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PET in Generalized Anxiety Disorder Joseph C. Wu, Monte S. Buchsbaum, Tamara G. Hershey, Erin Hazlett, Nancy Sicotte, and J. Chad Johnson
Positron emission tomography (PET) measurements of cerebral glucose use were made in 18 patients wit, generalized anxie~" disorder (GAD) during a passive viewing task off medication, and an active vigilance viewing task before and after medication or placebo treatment. In the passive viewing task, patients with GAD were compared with 15 normal controls. A significant difference in pattern of absolute brain metabolism was found. Patients showed lower absolute metabolic rates in basal ganglia and white matter. Relative metabolism was increased in the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the right precentral frontal gyrus. Significant left-right asymmetry of the parahippocampal gyri was not found in patients with GAD. An active vigtiance task resulted in activation of relative basal ganglia metaboii:m in patients. Benzodiazepine therapy resulted in decreases in absolute metabolic rates for cortical surface, limbic system, and basal ganglia and was not associated with normalization of patterns of glucose metabolism. Change in anxiety scores was significantly correlated with change in limbic system and basal ganglia for the placebo group. The normal--anxious difference in the basal ganglia and the change seen in this region after benzodiazepine treatment are suggestive of a role in anxiety for this structure.
In,roduction Generalized anxiety, disorder (GAD) is characterized by symptoms such as persistent worrying, hypervigilance, and autonomic hyperactivity (APA 1987), and is most commonly treated with benzodiazepines. Six functional neuroanatomic hypotheses of the site of anxiety can be proposed based on previous brain imaging and neuroanatomic studies: occipital lobe hyperactivity, hippocampal/temporal lobes hyperactivity, frontal lobes hypoactivity, basal ganglia-cerebellar imbalance, whole brain underarous~d, or whole brain overarousal. First, since both positron emission tomography (Persson et al 1985) and human autopsy studies (d'Argy et al 1988; Braestrup et al 1977) reveal the occipital lobe as having one of the greatest concentrations of benzodiazepine receptors in the brain, this region may be a candidate for the site of GAD. Frost et al (1986) also reported high levels of cortical be,azodiazapine receptor binding. We found a significant decrease in occipital cortex metabolism after benzodiazepine administration in patients with GAD (Buchsbaum et al 1987). Benzodiazepine receptors are r,~"'~',ef a complex that is corn-
From the Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvtne, CA 92717. Address reprint requests to Joseph Wu, M.D., D402, Med Sci I, UCI-CCM, h-vine, CA 92717. Received June 22, 1990: revised October 24, 1990. © 1991 Society of Biological Psychiatry
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posed of a ~/-aminobutyric acid (GABA) receptor and a chloride ionophore (Paul et a! 1981). Since most GABA neurons are thought to have their cell bodies and axon terminals within the cortex as local circuit neurons (Enna 1985), the inhibitory effects of benzodiazepines is compatible with the facilitation of local GABA activity. Quantitative EEG studies have demonstrated the sensitivity of the occipital cortex follo,:,ing benzodiazepine treatment (Buchsbaum et al 1985). Topographic mapping of GAD patients and normals also showed occipital differences (Buchsbaum et al 1985; Grillon and Buchsbaum 1987). Second, the limbic system involving the hippocampus, lying within the temporal lobe, has been hypothesized to be important in the modulation of emotions (Papez 1937; Gray 1982). Patients with panic disorders have been reported to have decreased left-right parahippocampal blood flows (Reiman et al 1986; Reiman 1987). Lactate-induced anxiety attacks have been reported to be associated with increased blood flow bilaterally in temporal poles and insular cortex (Reiman et al 1989a). Anticipatory anxiety has also been reported to show increased blood flow in the temporal cortex (Reiman et al 1989h). Third, the prefrontal cortex has also been hypothesized to play a role in anxiety through its projection to the entorhinal area of the temporal lobe, which in turn projects to the hippocampus (Gray 1982). An increase in frontal cortex metabolism is seen with moderate anxiety in no~rnals, as measured by the Speilberger State-Trait Anxiety Inventory, but even greater anxiety is associated with decreased metabolic activity (Reivich et al 1983). Increased left orbital frontal and bilateral prefrontal cortex metabolism has been reported in childhood-onset obsessive-compulsive disorder (Swedo et al 1989), which is considered one of the anxiety disorders (APA 1987). Fourth, other brain structures, such as the basal ganglia (Groenewegen et al 1982) and the cerebellum (Dietrichs 1984), have important limbic connections. The basal ganglia and the cerebellum have GABAergic terminals derived from local circuit neurones and axon collaterals of projection neurones (Ribak et al 1981) that are influenced by benzodiazepines. Reiman et al (1989b) noted that lactate-induced anxiety caused significant increases in the right and left putamen as well as the anterior cerebellar vermis. Heath et al (1984) have reported that cerebellar stimulation in animals modulates limbic system structures, including the hippocampus, amygdala, and septum. Obsessive-compulsive disorder (OCD) has been reported to show bilateral increase in caudate metabolism (Baxter et al 1987). A frontal-limbic-basal ganglia model of OCD has been proposed (Swedo et al 1989). Fifth, some earlier blood flow and cerebral metabolic studies suggested that anxiety was associated with increases in cerebral blood flow or metabolism. Kety (1950) noted that one subject who was very apprehensive had significantly increased cerebral metabolic rate for oxygen (CMRO:). Carlsson et al (1975, 1977) also noted increases in CMRO2 and cerebral blood flow for immobilized conscious rats that were blocked by propranolol or prior adrenalectomy. Systemically administered epinep.hrine had inconsistent or negligible effects on CMRO2 (Sokoloff 1959; Edvinsson and MacKenzie 1977). Ohata et al (1981) found that immobilization stress produced an overall decline in regional cerebral blood flow measured with [~4C]iodoantipyrine except at the frontal lobe. They also found that immobilization stress stimulated hype~entilation and reduced Pac02. After correcting for cerebrovascular constriction, Ohata et al (1981) still found that cerebral blood flow would increase by at most 20%. Glucose metabolism images were not affected by a change in Pac02 and did allow an evaluation of change in metabolism without this concomitant complication. Other investigators (Sharma and Dey 1986,
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1988) also found immobilization stress to diminish cerebral blood flow in conscious young rats. [3-car~olines, which ate anxiogenic inverse antagonists to benzodiazapine receptors, increase 6ae local cerebral glucose utilization in different brain regions, such as the cerebellum, thalamus, and limbic system (Ableitner and Herz 1987) in ~ a l s . Sixth, whole brain decreases in activity may be related to the behavioral inhibition postulated by Gray (1982) as part of the response to anxiety. Lower blood flow across the brain was found by Mathew et al (1982) in nine patients with GAD. E x p o s m to phobic stimuli to patients with OCD has been reported to result in marked decrease in virtually all cortical regions (Zohar et al 1989). Rodriguez et al (1989) found a negative correlation between regional cerebral blood flow and anxiety measures. Stewart et al (1988) found decreases or minimal increases in hemispheric blood flow in panic disorder patients who panicked after an infusion. However, no changes were seen in regional or global cerebral blood flow in state anxiety due to simple phobia (Mountz 1984). This article is the first report to date on differences in regional cerebral metabolism between normal controls and patients with GAD that allows us to directly compare the five anatomic sites in the two groups.
Methods Patients Eighteen right-handed patients [eight male and ten female, mean (+SD) 39.8 _+ 13.6 years] who met DSM-HI criteria for GAD entered and completed the study. Patients were diagnosed using a semistructured clinical interview. None of the patients met DSM-III criteria for panic disorders or a current episode of major depression. Patients were excluded if they had any other axis I psychiatric disorder or any other major medical illness. Patients were medication free for at least 3 weeks (confirmed by urine drug screening) and in good health as determined by medical history, physical examination, and laboratory analyses. Patients had to have a Hamilton Anxiety score of at least 18 (28 -+ 4.2) and were diagnosed by a psychiatrist within 2 weeks prior to the study. Patients were tested with the Hamilton Anxiety test at each of their three PET scans.
Healthy Subjects Healthy subjects were determined to be free of mental disorders and m~or medical illness on the basis of a semistructured psychiatric interview, physical examination, and laboratory analyses. There were five men and ten women with a mean age of 39.1 _ 12.8 years, all right-handed. Subjects were also excluded if they had any axis I diagnosis. Subjects who had first-degree relatives with a major psychiatric illness or were taking psychoactive medication were excluded.
Medication Trial The 18 patients were randomly assigned into two groups (8 in drug group, 10 in placebo group) using a double-blind, placebo-comrolled design. Patients received either three 7.5-mg clorazepate (tranxene) capsules per day for 21 days or three ma~,cNng placebo capsules.
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PET Scan Procedure Activation tasks were employed to minimize variance and to activate regions of the brain that are functionally tied into the pathophysiology of the illness. Hypervigilance has been reported as a symptom in anxiety. Consequently, a vigilance task was chosen. 't,~ fluorodeoxyglucose (F-'I~) PET procedure has been previously described for ilfis group of GAD patients and normal subjects (Buchsbaum et al 1987). Both groups were exposed to the degraded stimulus continuous performance test (CPT) during F I ~ uptake, but were only required to observe the stimuli passively (Buchsbaum et al 1987). In the second phase, for baseline and medication (scans 2 and 3), patients received the same stimuli but actively identified target stimuli during the CPT. Different tasks were employed for patient--control and pretreatment-posttreatment comparisons for two reasons. There were two pretreatment scans. The first ("the baseline") employed the visual stimuli but with no cognitive tasks. The second ("day 0") used the same visual stimuli but added a cognitive vigilance task with false feedback that was designed to stimulate anxiety. This sequence of scans allowed us to use a subtraction technique to identify regions of the brain involved with vigilance. The third scan continued the use of the cognitive vigilance task but tested the anxious subjects after placebo or medication.
Image Collection Between 45 and 100 rain after FDG injection, nine planes parallel to the canthomeatal line (CM) were obtained on the NeuroECAT IV scanner in the Brain Imaging Center of the Department of Psychiatry, University of California, Irvine. The top three slices were done at 95, 80, and 65 mm above the CM line, with shadow shield in and septa shields out, measured in plane resolution of 8 mm and axial resolution of 12 ram. The bottom six slices were done at 10 mm increments (55, 45, 35, 24, 15, and 5 mm) above the CM line with both shadow and septa shields in, measurement in plane resolution of 7.6 mm, and axial resolution of 10 ram. Scans were transformed to glucose metabolic rate as described elsewhere (Buchsbaum et al 1987; Sokoloff et al 1977).
Image Analysis Cortical metabolic rates were measured using a newly modified cortical peel technique previously described (Buchsbaum et al 1989; Figure i). Subcortical structures were assessed using stereotaxis coordinates derived from a standard neuroanatomic atlas (Matsui and Hirano 1978) as previously described (Buchsbaum et al 1987). Coordinates for the structures analyzed are included in Table 1. Data were analyzed both as absolute metabolic rate (ixmol/drn/min) and as relative rates (region of interest divided by whole slice metabolic rate). The global mean cerebral metabolic rate was calculated by averaging the mean glucose metabolism across the nine slices weighted for the number of pixels per slice.
