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Table of contents :
SPECT imaging in schizophrenia: effects of clinical presentation
Status of SPECT brain perfusion agents
SPECT brain imaging in psychiatric disorders: current clinical status
HMPAO-SPECT findings in opioid polydrug users – preliminary results
Temporal lobe involvement in schizophrenia and major depression: 99mTc-HMPAO-SPECT findings and their correlation to psychopathology
Effects of sleep deprivation on the limbic system and the frontal lobes in affective disorders: a study with Tc-99m-HMPAO
HMPAO-SPECT in memory disorders
The influence of regional atrophy on cerebral blood circulation patterns of psychiatric patients: a comparative study of SPECT, CT, and MRT findings
Physiology and pharmacology of central receptors: Relevant methodological aspects for the visualization of dopamine receptors
Measurement of the pharmacological influence on striatal dopamine D2 receptor: an [123I]-IBZM-SPECT study
Neuroimaging in schizophrenia
123I-IBZM SPECT brain imaging in schizophrenia
IBZM-SPECT during neuroleptic treatment
Clinical value of three-dimensional (3D) image presentation in single photon emission computed tomography
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Brain SPECT Imaging in Psychiatry

Brain SPECT Imaging in Psychiatry Edited by

F. Grünwald, S. Kasper, H.-J. Biersack, H.-J. Möller

w DE

G

Walter de Gruyter Berlin • New York 1995

Editors PD Dr. med. F. Grünwald Prof. Dr. med. H.-J. Bier sack D e p a r t m e n t o f Nuclear Medicine University o f B o n n Sigmund-Freud-Str. 25 D-53127 Bonn Germany

Prof. Dr. med. S. Kasper Department o f Psychiatry University o f Vienna Währinger Gürtel 1 8 - 2 0 A-1080 Wien Austria

Prof. Dr. med. H.-J. Möller D e p a r t m e n t o f Psychiatry University o f Munich Nußbaumstr. 7 D-80336 München Germany

Die Deutsche Bibliothek — Cataloging-in-Publication

Data

Brain S P E C T imaging in psychiatry / ed. by F. Griinwald ... — Berlin ; New York : de Gruyter, 1995 ISBN 3-11-014730-0 NE: Griinwald, Frank [Hrsg.]

© Copyright 1995 by Walter de Gruyter & Co., D-10785 Berlin. All rights reserved, including those of translation into foreign languages. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system without permission in writing from the publisher. Medical science is constantly developing. Research and clinical experience expand our knowledge, especially with regard to treatment and medication. For dosages and applications mentioned in this work, the reader may rely on the authors, editors, and publisher having taken great paints to ensure that these indications reflect the standard of knowledge at the time this work was completed. Nevertheless, all users are requested to check the package leaflet of the medication, in order to determine for themselves whether the recommentations given for the dosages or the likely contraindications differ from those given in this book. This is especially true for medication which is seldom used or has recently been put on the market and for medication whose application has been restricted by the German Ministry of Health. The quotation of registered names, trade names, trade marks, etc. in this copy does not imply, even in the absence of a specific statement that such names are exempt from laws and regulations protecting trade marks, etc. and therefore free for general use. Printing: Gerike GmbH. - Binding: Ltideritz & Bauer, Berlin. - Printed in Germany. Cover design: Rudolf Hiibler, Berlin

Preface Structural imaging by the means of computed tomography (CT) and magnetic resonance imaging (MRI) has been proven to be useful in various psychiatric diseases to contribute to differential diagnosis and to elucidate underlying pathomechanisms. Functional methods like PET or SPECT render possible the imaging of parameters like blood flow, glucose metabolism and receptor status. Whereas PET allows an absolute quantification of these parameters, SPECT imaging is based mainly on semiquantitative evaluation. In addition, there exist more radiopharmaceuticals for PET than for SPECT. Nevertheless, SPECT imaging is gaining importance in clinical and research applications. In clinical practice, SPECT is useful for differential diagnosis (e.g. dementia), in therapy control (e.g. schizophrenia) and in patient selection for therapy management (e.g. sleep deprivation) . In contrast to PET imaging, SPECT is available in almost all nuclear medicine departments and most private practices and is not associated with such a high financial and logistic demand as PET. Moreover, SPECT imaging has some methodological advantages compared to PET, since blood flow measurement using "chemical microspheres" like Tc—99m—ECD or Tc—99—HMPAO render possible a "freezing" of a cerebral blood flow pattern within a few seconds. Therefore, blood flow changes can be evaluated also in a stage in which the patient can not be imaged immediately. The development of new radiopharmaceuticals for blood flow imaging with SPECT and of new dedicated camera systems allow the detection of small perfusion defects and therefore contribute to the improved clinical application. Radiopharmaceuticals for dopamine D2 and benzodiazepine receptor imaging are commercially available now in most countries. On March 13, 1993, a symposium, entitled "Brain SPECT Imaging in Psychiatry" was held in Bonn. This book contains the contri-

Preface

VI

butions of scientists in the field of nuclear medicine as well as

from

psychiatric

fields.

