally valenced vs. neutral pictures.
18,19
In
particular, the International AIIective Picture System
20
provides an extremely well
characterized set oI visual stimuli Ior constructing such paradigms to assess
amygdala responses based on emotional valence or arousal.
Einally, several neuroimaging experiments oI classical Iear conditioning in
healthy human subjects have shown amygdala activation. A PET study in which vid-
eotapes oI snakes (conditioned stimulus, CS) were paired with shocks (uncondi-
tioned stimulus, US) showed a signiIicant correlation between rCBE changes in right
amygdala and electrodermal activity changes.
21,22
Another conditioning paradigm
23
entailed the presentation oI Iaces that had previously been paired with an aversive
burst oI white noise (CS+) or never paired with the noise (CS). Though the com-
parison oI the CS+ vs. CS conditions yielded activation in right thalamus, orbito-
Irontal cortex, and superior Irontal gyrus (but not amygdala), activation in thalamus
was positively correlated with activation in right amygdala as well as orbitoIrontal
cortex and basal Iorebrain. A third conditioning study
24
used PET and backward
masking techniques to study rCBE responses to conditioned Iace stimuli with and
without awareness. When all CS+ were compared to all CS, bilateral activation in
amygdala was observed; moreover, right amygdala activation was Iound in the con-
dition where subjects were aware, whereas leIt amygdala activation was Iound in the
condition where subjects were unaware oI the emotionally expressive Iace stimuli.
A single-trial IMRI study
25
oI both acquisition and extinction employed a colored
shape (CS) paired with a shock (US), and a diIIerent colored shape (CS-) never
paired with shock. Comparing CS with CS trials revealed activation in the peri-
amygdaloid cortex during early acquisition and amygdala activation during early ex-
tinction trials when no shocks were administered. Another single-trial IMRI study
26
involved an acquisition phase in which two neutral Iaces (CS) were presented paired
with a loud tone (US) and two other neutral Iaces were presented alone (CS-).
Whereas the CS vs. CS- contrast did not show amygdala activation, a time by event
type interaction revealed that IMRI signal in amygdala decreased over time in the
CS+ condition relative to the CS condition. Similar results were reported by the
same group
27
in a trace conditioning study; the Iindings implicated hippocampus as
well as amygdala in this Iunction. Einally, an IMRI paradigm has been developed us-
395 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
ing an aversive air puII (US) and diIIerent colored lights (CS+/) to engage the
amygdala in the context oI conditioning in pediatric subjects.
28
These various neu-
roimaging paradigms not only implicate the amygdala in human Iear conditioning,
but provide tools Ior probing the neural substrates oI acquisition and extinction
across the anxiety disorders.
Cognitive Activation Probes of Related Brain Regions
These probes include paradigms designed to probe anterior cingulate or hippoc-
ampal Iunction. Though numerous paradigms have been shown to activate various
sub-territories oI anterior cingulate cortex,
29
in our laboratory, we have Iocused on
developing a battery oI various Stroop-type tasks Ior studying anterior cingulate
Iunction in anxiety disorders. Our rationale was that the Iunction oI the anterior cin-
gulate likely to be oI greatest relevance to our interests is the capacity to suppress a
particular inIormation stream in Iavor oI another. In anxiety disorders, there is a
well-established deIicit in suppressing disorder-relevant inIormation in Iavor oI non-
disorder-relevant inIormation.
30
Indeed, a series oI IMRI studies have shown that a
rostral (pregenual) territory oI anterior cingulate is activated during the Emotional
Counting Stroop task where emotional inIormation must be suppressed in Iavor oI
non-emotional inIormation.
31
In contrast, a more dorsal/posterior subterritory oI
anterior cingulate cortex is activated when non-emotional inIormation must be sup-
pressed in Iavor oI other nonemotional inIormation.
29
This tool has now been ap-
plied to demonstrate deIiciencies in anterior cingulate recruitment in subjects with
anxiety disorders.
32
Similarly, there is a very wide array oI Iunctional imaging par-
adigms that yield reliable hippocampal activation, especially those that involve ex-
plicit learning and memory tasks.
33
Euture studies should seek to develop paradigms
related to contextual conditioning as probes oI hippocampal Iunction that might be
oI greatest relevance to the anxiety disorders.