Statistical Methods Brain System Analysis. In order to assess group difference in total brain organization, the brain was divided into eight main systems: lateral cortex (average of frontal, temporal, parietal, and occipital lobes), medial cortex (average of precuneus, paracentral, medial
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Table I. Stereotaxic Coordinates for Regions of Interest Matsui and Hirano plane
X Coordinate
Y Coord/r_aate
Left
Right
Left
Right
2 2 2 3 3 3 4 4 4 4 4 5 5 5 5 6 6 6 6 6 6 7 7 7
45.8 48.3 49.2 48.2 47.3 47.3 45.8 45.8 47.3 47.3 47.3 44.8 44.8 44.8 44.8 28.7 44.2 45.0 45.0 45.0 42.6 34.9 46.5 50.4
Posterior corpus callosum
7 7
50.4 50.4
Posterior cingulate Cingulate Frontal white matter
7 8 8
41.9 45.2 29.0
Caudate
8 8
39.6 31.3
8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 10
29.2 4i.7 44.4 37.5 35.5 45.2 25.8 44.4 45.2 45.1 32.8 41.3 21.3 32.6 37.0 45.1 34.4 36.9 31.5
54.2 51.7 50.8 51.8 52.7 52.7 54.2 54.2 52.7 52.7 52.7 55.2 55.2 55.2 55.2 71.3 55.8 55.0 55.0 55.0 57.4 65.1 53.5 49.6 49.6 49.6 58.1 54.8 71.0 60.4 68.7 70.8 58.3 55.6 62.5 64.5 54.8 74.2 55.6 54.8 54.9 67.8 58.7 78.7 67.4 63.0 54.9 65.6 63.1 68.5
24.4 54.8 70.4 22.4 59.7 74.6 16.2 26.9 40.1 53.9 73.7 16.8 28.6 42.7 67.4 20.1 lg.4 30.5 43.7 56.9 73.6 19.8 17.1 29.0 43.2 54.0 71.0 14.7 16.5 33.8 38.5 44.6 46.2 48.8 50.8 55.4 68.8 76.5 78.2 85.3 15.2 18.1 31.7 36.4 36.7 41.7 56.4 67.3 83.6 16.9
24.4 54.8 70.4 22.4 59.7 74.6 16.2 26.9 40.1 53.9 73.7 16.8 28.6 42.7 67.4 20.1 18.4 30.5 43.7 56.9 73.6 19.8 17.1 29.0 43.2 54.0 71.0 14.7 16.5 33.8 38.5 44.6 46.2 48.8 50.8 55.4 68.8 76.5 78.2 85.3 15.2 18.1 31.7 36.4 36.7 41.7 56.4 67.3 83.6 16.9
Stmctuie Superior frontal Paracentral Precuneus Superior frontal Paracentral Precuneus Superior frontal Antemmedial frontal Postemmedial frontal Paracentral Precuneus Superior frontal Medial frontal Cingulate Precuneus Frontal white matter Medial frontal Anterior cingulate Medial cingulate Posterior cingulate Precuneus Frontal white matter Medial frontal Anterior corpus callosum Medial corpus callosum
Putamen Posterior putamen Anterior thalamus Medial thalamus Lateral thalamus Posterior thalamus Posterior cingulate Optic radiation Anterior calcarine Posterior calcarine Anterior cinguiate Frontal white matter Caudate Medial temporal Putamen Globus pallidus Superior colliculus Hippocampus Fusiform Frontal white matter
(continued)
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Table 1. Continued
Structure Anterior cingulate Putamen Hippocampus Inferior colliculi Anterior rectal gyms Orbital gyms Posterior rectal gyms Amygdala Uncus Hippocampus Midbrain Anterior cerebellum Posterior cerebellum
X Coordinate
Y Coordinate
Matsui and Hirano plane
Left
Right
Left
Right
10 10 10 10 10 lI 1! !1 !1 11 11 11 Ii
41.7 31.5 30.6 44.4 44.3 34.8 45.2 32.2 33.0 32.2 43.5 39. ! 39.1
58.3 68.5 69.4 55.6 55.7 65,2 54.8 67.8 67.0 67.8 56.5 60.9 60.9
16.9 33.8 56.8 57.4 7.60 23.5 28.8 39.4 47.7 59.0 59.0 75.0 83.3
16.9 33.8 56.8 57.4 7.6 23.5 28.8 39.4 47.7 59.0 59.0 75.0 83.3
frontal, rectal gyfi, calcarine, and medial temporal), iimbic system (average of amygdala, hippocampus, and cingulate), basal ganglia (average of caudate, putamen, and globus pallidus), thalamus, white matter (average of frontal white matter, corpus collosum, and optic radiation), midbrain, and cerebellum. The regions were analyzed with a three-way analysis of variance (ANOVA) with group (GAD versus controls) as an independent measure. Regional metabolic rates for the eight brain systems and hemisphere (left, fight) served as within variables for the anxious--control comparison of the passive stimuli task. For the passive stimuli-active cognitive task comparison, a similar three-way ANOVA was performed, with task (passive stimuli versus active task) as a repeated measure and brain system and hemisphere as within-factor measures. A similar statistical design was used to compare the pretreatment and posttreatment conditions. A similar ANOVA was done for the structures of the basal ganglia (caudate, putamen, and globus pallidus) by themselves. Effects are reported with Huynh-Feldt reduced degrees of freedom. ANOVAs with significant iateractions were followed by post hoe t-tests. Repeated-measure factors provide a statisti:al method for comparing differences within individuals for the same brain regions over time or before and after a specific task. This c:nables a comparison for each individual structure using its own baseline for medication contrasts. This is statistically eqt, iv alent to a "subtraction technique" in which subjects' brain images are fitted to a standard brain template and then the mean of one such condition is compared with the mean of a second condition applied by Reiman et al (1989b). Our method has the advantage of yielding only a few F ratios which provide a systematic test of hemisphere asymmetries, differences between structures, and, when applied to absolute metabolic data, estimates oi: metabolic rate effects.
Cortical Lobe Analysis. The four cortical lobes have each been divided into four segments. A four-way ANOVA (Dixon 1982) was done with group (anxious, control) as an independent measure and lobe (frontal, temporal, parietal, occipital), lobar segments (four per lobe), and hemisphere (fight, left) as repeated measures to assess group difference
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| 187
Precentral M!
Iobule
Superi, frontal
gyrus ;ral occipita!
Inferi(
poral
/ Middle temporal Superior temporal Figure 1. Side view of brain reconstructed from the Matsui and Hirano (1978) atlas. Each sfice from no. 2 (80% of head height) through no. 11 (21% of head height) is iudicated. Four areas within each lobe are indicated by shading: frontal (superior, middle, inferior, and precentral), temporal (superior, middle, dorsal, and ventral inferior temporal gyrus), parietal (postcentral, supramarginal, superior parietal, and angular), and occipital (areas 17 and 18, and dorsal and ventral area 19). Each area is identified as the distance along the circumference of the atlas slice as a percent of ",he distance from the midline anterior to mid!ine posterior points. A listing of the percentage points is available from the authors. For each person, each PET slice was matched to the corresponding atlas slice; a computer algorithm then assessed the mean glucose along the outer 2 cm segment of a radius joining the slice center and the slice edge. Mean values along a sector of the circumference were then calculated; weighted averages across slices formed the gyral estimates.
in overall pattern of cortical lobe metabolism. Simple-interactions A N O V A s were done as follow-up for the occipital, temporal, and frontal lobes in order to test the specific hypotheses regarding these lobes aad anxiety.
Parahippocampal Gyri AsymmetoJAnalysis. Stereotaxic coordinates from the Reiman paper were translated into a set of stereGtaxic coordinates compatible with our software. Reiman et al (1984) use an absolute coordinate system in which the anterior c o m m i s s u r e posterior commissure (AC-PC) line is used to establish a reference horizontal plane. The center of a plane is used as the reference point for any particular plane. Structur.:s ~ e localized on the z axis by ~pecifying the distance above or below the reference plane. Within a plane, structures are localized on the x-y plane by specifying the distance left or right and forward or backward of the center point of the brain. Their reference plane is comparable to the 0°8 slice from the Matsui and Hirano (1978) arias in which the anterior commissure and the posterior commissure are clearly visible. We chose three subjects whose magnetic resonance images (MRIs) matched the 0°8 plane. The MRIs
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Figure 2. Basal Ganglia Metabolism. A common glucose scale shows the decrease in absolute glucose metabolic rate in the basal ganglia of two typical subjects with G.M~ on top row compa.-ed to two normal controls on bottom row.
that matched the z axis dimension specified in the Reiman article for the parahippoeampal gyri were chosen. The absolute scale of the MRI films are known. The x-y coordinates based on the Reiman article were noted on the films. Then a box was fitted to the brain. The relative percentage of the horizontal edge which lines up with the position marked by the Reiman approach were noted to p.rovide the x coordinates for our system. The relative percentage of the vertical edge of the box was similarly noted to provide the y coordinates for our system. The coordinates for the parahippocampal gyri in the Reiman analysis closely matched the coordinates for the h~ppocampal box on our 009 slice. A similar analysis was used to measure temporal pole metabolism for comparison between our anxious patients and our normal controls.
Results Anxious Versus Normal Comparison During the Passive Viewing Brain System Analysis. Anxious patients and controls showed significantly different patterns of brain metabolism with the absolute glucose metabolism rates (Table 2). Post hoc t-tests showed that the anxious patients had a significantly reduced basal ganglia (p
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Table 2. Regional Cerebral Glucose Metabolic Ratea'b Absolute metabolic rate Control (n = 15) Passive viewing
System Conical surface Medial cortex Limbic Thalamus Basal ganglia White matter Midbrain Cerebellum
26.1 31.6 21.9 29.6 30.9 18.7 19.9 20.4
-4- 5.9 ... 7.5 ± 4.6 _ 6.6 ... 6.4 +_ 4.2 ± 4.0 _+ 3.7
Relative metabolic rate Control (n = 15)
G A D (n = 18) Passive viewing 22.3 27.7 18.6 25.5 25.5 15.6 16.6 19.5
± ± ± ± -+ ± -
4.0 5.2 3.2 4.1 4.6' 3.1" 3.4 4.3
Vigilant viewing 22.6 27.8 18.5 25.1 26.8 16.7 16.2 19.1
± ± ± ± ± ± ± ±
3.6 4.6 2.9 4.8 3.6 2.8 2.6 2.9
Passive viewing 1.03 !.22 0.98 i.15 1.23 0.74 0.87 1.08
± ± ± _ ± ± ± _
0.06 0.07 0.08 0.10 0.06 0.07 0.08 0.15
G A D (n = 18) Passive viewing !.04 i.23 0.98 1.17 i.18 0.72 0.86 1.16
± ± ± ± ± ± ± ±
0.06 0.07 0.08 0.11 0.05 d 0.08 0.08 0.15 ~
Vigilant viewing 1.04 1.22 0.98 1.12 1.25 0.72 0.86 1.16
± _ ± ± _+ _ ± ±
0.05 0.05 0.07 0.12 0.08 0.08 0.11 0.18
aDam given as mean *-- SD. SAbsolute ANOVA: GAD passive viewing venus normal control passive viewing: system x group, F -- 2.55, df = 3.35, 103.83, p = 0.05. CGAD versus normal control (p < 0.05, t-test). '~GAD passive viewing versus GAD task (p < 0.05, t-test).
< 0.05) and white matter metabolic rate (Figure 2). Relative data (Table 2) did not show a significant group-by-system interaction, but exploratory post hoc t-tests showed that the relative cerebellar metabolism was significantly higher in the anxious subjects than in the controls (Figure 3). No significant differences in the hippocampus were seen in anxious patients compared to controls (Table 3). Left-fight parahippocampal gyri metabolic ratios were not found to be significantly different in subjects with GAD and controls (GAD, 0.90 _+ 0.25; NC, 0.99 _+ 0.18; p = 0.25, NS). When the basal ganglia absolute metabolic rate was subdivided into its three components, the globus pallidus and the putamen were found to be significantly lower than normals in the anxious subjects (Table 3). Temporal pole analysis shows a significant decrease m absolute glucose metabolic rates in anxious patients compared with normal controls (GAD, 9.8 _+ 3.2; NC, 12.6 _+ 3.7; t = 2.3, df = 27.9, p = 0.02),
Cor.fca! Lobes Ap~!ysis. The cortical lobe .A~!.OVA showed a significant lobe by segment by hemisphere by group interaction for relative metabolic data (Table 4) but not for absolute metabolic rate. Post hoc t-tests show that anxious patients have significantly higher relative metabolic rates than normal controls in the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the fight precentral frontal gyms (Figure 4). Follow-up simple-interaction three-way ANOVAs (group by segment by hemisphere) were done for each lobe. The occipital lobe showed a three-way interaction for relative data (F = 3.27, df = 3,29, p = 0.04; Table 5). The temporal lobe showed a significant two-way interaction ( F = 5.94, df = 1.44,44.74, p = 0.04; Table 5) for absolute metabolic rates. Post hoc t-tests indicated that superior temporal lobe was significantly decreased in anxious patients compared with controls. Global Brain Metabolism. The GAD patients did not show a global whole b~in metabolic rate decrease (GAD. 19.7 _+ 4.6: controls, 22.8 -+ 6.1, NS).