For

psychiatrists,

the

book

is

intended to give an overview of the state of the art of methodological including

aspects high

of

functional

resolution

SPECT

brain imaging

For nuclear medicine physicians,

imaging and

with

SPECT,

3D-presentation.

the book should

serve

as a

guideline for the questions which might be asked by the clinician of the "SPECT imager" and which characteristic results can be expected in the SPECT image. We gratefully acknowledge all the authors from Aachen, Amsterdam, Billerica, Bonn, Erlangen, Iowa City, London, Mainz, Mannheim, New York, Vienna for their contributions. Dr. J. Kleine of the Walter de Gruyter Verlag, Berlin, deserves special thanks for invaluable advice and constructive critisism. We thank all sponsors, who supported the symposium and the publication of this book (ADAC Laboratories, Amersham

Buchler

GmbH,

Duphar

Pharma

GmbH,

Du

Pont

Lilly Deutschland, Mallinckrodt GmbH, Upjohn GmbH). F. Grünwald, S. Kasper, H.-J. Biersack, H.-J. Möller

Pharma,

Contents N. C. Andreasen, K. Rezai, V. W. Swayze, D. S. O'Leary SPECT imaging in schizophrenia: effects of clinical presentation

1

R. C. Walovitch Status of SPECT brain perfusion agents

17

R. A. O'Connell SPECT brain imaging in psychiatric disorders: current clinical status . .

35

P. Danos, S. Kasper, E. Klemm, F. Grünwald, C. Krappel, K Broich, G. Höflich, B. Overbeck, H.-J. Biersack, H.-J. Möller HMPAO-SPECT findings in opioid polydrug users - preliminary results

59

E. Klemm, F. Grünwald, B. Overbeck, C. Menzel, O. Rieker, B. Briele, A. L. Hotze, H.-J. Biersack, R Danos, S. Kasper, K. Broich, C. Krappel, H.-J. Möller Temporal lobe involvement in schizophrenia and major depression: 99m Tc-HMPAO-SPECT findings and their correlation to psychopathology

73

H. Feistel, D. Ebert, G. Platsch, A. Barocka, W. Kaschka Effects of sleep deprivation on the limbic system and the frontal lobes in affective disorders: a study with Tc-99m-HMPAO

83

R. Horn, F. Grünwald, O. Rieker, E. Klemm, C. Menzel, H.-J. Möller, H.-J. Biersack HMPAO-SPECT in memory disorders

97

O. Sabri, H. Kaiser, C. Dickmann, U. Buell, M. Mull, A. Thron, R. Erkwoh The influence of regional atrophy on cerebral blood circulation patterns of psychiatric patients: a comparative study of SPECT, CT, and MRT findings 113 W. E. Müller Physiology and pharmacology of central receptors: Relevant methodological aspects for the visualization of dopamine receptors 129

VIII

Contents

Ch. Wöber, R. Strobl, C. Harasko-van der Meer, S. Asenbaum, S. Wenger, B. Küfferle, I. Podreka, T. Brücke Measurement of the pharmacological influence on striatal dopamine D2 receptor: an [ 123 I]-IBZM-SPECT study

147

N. P. L. G. Verhoeff Neuroimaging in schizophrenia

163

J. V. Lucey, L. S. Pilowsky, D. C. Costa, P. J. Ell, N. P. L. G. Verhoeff, R. W. Kerwin 123 I-IBZM SPECT brain imaging in schizophrenia 175 K. Broich, S. Kasper, P. Darios, H.-J. Möller, F. Grünwald, E. Klemm, H.-J. Biersack, A. Alavi IBZM-SPECT during neuroleptic treatment

193

S. Schlegel, R. Schlosser, A. Hillert, O. Nickel, A. Bockisch, K Hahn Iomazenil-SPECT imaging in psychiatric diseases

203

A. Bockisch Clinical value of three-dimensional (3D) image presentation in single photon emission computed tomography 209

SPECT IMAGING IN SCHIZOPHRENIA: EFFECTS OF CLINICAL PRESENTATION

Nancy C. Andreasen, M.D., Ph.D. The University of Iowa College of Medicine, Department of Psychiatry, Mental Health Clinical Research Center, Iowa City, IA 52242 Karim Rezai, M.D.* The University of Iowa College of Medicine, Department of Radiology, Iowa City, IA 5 2 2 4 2 Victor W. Swayze, II, M.D., Daniel S. O'Leary, Ph.D. The University of Iowa College of Medicine, Department of Psychiatry, Mental Health Clinical Research Center, Iowa City, IA 52242

This research was supported in part by NIMH Grants MH31593, MH40856 and MHCRC 4 3 2 7 1 , The Nellie Ball Trust Fund, Iowa State Bank & Trust Company, Trustee; and a Research Scientist Award, MH00625.

Single photon emission computed tomography (SPECT) offers many advantages for the study of clinical populations, such as those patients suffering from major mental illnesses.

It is easy to use in such clinical populations because the studies

require very little patient compliance, apart from the need to remain still during the acquisition phase.

In addition, SPECT is widely available and relatively inexpensive.

The major challenge for the study of these populations is to develop applications of SPECT that are clinically informative.

N. C. Andreasen et al.

2

Conventionally, nuclear medicine techniques are used to assist in differential diagnosis (e.g., tumors) or to assess the severity of dysfunction (e.g., cardiac injection fraction).

Application in psychiatric populations requires a somewhat different

perspective.

In this group some applications are clearly useful for differential

diagnosis, as in the case of the differential diagnosis of depression versus dementia in elderly individuals presenting with a mixed picture of cognitive complaints and dysphoric symptoms. [1,2]

Other major applications will require a somewhat

different orientation, however. One example, discussed elsewhere in this volume, is the use of SPECT to monitor the effects of treatment through neuroreceptor imaging. [3,4] Another application, illustrated in this paper, is to use SPECT in order to probe the pathophysiology of a particular illness and to relate patterns of blood flow to clinical presentation.

In a previous report that used xenon as a tracer, we have explored hypofrontality in schizophrenia in relation to both treatment status and pattern of clinical symptoms. [5] That study was done in the context of a large body of work examining hypofrontality.