POSTTRAUMATIC STRESS DISORDER
Amygdalocentric Model of Posttraumatic Stress Disorder
We previously presented a neurocircuitry model oI PTSD
2
that emphasizes the
role oI the amygdala, as well as its interactions with the hippocampus and medial
preIrontal cortex. BrieIly, this model hypothesizes hyper-responsivity within the
amygdala to threat-related stimuli, with inadequate top-down governance over the
amygdala by medial preIrontal cortex (speciIically, the rostral anterior cingulate cor-
tex) and the hippocampus. Amygdala hyperresponsivity mediates symptoms oI
hyperarousal and explains the indelible quality oI the emotional memory Ior the
traumatic event; inadequate inIluence by the anterior cingulate cortex underlies deI-
icits oI habituation; and decreased hippocampal Iunction underlies deIicits in iden-
tiIying saIe contexts, as well as accompanying explicit memory diIIiculties.
34
This
model represents a Iinal common pathophysiological pathway. Consequently, the
pathogenesis oI PTSD can be conceptualized as a Iear-conditioning process that is
superimposed over some diathesis, which could entail any combination oI pre-mor-
bid intrinsic amygdala hyper-responsivity, anterior cingulate deIiciency, hippocam-
396 ANNALS NEW YORK ACADEMY OF SCIENCES
pal deIiciency, or exaggerated susceptibility to stress. Eurther, chronic PTSD might
involve progressive deterioration oI Iunction within this system.
Functional Imaging Findings
An initial PET symptom provocation study oI PTSD
35
used a script-driven imag-
ery method Ior inducing symptoms. Eor the provoked vs. control conditions, in-
creased rCBE was Iound within right orbitoIrontal, insular, anterior temporal, and
visual cortex, as well as anterior cingulate cortex and the right amygdala. Decreases
in rCBE were observed within leIt inIerior Irontal (Broca`s area) and leIt middle tem-
poral cortex. Interpretations oI this initial study, with regard to the pathophysiology
oI PTSD, were limited by the absence oI a comparison group. A series oI subsequent
Iunctional imaging studies were conducted where comparisons were made between
subjects with PTSD and trauma-exposed subjects without PTSD, Ior contrasts be-
tween provoked vs. control conditions, to test hypotheses about the pathophysiology
oI PTSD. Convergent results have suggested that when exposed to reminders oI trau-
matic events (vs. control conditions), subjects with PTSD (vs. subjects without
PTSD) exhibit greater responses within the amygdala,
36,37
attenuated responses
within medial Irontal areas,
38-41
and exaggerated deactivation within other hetero-
modal Irontal cortical regions.
36,40
These Iindings Irom symptom provocation stud-
ies were interpreted as providing initial support Ior the amygdalocentric
neurocircuitry model oI PTSD.
To test this model Iurther, cognitive activation studies were used to measure the
Iunctional integrity at each node oI the circuit: medial preIrontal cortex, amygdala,
and hippocampus. Using an IMRI masked-Iaces probe oI amygdala response,
13
Rauch and colleagues
42
Iound that, in comparison to trauma-exposed subjects with-
out PTSD, subjects with PTSD exhibited exaggerated amygdala responses. The
group vs. condition contrast identiIied a locus in right dorsal amygdala. In an anal-
ysis oI data Irom each individual subject, it was shown that, in the context oI this
paradigm, BOLD response within the amygdala to masked-IearIul vs. masked-happy
Iaces within the amygdala correlated with an index oI PTSD symptom severity,
whereas BOLD response did not correlate with an index oI depression severity. Eur-
ther, an assessment oI the main eIIect oI condition across all subjects replicated the
Iinding that this contrast illustrates recruitment oI the amygdala in the absence oI
Irontal cortical activation. Thus, these Iindings were interpreted as additional evi-
dence oI hyper-responsivity oI the amygdala to threat-related stimuli in PTSD, even
when relatively dissociated Irom the top-down inIluences oI Irontal cortex. Interest-
ingly, more recently, Sheline and colleagues
43
used an analogous approach to study
patients with major depression. They Iound that, in comparison with healthy con-
trols, subjects with major depression exhibited exaggerated leIt amygdala responses
to masked-IearIul Iaces. Moreover, Sheline et al.
43
Iound that the magnitude oI leIt
amygdala activation correlated with an index oI depression severity rather than anx-
iety severity, and that this abnormal activation proIile returned towards normal with
successIul antidepressant medication treatment.
Using an IMRI-Emotional Stroop paradigm,
31
Shin and colleagues
32
Iound that,
in comparison to trauma-exposed subjects without PTSD, PTSD subjects exhibited
attenuated recruitment oI anterior cingulate cortex in the context oI a task that re-
quires suppressing processing oI trauma-related inIormation in Iavor oI general neg-
397 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
ative inIormation. This Iinding indicates deIicient Iunction oI anterior cingulate
cortex in PTSD.
