Brain perfusion abnormalities in drug-naive, lactate-sensitive panic patients: A SPECT study

BIOL PSYCHIATRY 1993;33:505-512

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Brain Perfusion Abnormalities in Drug-Naive, Lactate-Sensitive Panic Patients: A SPECT Study Mafia Teresa R. De Cristofaro, Antonella Sessarego, Alberto Pupi, Francesco Biondi, and Carlo Faravelli

Using single photon emission computed tomography (SPECT) and 99mTc-hexamethylpropyleneamine oxime (HM-PAO ), we assessed brain perfusion in seven patients with panic disorder (PD) and in five age-matched normal subjects at rest. No patient had ever received drug treatment for panic. All patients were sensitive to lactate-induced panic. Computed tomography (CT) scans did not reveal any morphological abnormalities of the brain in any of the PD patients. Two indices of cerebral perfusion were calculated; these demonstrated alterations of brain perfuswn in the PD group. Significant right-left asymmetry was found in the inferior frontal cortex of the PD patients. We also observed a significant blood flow increase in the left occipital cortex and a significant decrease in the hippocampal regions bilaterally. Although the changes seen in the inferior frontal cortex and occipital cortex may be related to anxiety experienced by the patients during the study, the pattern of hippocampal hypoperfusion appears to be characteristic of panic disorder. This suggests that the hippocampal structures may play an important role in the pathophysiology of panic disorder.

Key Words: Panic disorder, drug-naive patients, regional cerebral blood flow, SPECT, 99mTc-HMPAO

Introduction Brain abnormalities have been reported in panic disorder. These include changes in electroencephalographic mapping (Beauclair and Fontaine 1986; Edlund et al 1987; Lepola et al 1990), increased incidence of atrophy and focal abnormalities in the mesiotemporal regions on magnetic resonance imaging (MPd) (Fontaine et al 1990), and regional changes in brain perfusion and metabolism

From the Diparlimento di Fisiopatologia Clinica, Sezione di Medicina Nucleate, Universit~ di Fitenze (MTRDC, AP), and Dipartimento di Scienze Neurologiche e Psichiatriche, Istituto di Psichiatria, Universit~ di Fhenze (AS, FB, CF}; Firenze, Italy. Address reprint requests to MTR De Cristofaro, MD, Dipattimento di Fisiopatologia Clinica, Sezione di Medicina Nucleate, Viale Morgagni 85, 50134 Firenze, Italy. Accepted January 8, 1993. Received November 29, 1991. © 1993 Society of Biological Psychiatry

on emission computed tomography. The latter have been documented in PD patients both during panic attacks and during nonpanic conditions (Reiman et al 1984, 1986; Stewart et al 1988; Woods et al 1988; Reh-na,a et al 1989a; Nordahl et al 1990). The finding of an abnormal blood flow and metabolic asymmetry in the parahippocampal gyms in lactate-sensitive PD patients (Reiman et al 1986) is of particular interest, as these alterations were found during resting conditions in a brain region believed to be implicated in anxiety. These data suggest that a disturbed neuronal function may predispose to panic attacks. In the present work we employed single photon emission computed tomography (SPECT) and the blood flow tracer 99mTc-hexamethylpropyleneamine oxime (HM-PAO) to evaluate brain perfusion in a group of PD patients ex0006-3223693/$06.00

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amined while at rest. This group included only patients who were susceptible to lactate-induced panic.

Methods

Subjects Nine consecutive outpatients affected by panic disorder were studied using SPECT and HM-PAO. The following inclusion criteria were applied: (1) DSM-III-R diagnosis of panic disorder, (2) absence of other psychiatric disorders, (3) no specific drug treatment for panic disorder. Following the SPECT study, all patients underwent sodium lactate infusion during which seven of nine PD patients had a panic attack. The present report refers to these s e v e n cases.