Beginning with the early work of Franzen and Ingvar,

patients with schizophrenia have been noted to have decreased perfusion in frontal brain regions. [ 6 - 1 2 ]

Some studies have shown a relationship between decreased

perfusion during rest, while others have employed the cognitive challenge strategy. In our work, we used the Tower of London, which we selected because the task requires sequential planning of a series of moves, which is considered to be a classic frontal function. [13,14]

In that study we were able to collect a cohort of never-treated

patients suffering from schizophrenia and to compare them with a group of more chronic patients and healthy volunteers. The purpose of that facet of the study was to determine whether decreased frontal perfusion could be due to the effects of chronic

SPECT imaging in schizophrenia

3

neuroleptic treatment. We found the same pattern of hypofrontality in both the nevertreated group (the drug naives) and those who had been chronically treated ("the nonnaives"). Thus we were able to demonstrate that hypofrontality was neither an effect of treatment nor an effect of chronicity.

Another facet of the study was to explore the relationship between hypofrontality and negative symptoms. The negative symptoms of schizophrenia involve a decrease in cognitive and emotional activities such as fluency of thought and speech, emotional expression, and volition and drive. [15-18]

In one standard method for

assessing negative symptoms, the Scale for the Assessment of Negative Symptoms (SANS), negative symptoms include alogia, affective blunting, avolition, anhedonia, and possibly attention. [19] These negative symptoms are also relevant to the study of hypofrontality, in that they represent a loss or diminution of functions that are frequently considered to be classically frontal. In our xenon study, we also observed a relationship between hypofrontality and an increased rate of negative symptoms.

The present investigation reports on the extension of this work, using Tc99 HMPAO. Since HMPAO is a static tracer, it does not lend itself readily to the use of cognitive challenge tests. Consequently, this report focuses on cerebral blood flow in schizophrenia during the "resting state."

It illustrates the application of SPECT

imaging to the study of pathophysiology and clinical presentation.

This particular

approach emphasizes the study of groups rather than individual patients.

It is an

example of an attempt to understand underlying mechanisms of illness rather than differential diagnosis or monitoring of treatment.

N. C. Andreasen et al.

4

METHODS The sample of patients studied in this report were recruited by the Mental Health Clinical Research Center (MHCRC) at The University of Iowa College of Medicine. All patients admitted to this center receive a comprehensive psychiatric and neurological evaluation. Current and past psychiatric history is documented using the Comprehensive Assessment of Symptoms and History (CASH). [20] Clinical symptoms are also rated on a weekly basis using the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS). [21 ] Patients are withdrawn from all medications for a three week period in order to obtain a relatively pure picture of their clinical presentation, as well as to permit the study of neurobiological measures in the drug-free state.

The MHCRC also emphasizes the

recruitment of first episode and never-treated patients, so that the potentially confounding effects of long-term treatment and chronicity can be minimized or eliminated.

The patients included in this study consisted of 47 patients with a DSM-III-R diagnosis of schizophrenia.

Fourteen were drug-naive, while 33 were non-naive. All

patients were studied in the medication-free state and all gave informed consent.

The controls consisted of 12 healthy volunteers recruited from the community. They were screened using a shortened version of the CASH as a standardized structured interview to rule out the presence of any psychiatric symptomatology. In addition, the

SPECT imaging in schizophrenia controls also were assessed with a neurological and medical history, as well as a neurological examination in order to exclude a history of significant medical or neurological illness. All controls were also medication free, and all gave informed consent.

The SPECT imaging was obtained in the resting state in the following manner. All subjects received 10 mCi of Technetium-99m HMPAO intravenously while seated in a quiet, dimly lit room. SPECT imaging was begun 1 5 - 3 0 minutes later utilizing a triple-headed gamma camera (Trionix) equipped with a low-energy high-resolution collimator. Energy window was set at 15% on the photopeak of Technetium-99m. Data were acquired at 4° angular intervals into 64 x 64 matrices and reconstructed using a standard filtered backprojection method.

Analysis of Data

An experienced observer examined the brain images of each subject on a computer display and marked a set of fiduciary points. These points identified the base of the brain, the vertex, the anterior, posterior, right, and left margins of the brain, as well as the anterior margins of the temporal lobes. These landmarks were then used for fitting a template to each subject's brain image by the computer. Templates were predefined and stored in the computer memory and delineated specific regions-ofinterest (ROI). As shown in Figure 1, these ROI's sampled the following brain areas in transverse planes: cerebellum, temporal lobes, basal ganglia, frontal cortex, and the parietal cortex. Additionally, on a coronal slice at the level of the anterior margin of the temporal lobes, they sampled three frontal lobe regions labeled mesial, orbital, and dorsolateral frontal cortices.

5

N. C. Andreasen et al. Data analysis was carried out in an automated manner on an IBM PS2/50 computer. For each study the computer adjusted the size of the templates to that of the brain being analyzed and then extracted quantitative data reflecting Tc-99m HMPAO activity in each ROI. The raw counts were then normalized by dividing them by the mean total brain activity which was derived from averaging 6 transverse brain slices centered at the level of the basal ganglia. These values provided the input to the statistical aniysis as relative indices of regional cerebral blood flow.

RESULTS Table 1 presents comparisons for both overall brain blood flow and regional blood flow in the control group, the drug-naive patients and the non-naive patients. This table summarizes the results of statistical analysis in which tracer uptake in the cerebellum was used as a covariate. Although a variety of other covariates are possible (e.g., overall brain blood flow, hemispheric blood flow), the cerebellum was chosen as a reference region in these analyses because it is the most widely used. Table 1 shows the regression coefficients for both the drug-naive patients and the non-naive patients.