Recently completed PET studies have utilized explicit learning paradigms as
probes oI hippocampal Iunction in PTSD. Bremner et al.
44
reported relatively dimin-
ished activation oI hippocampus during the perIormance oI a verbal paired associ-
ates task in abuse survivors with PTSD. Using a word-stem completion task, Shin
and colleagues
45
Iound diminished recruitment oI hippocampus in IireIighters with
PTSD, relative to IireIighters without PTSD. Together, these results support the
model oI hippocampal dysIunction in PTSD.
Complementary Aeuroimaging Findings: Structure and Chemistry
Morphometric MRI studies oI PTSD have Iocused on subtle between-group diI-
Ierences with respect to hippocampal volume. The possibility oI reduced hippocam-
pal volume and Iunction was scientiIically appealing, given that studies oI chronic
stress in animals have shown degenerative changes within the hippocampus associ-
ated with chronic exposure to glucocorticoids.
46
In Iact, an initial series oI Iour stud-
ies showed smaller hippocampal volumes in adult subjects with PTSD vs. groups oI
healthy control subjects
34,4749
and/or trauma-exposed subjects without PTSD.
48
In
some instances, investigators showed that these Iindings survived statistical controls
Ior alcohol abuse or years oI education,
34,48
and that measures oI hippocampal vol-
ume correlated with measures oI verbal memory
34
or dissociative symptoms
49
as
well as indices oI trauma exposure and PTSD symptom severity.
48
In addition, a pre-
liminary MRS study, Iound signiIicantly reduced NAA levels in hippocampus Ior
PTSD vs. healthy control subjects.
50
However, subsequent MRI studies Iailed to
show hippocampal volume diIIerences when assessing children and adolescents with
PTSD,
51,52
and two longitudinal studies Iailed to Iind reductions in hippocampal
volumes over 6-month to 2-year Iollow-up periods.
53,54
Consequently, though initial
MRI and MRS Iindings provided support Ior the hypothesis that PTSD is associated
with reduced hippocampal size, which in turn is associated with cognitive deIicits
and PTSD symptoms, subsequent results have clouded the picture with regard to a
relationship between hippocampal volume and PTSD.
Summary
Taken together, imaging data support the current neurocircuitry model oI PTSD
that emphasizes the Iunctional relationship between a triad oI brain structures: the
amygdala, medial preIrontal cortex, and hippocampus. When exposed to reminders
oI traumatic events, subjects appear to recruit anterior paralimbic regions, while ex-
hibiting decreased activity within other heteromodal cortical areas. In comparison
with control subjects, however, patients with PTSD exhibit anterior cingulate activa-
tion oI diminished magnitude, but exaggerated rCBE increases within other paralim-
bic regions as well as the amygdala, and exaggerated decreases within widespread
areas that are associated with higher cognitive Iunctions. To date, whereas measures
398 ANNALS NEW YORK ACADEMY OF SCIENCES
oI hippocampal volume have been inconsistent, emerging Iunctional imaging Iind-
ings may be more convergent with regard to hippocampal dysIunction in PTSD.
SOCIAL ANXIETY DISORDER AND SPECIFIC PHOBIAS
Aeuroanatomical Models of Phobias
Phobias may represent the product oI dysregulated systems speciIic to assessing
potentially threatening stimuli or situations that are oI particular ethological signiI-
icance. Eor instance, iI humans have evolved a neural network speciIically designed
to assess social cues Ior threatening content and another to assess threats Irom small
animals, and so on, these might represent the neural substrates Ior the pathophysiol-
ogy underlying phobias. At this juncture, there are no cohesive neuroanatomically
based models Ior the phobias
55,56
; rather, it is Irom Iurther neuroimaging studies oI
the type described below that such models might arise.
Functional Imaging Findings
A single neutral state SPECT study oI SAD subjects and healthy control subjects
Iound no signiIicant between-group diIIerences in rCBE.
57
However, a PET symp-
tom provocation study contrasting public vs. private speaking conditions Iound
greater increases in amygdala rCBE and decreases in orbitoIrontal and insular cortex
in the SAD vs. the non-phobic group.
58
Cognitive activation studies have also impli-
cated the amygdala in SAD. Birbaumer et al.
59
used IMRI to study SAD subjects vs.
healthy control subjects, while they were exposed to slides oI neutral human Iaces
or aversive odors. In comparison with the control group, the SAD group exhibited
hyperresponsivity within the amygdala that was speciIic to the human Iace stimuli.
In a Iollow-up study, Schneider et al.