The patient group included five women and two men, all right-handed. Their mean age was 24.5 -+ 2.5 years (range = 21-27 years). Patients were administered the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott 1978) and met DSMIII-R criteria for panic disorder (APA 1987) on psychiatric interview (C.F.). Two patients had panic disorder without agoraphobia and five suffered from panic disorder with phobic avoidance. In all patients the onset of the illness began at the most 2 years prior to the study intake and the mean duration of illness was 10.5 -+ 7.6 months. Patients had no other neurologic or psychiatric disorder. None had ever been treated with tricyclic antidepressants or monoamine oxidase inhibitors, but some of them had taken benzodiazepines sporadically. However, they were kept drug-free for a period of at least 2 weeks prior to SPECT imaging. On the same day as the SPECT study, a CT scan of the brain was performed in all patients. Within 7 days of the SPECT (range = 3-7 days) the PD patients underwent sodium lactate infusion according to the procedure described by Liebowitz et al 0984). They were informed that this procedure might provoke an anxiety attack and that they could stop the infusion at any time. The criteria for lactate-induced panic were based on: (1) the subjective patient report of a severe or unequivocal anxiety attack similar to spontaneous ones, (2) a score of 20 or more on the Acute Panic Inventory (API) (Dillon et al 1987) and (3) investigator observations of the subject during the infusion. Five right-handed normal subjects (three women and two men) with a mean age of 27.8 _+ 6.9 years (range = 21-39) were recruited from the university staff and served as controls. No subject had a personal or family history of psychiatric disorders and all were in good health. None were taking medication at the time of the study. All of the patients and controls gave written informed consent for their participation in the study.

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SPECT Imaging EXPERIMENTALPROCEDURE. After their arrival at the Nuclear Medicine Unit, both patients and controls were taken on a tour of the facilities so as to minimize any anxiety associated with being in an unfamiliar environment. Then, each subject was placed in the supine position on the tomographic bed, in a room with minimum noise and low ambient light. An intravenous line was prepared 10 rain before the tracer injection. The tracer was prepared as described elsewhere (Bacciottini et al 1990) and 30 mCi of ~mTc-HM-PAO were injected as a fast bolus; subjects had their eyes and ears open during the injection. Immediately before SPECT scanning, the API was adminis~'ered in order to define the presence of panic during the tracer injection. SPECT scanning was started 20 rain after the HM-PAO injection and was performed using a dual-head rotating camera (Rotacamera, Siemens Gammasonics, Des Plaines, IL) equipped with ultra-high resolution collimators. Foc each camera head, the acquisition procedure consisted ,Jf 90 projections over a 360 ° rotation, with 64 × 64 r.iatrices and a linear sampling of 4.5 mm. Total ima.~ing time lasted about 30 rain. Lach subject's head was held in a plastic head-holder during scanning to prevent movements. The projection data were reconstructed using an iterative algorithm, which compensates for the cameracollimator geometrical response and affords an 8 mm FWHM (Formiconi et al 1989). DATA ANALYSIS. T h e brain tomographic volumes were orientated on the frontal-occipital line as previously described (De Cristofaro et al 1990). Four transaxial slices were selected in coixe~Volld~Jce with the planes passing through the centrum semiovale (supraventricular level), the middle of the lateral ventricles (midventricular level), the basal ganglia and thM~mus (midthalamic level), and the brain stem and cerebellum (cerebellar level). For each hemisphere, regions of interest (ROls) were manually drawn in the superior frontal cortex, the cinguiate gyms, the anterior cingulate gyms, the inferior frontal cortex, the occipital cortex, the temporal pole, and the cerebellum by using a stereotactic atlas (Talairach and Szikla 1967) to define the anatomic boundaries of the regions. In addition, using this atlas, a sagittal slice passing through the hippocampal structures was chosen for each hemisphere and ROls were drawn, which included the hippocampal formation. Because of the limited resolution of the SPECT system, it was not possible to distinguish: (1) the several components of the hippocampal formation (hippocampus proper, dentate gyms, subiculum) and (2) the latter from the surrounding structures (amygdala and parahippocampal gyms). Therefore, the ROI drawn in this region included the hippocampal formation, the amygdala, and part of the parahippocampal gyms. Mean counts per cubic centimeter were calculated for

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each RO| and these activity measures were used to construct two ratios: (1) an asymmetry index (AI), calculated for each region as the right-left difference divided by the mean of right and left: (R - L)/I(R + L)/2] x 100 (a positive value for this ratio reflects relative right hyperpeffusion); (2) a peffusion index (PI), calculated as the ratio of the activity density for the region of interest divided by the activity density for the whole brain. The latter was calculated by averaging the activity density across six adjacent transaxial slices. STATISTICAL ANALYSIS. All results are presented as means -v SEM. Differences in API scores and perfusion ratios (AI and PI) ~et,.,-ecn PD patients and controls were evaluated using the Mann-Whitney U test, with probability limits of p < 0.05 (one-tailed for API, two-tailed for Al and PI). The variability of the AI values was compared between groups using the F test of equality of variances.