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Figure 3. Cere~llar Metabolism. Individualized glucose ~cales are used which are automatically scaled to display the full scale and are better able to display relative:cerebellar metabofic differences. The subjects with GAD in the top row show greater relative cerebellar metabolism.
Passive Viewing Versus Vigilance Task Differences in Patients With GAD Clinical Response. The Hamilton Anxiety score for the active medication group prior to receiving the medication is 26.4 _ 3.0. After 3 weeks of clorazepate, their Hamilton Anxiety score was !6. ! _+ 3.8. The Hamilton Anxiety score for the placebo group at
Table 3. Regional Ce~bral Glucose Metabolic Rate at Baseline Limbic System, in Patients With GAD and Normal Controls: Absolute~ System/structure Limbic system Cingulate Hlppocampus Amygdala Basal ganglia
Caudate Putamen Globus pallidus °Data given as mean ± SD. ~ A D vers~s a~rmal controls (p < 0.05, t-test).
GAD 18.5 22.5 17.3 15.5 25.2 28.3 26.5 21.2
± ± ± ± ± ± ± ±
3.1 3.9 b 3.0 2.8 4.36 5.3 4.16 4.46
Normal controls 21.9 27.5 20.4 17.6 30.9 34.0 32.7 26.1
-± ± ± ± _ ± ±
4.6 5.9 4.5 4.4 6.4 7.8 6.5 5.7
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Figure 4. Temporal and Occipital Lobe Metabolism. Individualized glucose scales are used to show the increase in relative temporal and ~_,.cipit~_!me~bolism m subjects with GAD (top row).
day 0 was 24.3 _ 3.0. After 3 weeks of placebo, their Hamilton Anxiety score was 20.0 _ 5.6. The medicated group showed a significantly greater decrease in Hamilton Anxiety scores than did the placebo group (p = 0.0046, t-tes0.
P,rain System Analysis. When subjects were asked to perform the CPT task, there was a significant condition by structure interaction on the relative brain system analysis (Table 2). Post hoc t-tests indicate that the basal ganglia showed a significant increaze with the task (Figure 5). No significant condition interactions were found for the absolute aualysis.
Cortical Lobe Analysis. There was a significant condition by lobe by hemisphere interaction for both absolute ( F = 4.26, df = 3.12, p = 0.03) and relative metabolism ( F = 3.83, df = 1.82,25.49, p = 0.04). Right parietal lobe showed an increase with task whereas right temporal and right occipital lobe showed a decrease for both absolute and relative metabolic rates.
Anxiolytic Medication Versus Placebo Differences Brain System Analysis. GAD patients showed a significant decrease in brain absolute metabolic rates for different brain systems when treated with benzodiazepine. Exploratory post hoc t-testa were done to see the effects of benzc~liazepim:s on specific brain systems.
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Table 4. Regional Cerebral Glucose Metabolic Rate at Baseline in Conical Surface, in Patients With GAD and Normal Controls: Relativea'b GAD Cortical surface Frontal lobe Superior Mid Inferior Precentral Parietal lobe Posterior central Supramarginal Angular gyms Superior parietal Temporal lobe Superior Mid Inferior Posterior Occipital lobe d Area 19 Area 17 Inferior 17 Lateral 18
Left
Normal controls Right
Left
Right
1.07 1.07 I.! 1 1.12
± ± ± ±
0.07 0.09 0.09 0.08
1.04 1.12 !.!6 1.20
± ± ± ±
0.08 0.09 0.10 0.08 c
!.07 !,07 i.15 I.II
± ± ± ±
0.06 0.07 0.03 0.09
!.05 !.i0 1.16 !.13
± ± ± ±
0.05 0.06 0.04 0.06
1.06 1.00 !.01 0.94
± ± ± ±
0.11 0.10 0.10 0.16
1.11 !.08 !.06 0.97
± ± ± ±
0.08 0.1 ! 0.10 0.15
!.07 !.02 i.02 0.93
± ± +
0.08 0.07 0.11 0.18
1.09 !.09 1.07 0.97
± ± _ _
0.10 0.09 0.10 0.18
0.91 0.96 0.88 0.85
± ± ± ±
0.09 0.09 0.11 0.17
i.03 !.03 0.95 0.88
± ± ± ±
0.10 0.09 0.10 0.12 c
0.96 0.98 0.89 0.79
± ± ± ±
0.07 0.06 0.08 0.16
!.05 1.01 0.92 0.79
± ± ± ±
0.05 0.07 0.07 0.12
!.00 !.!2 !.21 0.98
± ± ± ±
0.09 0.11 0.IV 0.14
1.02 !.i7 1.20 0.99
± ± ± ±
0.08 0.15 0.13 0.18
1.02 !.!2 1.12 0.98
± ± ±
0.06 0.12 0.08 0.09
1.01 !.14 1.16 0.99
± ± ± ±
0.05 0.10 0.06 0.07
aData given as mean -" SD. bSignificant ANOVA interaction: lobe x segment x group, TSQ = 32. !, F = 2.64, df = 9.23 p = {3.03. cGAD versus normal control (vtest. p < 0.05). 'Z)ccipital lobe ANOVA: segment x hemisphere x group, TSQ = 10.5, F = 3.27, df = 3.27, p = 004.
The medication group showed significant decreases in absolute metabolic rate in cortical surface, limbic system, basal ganglia, and midbrain (Table = 6, Figure 5). Medial cortex showed a significant increase for relative metabolic rates for the medicated group compared with the placebo groups. ~'~ ~.
Cortical Lobe Analysis. GAD patients on active medication showed a - s ~ f i c a n t decrease in absolute metabolic rates across the four cortical lobes. Exploratory post hoc t-tests indicate that the right inferior area i7 of occipital cortex showed the greatest decrease after medication. Other cortical regions such as the frontal and temporal cortex also showed significant decreases. Significant correlations with change in Hamilton Anxiety scores were noted for change in the placebo group brain metabolic ratios for different brain systems (Table 6). Changes in Hamilton anxiety scores were positively correlated with change in limbic system for the placebo group. However, changes in Hamilton anxiety scores were negatively correlated with change in the basal ganglia for the placebo group. Interestingly, no significant correlations were noted for d~e medication group.
Discussion The study found higher relative metabolic rates for GAD patients in parts of the occipital, temporal, and frontal lobe metabolism and cerebellum relative to normal controls. The study also confirmed a decrease in absolute basal ganglia in GAD. The study did no*~
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| ! 93
Figure 5, A common glucose scale is used to show absolute metabolic differences for a typical subject with GAD during the passive viewing task, the active viewing task off medication, and after either active medication (top row) or placebo (bottom row). Active vigilance task results in an activation of basal ganglia (middle column) in the off-medication state compared to passive viewing (first column). P,~er active mexlication, subjects show a significant decrease in basal ganglia, cortical lobes (e.g. occiput), and limbic system (top right comer).
confirm the presence of significant right-left hippocampal asymmetries in GAD, as has been reported for panic disorders (Reiman et al 1986, 1989a), or global decreases in cortex metabolism, as indicated by blood flow studies (Mathew et al 1982). Relative occipital cortex overactivity in GAD patients is compatible with our previous finding that the occipital cortex showed among the highest decreases after be nzodiazepine treatment of anxiety (Buchsbaum et al 1987). Increased relative occipital activity could be due to hypervigilant behavior, a defining characteristic of anxiety (APA 1987). It is hypothesized that anxiety alters visual information processing as anxious subjects shift from foveal v;,~ion to peripheral vision to better scan the environment for threats (Shapiro and Lim 1989). Analysis of the temporal lobe revealed that the posterior temporal lobe was higher for relative metabolic rate and the superior temporal lobe was lower for absolute metabolic rate in GAD patients than normal controls. When the temporal poie is directly measured, however, anxious patients show significantly decreased absolute and relative metabolic rates compared with normal controls. This finding is inconsistent with the finding that
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Table 5. Regional Cerebral Glucose Metabolic Rate at Baseline in Cortical Surface, in Patients With GAD and Normal Controls" Almlu~ GAD
Normal controls
Superior Mid
20.7 ± 3.6 c 21.2 ± 3.5
21.1 ± 5.0 25.1 ± 5.2
Inferior Posterior
19.6 ± 3.7 18.5 ± 4.2
22.7 ± 4.6 19.6 ± 3.7
Temporal lobe
R~u~ Temporal lobe Superior Mid Inferior Posterior
GAD 0.97 0.99 0.92 0.87
± ± ± ±
0.09 0.08 0.10 0.13
Normal controls 1.00 0.99 0.90 0.79
_ ± ± ±
0.05 0.05 0.07 0.13
~Data given as mean - SD. ~ignificant ANOVA interaction: segment × group, F = 5.94, df = !.44,44.74, p = 0.01. ~GAD versus normal control (p < 0.0S, t-test). dSignificant ANOVA interaction: segment × group, WCPM$ = 0.03, F = 3.17, df = 3,93, p = 0.03.
blood flow increases in the temporal lobe in lactate-induced anxiety attacks (Reiman et al 1989a) and with anticipatory anxiety (Reiman et al 1989b), findings that suggest there is a heterogeneity in the regional activation of different portions of the temporal lobe, implying a highly complex organization for this structure. GAD patients in this study have a higher left inferior frontal gyms relative metabolism compared with normals. Increased left orbital frontal cortex metabolism has been reported in childhood-onset OCD (Swedo et al 1989). Ho.:ever, Swedo et al (1989) also reported bilateral prefrontal cortex metabolism increase in OCD, which is not seen in GAD. The increase seen in the left inferior frontal cortex metabolic ratio is consistent with the increases seen in bilateral front~ lobe metabolism ix normals with moderate anxiety (Reivich et al 1983). Our finding of increased left-to-fight frontal lobe metabolism is incompatible with the reports that anxious subjects had a higher fight than left cerebral metabolism compared with normal controls (Reivich et al 1983). The high relative cerebellar activity of GAD patients detected in the PET scans supports the h)~ohhesis of cerebella.- involvement in anxiety. Neurological testing and observation of over 400 patients suffering from various levels of anxiety revealed that 94% had evidence of cerebellar-vestibular dysfunction, suggesting an underlying mechanism of anxiety (Levinson 1989). Associations have also been noted between cerebellar-vestibular-related sensorimotor dysfunctions and symptoms of anxiety. The decreased absolute basal ganglia metabolic activity found in GAD patients in our study is not consistent with studies in the rat. Ableitner and Herz (1987) reported increased globus pallidus glucose metabolism after 13-carboline injection in rats, and Nehlig et al (1987) found an increase in rats' glucose metabolism in the caudate after caffeine injection. The injection of 13-carbolines into rats significantly increases the local cerebral glucose utilization in the cerebellum, thalamus, and limbic system (Ableitner and Herz 1987). Our findings in patients with GAD suggest a possible difference in neurobiology from those findings seen with panic disorder. Reiman (1987) found that panic disorder (PD) patients have abnormal hemisphere asymmetries in parahippocampal blood flow, blood
24.7 .4- 5.5
29.2 ± 5,5
20.8 -- 5.3
25.9 ± 6.7
27.5 - 6.2
18.8 ± 3.5
18.0 ± 5.5
21.6 ± 7.1
Cortical surface 21.6 ± 3.2 b
Medial cortex 26,8 ± 4.7
Limbic 18.0 ± 3.1 b
Thalamus 24.0 *- 4.3
Basal ganglia 25.6 ± 3.56
White matter 14.8 ± 2.5
3.0
Midbrain 15.2 -
Cerebellum 18.7 ± 3,6 19.7 ± 2.1
17.3 ± 1.9"
16.4 ± 2.7
28.0 ± 3.8 d
26.4 ± 5.6 c
20.0 ± 3.(F
28.9 ± 4.7 a
23.9 ± 4.(F
Baseline
17.1 ± 2.2
14.0 ± !.3
14.9 ± !.5
23.2 ± 3.1
21.7 ± 3.7
24.8 -- 1.3
24.8 ± 2.1
19.7 ± 1,8
Medication
G A D (Medicated group)
1.14 ± 0.21
0.83 -+ 0.14
0.72 ± O . I V
1.26 ± 0.09 t
1.12 ± 0.13
0.97 ~ 0.07 e
1.27 ± 0.06 °'c
1.05 ± 0.06
Ba~ILn,e
1.15 ± 0.17
0.85 ± 0.10
0.76 _+ 0.09
1.18 ± 0.08
1.08 ± 0.09
1.00 __ 0.06
1.20 .4- 0.04
1.05 ± 0.02
Placebo
G A D (Fiacebo group)
dd prime (baseline - treatment) correlation (p < 0.05). 'Positive correlation: Hamilton anxiety score (baseline - treatment) with baseline - treatment metabolism (p < 0.05). rNegative correlation; Hamilton anxiety score (baseline - treatment) with baseline - treatment metabolism (p < 0.05).