60
used IMRI to study SAD subjects vs. healthy
control subjects, in the context oI a classical conditioning paradigm; neutral Iace
stimuli were the conditioned stimuli, and odors (negative odor, odorless air) served
as the unconditioned stimuli. In response to conditioned stimuli associated with the
negative odor, the SAD group displayed signal increases within amygdala and hip-
pocampus, whereas healthy comparison subjects displayed signal decreases in these
regions.
Studies oI SPs to date have principally employed PET symptom provocation par-
adigms. Though an initial PET study, using older data analytic methods, Iound no
signiIicant changes in rCBE, a subsequent series oI studies yielded convergent re-
sults. During exposure to videotapes oI phobic material vs. control videotapes, snake
phobics
61
exhibited increases in rCBE within secondary visual cortex and rCBE de-
creases within preIrontal, posterior cingulate, and anterior temporopolar cortex, as
well as hippocampus. These Iindings were ostensibly replicated in an analogous
study oI spider phobics.
62,63
OI note, another PET study involving a cohort oI sub-
jects with a variety oI small animal phobias and in vivo exposure to phobia-related
and control stimuli Iound diIIerent results
64
; one explanation Ior these disparate
Iindings was that Rauch and colleagues measured rCBE while subjects had their eyes
closed whereas previous studies oI SPs were perIormed with subjects` eyes open.
Rauch et al.
64
Iound signiIicant rCBE increases within multiple anterior paralimbic
399 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
territories, leIt somatosensory cortex, and leIt thalamus. Dominant-sided somatosen-
sory cortical activation was interpreted in the context oI subjects` reports that they
engaged in tactile imagery, worrying that the phobic stimulus would come in bodily
contact with them. This was conceptualized as analogous to visual cortical activation
in the other SP studies, where exposures to phobic stimuli were mediated via the vi-
sual sensory modality. In this context, it is interesting to note that the amygdala is
known to project to sensory areas, and is believed to Iacilitate responsivity in those
areas when the amygdala is activated (such as in response to threatening stimuli in
the environment).
65
Complementary Aeuroimaging Findings: Structure and Chemistry
A single morphometric MRI study oI SAD vs. healthy control subjects
66
Iound
no volumetric diIIerences Ior total cerebrum, caudate, putamen, and thalamus; how-
ever, data regarding the amygdala and hippocampus were not reported. We could
Iind no structural MRI studies oI SPs, although we are aware that such research is
currently underway. Tiihonen et al.,
67
using SPECT and iodine-123-labeled-beta
CIT, Iound signiIicantly reduced striatal dopamine reuptake binding site density in
SAD subjects vs. healthy controls.
Summary
The neuroimaging literature pertaining to the phobias remains quite limited.
Studies oI SAD indicate exaggerated responsivity oI medial temporal lobe structures
during symptom provocation and in response to human Iace stimuli, as well as an
aberrant pattern oI activity within medial temporal lobe structures during aversive
conditioning with human Iace stimuli. This is consistent with a hypersensitive sys-
tem Ior the assessment or assignment oI threat to human Iaces, as a neural substrate
Ior the underpinnings oI social anxiety in SAD. Moreover, the preliminary Iinding
oI dopamine receptor abnormalities in SAD is consistent with theories oI dysregu-
lated reward as a Iactor in social deIicits.
56
Imaging Iindings in SPs suggest activa-
tion oI sensory cortex corresponding to stimulus inIlow associated with a
symptomatic state. Such results are consistent with a hypersensitive system Ior as-
sessment oI, or response to, speciIic threat-related cuesa system in which the
amygdala likely plays a central role; however, the available imaging data do not yet
provide clear anatomical substrates Ior the pathophysiology oI SPs.
PANIC DISORDER
Aeuroanatomical Models of Panic Disorder
Contemporary neurobiological models oI panic disorder (PD) have emphasized a
wide range oI disparate elements,
68
including dysregulated ascending noradrenergic
and/or serotonergic systems, aberrant responsivity to CO
2
at the level oI brain stem
(that is, 'Ialse suIIocation alarm), global cerebral abnormalities in lactate metabo-
lism, and abnormalities in the interactions between hippocampus and amygdala.
Whereas the behavioral sequelae oI recurrent panic attacks (such as agoraphobic
avoidance) can readily be explained on the basis oI learning theory and the Iear-
400 ANNALS NEW YORK ACADEMY OF SCIENCES
conditioning model, a satisIactory model oI PD must primarily explain the occur-
rence oI spontaneous panic episodes.