Results During the tracer injection and the following 20 rain, none of the PD patients experienced a panic attack. Nevertheless, the PD patients had higher scores on the API than the controls (mean score 11.5 ± 4.0 for PD, 2.2 --- 1.0 for controls); these approached, but did not reach, statistical significance. The CT study silc,wed no tissue alteration in any of the PD patients. The sulcal and ventricular spaces were within normal limits. Typical SPECT images for one PD patient and one control subject are shown in Figures 1 and 2. The visual inspection of these images demonstrates a homogeneous pattern of HM-PAO distribution in cortical and subcortical regions in the PD patient, similar to that observed in the control subject; only the hippocampal regions in the PD patients showed a reduced tracer uptake (Figure 2). ~' va, uc~ c~A~ ,~,. ~.~ ,,~'°lne asymme try index---' .... (mean -.~- ,,~,,,y, ported in Table 1. A significant difference in the A! means was found in the inferior frontal cortex, with the PD patients having higher AI values than the control subjects (p < 0.05). This finding indicates a relative increase in perfusion on the right side. When the variability of the AI values was compared between groups, a greater variability was observed in the cerebellum for the PD patients (F = 6.70, p < 0.05). Figures 3 and 4 show a graphical representation of perfusion indices, PI, for the two groups. The PD patients showed significantly lower PI values (p < 0.05) in the left and right hippocampal regions (0.90 __- 0.02 and 0.91 ___0.02, respectively) than the controls (0.99 --- 0.02 and 1.01 ± 0.4). Moreover, in the PD group a significant increase in PI values was observed in the left occipital cortex (1.35 - 0.01 for PD, !.24 ± 0.02 for controls;

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p < 0.05). For the remaining regions the two groups did not differ in PI, though the PD group showed a trend toward increased perfusion indices in the right inferior frontal cortex, the right occipital cortex, and the left temporal pole (p = 0.10).

Discussion Using SPECT and HM-PAO at rest, we found significant differences in brain perfusion between PD patients who were sensitive to lactate infusion, and age-matched normal subjects. Analysis of the asymmetry indices revealed abnormally high values for the inferior frontal cortex of the PD patients, whereas the perfusion indices were significantly higher in the left occipital cortex and significantly lower in the bilateral hippocampal region for the PD as opposed to the control group. In addition, there was a trend toward hyperperfusion in the right occipital cortex, the right inferior frontal cortex, and the left temporal pole. These results may be biologically important, as the changes in brain perfusion were detected in the early stages of panic disorder, when drug treatment had not yet been started. However, because of the small sample size and the large number of region comparisons, type I and type II errors may exist in our data and further studies on wider samples are needed to confirm our findings. The significant side-to-side perfusion asymmetry found in the inferior frontal cortex of the PD patients appears to be secondary to an increased regional cerebral blood flow (rCBF) on the right side. Indeed, the PD group showed higher perfusion indices in the right inferior frontal cortex; however, these were nonsignificantly different when compared with the control group. This finding is consistent with the positron emission tomography (PET) data of Nordahl et al (1990), which showed an increased glucose metabolism in the medial orbital frontal cortex (trend) and the right prefrontal cortex in a group of PD patients. Increased glucose metabolic rates have also been re~rted in the right frontal regions in normal subjects with anxiety (Reivich et al 1983).This suggests that right frontal area involvement in PD patients may be related to anxiety. Indeed, in our series the API scores were higher, though nonsignificantly, for the PD group. This indicates that the PD patients experienced anxiety at the time of the SPECT examination. Regional changes involving the frontal cortex were also observed in other anxiety disorders. Using PET, high relative glucose metabolic rates were demonstrated in the left inferior frontal gyrus of patients with generalized anxiety disorder (GAD) (Wu et al 1991). Several imaging studies of obsessive-compulsive disorder (OCD) reported increased brain perfusion and metabolism in the orbital prefrontal areas (Baxter et al 1987; Swedo et al 1989; Nordahl et al 1989; Machlin et al 1991). In OCD,