°Data given as mean ± SD. ~Medication group versus placebo group; baseline - treatment (p ' ( 0 . 0 5 ) . CMedication/placebo group: baseline - treatment versus 0 (p < 0.05).
Placebo
Baseline
G A D (Placebo group)
T a b l e 6. R e g i o n a l C e r e b r a l G l u c o s e M e t a b o l i c R a t e : A b s o l u t e a n d R e l a t i v e °
1.19 ± 0.15
0.88 ± 0.07
0.72 ± 0.03
1.24 ± 0.06
! . ! 2 ± 0,11
0.99 __ 0.07
1.22 ± 0.03 d
1.04 ± 0.03
Baseline
1.24 ± 0.21
0.85 ± 0.07
0.75 ± 0.07
1.23 +- 0.05
1.14 ± 0.09
1.00 ± 0.04
1.26 -~ 0.08
1.05 ± 0.03
Medication
G A D (Medic~1ed group)
~D
t~
mmm.
:>
S O
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volume, and oxygen metabolism, as assessed by PET. Change in left-right asymmetry in subjects with GAD were in the same direction as change reported for subjects with panic disorders. However, statistically significant limbic abnormalities were not found in our group of GAD patients. It is possible that patients with GAD may be a less homogenous group than subjects with panic disorder. Other psychobiological research suggests a difference in the pathophysiology of GAD and PD. Chamey et al (1989) compared noradrenergic neuronal functioning in PD and GAD patients and normal controls. Fifty percent of PD patients exhibited a noradrenergic neuronal hyperactivity, reactions not displayed by GAD or normal controls. The atlas methods used here are subject to the limitations of stereotaxic placement, accuracy in head positioning and repositioning, and scanner resolution. The limitations of stereotaxic placement are less marked for large structures such as the temporal lobe than for small structures such as the caudate nucleus. Differences between the Matsui and Hirano atlas used in this study and the Talairach atlas used in the Reiman studies are not. large. Although the Matsui and Hk"ano atlas used the CM line, a standard in ~imical use, and the Talairach atlas is based on the AC-PC, both portray the brain of a single individual and ~-~ not statistical standards. In a study of the angles between the CM, gabeUo-inion (GI), and AC-PC lines, mean differences under 2 degrees were found (Tokunaga et al 1977). The standard deviation of the angle between the CM and GI lines (2.8 degrees in males) is not significantly different from the standard deviation of the angle between the AC-PC line and the cranial frontooccipital line (2.1 degrees, F = 1.8, NS). The mean angle between the GI line used in the Reimaa study and the CM line used in our study was 1.5 degrees, with a standard deviation of 2.8 degrees. A difference of 1 SD would produce a difference in the elevation of the caudate nucleus of about 1.6 ram.
The effects reported here are for structure adequately imaged with a 7.6-ram in-plane and 9.9-ram axial resolution. The major gyri of the cortical surface are all several centimeters in size. Although the cortical ribbon surface is 3-5 mm thick, it is typically folded into a thicker strip similar in width to our cortical peel. The putamen, caudate, and cingulated gyrus all accommodate the 6 x 6 mm box easily in the horizontal plane and all are at least 20 mm or two 10-ram-thick planes high. Heterogeneity within the axial or horizontal plane would reduce the adequacy of the method. However, random variations caused by individual differences in brain proportions, vertical position of the planes acquired, and variation in head position and reposition would all tend to create random error and diminish group differences and/or medication effects. Although no ideal solution to these problems exist, the use of well crafted head holder and an MRI template provide advantages. During the task state, subjects showed an increase in relative basal ganglia metabolism and absolute and relative right parietal lobe metabolism. This finding is consistent with our studies in normal controls during a task-no task comparison (Buchsbaum et al 1990). Ri£~lt parietal lobe has been implicated in studies of attention (Heilman et al 1985). The increase in basal ganglia metabolism is consistent with increased motor activity during the task state. Although benzodiazepine treatment resulted in clinical improvement in anxiety, there was a lack of normalization of regional brain metabolism. For example, patients with generalized anxiety had decreased regional metabolism in basal ganglia compared with normals under the passive viewing condition. After treatment, this brain system showed
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an even greater decrease with benzodiazepine treatment. Other brain systems such as cortical surface and limbic system also show significant decreases with benzodiazepine treatment.
Spontaneous changes in Hamilton anxiety scores -,vere noted to be significantly correlated positively with metabolic ratios in the limbic system and negatively in the basal ganglia system for the placebo group. No significant correlations were found between Hamilton Anxiety score and regional brain metabolic ratios. This suggests that medications may decouple mood changes from the close association with regional brain metabolic ratios that is otherwise seen with spontaneous, natural mood changes. The absolute and relative brain system measures give apparently opposite findings for change resulting from placebo or medication. The medication group shows a decrease in absolute metabolism for the brain systems, whereas the relative metabolic ratios show an increase with medication for the subcortical systems. The opposite is trae for the placebo group. The absolute values show an increase whereas the relative values for the subcortical systems show a decrease. This apparent discrepancy is due to the fact that the cortex shows much greater changes than the subcortical system. Therefore the subcortical system lags in changes in either direction, resulting in apparently discrepant absolute and relative results.
In conclusion, our PET study of regional cerebral metabolism has shown that subjects with generafized anxiety disorder have elevated occipital lobe, temporal lobe, and frontal lobe metabolism relative to normal controls during a no-task state. Anxious subjects also showed decreased absolute basal ganglia metabolism and increased cerebellar-whole brain metabolic ratios compared with normals during the passive viewing state. Dur:mg the vigilance task, subjects showed a significant increase in relative basal ganglia metabolism and increase in right parietal lobe. Antianxiety medication resulted in a significant decrease in glucose metabolism in cortical lobes, limbic system, and basal ganglia compared with the placebo group.
References Ableitner A, Herz A (1987): Changes in local cerebral glucose utilization induced by the betacarbolines FG 7142 and DMCM reveal brain structures involved in the control of anxiety and seizure activity. J Ne~rosci 7:1047-1055. .A_m..eficanPsychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC, American Psychiatric Press, pp 235-253. Baxter LR, Phelps ME, Mazziotta JC, Guze BH, Schwartz IM, Selin CE (1987): Local cerebral glucose metabolic rates in c~bsessive-cornpulsivedisorder: A comparison with rates in unipolar depression and in normal controls. Arch Gen Psychiatry 44:211-218. Braestrup C, Albrechtsen R, Squires RF (1977): High densities of benzodiazepine receptors in human cortical areas. N~ture 269:702-704. Buchsbanm MS, Hazlett E, Si¢o~teN, Stein M, Wu J, Zetin M (1985): Topographic EEG changes with benzodiazepine administration in generalized anxiety disorder. 8iol Psychiatry 20:832842. Buchsbaum MS, Wu J, Haier R, et al (1987): Positron emission tomography assessment of effects of benzodiazepines on regional glucose metabolic rate in patients with anxiety disorder. Life Sci 40:2392-2400. Buchsbaum MS, Gillin CG, Wu JC, et al (1989): Regional cerebral glucose metabolism in human sleep assessed by positron emission tomography. Life Sci 45:1349-1357.
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Buchsbaum MS, Nuechterlein RH, Wu JC, et al (1990): Glucose metabolic rate in normals and schizophrenics during the continuous performance test assessed by positron emission tomography. Br J Psychiatry 156:216-227. Carlsson C, Hagerdal M, Sieajo BK (1975): Increase in cerebral oxygen uptake and blood flow in immobilization stress. Acta Physiol Scand 95:206-208. Carlsson C, Hagerdal M, Kaasik AE, Sieajo BK (1977): A catecholamine-mediated increase in cerebral oxygen uptake during immobili;~tion stress in rats. Brain Res 119:223-231. Charney DS, Woods SW, Heninger GR (1989): Noradrenergic function in generalized anxiety disorder: Effects of yohirnbine in healthy subjects and patients with generalized anxiety disorder. Psychiatry Res 27:173-182. d'Argy R, Gillberg PG, Stalnacke CG, etal (1988): In vivo and in vitro receptor autoradiography of the human brain using an 11C-labelled benzodiazepine analogue. Nel~rosci Leu 85:304-310. Dietrichs E (1984): Cerebellar autonomic function: Direct hypothalamocerebellar pathway. Science 223:591-593. Dixon WJ (1982): BMDP Biomedical Computer Program. Berkeley, CA: University of California Press. Edvinsson L, MacKenzie ET (1977): Amine mechanisms in the cerebral circulation. Pharmacol Rev 28:275-348. Enna SJ (1985): In Hales RE, Frances AJ (eds), American Psychiatric Association Annual Review. Washington, DC: American Psychiatric Press, pp 67--82. Frost JJ, Wagaer HN, Dannals RF, et al (1986): Imaging benzodiazepine receptors in man with [1~C]suriclone by positron emission tomography. Eur J Pharmacol 122:381-383. Gray JA (1982): The ~uropsychology of Anxiety: An Enquiry Into the Functions of the Septohippocampal System. New York: Oxford University Press. Grillon C, Buchsbaum MS (1987): EEG topography of response to visual stimuli in generalized anxiety disorder. Electroencephalogr Clin Neurophysiol 66:337-348. Groenewegen HJ, Room P, Wittner MP, Lohman AHM (1982): Cortical afferents of the nucleus accumbens septi in the cat, studied with anterograde and retrograde transport techniques. Neuroscience 7:977-995. Heath RG, Dempesy CW, Fontana CJ (1984): The cerebellar pacemaker for intractable behavioral disorders: Physiological mechanisms. In Davis R, Bloedel JR (eds), Cerebellar Stimulation for Spasticity and Seizures. Boca Raton, FL: CRC Press, pp 1-339. Heilman KM, Watson RT, Valenstein E (1985): Neglect and related disorders. In Heilman KM, Valenstein E (eds), Clinical Neuropsychology. New York: Oxford University Press. Kety SS (1950): Circulation and metabolism of the human brahi in health and disease. Am J Med 8:205-217. Levinson HN (1989): The cerebellar-vestibular predisposition to anxiety disorders. Percept Mot Skills 68:323-338. Mathew RJ, Weinman ML, Claghorn JL (1982): Anxiety and cerebral blood flow. In Mathew RJ (ed), The Biology of Anxiety. New York: Brarmer/Mazel. Matsui T, Hirano A (1978): An Atlas of the Human Brain for Computerized Tomography. Tokyo: Igaku-Shoin. Mountz JM, Modell JG, Wilson MW, et al (1984): Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia. Arch Gen Psychiatry 46:501-504. Nehlig A, Daval J, Pereira de Vasconceles A, Boyet S (1987): Caffeine-diazepani interaction and local cerebral glucose utilization in the conscious rat. Brahz Res 419:272-278. Ohata M, Fredericks WR, Sundaram U, Rapoport SI (1981): Effects of immobilization stress on regional cerebral blood flow in the conscious rat. J Cereb Blood Flow Metab 1:187-194. Papez JW (1937): A proposed mechanism of emotion. Arch Neurol Psychiatry 38:725-743. Paul SM, Marangos PJ, Skolnick P (1981): The benzodiazepine-GABA-chloride ionophore receptor complex: Common site of minor tranquilizer action. Biol Psychiatry 16:213-229.