A s Table 1 indicates, the naive patients and the non-naive patients have a different pattern of blood flow, as inferred from the regression coefficients. The drugnaive patients differ significantly from the controls on nearly all measures. They have a decrease in whole brain blood flow, white matter flow, most cortical subregions, and the caudate. The non-naive patients differ from the controls, however, primarily in frontal regions.

Specifically, they differ in mesial frontal and orbital frontal regions

SPECT imaging in schizophrenia on both the left and the right.

Both the non-naive and naive patients display

hypofrontality, but the hypofrontality is relatively nonspecific in the drug-naive patients. TABLE 1 COMPARISON OF H M PAO REGRESSION COEFFICIENTS IN CONTROLS VERSUS DRUG-NAIVE OR NON-NAIVE SCHIZOPHRENIC PATIENTS* Non-Naives(NN) Naives(N) Controls(C) CvsN C vs NN (n=14) (n=33) (n-12) REGION Brain .954 .717 .861 .03 NS Total White Matter .592 .792 .03 NS .926 Left .904 .608 .818 .03 NS Right Caudate 1.129 .813 1.042 .03 NS Left .901 1.008 .03 NS Right .980 Temporal .748 .900 .03 NS .953 Left .987 .724 .949 .03 NS Right Parietal .897 .764 .740 NS Left .03 .984 .686 .799 .03 NS Right Frontal .970 .708 .746 .03 NS Left .844 Right .950 .645 .03 NS Mesial Frontal Left 1.161 .561 .578 .03 .03 Right .990 .589 .627 .03 .03 Orbital Frontal Left 1.037 .533 .578 .03 .03 .891 .627 Right .636 .04 .03 Dorsolateral Frontal Left .918 .710 .774 NS NS Right .945 .728 .796 NS NS Cerebellar Radioactive Uptake Used at the Covariate * * Significance tests are one-tailed

This sample is examined from another perspective in Table 2. The entire group of patients was subdivided into those who had high negative symptoms and those who had low negative symptoms. Patients were considered to have high negative symptoms if

7

N. C. Andreasen et al.

8

they had at least two negative symptoms rated as marked or severe; because of the controversial

nature of attentional impairment, only alogia, affective

avolition, and anhedonia were used for this classification.

blunting,

All other patients were

placed in the low negative group. TABLE 2 COMPARISON OF HMPAO UPTAKE IN FRONTAL REGIONS IN PATIENTS WITH LOW V E R S U S HIGH NEGATIVE S Y M P T O M S * Negative Symptoms p** Low High t (n=27) (n=20) FRONTAL REGION Mesial Frontal Left 1.82 107.31 96.98 .03 Adjt. Mean 4.20 3.70 Std. Error Right 104.71 97.19 1.46 .08 Adjt. Mean 3.36 3.90 Std. Error Orbital Frontal Left 96.125 87.88 1.65 .05 Adjt. Mean 3.26 3.79 Std. Error Right 1.11 .14 91.630 88.55 Adjt. Mean 2.11 Std. Error 1.811 Dorsolateral Frontal Left 114.59 111.56 0.95 .17 Adjt. Mean 2.08 2.42 Std. Error Right 116.83 109.48 2.22 .02 Adjt. Mean Std. Error 2.16 2.51

A s Table 2 indicates, the high negative symptom patients had lower count rates in many of the frontal regions than did the low negative patients. A s in the regression analyses, these analyses of mean differences were corrected by using cerebellar HMPAO uptake as a covariate. The high negative patients had significantly lower uptake in left mesial frontal, left orbital frontal, and right dorsolateral frontal regions.

Trends for

lower uptake were noted in all other regions. These data suggest that hypofrontality is

9

SPECT imaging in schizophrenia related to negative symptoms.

This relationship appears to be stronger than the

relationship with medication status or course of illness.

DISCUSSION This study

has addressed four issues:

Does hypofrontality

occur in

schizophrenia? Does hypofrontality involve a specific region of the frontal lobes? Is it an effect of treatment? Is it associated with negative symptoms?

As we have discussed previously, the concept of hypofrontality, much like schizophrenia itself, it is not a unitary construct. [5,22]

The literature suggests a

variety of possible definitions of hypofrontality, depending on how it is measured. Studies of hypofrontality have used both the resting state and cognitive challenges. They have also examined blood flow metabolic activity in the frontal lobes in isolation or in relation to other parts of the brain. At its simplest level, hypofrontality is sometimes defined as decreased activity in frontal regions, independent of the state of the patient or activity in the remainder of the brain.

More sophisticated definitions apply various

corrections for overall brain activity, such as the cerebellum, the ipsilateral hemisphere, or whole brain blood flow. The cerebellum appears to be a reasonable covariate or correction factor when the resting state is studied.

When cognitive

challenge paradigms are applied, however, global differences often occur in whole brain activity, making it more necessary to determine whether increased frontal flow is differentially greater in response to a cognitive challenge than flow in the remainder of the brain.

This study using HMPAO SPECT is consistent with a large body of literature supporting the presence of hypofrontality in schizophrenia. Both the drug naive and the

N. C. Andreasen et al. non-naive patients show significantly lower flow in frontal regions than the normal control group.

The two patient groups show their decreased frontal flow within a

somewhat different "whole brain context," however. The drug naive patients have significantly lower flow in nearly all brain regions studied.