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SUPRAVENTRICULAR

MIDTHALAMIC

CEREBELLAR

NC

PD

Figure I. SPECT axial images from a normal control (NC) and a PD patient (PD) at the supraventricular, midthalamic, and cerebellar levels. In these images, subject's left is at fight.

these frontal abnormalities were associated with increases in brain perfusion and metabolism in the caudate nuclei and the anterior cingulate gyri, thus supporting the hypothesis that the manifestations of OCD are mediated off ,.,~o,,.,,,,.,,,.,,, of a ~....,ol 1 ~ . i;m~,l~ ~,~o~1 no..i;o i ~ _ (Swedo et al 1989; Baxter et al 1990). It is interesting to note that neither the PET studies of Reiman et al (1984, 1989a), Nordahl et al (1990), nor our study have revealed that the anterior cingulate gyri or the caudate nuclei are thus involved in PD patients. However, Nordahl et al (1990) found a trend toward a decrease in glucose metabolism in the anterior cingulate gyri of PD patients, which they associated with art altered attentional state during the behavioral task. In our series of PD patients we also found a trend to increased cerebral blood flow in occipital regions, both in the left and right hemisphere. Similarly, increased cerebral blood flow in the occipital lobe has been reported in PD patients during lactate-induced panic attacks (Stewart et al 1988). The pattern of occipital hyperperfusion in PD is

consistent with that observed in GAD. Wu et al (1991) reported increased glucose metabolism in the left occipital cortex of GAD patients, thus suggesting an association with hypervigilance, a characteristic symptom of anxie,~'. Our findings of bilateral hippocampal hypoperfusion in PD appear to be in contrast with data reported by other investigators who studied this anxiety disorder using PET. Reiman et al (1984) observed no change in hippocampal blood flow, but they found (1984, 1986) ar~ abnormal asymmetry of the parahippocampal blood flow and oxygen metabolism in lactate-sensitive PD patients, probably reflecting an absolute increase on the right side. in their series of PD patients studied during the performance of an auditory discrimination task, Nordahl et al (1990) analyzed a brain region that included both the hippocampal and the parahippocampal structures. Here they found a significant asymmetry in glucose metabolism in PD patients when compared with normal subjects. Consistent with the findings by Reiman et al, this asymmetry appears to b* related

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LEFT

RIGHT m

!!iii!i!i!iiii!!i NC

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Figure 2. SPECT sagittal slices from a normal control (NC) and a PD patient (PD) passing through the hippocampal structures. In the PD patient a reduced perfusion can be seen in the hippoeampal regions (white arrows).

Table 1. Asymmetry Indices in PD Patients and Normal Controls Asymmetry index (%)"

Brain region Superior frontal cortex Cingulate ,yrus Anterior cingulate gyms Inferior frontal cotex Temporal pole Hippocampal region O~cipitai cortex Cerebellum

kloI'rosI controls

PD patients 1.27 -2.95 -0.44 5.15 -0.43 -0.47 -2.17 -4.49

_-_ 1.37 ± 1.85 _.* 0.52 ± 3.09 b ± 3.79 ± 3.31 ± 1.32 ± 1.74

- 1.55 -1.02 4.81 -2.15 7.53 0.64 0.36 -3.37

aData given as mean --. SEM. bSignificant difference in AI means between groups (p < 0.05).

_ __ ± ± ± ± ± ±

1.60 1.74 5.36 !.72 2.57 3.69 i.18 0.79

to increased glucose metabolic rates on the right side. Methodological factors, in particular the methods of region analysis, may account for discrepancies between our findings and those of these previous PET studies. Our method for localizing the hippocampal structures differs from that of previous studies in that we used sagittal rather than axial slices. The use of tomographic instrumentation, which detects the whole brain volume without separating adjacent slices (e.g., rotating gamma camera), allows a more accurate drawing of ROIs on tomographic planes other than the axial one. On the sagittai view, the hippocampal formation may be represented along its long axis. Thus, in our study the ROI drawn on the sagittal slice included the entire hippocampal formation and, because of the limited spatial resolution, the amygdala and part of ~ e pzrahippocampal gyms. Therefore, the discrepancies between the studies may, in pmi, be attributed to the different brain

