B
RIEF
R
EPORTS
Regional Cerebral Metabolism Associated with Anxiety
Symptoms in Affective Disorder Patients
Elizabeth A. Osuch, Terence A. Ketter, Timothy A. Kimbrell, Mark S. George,
Brenda E. Benson, Mark W. Willis, Peter Herscovitch, and Robert M. Post
Background: We studied the relationship between
re-gional cerebral metabolism and the severity of anxiety in
mood disorder patients, controlling for depression
severity.
Methods: Fifty-two medication-free patients with
unipo-lar or bipounipo-lar illness underwent positron emission
tomog-raphy with [
18F]-fluorodeoxyglucose. Hamilton
Depres-sion Rating Scale and Spielberger Anxiety-State Scale
scores were obtained for the week of the scan. Analyses
were performed on globally normalized images and were
corrected for multiple comparisons.
Results: After covarying for depression scores, age, and
gender, Spielberger Anxiety-State Scale scores correlated
directly with regional cerebral metabolism in the right
parahippocampal and left anterior cingulate regions, and
inversely with metabolism in the cerebellum, left fusiform,
left superior temporal, left angular gyrus, and left insula.
In contrast, covarying for anxiety scores, age, and gender,
Hamilton Depression Rating Scale scores correlated
di-rectly with regional cerebral metabolism in the bilateral
medial frontal, right anterior cingulate, and right
dorso-lateral prefrontal cortices.
Conclusions: Comorbid anxiety symptoms are associated
with specific cerebral metabolic correlates that partially
overlap with those in the primary anxiety disorders and
differ from those associated with depression severity.
Biol Psychiatry 2000;48:1020-1023 © 2000 Society of
Biological Psychiatry
Key Words: Anxiety, depression, neuroimaging, positron
emission tomography, cerebral metabolism, affective
disorders
Introduction
P
atients with primary affective disorders often have
prominent comorbid anxiety symptoms that impact
behavior and response to treatment (McElroy et al, in
press). Previous functional brain imaging studies in
affec-tive disorders have not always addressed the contribution
of anxiety symptoms to the patterns of regional brain
activity observed.
Several investigators have studied a variety of primary
anxiety disorders as well as anxiety induced in normal
subjects. The right, compared with the left,
parahippocam-pal gyrus has been found to have increased regional
cerebral blood flow and metabolism in subjects with
primary anxiety disorders, i.e., panic disorder (Nordahl et
al 1990; Reiman et al 1984, 1986). Increases in regional
cerebral glucose metabolism (rCMRglu) in the insular
cortex, right frontal and posterior medial orbitofrontal
cortices, and lenticular nucleus have been found to be
associated with symptom provocation in three anxiety
disorders,
including
obsessive-compulsive
disorder
(OCD), simple phobia, and posttraumatic stress disorder
(PTSD) (Rauch et al 1997). Other brain areas associated
with anxiety include the left inferior parietal lobe in panic
disorder (Nordahl et al 1990) and secondary visual cortex,
hippocampus, prefrontal and orbitofrontal cortices,
tempo-ral poles, and posterior cingulate gyrus in simple phobias
(Fredrikson et al 1995). Lucey et al (1997) found
de-creased regional cerebral blood flow in superior frontal
cortices and right caudate in both OCD and PTSD patients
compared to healthy control subjects.
Studies of anxiety provoked in healthy control subjects
have demonstrated increased rCMRglu in the left anterior
cingulate gyrus (Chua et al 1999; Kimbrell et al 1999) left
inferior frontal, temporal, and cuneus gyri (Kimbrell et al
1999), and orbitofrontal, inferior frontal, and left insula
(Chua et al 1999). Kimbrell et al (1999) also showed
decreased rCMRglu in right posteriotemporoparietal
cor-tex, right superior frontal, and right medial frontal cortices
with anxiety induction in these same subjects.
These findings in diverse anxiety patient populations
and healthy volunteers with induction of anxiety indicate
several regions of general overlap, such as frontal and
From the Department of Psychiatry, Uniformed Services University of the Health Sciences (EAO), Biological Psychiatry Branch, National Institute of Mental Health, National Institutes of Health (BEB, MWW, RMP), and the PET Department, National Institutes of Health Clinical Center (PH), Bethesda, Maryland; Stanford University School of Medicine, Stanford, California (TAKe); North Little Rock VA Medical Center, North Little Rock, Arkansas (TAKi); and Medical University of South Carolina, Charleston (MSG). Address reprint requests to Robert M. Post, M.D., NIMH/NIH, 10 Center Drive
MSC-1272, Bldg. 10, Rm. 3N-212, Bethesda MD 20892.