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Persson A, Ehrin E, Eriksson L, et al (1985): Imaging of ttC-labelled Ro 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography. J Psychiatr Res 19:609-622.
Reiman EM (1987): The study of panic disorder using positron emission tomography. Psychiatry Dev 5:63-78. Reiman E, Raichle M, Butler K, et al (1984): A focal brain abnormality in panic disorder, a severe form of anxiety. Nature 310:683-685. Reiman EM, Raichle ME, Robins E, et al (1986): The application of positron emission tomography to the study of panic disorder. Am J Psychiatry 143:469-477. Reiman EM, Fussclman MJ, Fox PT, Raichle ME (1989a): Neuroanatomical correlates of anticipatory anxiety. Science 243:1071-1074. Reiman ElM, Raichle ME, Robins E, et al (1989b): Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry 46:493-500. Reivich M, Gur Re Alavi A (1983): Positron emission tomographic studies of sensory stimuli, cognitive processes and anxiety. Hum Neurobiology 2:25-33. Ribak CE, Vaughn JE, Barber RP (1981): Immunocytochemical localization of GABAergic neurones at the electron microscopical level. Histochem J 13:555-582. Rodriguez G, Cogomo P, Gris A, et al (1989): Regional cerebral blood flow and anxiety: A correlation sPddy in neurologically normal patients. J Cereb Blood Flow Metab 9:410--416. Shapiro KL, Lira A (1989): The impact of anxiety on visual attention to central and peripheral events. Behav Res Ther 27:345-351. Sharma HS, Dey PK (1986): Influence of long-term immobilization stress on regional blood-brain barrier permeabili~, cerebral blood flow, and 5-HT level in consciou3 normotensive young rats. J Neurol Sci 72:61-76. Sharma HS, Dey Plg (1988): EEG changes following increased blood-brain permeability under long-term immobiiization stress in young rats. Neurosci Res 5:224-239. Sokoloff L (1953): ]he action of drugs on the cerebral circulation. Pharmacol Rev 1:1-65. Sokoloff L, Reivich M, Kennedy C, et al (1977): The [m4C] deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897-916. Stewart RS, Devous MD, Rush AJ, Lane L, Bonte FJ (1988): Cerebral blood flow changes during sodium-.~actate-induced panic attacks. Am J Psychiatry 145:442 A.A.9. Swedo SE, Schapiro MB, Grady CL, et al (1989): Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry 46:518-523. Tokunaga A, Takase M, Otani K (1977): The glabella-inion line as a baseline for CT scanning of the brain. Neuroradiolo&y 14:67-71. Zohar J, lnsel TR, Berman KF, Foa EB, Hill JL, Weinberger DR (1989): Anxiety and cerebral blood flow during behavioral challenge. Arch Gen Psychiatry 46:505-510.
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PET in Generalized Anxiety Disorder Joseph C. Wu, Monte S. Buchsbaum, Tamara G. Hershey, Erin Hazlett, Nancy Sicotte, and J. Chad Johnson
Positron emission tomography (PET) measurements of cerebral glucose use were made in 18 patients wit, generalized anxie~" disorder (GAD) during a passive viewing task off medication, and an active vigilance viewing task before and after medication or placebo treatment. In the passive viewing task, patients with GAD were compared with 15 normal controls. A significant difference in pattern of absolute brain metabolism was found. Patients showed lower absolute metabolic rates in basal ganglia and white matter. Relative metabolism was increased in the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the right precentral frontal gyrus. Significant left-right asymmetry of the parahippocampal gyri was not found in patients with GAD. An active vigtiance task resulted in activation of relative basal ganglia metaboii:m in patients. Benzodiazepine therapy resulted in decreases in absolute metabolic rates for cortical surface, limbic system, and basal ganglia and was not associated with normalization of patterns of glucose metabolism. Change in anxiety scores was significantly correlated with change in limbic system and basal ganglia for the placebo group. The normal--anxious difference in the basal ganglia and the change seen in this region after benzodiazepine treatment are suggestive of a role in anxiety for this structure.
In,roduction Generalized anxiety, disorder (GAD) is characterized by symptoms such as persistent worrying, hypervigilance, and autonomic hyperactivity (APA 1987), and is most commonly treated with benzodiazepines. Six functional neuroanatomic hypotheses of the site of anxiety can be proposed based on previous brain imaging and neuroanatomic studies: occipital lobe hyperactivity, hippocampal/temporal lobes hyperactivity, frontal lobes hypoactivity, basal ganglia-cerebellar imbalance, whole brain underarous~d, or whole brain overarousal. First, since both positron emission tomography (Persson et al 1985) and human autopsy studies (d'Argy et al 1988; Braestrup et al 1977) reveal the occipital lobe as having one of the greatest concentrations of benzodiazepine receptors in the brain, this region may be a candidate for the site of GAD. Frost et al (1986) also reported high levels of cortical be,azodiazapine receptor binding. We found a significant decrease in occipital cortex metabolism after benzodiazepine administration in patients with GAD (Buchsbaum et al 1987). Benzodiazepine receptors are r,~"'~',ef a complex that is corn-
From the Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvtne, CA 92717. Address reprint requests to Joseph Wu, M.D., D402, Med Sci I, UCI-CCM, h-vine, CA 92717. Received June 22, 1990: revised October 24, 1990. © 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
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posed of a ~/-aminobutyric acid (GABA) receptor and a chloride ionophore (Paul et a! 1981). Since most GABA neurons are thought to have their cell bodies and axon terminals within the cortex as local circuit neurons (Enna 1985), the inhibitory effects of benzodiazepines is compatible with the facilitation of local GABA activity. Quantitative EEG studies have demonstrated the sensitivity of the occipital cortex follo,:,ing benzodiazepine treatment (Buchsbaum et al 1985). Topographic mapping of GAD patients and normals also showed occipital differences (Buchsbaum et al 1985; Grillon and Buchsbaum 1987). Second, the limbic system involving the hippocampus, lying within the temporal lobe, has been hypothesized to be important in the modulation of emotions (Papez 1937; Gray 1982). Patients with panic disorders have been reported to have decreased left-right parahippocampal blood flows (Reiman et al 1986; Reiman 1987). Lactate-induced anxiety attacks have been reported to be associated with increased blood flow bilaterally in temporal poles and insular cortex (Reiman et al 1989a). Anticipatory anxiety has also been reported to show increased blood flow in the temporal cortex (Reiman et al 1989h). Third, the prefrontal cortex has also been hypothesized to play a role in anxiety through its projection to the entorhinal area of the temporal lobe, which in turn projects to the hippocampus (Gray 1982). An increase in frontal cortex metabolism is seen with moderate anxiety in no~rnals, as measured by the Speilberger State-Trait Anxiety Inventory, but even greater anxiety is associated with decreased metabolic activity (Reivich et al 1983). Increased left orbital frontal and bilateral prefrontal cortex metabolism has been reported in childhood-onset obsessive-compulsive disorder (Swedo et al 1989), which is considered one of the anxiety disorders (APA 1987). Fourth, other brain structures, such as the basal ganglia (Groenewegen et al 1982) and the cerebellum (Dietrichs 1984), have important limbic connections. The basal ganglia and the cerebellum have GABAergic terminals derived from local circuit neurones and axon collaterals of projection neurones (Ribak et al 1981) that are influenced by benzodiazepines. Reiman et al (1989b) noted that lactate-induced anxiety caused significant increases in the right and left putamen as well as the anterior cerebellar vermis. Heath et al (1984) have reported that cerebellar stimulation in animals modulates limbic system structures, including the hippocampus, amygdala, and septum. Obsessive-compulsive disorder (OCD) has been reported to show bilateral increase in caudate metabolism (Baxter et al 1987). A frontal-limbic-basal ganglia model of OCD has been proposed (Swedo et al 1989). Fifth, some earlier blood flow and cerebral metabolic studies suggested that anxiety was associated with increases in cerebral blood flow or metabolism. Kety (1950) noted that one subject who was very apprehensive had significantly increased cerebral metabolic rate for oxygen (CMRO:). Carlsson et al (1975, 1977) also noted increases in CMRO2 and cerebral blood flow for immobilized conscious rats that were blocked by propranolol or prior adrenalectomy. Systemically administered epinep.hrine had inconsistent or negligible effects on CMRO2 (Sokoloff 1959; Edvinsson and MacKenzie 1977). Ohata et al (1981) found that immobilization stress produced an overall decline in regional cerebral blood flow measured with [~4C]iodoantipyrine except at the frontal lobe. They also found that immobilization stress stimulated hype~entilation and reduced Pac02. After correcting for cerebrovascular constriction, Ohata et al (1981) still found that cerebral blood flow would increase by at most 20%. Glucose metabolism images were not affected by a change in Pac02 and did allow an evaluation of change in metabolism without this concomitant complication. Other investigators (Sharma and Dey 1986,
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1988) also found immobilization stress to diminish cerebral blood flow in conscious young rats. [3-car~olines, which ate anxiogenic inverse antagonists to benzodiazapine receptors, increase 6ae local cerebral glucose utilization in different brain regions, such as the cerebellum, thalamus, and limbic system (Ableitner and Herz 1987) in ~ a l s . Sixth, whole brain decreases in activity may be related to the behavioral inhibition postulated by Gray (1982) as part of the response to anxiety. Lower blood flow across the brain was found by Mathew et al (1982) in nine patients with GAD. E x p o s m to phobic stimuli to patients with OCD has been reported to result in marked decrease in virtually all cortical regions (Zohar et al 1989). Rodriguez et al (1989) found a negative correlation between regional cerebral blood flow and anxiety measures. Stewart et al (1988) found decreases or minimal increases in hemispheric blood flow in panic disorder patients who panicked after an infusion. However, no changes were seen in regional or global cerebral blood flow in state anxiety due to simple phobia (Mountz 1984). This article is the first report to date on differences in regional cerebral metabolism between normal controls and patients with GAD that allows us to directly compare the five anatomic sites in the two groups.
Methods Patients Eighteen right-handed patients [eight male and ten female, mean (+SD) 39.8 _+ 13.6 years] who met DSM-HI criteria for GAD entered and completed the study. Patients were diagnosed using a semistructured clinical interview. None of the patients met DSM-III criteria for panic disorders or a current episode of major depression. Patients were excluded if they had any other axis I psychiatric disorder or any other major medical illness. Patients were medication free for at least 3 weeks (confirmed by urine drug screening) and in good health as determined by medical history, physical examination, and laboratory analyses. Patients had to have a Hamilton Anxiety score of at least 18 (28 -+ 4.2) and were diagnosed by a psychiatrist within 2 weeks prior to the study. Patients were tested with the Hamilton Anxiety test at each of their three PET scans.