One possibility is that a core physiological (that is, normal) anxiety response, me-
diated by normal anxiety/Iear circuitry, is recruited spontaneously as an aberrant
event, due to homeostatic deIicits. This Iits well with the suIIocation alarm model,
as well as theories regarding Iundamental monoaminergic dysregulation. Another
possibility, is that panic attacks evolve in the context oI what should be minor anxi-
ety episodes, because oI Iailures in the systems responsible Ior limiting such normal
responses; similar to the aIorementioned model oI PTSD, hippocampal deIicits
might underlie such a mechanism in the case oI PD. Einally, we should consider that
panic episodes described as spontaneous (that is, without identiIiable precipitants)
could reIlect anxiety responses to stimuli that are not processed at the conscious (that
is, explicit) level, but instead, recruit anxiety circuitry without awareness (that is, im-
plicitly). This is an intriguing concept, since there is strong evidence that the
amygdala can be recruited into action in the absence oI awareness that a threat-relat-
ed stimulus has been presented.
13
By this model, PD might be characterized by Iun-
damental amygdala hyper-responsivity to subtle environmental cues, triggering Iull-
scale threat-related responses in the absence oI conscious awareness.
Functional Imaging Findings
In an initial PET neutral-state study, Reiman et al.
69
Iound that in comparison
with controls, a subset oI PD patients who were vulnerable to lactate-induced panic
exhibited lower leIt/right ratios oI parahippocampal rCBE. In a resting-state SPECT
study, DeCristoIaro et al.
70
Iound that in comparison with control subjects, PD sub-
jects exhibited elevated rCBE in the leIt occipital cortex and reduced rCBE in the
hippocampal area bilaterally. In a neutral-state PET-EDG study, in comparison with
normal control subjects, subjects with PD exhibited a lower leIt/right hippocampal
ratio oI rCMRglu.
71
In contrast, another PET-EDG study Iound that in comparison
with normal control subjects, PD subjects exhibited elevated rCMRglu in the leIt
hippocampus and parahippocampal area, but reduced rCMRglu in right inIerior
parietal and right superior temporal regions.
72

Three symptom provocation studies oI PD, all oI which employed pharmacologic
challenges, have been published. Stewart et al.
73
used the xenon inhalation method
in conjunction with SPECT to measure CBE in superIicial cortical areas during lac-
tate-induced panic; in comparison with normal controls and PD subjects who did not
experience lactate-induced panic attacks, the PD subjects who experienced lactate-
induced panic attacks displayed global cortical decreases in CBE. Woods et al.
74
em-
ployed SPECT and yohimbine inIusions and Iound that, in comparison to the normal
control subjects, PD subjects experienced increased anxiety and exhibited decreased
rCBE in bilateral Irontal cortex. In a PET study, Reiman et al.
75
showed that in com-
parison with normal subjects and PD subjects who did not experience lactate-
induced panic, PD subjects with lactate-induced panic episodes exhibited rCBE
increases in bilateral temporopolar cortex and bilateral insular cortex/claustrum/
putamen. OI note, the temporopolar Iindings were subsequently questioned as pos-
sibly reIlecting extracranial artiIacts Irom muscular contractions.
76,77
In a Iourth
report, a spontaneous panic attack was captured during in a single case
78
; the PET
401 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
data showed decreased rCBE in right orbitoIrontal, anterior cingulate, area 25, and
anterior temporal cortex during the acute event.
OI relevance, BenkelIat and colleagues
76
studied pharmacologically induced
anxiety attacks in psychiatrically healthy subjects. They used cholecystokinin tet-
rapeptide (CCK-4) inIusions as the method Ior producing a reliable panic response;
saline inIusions were given during control conditions. Subjects were also studied in
an anticipatory anxiety condition during which they expected to receive CCK-4, but
were actually injected with saline. The anticipatory anxiety condition was associated
with rCBE increases within leIt orbitoIrontal cortex and cerebellum; the CCK-4 con-
dition was associated with rCBE increases in anterior cingulate cortex, cerebellum,
and a bilateral region spanning insula, claustrum, and amygdala. Signal increases
were also observed in the vicinity oI bilateral anterior temporal poles; however, these
were attributed to artiIacts Irom extracranial sources. Using similar methods, Javen-
mard and colleagues
79
extended this work by sampling the induced panic episodes
at two diIIerent time points (Iirst minute or second minute aIter CCK-4 bolus injec-
tion). They Iound that the early phase was associated with rCBE increases within the
hypothalamic region; the late phase was associated with rCBE increases in the claus-
trum-insular region; both phases were associated with rCBE decreases in the medial
Irontal region. In contrast to results Irom their previous study, an anticipatory anxi-
ety condition was associated with rCBE increases in anterior cingulate cortex and
decreases in visual cortical areas.
Nordahl et al.