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Ant. Inferior Temporal Hippoca. Occipital Cerel~el. Cingulate AS Codex Pole Region Gyros Cingulate Frontal Frontal Gyros Codex Codex

1.85 1.65

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C3 z

Figure 3. Left peffusion indices in normal controls (NC) and PD patients (PD). Open symbols indicate the individual values; solid symbols, group means; error bars, SEM,

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Inferior Temporal Hippoca. Occipital Cerebel. Cingulate Ant. A~ Pole Region Cortex Gyros Cingulate Frontal Frontal Codex Gyros Codex

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Figure 4. Right perfusion indices in normal controls (NC) and PD patients (PD). Open symbols indicate the individual values; solid symbols, group means; error bars, SEM.

PP~ N¢ I PD NC

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regions examined (hippocampal-parahippocampal region versus hippocampal region) and the different hippocampal volumes sampled (samples of hippocampus versus entire hippocampal formation). Moreover. as the hippocampal formation does not have a linear shape but is rather curvilinear and bulges into the temporal horn of the lateral ventricle, our hippocampal ROIs also included some partial volume areas. This caused underestimation of the hippocampal blood flow. However, the differences in the hippocampal perfusion indices observed between the PD and control groups cannot be attributed uniquely to an uncorrected tissue sampling, as the CT scans performed

PD NC I PD NC I

PD I

in PD patients did not show ventricular or sulcal enlargement. The differences between the studies may also result from the duration of illness and medication status of patients as well as activation states during the study. In the series of PD patients studied by Reiman et al 0984), subjects were not evaluated on the basis of the duration of illness and some of them were taking medication at the time of scanning. In the study by Nordahl et al (1990), the mean duration of illness was 10.9 years, and 10 of 12 PD patients had not received medication for an average of about 20 days. In our series the mean duration is less

SPECT

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than I year and PD patients never received specific drug treatment for panic. Thus, hippocampal hypoperfusion might be an abnormality that is present during the early stages of the illness and fades after drug treatment. Although effects on cerebral blood flow and glucose metabolism have been reported for some psychotropic agents (De Lisi et al 1985; Mathew et al 1985; Buchsbaum et al 1987), issues regarding the length of drug withdrawal have still not been solved. Moreover, differences in functional cerebral parameters may exist between drug-naive and drugfree patients. In addition, unlike the previous PET studies, the subjects in our study were studied without sensory deprivation (eyes and ears open) or behavioral tasks. Finally, chronic hyperventilation and low carbon dioxide (PCO2) levels have been described in panic disorder at rest (Liebowitz et al 1985; Gorman et al 1986). As we did not monitor the arterial PCOz levels in our series during tracer injection, it is possible that the hippocampal hypoperfusion observed in the PD patients is secondary to decreased PCO2. Because regional changes in cerebral blood flow due to variations in PCO2 have not yet been determined in humans, the procedures commonly used for correcting the rCBF measurements affected by changes in PCO2 are based on the relationship between cerebral blood flow and PCO2 experimentally determined for the whole brain and described by the following equation (Grubb et al 1974): CBF = 1.8 PCO2- 16.75 However, relative measurements of brain perfusion, performed by calculating ROI ratios, are less affected by variations in PCO2 than absolute measurements and, on the basis of the parameters of the above equation, the weight of correction is minimal when the values of ROI ratios are near 1. In this study, hippocampal hypoperfusion in PD was found in the absence of morphological abnormalities on CT scans, indicating that this rCBF abnormality may be related to an altered neuronal function. Recently, an MRI study of PD patients (Fontaine et al 1990) showed the presence of tissue abnormalities and atrophy in the medial region of the temporal poles, particularly in the right hemisphere. The incidence of these MRI abnormalities (40%) is higher than that reported in CT studies of PD (Uhde and Kellner 1987; Lepola et al 1990) and this may be related to the greater sensitivity of MRI in detecting and

Rel~rences American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC, American Psychiatric Press, pp 235-239. Bacciottini L, Lunghi F, Pupi A, et al (1990): Evaluation of