Thus they appear to

display a generalized decreased in cerebral metabolic activity during rest.

If one

inspects the regression coefficients in detail, then it appears that they are particularly low in mesial and frontal regions, reaching a coefficient as low as .33 in the left orbital region. On the other hand, the non-naive patients have a relatively specific decrease in flow in the mesial and orbital frontal regions.

This study focuses on hypofrontality in the resting state. While some of the earlier studies of hypofrontality examined frontal lobe activity during this state, more recently studies have tended to focus on frontal response to cognitive challenges. Many of these studies have reported a relative decrease in the dorsolateral frontal cortex in response to a cognitive challenge, such as the Wisconsin Card Sorting Test.

It is

noteworthy that this study does not find any decrease in dorsolateral cortex in either group during the resting state. This may be consistent with the role of the dorsolateral cortex in so-called "executive functions," while the more central frontal regions may be associated with cognitive functions that draw on arousal, alertness, and the focusing of attention.

The regions designated as "frontal" in this study are relatively crude and inevitably involve some partial voluming.

It is possible that the mesial and orbital

frontal regions contain some portion of the cingulate gyrus. It is also noteworthy that these regions are quite similar to those that our own group has shown to represent hypofrontality in response to the cognitive challenge involved in the Tower of London.

SPECT imaging in schizophrenia These decreases in activity in midline frontal regions are consistent with a number of other observations that we have made in our studies of schizophrenia. In four independent MR studies, we have observed decreased thalamic size. [23-26]

We

have also reported on midline developmental anomalies in schizophrenia. [27]

In a

recent study we have discussed the role of midline reticulo-thalamic-cingulate-frontal circuits in information processing and sensory gating. [26] These regions may play an important role in producing both the positive and negative symptoms of schizophrenia, since a defect in this area would impair the patient's ability to process stimuli, prioritize information, and differentiate the relevant from the irrelevant or the dangerous from the benign. It is important that future studies of hypofrontality address not only its presence or absence, but also its mesial versus lateral location in relation to both cognitive activation and rest, as well as in relation to types of symptoms present.

This study has also explored the question of whether hypofrontality is an effect of treatment.

It appears rather clearly that hypofrontality is present in both drug-

naive and chronically treated patients.

Our findings are consistent with our own

previous work suggesting hypofrontality to be present early in the illness and in untreated individuals. [5] These findings are not consistent with earlier work that has suggested that chronic neuroleptic treatment may produce either an irreversible or reversible "frontal leukotomy"

by blocking the dopamine tracts that provide

interconnections between the basal ganglia and the frontal lobes. [28]

Finally, this study has demonstrated yet again that decreased frontal activity is associated with negative symptoms. In this particular study the association is strongest

12

N. C. Andreasen et al. with mesial and orbital frontal regions, although a significant relationship is also seen between negative symptoms and the right dorsolateral prefrontal cortex. The latter is somewhat surprising, since most studies have reported decreased activity on the left side; however, the preponderance of studies showing decreased frontal activity in dorsolateral regions have involved the use of a cognitive challenge, in contrast to the resting state used in this particular study. These findings appear to solidly support a relationship between decreased activity in midline arousal regions of the brain and the presence of negative symptoms.

Frontal

Parietal ROIs

E

Frontal ROI's

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Flaum M, Swayze VW, O'leary DS, Yuh WTC, Ehrhardt JC, Arndt SV, Andreasen NC: Brain morphology in schizophrenia: Effects of diagnosis, laterality and gender. Am J Psychiatry, (submitted)

26.

Andreasen NC, Arndt S, Swayze VW, II, Cizadlo T, Flaum M, O'Leary D, Ehrhard J, Yuh WTC: Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging, (submitted 4/94)

S P E C T imaging in schizophrenia 27.

Cleghorn JM, Garnett ES, Nahmias C, Firnau G, Brown GM, Kaplan R, Szechtman H, Szechtman B: Increased frontal and reduced parietal glucose metabolism in acute untreated schizophrenia. Psychiatry Res 1989; 28:119-133

28.

Swayze V W II, Andreasen NC, Ehrhardt JC, Alliger R, Cohen G: Developmental abnormalities of the corpus callosum in schizophrenia. Arch Neurol 1990; 47:805-808

15

STATUS OF SPECT BRAIN PERFUSION AGENTS

Richard C. Waloviteh Metasyn Inc., 71 Rogers Street, Cambridge, MA 02142-1118, (617) 499-1403

In this review, an overview on the development of SPECT brain imaging is given with an emphasis on the chemical and pharmacological properties of brain perfusion radiopharmaceuticals. Special emphasis is given to the Tc99m SPECT brain perfusion agents since they represent the majority of clinical SPECT brain imaging studies. Computed tomography (CT) and magnetic resonance imaging (MRI) are valuable diagnostic techniques for defining structural changes in the brain. Since changes in perfusion usually precede structural changes, SPECT imaging of brain function offers the potential for earlier diagnosis and subsequent intervention. In addition to providing an early diagnosis, functional brain imaging may be valuable in conditions where structural lesions are not an integral part of the disease pathology such as in dementia. Extensive research has been conducted to understand the physiology of brain tissue in a variety of CNS conditions using functional neuroimaging with both positron and gamma emitting radionuclides. At present, SPECT brain radiopharmaceuticals have not been developed that can trace metabolic pathways. In contrast, positron emission tomography (PET) has been used for over a decade and has been demonstrated to be a sensitive and quantitative technique for determining the functional status of brain tissue using tracer of blood flow, metabolism and receptors [20]. Because of the quantitative nature of PET studies, one can obtain rigorous evaluation and understanding of specific pathophysiological processes. However, the expense of establishing a PET facility is approximately tenfold greater than for SPECT brain imaging, and PET imaging procedures are more expensive [28]. This in part probably explains its slow acceptance into the everyday practice of medicine. The clinical utility of SPECT brain perfusion imaging has only recendy been realized. Since the late 19th century, it was known that a close coupling exists between regional perfusion, metabolism and neuronal activity [38].

