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Table 6. Functional Neuroimaging Findings in Panic Disorder [Positron Emission Tomography/Single Photon Emission Computed
Tomography]
Mea
Study
Subjects
No. of Subjects
n
(female)
Age
Comorbid Agoraphobia
Medicati
Imaging
on Status
Method
Ventromedial
Study Paradigm
Amygdala
Hippocampus
Prefrontal
Cortex
(SD)
Other Brain
Regions
Studies Whose Results Indicate Amygdalar Involvement
Neutral State
PD
12(9)
29.8
(6.2)
Sakai, 2005
Free for at
In resting state
least
2 weeks
[41]
FDGPET
HC
22(14)
26.3
(without
experiencing panic
Bilateral amygdala glucose
uptake▲
Bilateral
hippocampus
glucose uptake▲
No significant
difference
attacks during
Bilateral
thalamus,
midbrain, caudal
pons, medulla and
cerebellum
glucose update▲
scans)
(6.8)
Off
medicatio
Bilateral
n for at
thalamus, bilateral
least
PD
7 (3)
Malizia, 1998
38.1
Never
(18.4
have had
)
a
prescripti
[42]
on for
basal ganglia,
Neutral state
6 months.
(Nobody
experienced a
11
[ C]Flu
panic attack either
mazenil-
during the
PET
scanning session
or during the
benzodiaz
preparation
epines for
period).
anxiety.
Bilateral amygdala/hippocampus benzodiazepine
receptor binding▼
Bilateral medial
bilateral lateral
frontal, bilateral
temporal, bilateral
orbitofrontal, and
medial/lateral
anterior cingulate
occipital, bilateral
regional
anterior/dorsolater
benzodiazepine
al prefrontal, and
receptor
right insula
binding▼
regional
benzodiazepine
receptor
HC
8 (0)
binding▼
38.9
(9.0)
TCA for
at least
Bilateral inferior
4 weeks
Kaschka, 1995
PD with dysthymia or mild
[43]
depression
9 (4)
30.2
with
Iomazeni
(9.8)
steady-
l-SPECT
state
serum
levels
temporal, and
Resting state
Left medial inferior temporal regional activity index▼
bilateral inferior
frontal regional
activity index▼
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within a
range of
150200 ng/ml
.
TCA with
steadystate
serum
Patients with a history of
dysthymia
9 (4)
29.0
levels
(8.5)
within a
range of
150200 ng/ml
.
Symptom Provocation
Anticipatory
anxiety: Left
precentral gyrus,
At rest
Anticipatory
(after
PD
17(12)
Boshuisen,
18 or
2002 [44]
older
Free for at
least
3 weeks
the
Anticipatory anxiety:
pentag
Significantly deactivated
15
H2 O
astrin
on the right side
PET
challe
scan,
nge)
anxiety:
Orbitofrontal
cortex, and the
anterior cingulate
gyrus▲
ctivity▼
Anticipatory
anxiety: The left
parahippocampus,
the superior
temporal gyrus,
before
the hypothalamus,
[15O]H2
and
and the midbrain
O PET
after a
activity▲
pentaga
strin
The
challen
parahippocampus,
ge
Before
the precentral
the
gyrus, the inferior
pentag
Anterior cingulate
frontal gyrus
astrin
cortex▼
activity and the
challe
HC
left insula
anterior insula▼
nge
21(12)
The superior
temporal lobe and
the midbrain▼-
Javanmard,
Right handed, naive to CCK-
1999 [45]
4 injection HC
Any
20(10)
30
individual
s who
[15O]H2
O PET
Early
scan or
late
Early
scan
Early scan:
Hypothalamic
Medial frontal
region rCBF▲
region▲
Occipital regions
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used any
scan
Anticipatory
psychoact
coverin
anxiety: Anterior
ive
g the
cingulate region
medicatio
first or
rCBF▲
n within a
the
rCBF▼
Claustrum-insular
week
second
prior to
minute
the
after
Late
scanning
CCK-4
scan
region rCBF▲
Left superior
Right amygdala rCBF▲
temporal rCBF▲
were
bolus
Cerebellar
excluded
injectio
rCBFd▲
n,
respecti
vely
Procai
Bilateral
ne
parahippocampal
Limbic
gyri, left insular
stimula
ServanSchreiber,
HC
10(5)
1998 [46]
cortex rCBF▲
tion
20.4
15
(3.66
)
[ O]H2
with
O PET
intrave
nous
Anterior cingulate
Bilateral amygdala rCBF▲
gyrus activation▲
Placeb
procain
Left inferior
parietal lobule,
right thalamus,
bilateral
o
cerebellum rCBF
e
and right
pulvinar▼
CCK-4
Male
Anticipatory
26.4
Anticipatory
(4.0)
/
Benkelfat,
1995 [47]
HC
Free for
8(3)
1 week
Fem
MRI
Bilateral claustrum-insular-
anxiety condition:
anxiety condition:
Cerebellum
Left orbitofrontal
rCBF▲ rCBF in
[15O]H2
Placebo (with or
cortical rCBF▲
the bilateral
O PET
without
CCK-4 condition:
region adjacent to
anticipation)
Left anterior
the
cingulate▲
frontotemporal
ale
amygdalar region CBF▲
23.7
poles▲
(1.5)
Treatment-Related
Bilateral
precentral gyrus,
Paroxetin
Sim, 2010 [48]
PD
5
42.6
(7.0)
e (12.537.5 mg/d
ay) for
12 weeks
FDG-
12 weeks of
PET
paroxetine trial
Right amygdala glucose
metabolism▲ after
treatment
bilateral middle
No significant
No significant
frontal gyrus,
difference
difference
right caudate
body, right
putamen, left
insula, left
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parahippocampal
gyrus, left inferior
frontal gyrus
glucose
metabolism▲
after treatment
Medicatio
Untreated PD
9
n-free for
3 months
Openlabel
Untreated vs.