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determining the extent of parenchymal changes and cortical atrophy. Therefore, the different sensitivity of CT compared to MRI may explain the lack of morphological abnormalities observed in our group of PD patients. On the other hand, ~ e hippocarnpal hypoperfusion found in this study may represent a functional change (reduced blood supply) that precedes the appearance of a structural brain damage. It has been demonstrated that the locus coeruleus, a brain region believed to play an important role in the pathogenesis of panic disorder, innervates the brain microvessels (Kalaria et al 1989) and its stimulation provokes a vasoconstrictive effect (Ohta et al 1991). Moreover, the chemical stimulation of locus coeruleus neurons in experimental animals (rats) decreases regional cerebral blood flow in several brain regions (Sinha and Weiss 19911. PET studies examining the hippocampal regions in other anxiety disorders have not demonstrated abnormalities in these brain regions (Swedo et al 1989; Mountz et al 1989; Nordahl et al 1989; Wu et al 1991). Moreover, the hipIx)campus does not appear to be involved in the production of normal anticipatory anxiety (Reiman et al 1989b). These data suggest that hippocampal hypoperfusion may be a characteristic pattern of PD. However, because emotion and anxiety represent only some of the functions of these brain regions, we would expect that this pattern alone would not differentiate PD patients from patients with other diseases that involve the hippocampal regions. To our knowledge this is the first report on brain perfusion imaging with HM-PAO and high-resolution SPECT in a selected group of PD patients. Even though our results demonstrate the ability of SPECT to detect brain perfusion changes in PD, further studies are needed. More specifically, the use of quantitative methods to estimate brain perfusion (Pupi et al 1991) may be useful in evaluating the level of hippocampal hypoperfusion and its role in the pathophysiology of panic disorder. The authorswish to thank Dr. GiorgioAibanesi,L~r.t~enedettaGuerrirti Degli lmaocenti,and Dr. RosangelaFrassine for their help in managing the patients;Dr. Rossana Fargnolifor the evaluationof CT images;Mr. Giannetto Corals for the developmentof the PC image representation software; and Dr. ElizabethGuerin for her assistance in preparingthe manuscript. We are also gratefulto the techniciansof the NuclearMedicine Unit for their collaboration. This work was supportedby MURSTfundingfor two of the authors (A.P. and C.F.).

technetium 99m cyclobutylpropylene amine oxime as a potential brain perfusion imaging agent for SPET. Eur J Ndcl Med 17:242-247. Baxter LR, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM.

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Selin CE (P,87): Local cerebral glucose metabolic rates in obsessive-compulsive disorder: A comparison with rates in unipolar depression and in normal controls. Arch Gen Psychiatry 44:21 !-218. Baxter LR, Schwartz JM, Guze BH, Bergman K, Szuba M (1990): PET imaging in obsessive compulsive disorder with and without depression. J Clin Psychiatry 51(suppl):61-69. Beauclair L, Fontaine R (1986): Epileptiform Abnormalities in Panic Disorder. Society of Biological Psychiatry, 41st Annual Convention & Scientific Program No 96, p 148. 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 40:2393-2400. De Cristofaro MTR, Mascalchi M, Pupi A, et al (1990): Subcortical arteriosclerotic encephalopathy: Single photon emission computed tomography--magnetic resonance imaging correlation. Am J Physiol Imaging 5:68-74. De Lisi LE, Holcomb HH, Cohen RM, et al (1985): Positron emission tomography in schizophrenic patients with and without neuroleptie medication. J Cereb Blood Flow Metab 5:201206. Dillon DJ, Gorman JM, Liebowitz MR, Fyer AJ, Klein DF (1987): Measurement of lactate-induced panic and anxiety. Psychiatry Res 20:97-105. Edlund MJ, Swarm AC, Clothier J (1987): Patients with panic attacks and abnormal EEG results. Am d Psychiatry 144:508509. Fontaine R, Breton G, Dery R, Fontaine S, Elie R (1990): Temporal lobe abnormalities in panic disorder: An MRI study. Biol Psychiatry 27:304-310. Formiconi AR, Pupi A, Passed A (1989): Compensation of spatial system response in SPECT with conjugate gradient reconstruction technique. Phys Med Biol 34:69-84. Gorman JM, Liebowitz MR, Fyer AJ, Fyer MR, Klein DF (1986): Possible respiratory abnormalities in panic disorder. Psychopharmacol Bull 22:797-801. Gmbb RL, Raichle ME, Eichling JO, Ter-Pogossian M (1974): The effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular mean transit time Stroke 5:630-639. Kalaria RN, Stockmeier CA, Harik SI ( 1989): Brain microvessels are innervated by locus coeruleus noradrenergic neurones Neurosci Len 97:203-208. Lepola U, Nousiainen U, Puranene M, Riekkinen P, Rimon R (1990): EEG and CT findings in patients with panic disorder. Biol Psychiatry 28:721-727. Liebowitz MR, Fyer AJ, Gorman, JM, et al (1984): Lactate provocation of panic attacks. I. Clinical and behavioural findings. Arch Gen Psychiatry 41:764-770. Liebowitz MR, Gorman JM, Fyer AJ, et al (1985): Lactate provocation of panic attacks. II. Biochemical and physiological findings. Arch Gen Psychiatry 42:709-719. Machlin SR, Harris GJ, Pearlson GD, Hoehn-Saric R, Jeffery P, Camargo EE (1991): Elevated medial-frontal cerebral blood flow in obsessive-compulsive patients: ASPECT study. Am J Psychiatry 148:1240-1242. Mathew RJ, Wilson WH, Daniel DG (1985): The effect of non-