80
used PET-EDG methods to study imipramine-treated subjects
with PD. With respect to rCMRglu, they Iound a rightward shiIt in asymmetry within
hippocampus and posterior inIerior Irontal cortex, similar to that which they previ-
ously observed in non-treated patients with PD.
71
Eurther, in comparison with the
untreated group, the imipramine treated group exhibited rCMRglu decreases in pos-
terior orbitoIrontal cortex. Nordahl et al. noted that this diIIerence bears resem-
blance to changes observed in OCD Iollowing successIul treatment.
1,81
Complementary Aeuroimaging Findings: Structure and Chemistry
Although morphometric MRI studies oI PD are yet to be published, there is a con-
siderable literature exploring possible neurochemical abnormalities in PD. Dager et
al.
82
used MRS to measure brain lactate levels during hyperventilation in treatment
responsive PD patients vs. healthy comparison subjects. The PD group showed a sig-
niIicantly greater rise in brain lactate in response to the same level oI hyperventila-
tion, though there were no signiIicant between-group diIIerences in blood lactate
levels either beIore or aIter hyperventilation. The authors proposed that patients with
PD might accrue higher levels oI brain lactate during hyperventilation as a conse-
quence oI an exaggerated rCBE decrease in response to hypocapnia. In a Iollow-up
study, Dager et al.
83
subsequently used MRS to show that, in comparison to control
subjects, PD subjects exhibited a signiIicantly greater brain lactate level during lac-
tate inIusion. These data are consistent with reduced clearance, rather than higher
production, oI lactate in PD. Eurther, the broad distribution oI this phenomenon sug-
gests a global or widespread abnormality in cerebral vascular Iunction in PD.
Receptor characterization studies oI PD have Iocused on benzodiazepine (BZ)
binding. In a SPECT study, using iodine-123-labeled-iomazenil, in comparison with
controls, subjects with PD exhibited a greater leIt/right ratio in BZ receptor uptake,
402 ANNALS NEW YORK ACADEMY OF SCIENCES
especially in preIrontal cortex.
84
In a PET study, using carbon-11-labeled Ilumaze-
nil, in comparison to a control group, the PD group exhibited a global reduction in
BZ binding, which was most pronounced in right orbitoIrontal and right insular cor-
tex.
85
Whereas these two initial experiments may have been conIounded by prior
treatment, Brandt et al.
86
used SPECT and iodine-123-labeled iomazenil to study
medication-naive PD subjects vs. healthy controls. The PD group exhibited signiIi-
cantly elevated BZ receptor binding within right supraorbital Irontal cortex, as well
as a trend toward elevated binding in the right temporal cortex.
Summary
Taken together, the neuroimaging data on PD suggest abnormalities in hippocam-
pal activity at rest; during a symptomatic state, patients exhibit activation oI insular
and motor striatal regions, as well as reduced activity in widespread cortical regions
including preIrontal cortex. MRS studies oI brain lactate implicate a global phenom-
enon consistent with an exaggerated hemodynamic response to hypocapnea. Simi-
larly, receptor binding studies suggest widespread abnormalities in the GABAergic/
BZ system, which also appear to be most pronounced in insular and preIrontal re-
gions; these Iindings also highlight the importance oI considering prior exposure to
psychotropic medications. Consistent with prevailing neurobiological models oI PD,
it is possible that Iundamental abnormalities in monoaminergic neurotransmitter
systems, originating in the brain stem, underlie the abnormalities oI metabolism, he-
modynamics, and chemistry Iound in widespread territories oI cortex. Eurther, re-
gional abnormalities within the medial temporal lobes provide some support Ior
theories regarding hippocampal or amygdala dysIunction in PD.
OBSESSIVE-COMPULSIVE DISORDER
Corticostriatal Model of Obsessive-Compulsive Disorder
The prevailing model oI obsessive-compulsive disorder (OCD) pathophysiology
Iocuses on cortico-striato-thalamo-cortical circuitry.
3
One hypothesis suggests that
primary pathology within the striatum (speciIically, the caudate nucleus) leads to in-
eIIicient gating at the level oI the thalamus, which results in hyperactivity within or-
bitoIrontal cortex (corresponding to the intrusive thoughts) and hyperactivity within
anterior cingulate cortex (corresponding to anxiety, in a non-speciIic manner). Eur-
ther, by this model, compulsions are conceptualized as repetitive behaviors that are
perIormed to recruit the ineIIicient striatum so as to ultimately achieve thalamic gat-
ing, and hence, neutralize the unwanted thoughts and anxiety. OI note, though
amygdalocentric models oI OCD have also been proposed,
3
such models are perhaps
most useIul in considering the neural substrates oI behavior therapy as an eIIective
treatment Ior OCD.