treatment
control: Binding
with
measure receptor
paroxetine
hydrochlo
Nash, 2008
[49]
Treated PD with SSRI
7
potential in the
binding in patients
ride or
5-HT1A-
sertraline
PET
(1 patient:
PD in the
Untreated vs. control:
untreated state and
Binding potential in the
after recovery on
amygdala▼
treatment with
daily dose
Treated vs. control:
Binding potential
in the
hippocampus▼
Treated vs.
untreated: Binding
lateral temporal
potential in the
cortex▼ Treated
orbitofrontal
vs. control:
cortex▼
Binding potential
SSRIs
50 mg,
raphe and anterior
in the raphe and
anterior medial
duration
temporal cortex▼
of
treatment
24 months
)
HC
19
Studies Whose Results Do Not Indicate Amygdalar Involvement or Those Which Did Not Assess Amygdalar Regions
Spontaneous Panic Attack
Healthy volunteer
1(1)
Right posterior
42
orbitofrontal
rCBF▼
Spontaneous panic
15
Fischer, 1998
None
[50]
Healthy volunteer
5(5)
None
[ O]H2
O PET
attack during fear
conditioning with
24(2.
electric shocks and
5)
visual white noise
No significant difference
No significant
difference
Right anterior
cingulate rCBF▼
Right prelimbic
rCBF▼
Neutral State
Right temporal
cortical rCBF▼
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▲ Left/right
41.6
PD
22(20)
(11.5
n=9
)
Eren, 2003
HMPAO
[51]
19(16)
In neutral state
-SPECT
35.8
HC
No significant difference
99mTc-
of the left/right rCBF ratios
in the medial temporal
regions
(10.7
No significant
difference of the
left/right rCBF
ratios in the medial
temporal regions
)
PD
(6)
rCBF ratios in the
medial frontal
ratios in the
significant after
inferior frontal
multiple
cortex.
comparison
correction.)
44.5
Left
(4.2)
parahippocampal
area glucose
In neutral state
Bisaga, 1998
Free for
FDG-
[52]
1 month
PET
HC
(6)
▼Left/right rCBF
region. (Not
(Lactate infusion
was begun after
39.8
completion of the
(9.3)
scan)
Left hippocampus
No significant difference
glucose
metabolism ▲
metabolism▲
No significant
difference
Right inferior
parietal, right
superior temporal
brain regions
glucose
metabolism▼
PD
7 (5)
24.5
n = 2 had panic disorder without agoraphobia n = 5
(2.5)
suffered from panic disorder with phobic avoidance.
De Cristofaro,
Free for at
Inferior frontal
least
2 weeks
99mTcHMPAO
1993 [53]
Due to limited resolution
In neutral state
-SPECT
HC
5 (3)
27.8
Bilateral
cortex rCMRglu
of the images, hippocampal
hippocampal
No significant
asymmetry
regions may include
regions blood
difference
index▲ Left
amygdalar regions
flow▼
occipital cortex
blood flow▲
(6.9)
n=1
drug-
PD
12 (7)
Nordahl, 1990
naive
Left anterior
n = 1 free
cingulate region
35.5
for at least
metabolic rates▼
(11.4
1 year
Left medial orbital
)
n = 10
free for
[54]
FDGPET
20.3 (SD
Auditory
discrimination
Left/right
Not assessed
task
hippocampal ratio
frontal region
metabolic rates▲
of rCMRglu▼
Left inferior
parietal lobe
metabolic rates▼
10.19)
Right prefrontal
days
region metabolic
rates▲
HC
Reiman, 1986
[55]
30 (14)
33.3
(9.8)
34
PD
16 (11)
(Ran
ge
n = 4 were
None had extensive phobic avoidance (i.e.,
receiving
agoraphobia)
tricyclic
antidepres
Left/right ratios of
[15O]H2
O,
15
[ O]CO,
In neutral state
Not assessed
Not assessed
Not assessed
parahippocampal
rCBF , whole
brain
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22–
52)
metabolism▼ in
sants and
and
alprazola
[15O]O2
lactate-induced
m.
PET
panic-vulnerable
PD patients
relative to HC.