Received November 30, 1999; revised May 1, 2000; accepted May 5, 2000.
temporal cortices and insula. The purpose of this study
was to identify changes in rCMRglu associated with the
severity of anxiety symptoms (controlling for depression
severity) in patients diagnosed with an affective disorder
and to differentiate these from rCMRglu associated with
severity of depression. We expected to find associations
between anxiety and rCMRglu in frontal, insular, and
temporal areas.
Methods and Materials
Fifty-two patients (mean age 39.8 years, SD5 12.7, range5
20 – 65; 23 male), with a primary affective disorder (25 unipolar, 27 bipolar), who were free of medication for at least two weeks, underwent positron emission tomography (PET) studies using [18
F]-fluorodeoxyglucose (FDG) after being given a complete description of the study and giving their written informed consent. Subjects were participants in studies of treatment interventions and underwent assessments and PET scans as part of those studies. The population comprised both treatment-refractory inpatients and 18 less treatment-refractory, unipolar outpatients (Little et al 1996). The mean duration of illness was 18.4 years (SD59.5) for the bipolar group and 25.6 years (SD514.0) for the unipolar group.
Weekly modified Spielberger Anxiety-State Scale (SAnx) and weekly Hamilton Depression Rating (HAMD) Scale ratings were performed in the same week as the scan, i.e., 1 day before the scan or up to 6 days after the scan. The modified SAnx consisted of the Spielberger Anxiety-State Scale with instructions asking subjects to describe each item in reference to their symptoms in the past week (Spielberger et al 1983). This intermediate time frame was used in these subjects with affective disorders to minimize interference from previous manic episodes, previous resolved anxious depressive episodes, or previous symptom-free times that might occur if a typical Trait-Anxiety scale were used. We also wanted to focus on the subjects’ general state of baseline anxiety as distinguished from any acute anxiety related to the scan itself. Thus, the modified SAnx used here is a measure of comorbid anxiety symptoms during each patient’s affective state in the week of the scan.
PET Acquisition and Analysis
Following the injection of 5 mCi of FDG, subjects had their eyes covered and performed an auditory continuous performance task (Kimbrell et al 1999) during a 30 min uptake period. Positron emission tomography images were then obtained with a Scan-ditronix (Bartlett, TN) PC2048-15B tomograph (in-plane resolu-tion;7 mm), in four sets of 7 slices, to provide 28 interleaved slices 3.4 mm apart. The images were combined with measure-ments of arterial plasma FDG activity and glucose to obtain quantitative images of rCMRglu.
Images were resized/resliced and stereotactically normalized to the Talairach atlas (Talairach and Tournoux 1988). Voxelwise Pearson correlations were performed, covaring for age, gender, and SAnx or HAMD score, using Statistical Parametric Mapping for images normalized to their global gray matter mean resulting
in Z maps (Friston et al 1991). These Z maps were then submitted to cluster analysis (Friston et al 1994) with a Z threshold of 1.96 (two-tailed p5.05) and a cluster probability threshold of p5.05. Cluster analysis considers the smoothness of the Z map in determining the effective independence of the multiple comparisons in the total brain volume analyzed.
Results
Mean SAnx was 47.1
6
12.7 (range
5
21–74) and HAMD
was 22.2
6
9.7 (range
5
3– 42). There was no significant
difference in SAnx or HAMD scores between unipolar and
bipolar groups. SAnx and HAMD were highly correlated
(r
5
.62, p
,
.0001, n
5
52).
SAnx correlated directly with rCMRglu in right
para-hippocampal gyrus and the left anterior cingulate gyrus
bordering the callosum (from Talairach coordinate Z
5
1
16 to Z
5 1
32) after covarying for age, gender, and
HAMD scores. In the same analysis, SAnx correlated
inversely with rCMRglu in left fusiform gyrus, left
supe-rior temporal region, left angular gyrus, left insula, and
bilateral lateral cerebellum (Figure 1, top). Alternatively,
after covarying for age, gender, and SAnx, HAMD scores
correlated directly with rCMRglu in bilateral medial
fron-tal, right anterior cingulated, and right dorsolateral
pre-frontal cortices. There were no significant inverse
corre-lations between rCMRglu and HAMD (Figure 1, bottom).
When the bipolar patients (n
5
27) and unipolar
patients (n
5
25) were considered separately, the analysis
was weakened by the reduced number of subjects.
How-ever, the bipolar subgroup analysis contained inverse
correlations between SAnx and rCMRglu in the left
superior temporal region, left insula, and bilateral lateral
cerebellum. The unipolar subgroup analysis contained a
direct correlation in the inferior anterior cingulate gyrus
and an inverse correlation in the right cerebellum (not
shown).