Functional Imaging Findings
Neutral-state paradigms employing PET and SPECT have most consistently in-
dicated that patients with OCD exhibit increased regional brain activity within orb-
itoIrontal and anterior cingulate cortex, in comparison with normal control
403 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
subjects.
8792
Observed diIIerences in regional activity within the caudate nucleus
have been less consistent.
87,91
Pre-/posttreatment studies
81,9397
have likewise indicated attenuation oI abnor-
mal regional brain activity within orbitoIrontal cortex, anterior cingulate cortex, and
caudate nucleus associated with treatment. Moreover, similar changes have been ob-
served Ior both pharmacologic and behavioral therapies.
81,96
Treatment studies have
also consistently indicated that the magnitude oI Irontal activity prior to pharmaco-
therapy predicts subsequent response to serotonergic reuptake inhibitors
9799
; spe-
ciIically, lesser magnitude oI orbitoIrontal hyperactivity is predictive oI superior
treatment response. OI note, Brody and colleagues
98
Iound that pre-treatment rCM-
Rglu in leIt orbitoIrontal cortex diIIerentially predicted response to cognitive behav-
ior therapy vs. Iluoxetine in patients with OCD; lower pre-treatment leIt
orbitoIrontal rCMRglu was associated with better response to Iluoxetine, but higher
pre-treatment leIt orbitoIrontal rCMRglu was associated with better response to cog-
nitive behavior therapy.
Symptom provocation studies employing PET
100,101
as well as Iunctional
MRI
102
have also most consistently shown increased brain activity within anterior/
lateral orbitoIrontal cortex, anterior cingulate cortex, and caudate nucleus associated
with the OCD symptomatic state. Qualitative comparisons with other anxiety disor-
ders have emphasized the relative speciIicity oI anterior/lateral orbitoIrontal and
caudate activation in OCD, whereas activation oI posteromedial orbitoIrontal and
anterior cingulate cortex has been observed non-speciIically across other anxiety
disorders and normal anxiety states.
1,3
However, one study using highly provocative
stimuli did note activation in the amygdala, not seen in control subjects exposed to
analogous stimuli.
102

Two cognitive activation studies oI OCD have been conducted
103,104
employing
an implicit (that is, non-conscious) learning paradigm to probe striatal Iunc-
tion.
105,106
An initial study was perIormed using PET,
103
and then the Iindings were
replicated using Iunctional MRI.
104
In both studies, while patients with OCD exhib-
ited normal perIormance on the learning task, brain activity proIiles indicated that
they Iailed to normally recruit striatum, and instead activated hippocampal regions
typically associated with conscious inIormation processing. Cognitive activation
studies oI OCD employing probes oI amygdala and anterior cingulate Iunction are
in progress.
Complementary Aeuroimaging Findings: Structure and Chemistry
Eindings Irom several mMRI studies oI OCD suggest volumetric abnormalities
involving the striatum,
107110
though the precise nature oI these abnormalities has
been inconsistent, and there have also been negative studies.
111
Elevated thalamic
volume has also been reported in association with OCD
112,113
; interestingly, thala-
mic volumes return toward normal Iollowing medication
112
but not behavioral ther-
apy.
113
One large mMRI study Iound reduced orbitoIrontal cortical and amygdala
volumes in OCD vs. healthy control subjects,
114
although these Iindings await
replication.
Several MRS studies have been perIormed to measure NAA concentrations in pa-
tients with OCD vs. healthy comparison subjects. Ebert and colleagues
115
Iound
that, in comparison with healthy control subjects, OCD subjects exhibited reduced
404 ANNALS NEW YORK ACADEMY OF SCIENCES
relative NAA levels in right striatum as well as anterior cingulate cortex. Similarly,
Bartha and colleagues
116
Iound reduced leIt striatal NAA concentrations in OCD
subjects vs. matched controls. Eitzgerald et al.
117
have also reported reduced NAA
levels within the medial thalamus bilaterally, but not the lateral thalamus. The Iind-
ings oI these MRS-NAA studies have been viewed as convergent with those Irom
mMRI studies. Reduced NAA is likewise consistent with primary pathology within
the striatum and/or thalamus associated with subtle volumetric abnormalities or re-
duced indices oI healthy neuronal density. MRS has also been used to demonstrate
elevated glutamatergic concentrations within the striatum oI a child with OCD
118
;
elevated striatal glutamate levels were attenuated towards normal Iollowing success-
Iul pharmacotherapy. Given that glutamate is the principal transmitter mediating Ir-
ontostriatal communication, these Iindings are consistent with the prevailing
neurocircuitry model oI OCD. SpeciIically, orbitoIrontal hyperactivity in OCD is ap-
parently mirrored by elevated glutamate at the site oI orbitoIrontal ramiIications in
striatum. Eurthermore, as orbitoIrontal hyperactivity is attenuated with successIul
treatment, so too is the elevated concentration oI glutamate within the striatum.