18

R. C. Walovitch

Because neuronal activity is closely coupled to glucose utilization and blood flow, it is possible that perfusion imaging studies could help explain which neuronal pathways are activated during sensory processing or disrupted during various diseases. Many of the early blood flow studies were directed at basic research questions such as mapping brain function. Much of this work was initiated in the 70's by Obrist, Ingvar and Lassen using the freely diffusible noble gas Xenon 133 p i e 133) by intra-arterial or inhalation techniques [21]. Because of the inert property of Xe 133, absolute quantification of regional cerebral blood flow (rCBF) can be calculated using the autoradiographic principles [17]. At the time, this technique was a two dimensional imaging technique involving multiple scintillation probes positioned around the head. These early function- anatomy studies often involved two or more imaging studies, a baseline study and at least one study in which the subject's brain was activated with some type of stimulus. The effect of stimulation was determined by subtracting the baseline image results from those obtained during the stimuli. The different image generated from this subtraction indicated what brain regions were selectively affected by the activation (see Figure 1).

Figure 1. Transverse SPECT brain images of Tc99m bicisate in a normal subject. In the baseline study (left image), Tc99m bicisate was administered to the subject with eyes open and imaging was initiated 30 min later. In the activation study (middle image), Tc99m bicisate was administered to the subject during the presentation of a visual activation paradigm (flashing concentric checkerboard pattern) and imaging was initiated 30 min later. Far right image shows the difference between baseline and activation images. Images provided courtesy of Dr. T. Hill, Deaconess Hosp., Boston, Ma.

Status of SPECT brain perfusion agents

19

Although Xe 133 is an excellent tracer for the quantitation of blood flow and the performance of repeat imaging studies, it possesses major limitations such as low photon energy producing considerable attenuation and resulting in poor spatial resolution. In addition, the Xe 133 scattered from the nasal passage produces artificially increased activity observed in the frontal regions as compared to radiopharmaceutical perfusion tracers (see Figure 2).

Figure 2. Transverse SPECT brain images of a patient after administration of Tc99m bicisate and Xenon 133. Note the Xenon scatter in the nasal passages which produced artificially high activity in the anterior frontal regions and a slight masking of the frontal perfusion defect. In addition, the low energy of the frontal defect photons of Xenon are more attenuated by the head holder than are those of Tc99m. Note the clear increase in activity in the occipital lobe. This attenuation is most pronounced in the posterior parietal region. Images provided courtesy of Dr. O. Paulson, Rigshospital, Copenhagen, Denmark. In the early 80's with the invention of instrumentation for tomographic Xe 133 studies, great improvements were made in the ability to map brain function. In part, this was due to the

20

R. C.Walovitch

ability to better appreciate the contributions of deep brain structures (i.e., thalamus and extrapyramidal motor system) as gating systems for neuronal circuitry. Unfortunately, these SPECT systems were specialized, expensive and designed as dedicated brain imaging systems which had to obtain multiple images during the clearance of the Xe 133. These early systems also provided only three (2 cm) transverse slices, the center of which was separated by 4 cm. This non-contiguous sampling of brain tissue complicated the ability to localize pathology. In comparison to X e 133 in the early 80's, a new generation of SPECT brain perfusion imaging agents based on iodine were being developed These agents which had more stable intracerebral distribution, therefore, effectively "capturing" the regional cerebral perfusion pattern which existed at the time of injection [48], These radiopharmaceuticals were based on iodine because of its ease of incorporation into biologically active molecules without concomitant loss of biological activity. The 123 isotope of iodine (1-123) was selected because its physical properties of a short half-life (13 hours) and primary gamma emission (159 KeV) were better suited for nuclear imaging than other isotopes of iodine. The dosimetry characteristic of the gamma emission of 1-123 limited the injected dose to approximately 5 mCi. However, it was felt that if an I-123 agent could be developed that was well extracted and retained in brain tissue, sufficient counts could be obtained so that SPECT studies could be performed in less than an hour. Such an agent would be imaged using standard rotational gamma camera SPECT instrumentation. Since the brain capillaries are not fenestrated, transport from the blood to brain tissue for larger molecules would have to be mediated by either diffusion or facilitated transport. For perfusion tracers, the uptake needed to be mediated by diffusion, since facilitated transport systems were saturable and would not be able to produce a sufficient high percent injected dose

(% ID) for SPECT without some

other mechanism for transport. Therefore, agents were developed that are neutral lipid-soluble molecules of moderate molecular weight (between 250-450 mol. wt.). Due to the lipophilicity of the agent, they diffuse across the blood brain barrier (BBB) and are incorporated in the lipid bilayers of cells where they washout unless there is some type of a retention mechanism which captures the agent in the brain. The extent of brain extraction and retention for these agents is less than 100, therefore, these agents will underestimate absolute blood flow, particularly at high flow rates where the "curvilinear relationship" to actual flow is noted with a decreasing incremental uptake of the radiopharmaceutical at the highest rates of flow [1,12, 16, 32,40]. Although these agents needed to be lipophilic, very lipophilic molecules, (i.e., oil/water partition coefficients of greater than 1000) are not good brain agents because they would be