Discussion
Severity of anxiety symptoms in affective disorder
pa-tients was positively correlated with rCMRglu in the right
parahippocampal and left anterior cingulate regions. The
increase in the right parahippocampal gyrus is consistant
with findings in other subject populations, such as those
with panic disorder (Nordahl et al 1990; Reiman et al
1984, 1986). Increases in rCMRglu in the left anterior
cingulate gyrus converge with findings in healthy control
subjects with self-induced anxiety (Chua et al 1999;
Kimbrell et al 1999). The mild inverse relationship
be-tween anxiety and rCMRglu in the left insula found here is
interesting in light of previous findings of increases in this
region with anxiety provocation in anxiety disorder
pa-rCMRglu and Anxiety in Mood Disorders BIOL PSYCHIATRY 1021
tients (Rauch et al 1997) and with anticipatory anxiety in
healthy control subjects (Chua et al 1999). It is becoming
evident that these areas are consistently associated with
anxiety across diverse populations and functional imaging
methodologies. Contrary to our hypothesis, we found no
significant correlations between SAnx and rCMRglu in
frontal regions except for the anterior cingulate gyrus.
The direct and inverse relationships to anxiety
symp-toms were distinct from those that correlated with
depres-sive symptoms. Depression (when controlling for anxiety),
correlated positively with bilateral sub- and pregenual
structures. These areas have previously been associated
with severity of depression in unipolar and/or bipolar
patients (Bench et al 1993; Drevets et al 1995; Mayberg et
al 1997), although sometimes inversely (Drevets 1999).
Because of the high comorbidity between depression and
anxiety in affectively ill patients, failure to covary for
anxiety symptoms when assessing cerebral correlates of
depressive symptoms (and vice versa) may lead to
erro-neous conclusions about underlying neural substrates.
Anxiety measured with the modified SAnx represents
each subjects’ anxiety during the week of the scan, and not
trait-anxiety or the state of anxiety specifically during the
scan itself. This is a different representation of the level of
anxiety associated with the patients’ affective states than
either of the other time frames. An analysis with anxiety
measured in other contexts and with other scales may yield
results different from those reported here.
The heterogeneity of the subjects may have resulted in
an attenuation of some of the significant differences in the
relationships of anxiety to rCMRglu within different
patient subgroups. It might also be argued, however, that
the power offered by the large sample size and the
inclusion of both bipolar and unipolar treatment refractory
and treatment responsive patients, studied across a range
of depression severities, adds to the validity of the results.
The convergence of the findings in this preliminary study
of anxiety in patients with primary affective illness with
those in the literature in patients with primary anxiety
disorders and with anxious healthy control subjects
sug-Figure 1. Regional cerebral glucose metabolism correlations with mood ratings in 52 mood disorder patients controlling for age and gender. Statistical parametric maps displayed on transverse sections depicting regions of direct or positive (red scale) and indirect or negative (blue scale) correlations with modified Spielberger Anxiety-State Scale (SAnx) covarying for Hamilton Depression Rating Scale (HAMD) score at the top, and correlations with HAMD covarying for SAnx at the bottom. Spielberger Anxiety-State Scale score is positively correlated with right parahippocampal (Zmax53.41 [maximum Z value for cluster]; p5.006; X5 138, Y5 224, Z5
28 [Talairach X, Y, Z]) and left anterior cingulate gyri (two peaks at Zmax53.10; p5.002; X5 210, Y5 128, Z5 120 and
Zmax53.09; p5.002; X5 28, Y5 18, Z5 132) and negatively correlated with bilateral cerebellum (Zmax53.06; p5.002; X5 124, Y5 254, Z5 220 and Zmax52.75; p5.006; X5 232, Y5 252, Z5 220), left fusiform gyrus (Zmax53.35; p5 .0008; X5 248, Y5 250, Z5 212), left superior temporal gyrus (Zmax53.24; p5.001; X5 252, Y5 218, Z50), and left angular gyrus (Zmax53.17; p5.002; X5 238, Y5 258, Z5 132). There was also a less significant correlation in the left insula (Zmax52.25; p5.02; X5 238, Y5 218, Z5 112). Hamilton Depression Rating Scale score is positively correlated with the bilateral medial frontal (right and left peaks at Zmax53.52; p5.0004; X5 14, Y5 132, Z5 212 and Zmax53.68; p5.0002; X5 26, Y5 160, Z50, respectively), right anterior cingulate (Zmax53.18; p5.002; X5 12, Y5 140, Z5 14), and right dorsolateral prefrontal regions (Zmax53.04; p5.002; X5 142, Y5 132, Z50). There were no negative correlations with HAMD scores in this sample. Statistical threshold for inclusion is a Z score of.1.96 and a p value of,.05 to correct for multiple comparisons using cluster analysis.
1022 BIOL PSYCHIATRY E.A. Osuch et al
gests that right parahippocampal and left cingulate gyri,
and left insula are fundamental neural substrates related to
anxiety.
The support of the Theodore and Vada Stanley Foundation to T.A. Kimbrell and M.W. Willis is gratefully acknowledged.
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