Summary
Taken together, the neuroimaging data on OCD suggest dysregulation oI activity
within cortico-striato-thalamo-cortical circuitry. The orbitoIrontal-caudate circuit is
speciIically implicated in OCD, whereas paralimbic cortex, including anterior cin-
gulate cortex, has been conceptualized as mediating non-speciIic aspects oI the anx-
ious state. Models that posit primary striatal pathology Iind support Irom mMRI
studies showing reduced striatal volume as well as MRS results oI reduced striatal
NAA, indicating decreased healthy neuronal density in that region. Hyperactivity
within orbitoIrontal cortex is associated with the obsessional symptomatic state.
Eurther, in normal subjects, the perIormance oI routinized procedures does Iacilitate
striatal recruitment in the service oI thalamic gating, whereas this pattern is not
readily demonstrated in patients with OCD. These imaging data Iurther support the
working model oI striatal pathology and striatothalamic ineIIiciency, together with
orbitoIrontal hyperactivity. Perhaps oI greatest clinical relevance, the magnitude oI
orbitoIrontal hyperactivity in OCD predicts response to treatment, with less severe
abnormalities heralding superior response to serotonergic medication. Although
there is little evidence that the amygdala plays an important role in the pathophysi-
ology oI OCD, it remains plausible that corticoamygdalar circuitry mediates the
eIIects oI behavior therapy.
CONCLUSIONS AND FUTURE DIRECTIONS
Neuroimaging research has had a great inIluence on neurobiological models oI
anxiety disorders. While the amygdala is central to theories oI pathophysiology in
PTSD and SAD, corticostriatal pathways are emphasized in OCD, diIIuse abnormal-
ities characterize PD, and cohesive models oI SPs remain to be developed. In con-
trast, the possibility exists that behavioral therapy, which is an eIIective treatment
across the anxiety disorders, may involve corticoamygdalar pathways as its chieI
neural substrate. Advances in our understanding oI normal amygdala Iunction will
405 RAUCH et al.: AMYGDALA NEUROIMAGING IN ANXIETY DISORDERS
Iacilitate progress in elucidating the pathophysiology oI these disorders as well as
their treatments.
The current review highlights several potential directions Ior Iuture research in
this domain. Eirst, it will be important to expand upon existing data with studies oI
larger numbers oI subjects and with attention to issues oI comorbidity. Similarly, the
use oI psychiatric control groups will be essential to establish the speciIicity versus
generalizability oI imaging abnormalities associated with these conditions. Second,
initial Iindings oI lateralized diIIerences in amygdala responses need more thorough
investigation. In particular, it is intriguing to consider that certain anxiety disorders
might be characterized by abnormalities in the dynamic proIile oI response to poten-
tially threatening stimuli within the right amygdala. Conversely, mood disorders,
characterized by relatively stable (that is, tonic or enduring over longer time Irames)
negative response biases, might be characterized by abnormal amygdala responses
within the leIt amygdala. In Iact, paradigms speciIically designed to probe amygdala
responses over various time scales might prove to be powerIul tools Ior dissecting
these diIIerences among psychiatric disorders. Eurthermore, attention to habituation
and extinction proIiles within the amygdala may represent a valuable strategy Ior ad-
vancing our understanding oI behavior therapy. Along these lines, cutting edge phar-
maceutical research might newly emphasize the potential Ior novel medications to
truly augment response to behavior therapy by accelerating the habituation or extinc-
tion process. Third, with advances in genetics as well as evidence Ior heritability oI
anxiety disorders, Iuture research will likely seek to incorporate neuroimaging end-
points as potential endophenotypes (or extended phenotypes) in genetic investiga-
tions. Einally, as the current paper reIlects, neuroimaging research and
neurobiological models oI psychiatric disorders are evolving beyond a Iocus on in-
dividual brain loci. Interpretations oI regional neural responses in the context oI
broader systems or circuits promise to enrich our understanding oI normal brain
Iunction as well as pathophysiological processes. As illustrated in the current review,
our perspective on the amygdala and its role in anxiety disorders will be enhanced
by appreciating its interactions with Irontal cortex, the hippocampus, and the stria-
tum as well as ascending monoaminergic projections, local GABAergic neurons, and
neuroendocrine inIluences.
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