Healthy Subjects Healthy subjects were determined to be free of mental disorders and m~or medical illness on the basis of a semistructured psychiatric interview, physical examination, and laboratory analyses. There were five men and ten women with a mean age of 39.1 _ 12.8 years, all right-handed. Subjects were also excluded if they had any axis I diagnosis. Subjects who had first-degree relatives with a major psychiatric illness or were taking psychoactive medication were excluded.
Medication Trial The 18 patients were randomly assigned into two groups (8 in drug group, 10 in placebo group) using a double-blind, placebo-comrolled design. Patients received either three 7.5-mg clorazepate (tranxene) capsules per day for 21 days or three ma~,cNng placebo capsules.
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PET Scan Procedure Activation tasks were employed to minimize variance and to activate regions of the brain that are functionally tied into the pathophysiology of the illness. Hypervigilance has been reported as a symptom in anxiety. Consequently, a vigilance task was chosen. 't,~ fluorodeoxyglucose (F-'I~) PET procedure has been previously described for ilfis group of GAD patients and normal subjects (Buchsbaum et al 1987). Both groups were exposed to the degraded stimulus continuous performance test (CPT) during F I ~ uptake, but were only required to observe the stimuli passively (Buchsbaum et al 1987). In the second phase, for baseline and medication (scans 2 and 3), patients received the same stimuli but actively identified target stimuli during the CPT. Different tasks were employed for patient--control and pretreatment-posttreatment comparisons for two reasons. There were two pretreatment scans. The first ("the baseline") employed the visual stimuli but with no cognitive tasks. The second ("day 0") used the same visual stimuli but added a cognitive vigilance task with false feedback that was designed to stimulate anxiety. This sequence of scans allowed us to use a subtraction technique to identify regions of the brain involved with vigilance. The third scan continued the use of the cognitive vigilance task but tested the anxious subjects after placebo or medication.
Image Collection Between 45 and 100 rain after FDG injection, nine planes parallel to the canthomeatal line (CM) were obtained on the NeuroECAT IV scanner in the Brain Imaging Center of the Department of Psychiatry, University of California, Irvine. The top three slices were done at 95, 80, and 65 mm above the CM line, with shadow shield in and septa shields out, measured in plane resolution of 8 mm and axial resolution of 12 ram. The bottom six slices were done at 10 mm increments (55, 45, 35, 24, 15, and 5 mm) above the CM line with both shadow and septa shields in, measurement in plane resolution of 7.6 mm, and axial resolution of 10 ram. Scans were transformed to glucose metabolic rate as described elsewhere (Buchsbaum et al 1987; Sokoloff et al 1977).
Image Analysis Cortical metabolic rates were measured using a newly modified cortical peel technique previously described (Buchsbaum et al 1989; Figure i). Subcortical structures were assessed using stereotaxis coordinates derived from a standard neuroanatomic atlas (Matsui and Hirano 1978) as previously described (Buchsbaum et al 1987). Coordinates for the structures analyzed are included in Table 1. Data were analyzed both as absolute metabolic rate (ixmol/drn/min) and as relative rates (region of interest divided by whole slice metabolic rate). The global mean cerebral metabolic rate was calculated by averaging the mean glucose metabolism across the nine slices weighted for the number of pixels per slice.
Statistical Methods Brain System Analysis. In order to assess group difference in total brain organization, the brain was divided into eight main systems: lateral cortex (average of frontal, temporal, parietal, and occipital lobes), medial cortex (average of precuneus, paracentral, medial
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Table I. Stereotaxic Coordinates for Regions of Interest Matsui and Hirano plane
X Coordinate
Y Coord/r_aate
Left
Right
Left
Right
2 2 2 3 3 3 4 4 4 4 4 5 5 5 5 6 6 6 6 6 6 7 7 7
45.8 48.3 49.2 48.2 47.3 47.3 45.8 45.8 47.3 47.3 47.3 44.8 44.8 44.8 44.8 28.7 44.2 45.0 45.0 45.0 42.6 34.9 46.5 50.4
Posterior corpus callosum
7 7
50.4 50.4
Posterior cingulate Cingulate Frontal white matter
7 8 8
41.9 45.2 29.0
Caudate
8 8
39.6 31.3
8 8 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 10
29.2 4i.7 44.4 37.5 35.5 45.2 25.8 44.4 45.2 45.1 32.8 41.3 21.3 32.6 37.0 45.1 34.4 36.9 31.5
54.2 51.7 50.8 51.8 52.7 52.7 54.2 54.2 52.7 52.7 52.7 55.2 55.2 55.2 55.2 71.3 55.8 55.0 55.0 55.0 57.4 65.1 53.5 49.6 49.6 49.6 58.1 54.8 71.0 60.4 68.7 70.8 58.3 55.6 62.5 64.5 54.8 74.2 55.6 54.8 54.9 67.8 58.7 78.7 67.4 63.0 54.9 65.6 63.1 68.5
24.4 54.8 70.4 22.4 59.7 74.6 16.2 26.9 40.1 53.9 73.7 16.8 28.6 42.7 67.4 20.1 lg.4 30.5 43.7 56.9 73.6 19.8 17.1 29.0 43.2 54.0 71.0 14.7 16.5 33.8 38.5 44.6 46.2 48.8 50.8 55.4 68.8 76.5 78.2 85.3 15.2 18.1 31.7 36.4 36.7 41.7 56.4 67.3 83.6 16.9
24.4 54.8 70.4 22.4 59.7 74.6 16.2 26.9 40.1 53.9 73.7 16.8 28.6 42.7 67.4 20.1 18.4 30.5 43.7 56.9 73.6 19.8 17.1 29.0 43.2 54.0 71.0 14.7 16.5 33.8 38.5 44.6 46.2 48.8 50.8 55.4 68.8 76.5 78.2 85.3 15.2 18.1 31.7 36.4 36.7 41.7 56.4 67.3 83.6 16.9
Stmctuie Superior frontal Paracentral Precuneus Superior frontal Paracentral Precuneus Superior frontal Antemmedial frontal Postemmedial frontal Paracentral Precuneus Superior frontal Medial frontal Cingulate Precuneus Frontal white matter Medial frontal Anterior cingulate Medial cingulate Posterior cingulate Precuneus Frontal white matter Medial frontal Anterior corpus callosum Medial corpus callosum
Putamen Posterior putamen Anterior thalamus Medial thalamus Lateral thalamus Posterior thalamus Posterior cingulate Optic radiation Anterior calcarine Posterior calcarine Anterior cinguiate Frontal white matter Caudate Medial temporal Putamen Globus pallidus Superior colliculus Hippocampus Fusiform Frontal white matter
(continued)
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Table 1. Continued
Structure Anterior cingulate Putamen Hippocampus Inferior colliculi Anterior rectal gyms Orbital gyms Posterior rectal gyms Amygdala Uncus Hippocampus Midbrain Anterior cerebellum Posterior cerebellum
X Coordinate
Y Coordinate
Matsui and Hirano plane
Left
Right
Left
Right
10 10 10 10 10 lI 1! !1 !1 11 11 11 Ii
41.7 31.5 30.6 44.4 44.3 34.8 45.2 32.2 33.0 32.2 43.5 39. ! 39.1
58.3 68.5 69.4 55.6 55.7 65,2 54.8 67.8 67.0 67.8 56.5 60.9 60.9
16.9 33.8 56.8 57.4 7.60 23.5 28.8 39.4 47.7 59.0 59.0 75.0 83.3
16.9 33.8 56.8 57.4 7.6 23.5 28.8 39.4 47.7 59.0 59.0 75.0 83.3
frontal, rectal gyfi, calcarine, and medial temporal), iimbic system (average of amygdala, hippocampus, and cingulate), basal ganglia (average of caudate, putamen, and globus pallidus), thalamus, white matter (average of frontal white matter, corpus collosum, and optic radiation), midbrain, and cerebellum. The regions were analyzed with a three-way analysis of variance (ANOVA) with group (GAD versus controls) as an independent measure. Regional metabolic rates for the eight brain systems and hemisphere (left, fight) served as within variables for the anxious--control comparison of the passive stimuli task. For the passive stimuli-active cognitive task comparison, a similar three-way ANOVA was performed, with task (passive stimuli versus active task) as a repeated measure and brain system and hemisphere as within-factor measures. A similar statistical design was used to compare the pretreatment and posttreatment conditions. A similar ANOVA was done for the structures of the basal ganglia (caudate, putamen, and globus pallidus) by themselves. Effects are reported with Huynh-Feldt reduced degrees of freedom. ANOVAs with significant iateractions were followed by post hoe t-tests. Repeated-measure factors provide a statisti:al method for comparing differences within individuals for the same brain regions over time or before and after a specific task. This c:nables a comparison for each individual structure using its own baseline for medication contrasts. This is statistically eqt, iv alent to a "subtraction technique" in which subjects' brain images are fitted to a standard brain template and then the mean of one such condition is compared with the mean of a second condition applied by Reiman et al (1989b). Our method has the advantage of yielding only a few F ratios which provide a systematic test of hemisphere asymmetries, differences between structures, and, when applied to absolute metabolic data, estimates oi: metabolic rate effects.
Cortical Lobe Analysis. The four cortical lobes have each been divided into four segments. A four-way ANOVA (Dixon 1982) was done with group (anxious, control) as an independent measure and lobe (frontal, temporal, parietal, occipital), lobar segments (four per lobe), and hemisphere (fight, left) as repeated measures to assess group difference
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Precentral M!
Iobule
Superi, frontal
gyrus ;ral occipita!
Inferi(
poral
/ Middle temporal Superior temporal Figure 1. Side view of brain reconstructed from the Matsui and Hirano (1978) atlas. Each sfice from no. 2 (80% of head height) through no. 11 (21% of head height) is iudicated. Four areas within each lobe are indicated by shading: frontal (superior, middle, inferior, and precentral), temporal (superior, middle, dorsal, and ventral inferior temporal gyrus), parietal (postcentral, supramarginal, superior parietal, and angular), and occipital (areas 17 and 18, and dorsal and ventral area 19). Each area is identified as the distance along the circumference of the atlas slice as a percent of ",he distance from the midline anterior to mid!ine posterior points. A listing of the percentage points is available from the authors. For each person, each PET slice was matched to the corresponding atlas slice; a computer algorithm then assessed the mean glucose along the outer 2 cm segment of a radius joining the slice center and the slice edge. Mean values along a sector of the circumference were then calculated; weighted averages across slices formed the gyral estimates.
in overall pattern of cortical lobe metabolism. Simple-interactions A N O V A s were done as follow-up for the occipital, temporal, and frontal lobes in order to test the specific hypotheses regarding these lobes aad anxiety.
Parahippocampal Gyri AsymmetoJAnalysis. Stereotaxic coordinates from the Reiman paper were translated into a set of stereGtaxic coordinates compatible with our software. Reiman et al (1984) use an absolute coordinate system in which the anterior c o m m i s s u r e posterior commissure (AC-PC) line is used to establish a reference horizontal plane. The center of a plane is used as the reference point for any particular plane. Structur.:s ~ e localized on the z axis by ~pecifying the distance above or below the reference plane. Within a plane, structures are localized on the x-y plane by specifying the distance left or right and forward or backward of the center point of the brain. Their reference plane is comparable to the 0°8 slice from the Matsui and Hirano (1978) arias in which the anterior commissure and the posterior commissure are clearly visible. We chose three subjects whose magnetic resonance images (MRIs) matched the 0°8 plane. The MRIs
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Figure 2. Basal Ganglia Metabolism. A common glucose scale shows the decrease in absolute glucose metabolic rate in the basal ganglia of two typical subjects with G.M~ on top row compa.-ed to two normal controls on bottom row.
that matched the z axis dimension specified in the Reiman article for the parahippoeampal gyri were chosen. The absolute scale of the MRI films are known. The x-y coordinates based on the Reiman article were noted on the films. Then a box was fitted to the brain. The relative percentage of the horizontal edge which lines up with the position marked by the Reiman approach were noted to p.rovide the x coordinates for our system. The relative percentage of the vertical edge of the box was similarly noted to provide the y coordinates for our system. The coordinates for the parahippocampal gyri in the Reiman analysis closely matched the coordinates for the h~ppocampal box on our 009 slice. A similar analysis was used to measure temporal pole metabolism for comparison between our anxious patients and our normal controls.