35
(Ran
HC
2 5(9)
ge
19–
74)
PD
10
Left/right ratios of
parahippocampal
rCBF▼in patients
[15O]H2
Reiman, 1984
[56]
O PET
HC
In neutral state
No significant difference
No significant
No significant
difference
difference
6
who had a
positive response
to lactate infusion
compared with
those without and
HC.
Symptom Provocation
Untreated PD
5 (4) / One female
27.2
subject excluded later
(3.2)
No significant
None
difference /
Baseline
15
Kent, 2005
[ O]H2
[57]
O PET
HC
5 (3)
31.6
Doxapram
intravenous
No significant difference
injection
No significant
difference
orbitofrontal
rCBF predicted
anxiety scores in
response to
(6.8)
doxapram
injection
Reiman, 1989
[58]
PD Group 1 (Positive
lactate-induced anxiety
attack)
8 (5)
28
n=1
(Ran
taking
[15O]H2
Sodium lactate
ge
150 mg/d
O PET
infusion
22–
of oral
▲Blood flow
No significant difference
No significant
No significant
increase in
difference
difference
bilateral temporal
poles, bilateral
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35)
38
(Ran
PD Group 2 (Negative
lactate-induced anxiety
9 (5)
ge
28–
attack)
52)
imipramin
insular cortex,
e
claustrum, lateral
hydrochlo
putamen, near the
ride All
superior
other
colliculus, or the
patients
left anterior
medicatio
cerebellar vermis
n free for
in patients who
at least
panicked
2 weeks
compared with
those who did not
and HC.
25
(Ran
HC
15 (8)
ge
22–
30)
Patie
PD
10
nts
All
who
tricyclic
panic
antidepres
Total left
ked
sant,
hemispheric blood
flow▼ in patients
34.3
MAOI, or
(11.3
alprazola
who panicked
)/
m-naive,
than those who
Patie
n=7
Stewart, 1988
nts
medicatio
[59]
who
n-free,
Xenon133
SEPCT
did not and HC.
Sodium lactate
infusion
Not assessed
Not assessed
Not assessed
did
n=2
not
oxazepam
increase in
panic
,n=1
patients who
ked
clorazepat
panicked that
34.2
e
those who did not
blood flow
(7.4)
HC
5
PD
6 (4)
▲Bilateral
occipital regional
and HC.
31.6
(4.8)
▼Bilateral frontal
30(3)
blood flow
99mTc-
Woods, 1988
HMPAO
[60]
HC
6 (4)
30(1
0)
-SPECT
Yohimbine
infusion
decrease by
Not assessed
Not assessed
Not assessed
yohimbine
infusion relative
to placebo
infusion.
Page 8 of 10
Treatment-Related
Fluoxetin
e or
cognitive
behavioral
Bilateral medial
therapySakai, 2006
[61]
PD
12(9)
29.8
(6.2)
naive and
medicatio
n free for
Before and after
FDGPET
2 weeks
prefrontal cortex
10 sessions of
cognitive-
No significant difference
behavioral therapy
Right hippocampus
glucose
Left cerebellum,
glucose
utilization▲ Left
and pons glucose
utilization▼
anterior cingulate
utilization▼
for 6 months
glucose
prior to
utilization▼
study
enrollmen
t.
Right
superior/middle/in
ferior frontal▼
Right
Right medial
frontal▼ Left
PD assigned to
antidepressant treatment
medial frontal▲
6
superior/middle/tr
ansverse
temporal▼ Left
middle frontal▲
Left
superior/middle/tr
CBT or
Prasko, 2004
antidepres
FDG-
[62]
sants for
PET
3 months
Before and after
treatment for
No significant difference
3 months
No significant
ansverse
difference
temporal▲
Right
superior/inferior
frontal▼ Right
inferior
temporal▼ Left
PD assigned to CBT
inferior frontal▲
6
Left middle
temporal▲
Insula▲
6 weeks
Continuous
of
Nordahl, 1998
[63]
Imipramine-treated PD
9(4)
33.3
(7.2)
treatment
with
imipramin
e,
including
auditory
FDG-
performance task
PET
to give a
standardized
condition
Not assessed
Abnormally low
L/R hippocampal
Posterior orbital
frontal
rCMRglc▼
Left/right
posterior inferior
prefrontal
rCMRglc ratio▼
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2 weeks at
their final
dose with
a range of
50–
150 mg
1 had
never
been on
medicatio
n 1 had
been of of
medicatio
Untreated PD
12(7)
35.5(
11.4
ns for
more than
1 year
n = 10 the
ange of
time off
medicatio
ns was
20.3_ + 1
0.19 days
HC
43(22)
30.2(
9.2)
Abbreviations : CBT, cognitive behavioral therapy; CCK-4, cholecystokinin tetrapeptide; FDG, 18 F-fluorodeoxyglucose; HC, healthy control; MAOI, monoamine
oxidase inhibitor; MDD, major depressive disorder; PD, panic disorder; rCBF, regional cerebral blood flow; SD, standard deviation; SPECT, single photon emission
computed tomography; SSRI, selective serotonin reuptake inhibitors; 99mTc-HMPAO, 99mTc-hexamethylpropyleneamineoxime.
*Results from these studies [55,56,58] were subsequently retracted.
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