Status of S P E C T brain perfusion agents

21

retained by the lungs, red blood cells or protein to such an extent that very little free material would be available for brain uptake. In addition, if the circulating activity is a substantial percentage of the overall dose, than over time further brain uptake would occur. This type of a prolonged brain input function would be a disadvantage, particularly in patients in which transient changes in blood flow are being measured such as in ictal epilepsy. Since 1-123 is a cyclotron product, it must be transported daily from the production site to the imaging facility. This has caused problematic commercialization of these agents. At present, no 1-123 brain imaging agents are available in the U.S. Oldendorf, in 1978, postulated that the development of brain perfusion agents could be done with technetium 99m (Tc99m), a nuclide which does not have the same limitations for distribution as 1-123 [35]. Tc99m is easily produced (from molybdenum 99) with a small on-site generator. The isotope emission is ideally suited to the gamma cameras currently in use. However, the chemistry of these agents is complex. These agents must be neutral, lipophilic Tc99m chelate complexes that cross the B B B easily and are retained in brain tissue by some trapping mechanism. A variety of chelate systems have been developed. Since the molecular weight of these chelate systems is a few hundred daltons, molecule derivatization with large functional groups is problematic. These bulky chelate systems decrease greatly the ability of these radiopharmaceuticals to show the appropriate structure activity relationship needed to bind with high affinity to a receptor site. The first Tc99m brain perfusion agent commercially available in most countries was Tc99m exametazime (Ceretec™, Tc99m HMPAO). The development of the Tc99m brain perfusion imaging agents has lead to the emergence of powerful clinical methods for SPECT brain imaging which promises to become important in the routine evaluation of patients with CNS disorders. Today, approximately 300,000 SPECT brain perfusion imaging studies are performed worldwide with equal distribution between Europe, U.S. and Japan (Figure 3). Greater than 95% of these studies are performed using Tc99m and 1-123 agents. Although the majority of studies are being performed using Tc99m exametazime, 1-123 Iofetamine is commercially available in Japan and is often used. The small size and high population density of Japan has made commercial distribution of I-123 agents feasible. 1-123 Iofetamine was the first SPECT radiopharmaceutical commercially available in the U.S. In the 80's, 1-123 Iofetamine and another 1-123 labeled amine, I-123-labeled N,N,N'trimethyl-N'-[2 hydroxy-3 methyl-5 iodobentyl]-l,3-propanediamine (HIPDM), were being used worldwide in the clinical evaluation of brain perfusion.

R. C. Walovitch

22

Brain Perfusion Studies

1992

Japan

Europe

US

Figure 3. Rate of growth of SPECT brain perfusion imaging in the United States, Europe and Japan. At present, few radiopharmaceuticals are commercially available for imaging of regional cerebral perfusion or blood flow. Table 1 is an overview of some of the major properties of three SPECT commercially available brain radiopharmaceuticals which have been well characterized. A limitation of Table 1, is that comparisons between the radiopharmaceuticals are not based on studying the same subject with all three tracers with the exception of the extraction fraction. In Table 1, the "duration of perfusion image" is shown, while brain T1/2 is not, since brain residence time of 1-123 Iofetamine is much greater than the time period when brain perfusion images can be acquired [5,14], Although 1-123 Iofetamine is a structural analog of d-amphetamine, its initial cerebral distribution corresponded closely to that

Status of SPECT brain perfusion agents

23

of regional cerebral perfusion. However, over time the cerebral distribution of 1-123 Iofetamine is altered so that the agent no longer reflects a perfusion pattern of distribution on delayed imaging [5,14,20]. A prognostic role for delayed imaging in stroke patients following 1-123 Iofetamine injection has been suggested [29]. It has been hypothesized that patients having perfusion defects which show less contrast over time will have a better prognosis than those stroke patients with more stable perfusion abnormalities. This requires that the patient be imaged within a few minutes post-injection and again a few hours later. However, the literature is conflicting on this point and its value remains to be proven in a multicenter trial.

Table 1.

Characteristics of Brain Perfusion Radiopharmaceuticals

Tc99m-Bicisate

Tc99m Exametazime

1-123 Iofetamine

ECD

HMPAO

IMP

Trade Name

Neurolite®

Ceretec™

SPECTamine®

Radionuclide

Tc99m

Tc99m

1123

Radiochemical Stability

>6 hrs.

24

>24 hrs.

1-2 hrs.

47

86

Common Name

Brain Perfusion Image Extraction Fraction*

63

Mechanism of Brain Retention

Acid Hydrolysis

Glutathione Chelation

Amine Binding/ Deamination

24 hr. Whole Body Retention (%)

15

65

70

Table 1. Characteristics of Tc99m bicisate, Tc99m exametazime and 1-123 Iofetamine. Data on duration of brain perfusion image is from reference 44 and on extraction fraction from reference 41. Mechanism of retention and whole body retention is from reference 30.