Results Anxious Versus Normal Comparison During the Passive Viewing Brain System Analysis. Anxious patients and controls showed significantly different patterns of brain metabolism with the absolute glucose metabolism rates (Table 2). Post hoc t-tests showed that the anxious patients had a significantly reduced basal ganglia (p
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Table 2. Regional Cerebral Glucose Metabolic Ratea'b Absolute metabolic rate Control (n = 15) Passive viewing
System Conical surface Medial cortex Limbic Thalamus Basal ganglia White matter Midbrain Cerebellum
26.1 31.6 21.9 29.6 30.9 18.7 19.9 20.4
-4- 5.9 ... 7.5 ± 4.6 _ 6.6 ... 6.4 +_ 4.2 ± 4.0 _+ 3.7
Relative metabolic rate Control (n = 15)
G A D (n = 18) Passive viewing 22.3 27.7 18.6 25.5 25.5 15.6 16.6 19.5
± ± ± ± -+ ± -
4.0 5.2 3.2 4.1 4.6' 3.1" 3.4 4.3
Vigilant viewing 22.6 27.8 18.5 25.1 26.8 16.7 16.2 19.1
± ± ± ± ± ± ± ±
3.6 4.6 2.9 4.8 3.6 2.8 2.6 2.9
Passive viewing 1.03 !.22 0.98 i.15 1.23 0.74 0.87 1.08
± ± ± _ ± ± ± _
0.06 0.07 0.08 0.10 0.06 0.07 0.08 0.15
G A D (n = 18) Passive viewing !.04 i.23 0.98 1.17 i.18 0.72 0.86 1.16
± ± ± ± ± ± ± ±
0.06 0.07 0.08 0.11 0.05 d 0.08 0.08 0.15 ~
Vigilant viewing 1.04 1.22 0.98 1.12 1.25 0.72 0.86 1.16
± _ ± ± _+ _ ± ±
0.05 0.05 0.07 0.12 0.08 0.08 0.11 0.18
aDam given as mean *-- SD. SAbsolute ANOVA: GAD passive viewing venus normal control passive viewing: system x group, F -- 2.55, df = 3.35, 103.83, p = 0.05. CGAD versus normal control (p < 0.05, t-test). '~GAD passive viewing versus GAD task (p < 0.05, t-test).
< 0.05) and white matter metabolic rate (Figure 2). Relative data (Table 2) did not show a significant group-by-system interaction, but exploratory post hoc t-tests showed that the relative cerebellar metabolism was significantly higher in the anxious subjects than in the controls (Figure 3). No significant differences in the hippocampus were seen in anxious patients compared to controls (Table 3). Left-fight parahippocampal gyri metabolic ratios were not found to be significantly different in subjects with GAD and controls (GAD, 0.90 _+ 0.25; NC, 0.99 _+ 0.18; p = 0.25, NS). When the basal ganglia absolute metabolic rate was subdivided into its three components, the globus pallidus and the putamen were found to be significantly lower than normals in the anxious subjects (Table 3). Temporal pole analysis shows a significant decrease m absolute glucose metabolic rates in anxious patients compared with normal controls (GAD, 9.8 _+ 3.2; NC, 12.6 _+ 3.7; t = 2.3, df = 27.9, p = 0.02),
Cor.fca! Lobes Ap~!ysis. The cortical lobe .A~!.OVA showed a significant lobe by segment by hemisphere by group interaction for relative metabolic data (Table 4) but not for absolute metabolic rate. Post hoc t-tests show that anxious patients have significantly higher relative metabolic rates than normal controls in the left inferior area 17 in the occipital lobe, right posterior temporal lobe, and the fight precentral frontal gyms (Figure 4). Follow-up simple-interaction three-way ANOVAs (group by segment by hemisphere) were done for each lobe. The occipital lobe showed a three-way interaction for relative data (F = 3.27, df = 3,29, p = 0.04; Table 5). The temporal lobe showed a significant two-way interaction ( F = 5.94, df = 1.44,44.74, p = 0.04; Table 5) for absolute metabolic rates. Post hoc t-tests indicated that superior temporal lobe was significantly decreased in anxious patients compared with controls. Global Brain Metabolism. The GAD patients did not show a global whole b~in metabolic rate decrease (GAD. 19.7 _+ 4.6: controls, 22.8 -+ 6.1, NS).
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Figure 3. Cere~llar Metabolism. Individualized glucose ~cales are used which are automatically scaled to display the full scale and are better able to display relative:cerebellar metabofic differences. The subjects with GAD in the top row show greater relative cerebellar metabolism.
Passive Viewing Versus Vigilance Task Differences in Patients With GAD Clinical Response. The Hamilton Anxiety score for the active medication group prior to receiving the medication is 26.4 _ 3.0. After 3 weeks of clorazepate, their Hamilton Anxiety score was !6. ! _+ 3.8. The Hamilton Anxiety score for the placebo group at
Table 3. Regional Ce~bral Glucose Metabolic Rate at Baseline Limbic System, in Patients With GAD and Normal Controls: Absolute~ System/structure Limbic system Cingulate Hlppocampus Amygdala Basal ganglia
Caudate Putamen Globus pallidus °Data given as mean ± SD. ~ A D vers~s a~rmal controls (p < 0.05, t-test).
GAD 18.5 22.5 17.3 15.5 25.2 28.3 26.5 21.2
± ± ± ± ± ± ± ±
3.1 3.9 b 3.0 2.8 4.36 5.3 4.16 4.46
Normal controls 21.9 27.5 20.4 17.6 30.9 34.0 32.7 26.1
-± ± ± ± _ ± ±
4.6 5.9 4.5 4.4 6.4 7.8 6.5 5.7
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Figure 4. Temporal and Occipital Lobe Metabolism. Individualized glucose scales are used to show the increase in relative temporal and ~_,.cipit~_!me~bolism m subjects with GAD (top row).
day 0 was 24.3 _ 3.0. After 3 weeks of placebo, their Hamilton Anxiety score was 20.0 _ 5.6. The medicated group showed a significantly greater decrease in Hamilton Anxiety scores than did the placebo group (p = 0.0046, t-tes0.
P,rain System Analysis. When subjects were asked to perform the CPT task, there was a significant condition by structure interaction on the relative brain system analysis (Table 2). Post hoc t-tests indicate that the basal ganglia showed a significant increaze with the task (Figure 5). No significant condition interactions were found for the absolute aualysis.
Cortical Lobe Analysis. There was a significant condition by lobe by hemisphere interaction for both absolute ( F = 4.26, df = 3.12, p = 0.03) and relative metabolism ( F = 3.83, df = 1.82,25.49, p = 0.04). Right parietal lobe showed an increase with task whereas right temporal and right occipital lobe showed a decrease for both absolute and relative metabolic rates.
Anxiolytic Medication Versus Placebo Differences Brain System Analysis. GAD patients showed a significant decrease in brain absolute metabolic rates for different brain systems when treated with benzodiazepine. Exploratory post hoc t-testa were done to see the effects of benzc~liazepim:s on specific brain systems.
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Table 4. Regional Cerebral Glucose Metabolic Rate at Baseline in Conical Surface, in Patients With GAD and Normal Controls: Relativea'b GAD Cortical surface Frontal lobe Superior Mid Inferior Precentral Parietal lobe Posterior central Supramarginal Angular gyms Superior parietal Temporal lobe Superior Mid Inferior Posterior Occipital lobe d Area 19 Area 17 Inferior 17 Lateral 18
Left
Normal controls Right
Left
Right
1.07 1.07 I.! 1 1.12
± ± ± ±
0.07 0.09 0.09 0.08
1.04 1.12 !.!6 1.20
± ± ± ±
0.08 0.09 0.10 0.08 c
!.07 !,07 i.15 I.II
± ± ± ±
0.06 0.07 0.03 0.09
!.05 !.i0 1.16 !.13
± ± ± ±
0.05 0.06 0.04 0.06
1.06 1.00 !.01 0.94
± ± ± ±
0.11 0.10 0.10 0.16
1.11 !.08 !.06 0.97
± ± ± ±
0.08 0.1 ! 0.10 0.15
!.07 !.02 i.02 0.93
± ± +
0.08 0.07 0.11 0.18
1.09 !.09 1.07 0.97
± ± _ _
0.10 0.09 0.10 0.18
0.91 0.96 0.88 0.85
± ± ± ±
0.09 0.09 0.11 0.17
i.03 !.03 0.95 0.88
± ± ± ±
0.10 0.09 0.10 0.12 c
0.96 0.98 0.89 0.79
± ± ± ±
0.07 0.06 0.08 0.16
!.05 1.01 0.92 0.79
± ± ± ±
0.05 0.07 0.07 0.12
!.00 !.!2 !.21 0.98
± ± ± ±
0.09 0.11 0.IV 0.14
1.02 !.i7 1.20 0.99
± ± ± ±
0.08 0.15 0.13 0.18
1.02 !.!2 1.12 0.98
± ± ±
0.06 0.12 0.08 0.09
1.01 !.14 1.16 0.99
± ± ± ±
0.05 0.10 0.06 0.07
aData given as mean -" SD. bSignificant ANOVA interaction: lobe x segment x group, TSQ = 32. !, F = 2.64, df = 9.23 p = {3.03. cGAD versus normal control (vtest. p < 0.05). 'Z)ccipital lobe ANOVA: segment x hemisphere x group, TSQ = 10.5, F = 3.27, df = 3.27, p = 004.
The medication group showed significant decreases in absolute metabolic rate in cortical surface, limbic system, basal ganglia, and midbrain (Table = 6, Figure 5). Medial cortex showed a significant increase for relative metabolic rates for the medicated group compared with the placebo groups. ~'~ ~.
Cortical Lobe Analysis. GAD patients on active medication showed a - s ~ f i c a n t decrease in absolute metabolic rates across the four cortical lobes. Exploratory post hoc t-tests indicate that the right inferior area i7 of occipital cortex showed the greatest decrease after medication. Other cortical regions such as the frontal and temporal cortex also showed significant decreases. Significant correlations with change in Hamilton Anxiety scores were noted for change in the placebo group brain metabolic ratios for different brain systems (Table 6). Changes in Hamilton anxiety scores were positively correlated with change in limbic system for the placebo group. However, changes in Hamilton anxiety scores were negatively correlated with change in the basal ganglia for the placebo group. Interestingly, no significant correlations were noted for d~e medication group.