sedating doses of diazepam on regional cerebral blood flow. Biol Psychiatry 20:1109-1116. Mountz JM, Modell JG, Wilson MW, et al (1989): Positron emission tomographic evaluation of cerebral blood flow during state anxiety in simple phobia. Arch Gen Psychiatry 46:501504. NordLhl TE, Benkelfat C, Semple WE, Gross M, King AC, Cohen RM (1989): Cerebral glucose metabolic rates in obsessive compulsive disorder. Neuropsychopharmacology 2:2328. Nordahl TE, Semple WE, Gross M. et al (1990): Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacology 3:261-272. Ohta K, Gotoh F. Shimazu K, et al (1991): Locus coeruleus alters intraparenchymal vasoconstrictive activities following subarachnoid hemorrhage: Dissociation from superior cervical ganglion. J Cereb Blood Flow Metab 11 (suppl 2):$244. Pupi A, De Cristofaro MTR, Bacciottini L, et al (19~;): An analysis of the medal input curve for technetium-99m-HMPAO: Quantification of rCBF using single-photon emission computed tomography. J N u d Med 32:1501-1506. Reiman EM, Raichle ME, Butler FK, Herscovitch P, Robins E (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, Raichle ME, Robins E, et al (1989a): Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry 46:493-500. Reiman E, Fusselman MI, Fox PT, Raichle ME (1989b): Neuroanatomical correlates of anticipatory anxiety. Science 243~!071-1074. Reivich M, Gur R, Alavi A (1983): Positron emission tomographic studies of sensory stimuli, cognitive processes and anxiety. Hum Neurobiol 2:25-33. Sinha AK, Weiss HR (1991): Chemical stimulation of locus coeruleus neurones reduces regional cerebral blood flow in rat. J Cereb Blood Flow Metab 11 (suppl 2):$690. Spitzer RL, Endicott J (1978): Schedule for Affective Disorders and Schizophrenia--Lifetime Version (SADS-L). New York: New York State Psychiatric Institute, Biometrics Research Department. Stewart RS, Devous MD, Rush AJ, Lane L, Bonte FJ (1988): Cerebral blood flow changes during sodium-lactate-induced panic attacks. Am J Psychiatry 145:442-449. Swedo SE, Shapiro MB, Grady CL, et al (1989): Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry 46:518-523. Talairach JT, Szikla G (1967): Atlas d'Anatomie Stdrdotaxi~iue du Tdlencdphale. Paris: Masson. Uhde TW, Kellner CH (1987): Cerebral ventricular size in panic disorder. J Affective Disord 12:175-178. Woods SW, Koster K, Krystal JK, et al (1988): Yohimbine alters regional cerebral blood flow in panic disorder. Lancet 2:678. Wu JC, Buchsbaum MS, Hershey TG, Hazier E, Sicotte N, Johnson JC (i991): PET in generalized anxiety disorder. Biol Psychiatry 29:1181-1199.