Discussion The study found higher relative metabolic rates for GAD patients in parts of the occipital, temporal, and frontal lobe metabolism and cerebellum relative to normal controls. The study also confirmed a decrease in absolute basal ganglia in GAD. The study did no*~
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Figure 5, A common glucose scale is used to show absolute metabolic differences for a typical subject with GAD during the passive viewing task, the active viewing task off medication, and after either active medication (top row) or placebo (bottom row). Active vigilance task results in an activation of basal ganglia (middle column) in the off-medication state compared to passive viewing (first column). P,~er active mexlication, subjects show a significant decrease in basal ganglia, cortical lobes (e.g. occiput), and limbic system (top right comer).
confirm the presence of significant right-left hippocampal asymmetries in GAD, as has been reported for panic disorders (Reiman et al 1986, 1989a), or global decreases in cortex metabolism, as indicated by blood flow studies (Mathew et al 1982). Relative occipital cortex overactivity in GAD patients is compatible with our previous finding that the occipital cortex showed among the highest decreases after be nzodiazepine treatment of anxiety (Buchsbaum et al 1987). Increased relative occipital activity could be due to hypervigilant behavior, a defining characteristic of anxiety (APA 1987). It is hypothesized that anxiety alters visual information processing as anxious subjects shift from foveal v;,~ion to peripheral vision to better scan the environment for threats (Shapiro and Lim 1989). Analysis of the temporal lobe revealed that the posterior temporal lobe was higher for relative metabolic rate and the superior temporal lobe was lower for absolute metabolic rate in GAD patients than normal controls. When the temporal poie is directly measured, however, anxious patients show significantly decreased absolute and relative metabolic rates compared with normal controls. This finding is inconsistent with the finding that
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Table 5. Regional Cerebral Glucose Metabolic Rate at Baseline in Cortical Surface, in Patients With GAD and Normal Controls" Almlu~ GAD
Normal controls
Superior Mid
20.7 ± 3.6 c 21.2 ± 3.5
21.1 ± 5.0 25.1 ± 5.2
Inferior Posterior
19.6 ± 3.7 18.5 ± 4.2
22.7 ± 4.6 19.6 ± 3.7
Temporal lobe
R~u~ Temporal lobe Superior Mid Inferior Posterior
GAD 0.97 0.99 0.92 0.87
± ± ± ±
0.09 0.08 0.10 0.13
Normal controls 1.00 0.99 0.90 0.79
_ ± ± ±
0.05 0.05 0.07 0.13
~Data given as mean - SD. ~ignificant ANOVA interaction: segment × group, F = 5.94, df = !.44,44.74, p = 0.01. ~GAD versus normal control (p < 0.0S, t-test). dSignificant ANOVA interaction: segment × group, WCPM$ = 0.03, F = 3.17, df = 3,93, p = 0.03.
blood flow increases in the temporal lobe in lactate-induced anxiety attacks (Reiman et al 1989a) and with anticipatory anxiety (Reiman et al 1989b), findings that suggest there is a heterogeneity in the regional activation of different portions of the temporal lobe, implying a highly complex organization for this structure. GAD patients in this study have a higher left inferior frontal gyms relative metabolism compared with normals. Increased left orbital frontal cortex metabolism has been reported in childhood-onset OCD (Swedo et al 1989). Ho.:ever, Swedo et al (1989) also reported bilateral prefrontal cortex metabolism increase in OCD, which is not seen in GAD. The increase seen in the left inferior frontal cortex metabolic ratio is consistent with the increases seen in bilateral front~ lobe metabolism ix normals with moderate anxiety (Reivich et al 1983). Our finding of increased left-to-fight frontal lobe metabolism is incompatible with the reports that anxious subjects had a higher fight than left cerebral metabolism compared with normal controls (Reivich et al 1983). The high relative cerebellar activity of GAD patients detected in the PET scans supports the h)~ohhesis of cerebella.- involvement in anxiety. Neurological testing and observation of over 400 patients suffering from various levels of anxiety revealed that 94% had evidence of cerebellar-vestibular dysfunction, suggesting an underlying mechanism of anxiety (Levinson 1989). Associations have also been noted between cerebellar-vestibular-related sensorimotor dysfunctions and symptoms of anxiety. The decreased absolute basal ganglia metabolic activity found in GAD patients in our study is not consistent with studies in the rat. Ableitner and Herz (1987) reported increased globus pallidus glucose metabolism after 13-carboline injection in rats, and Nehlig et al (1987) found an increase in rats' glucose metabolism in the caudate after caffeine injection. The injection of 13-carbolines into rats significantly increases the local cerebral glucose utilization in the cerebellum, thalamus, and limbic system (Ableitner and Herz 1987). Our findings in patients with GAD suggest a possible difference in neurobiology from those findings seen with panic disorder. Reiman (1987) found that panic disorder (PD) patients have abnormal hemisphere asymmetries in parahippocampal blood flow, blood
24.7 .4- 5.5
29.2 ± 5,5
20.8 -- 5.3
25.9 ± 6.7
27.5 - 6.2
18.8 ± 3.5
18.0 ± 5.5
21.6 ± 7.1
Cortical surface 21.6 ± 3.2 b
Medial cortex 26,8 ± 4.7
Limbic 18.0 ± 3.1 b
Thalamus 24.0 *- 4.3
Basal ganglia 25.6 ± 3.56
White matter 14.8 ± 2.5
3.0
Midbrain 15.2 -
Cerebellum 18.7 ± 3,6 19.7 ± 2.1
17.3 ± 1.9"
16.4 ± 2.7
28.0 ± 3.8 d
26.4 ± 5.6 c
20.0 ± 3.(F
28.9 ± 4.7 a
23.9 ± 4.(F
Baseline
17.1 ± 2.2
14.0 ± !.3
14.9 ± !.5
23.2 ± 3.1
21.7 ± 3.7
24.8 -- 1.3
24.8 ± 2.1
19.7 ± 1,8
Medication
G A D (Medicated group)
1.14 ± 0.21
0.83 -+ 0.14
0.72 ± O . I V
1.26 ± 0.09 t
1.12 ± 0.13
0.97 ~ 0.07 e
1.27 ± 0.06 °'c
1.05 ± 0.06
Ba~ILn,e
1.15 ± 0.17
0.85 ± 0.10
0.76 _+ 0.09
1.18 ± 0.08
1.08 ± 0.09
1.00 __ 0.06
1.20 .4- 0.04
1.05 ± 0.02
Placebo
G A D (Fiacebo group)
dd prime (baseline - treatment) correlation (p < 0.05). 'Positive correlation: Hamilton anxiety score (baseline - treatment) with baseline - treatment metabolism (p < 0.05). rNegative correlation; Hamilton anxiety score (baseline - treatment) with baseline - treatment metabolism (p < 0.05).
°Data given as mean ± SD. ~Medication group versus placebo group; baseline - treatment (p ' ( 0 . 0 5 ) . CMedication/placebo group: baseline - treatment versus 0 (p < 0.05).
Placebo
Baseline
G A D (Placebo group)
T a b l e 6. R e g i o n a l C e r e b r a l G l u c o s e M e t a b o l i c R a t e : A b s o l u t e a n d R e l a t i v e °
1.19 ± 0.15
0.88 ± 0.07
0.72 ± 0.03
1.24 ± 0.06
! . ! 2 ± 0,11
0.99 __ 0.07
1.22 ± 0.03 d
1.04 ± 0.03
Baseline
1.24 ± 0.21
0.85 ± 0.07
0.75 ± 0.07
1.23 +- 0.05
1.14 ± 0.09
1.00 ± 0.04
1.26 -~ 0.08
1.05 ± 0.03
Medication
G A D (Medic~1ed group)
~D
t~
mmm.
:>
S O
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volume, and oxygen metabolism, as assessed by PET. Change in left-right asymmetry in subjects with GAD were in the same direction as change reported for subjects with panic disorders. However, statistically significant limbic abnormalities were not found in our group of GAD patients. It is possible that patients with GAD may be a less homogenous group than subjects with panic disorder. Other psychobiological research suggests a difference in the pathophysiology of GAD and PD. Chamey et al (1989) compared noradrenergic neuronal functioning in PD and GAD patients and normal controls. Fifty percent of PD patients exhibited a noradrenergic neuronal hyperactivity, reactions not displayed by GAD or normal controls. The atlas methods used here are subject to the limitations of stereotaxic placement, accuracy in head positioning and repositioning, and scanner resolution. The limitations of stereotaxic placement are less marked for large structures such as the temporal lobe than for small structures such as the caudate nucleus. Differences between the Matsui and Hirano atlas used in this study and the Talairach atlas used in the Reiman studies are not. large. Although the Matsui and Hk"ano atlas used the CM line, a standard in ~imical use, and the Talairach atlas is based on the AC-PC, both portray the brain of a single individual and ~-~ not statistical standards. In a study of the angles between the CM, gabeUo-inion (GI), and AC-PC lines, mean differences under 2 degrees were found (Tokunaga et al 1977). The standard deviation of the angle between the CM and GI lines (2.8 degrees in males) is not significantly different from the standard deviation of the angle between the AC-PC line and the cranial frontooccipital line (2.1 degrees, F = 1.8, NS). The mean angle between the GI line used in the Reimaa study and the CM line used in our study was 1.5 degrees, with a standard deviation of 2.8 degrees. A difference of 1 SD would produce a difference in the elevation of the caudate nucleus of about 1.6 ram.
The effects reported here are for structure adequately imaged with a 7.6-ram in-plane and 9.9-ram axial resolution. The major gyri of the cortical surface are all several centimeters in size. Although the cortical ribbon surface is 3-5 mm thick, it is typically folded into a thicker strip similar in width to our cortical peel. The putamen, caudate, and cingulated gyrus all accommodate the 6 x 6 mm box easily in the horizontal plane and all are at least 20 mm or two 10-ram-thick planes high. Heterogeneity within the axial or horizontal plane would reduce the adequacy of the method. However, random variations caused by individual differences in brain proportions, vertical position of the planes acquired, and variation in head position and reposition would all tend to create random error and diminish group differences and/or medication effects. Although no ideal solution to these problems exist, the use of well crafted head holder and an MRI template provide advantages. During the task state, subjects showed an increase in relative basal ganglia metabolism and absolute and relative right parietal lobe metabolism. This finding is consistent with our studies in normal controls during a task-no task comparison (Buchsbaum et al 1990). Ri£~lt parietal lobe has been implicated in studies of attention (Heilman et al 1985). The increase in basal ganglia metabolism is consistent with increased motor activity during the task state. Although benzodiazepine treatment resulted in clinical improvement in anxiety, there was a lack of normalization of regional brain metabolism. For example, patients with generalized anxiety had decreased regional metabolism in basal ganglia compared with normals under the passive viewing condition. After treatment, this brain system showed
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an even greater decrease with benzodiazepine treatment. Other brain systems such as cortical surface and limbic system also show significant decreases with benzodiazepine treatment.
Spontaneous changes in Hamilton anxiety scores -,vere noted to be significantly correlated positively with metabolic ratios in the limbic system and negatively in the basal ganglia system for the placebo group. No significant correlations were found between Hamilton Anxiety score and regional brain metabolic ratios. This suggests that medications may decouple mood changes from the close association with regional brain metabolic ratios that is otherwise seen with spontaneous, natural mood changes. The absolute and relative brain system measures give apparently opposite findings for change resulting from placebo or medication. The medication group shows a decrease in absolute metabolism for the brain systems, whereas the relative metabolic ratios show an increase with medication for the subcortical systems. The opposite is trae for the placebo group. The absolute values show an increase whereas the relative values for the subcortical systems show a decrease. This apparent discrepancy is due to the fact that the cortex shows much greater changes than the subcortical system. Therefore the subcortical system lags in changes in either direction, resulting in apparently discrepant absolute and relative results.
In conclusion, our PET study of regional cerebral metabolism has shown that subjects with generafized anxiety disorder have elevated occipital lobe, temporal lobe, and frontal lobe metabolism relative to normal controls during a no-task state. Anxious subjects also showed decreased absolute basal ganglia metabolism and increased cerebellar-whole brain metabolic ratios compared with normals during the passive viewing state. Dur:mg the vigilance task, subjects showed a significant increase in relative basal ganglia metabolism and increase in right parietal lobe. Antianxiety medication resulted in a significant decrease in glucose metabolism in cortical lobes, limbic system, and basal ganglia compared with the placebo group.
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