In contrast to the change in image to lesion contrast over time, observed with the I-123 amine, distribution is unchanged over time with Tc99m bicisate and Tc99m exametazime. In general,

24

R. C. Walovitch

the results of intra-subject comparative studies between the various brain perfusion radiopharmaceuticals have shown similar distribution in the first hour after intravenous injection with only small differences in lesion contrast and image quality (3,11,15, 30,47). Differences in image quality have been attributable to both pharmacokinetic differences and differences in gamma emission between radiopharmaceuticals labeled with different radionuclides (i.e., 1-123 vs. Tc99m). High resolution instrumentation and good quality SPECT imaging techniques can help to minimize differences due to the gamma emission energy of different radiopharmaceuticals. In addition, differences in image quality and lesion contrast have been attributed to differences in brain extraction and/or the brain to non-brain tissue ratio. Multiple small studies have evaluated Tc99m bicisate and Tc99m exametazime kinetics in the same subject population [3,26,42,45,47]. Taken collectively, these studies have shown that Tc99m exametazime is eliminated from the body more slowly than Tc99m bicisate. Both agents undergo rapid uptake in brain tissue with a perfusion pattern of distribution which is unchanged over time. Although, Tc99m exametazime has slower brain washout as compared to Tc99m bicisate (approximately 1% and 6% washout per hour, respectively), the brain retention of Tc99m bicisate is sufficient so that high quality single headed rotating gamma camera SPECT brain imaging studies may be performed [25-26]. Tc99m bicisate images showed significantly less brain background activity, and lower blood activity as compared to Tc99m exametazime images [26]. These differences may help increase visualization of the perfusion defects. In an intra-subject comparison of Tc99m bicisate to Tc99m exametazime in dementia and stable stroke patients, showed by SPECT brain region of interest (ROI) analysis, cortical lesions were more pronounced with Tc99m bicisate than with Tc99m exametazime [3,47]. A limited number of SPECT brain perfusion imaging studies have been performed using noncommercially available radiopharmaceuticals such as H-201 DDC and 1-123 HIPDM [9,20, 22,39,43,45]. At present, a number of Tc99m SPECT brain perfusion tracers are under development for potential commercialization. Unfortunately, the pharmacokinetic and tracer kinetic properties of these agents do not appear to offer any major advantages as compared to Tc99m exametazime or Tc99m bicisate [10]. The major limitation of the present Tc99m perfusion tracer is their flow limited brain extraction which make quantitative determination of absolute flow, particularly during hyperperfusion, difficult.

Status of SPECT brain perfusion agents

25

As early as 1981, LaFrance reported the uptake of 1-123 Iofetamine in brain tumors not related to perfusion [19]. In patients, over and underestimation of blood flow have been observed [41]. However, this lack of linearity of SPECT brain agents during high flow conditions such as an epileptic seizure has had little impact on the value of these agents in the localization of seizure foci. In seizure foci, blood flow is greatly increased during ictus and the detection of foci can be done by visual assessment. However, most of these studies have been conducted with I-123 labeled amines which are no longer commercially available [6,23,24,27]. Commercially available Tc99m exametazime is not radiochemically stable, therefore, it can not be prepared ahead of time which makes ictal imaging studies logistically impractical. Although Tc99m bicisate is radiochemically stable, its sensitivity in ictal imaging is not known. Hypoperfusion is also observed in cerebrovascular disease patients who are imaged during an activation study (e.g., acetazolamide) or in the subacute phase of stroke. Striking discrepancies in the intracerebral distribution of brain perfusion agents have sometimes been observed during conditions of hyperperfusion particularly in cerebrovascular disease (CVD). In subacute stroke patients, in a comparison of Tc99m exametazime to Xe 133, Lassen reported "hyperfixation" of Tc99m exametazime [41]. In contrast, Tc99m bicisate has been reported to show "hypoperfusion" in subacute stroke patients who on imaging with Tc99m exametazime and 1-123 Iofetamine show hyperperfusion (Figure 4) [33]. Taken collectively, major differences in SPECT brain radiopharmaceutical distribution are seen in a small percentage of all cases. These differences usually are isolated to the imaging of non-brain tissue (i.e., tumor tissue), in situations where perfusion and metabolism are uncoupled and in imaging studies with 1-123 Iofetamine many hours after injection. It has been hypothesized that differences in cerebral distribution of SPECT brain tracers are due to the retention mechanisms of these agents in the brain. 1-123 Iofetamine retention has been postulated to be related to a number of different factors including the concentration of high capacity low affinity amine binding sites [20,31]. Tc99m exametazime retention is believed to be related to glutathione concentration in brain tissue [34], Tc99m bicisate retention has been shown to be related to its enzymatic hydrolysis to a polar acid product which is trapped in the brain but rapidly eliminated from the rest of the body [46]. The decreased retention of Tc99m bicisate in the region of luxury perfusion, in the subacute phase of stroke, is postulated to be due to a decrease in the rate of the metabolic trapping enzymes ("esterase") or to a breakdown in the local BBB. The enzyme system responsible for this metabolic transformation of Tc99m

26

R. C. Walovitch

bicisate has not yet been elucidated. Although the metabolic transformation of Tc99m bicisate is saturable in-vitro, the in-vivo brain concentration of Tc99m bicisate is so low that enzymatic saturation is unlikely. These results are supported by preclincial data which show no pharmacodynamic effects of Tc99m bicisate at greater than 50 times of the maximum human dose [44].

Figure 4. Figure 4 shows SPECT brain images of a subacute stroke patient after administration of I-123 Iofetamine (IMP), Tc99m exametazime (HMPAO) and Tc99m bicisate (ECD). Cerebral angiography on day one showed occlusion of the right anterior cerebral artery and anterior trunk of the middle cerebral artery. Recanalization of these occluded vessels occurred on day six. SPECT imaging with 1-123 Iofetamine (11 day post stroke) and Tc99m exametazime (13 days post stroke) show areas of increased tracer uptake in the same region that demonstrated decreased tracer uptake on the Tc99m bicisate images (12 days post stroke). Imaging data is courtesy of Dr. J. Nakagawara, Nakamura Memorial Hospital, Sapporo, Japan.

In addition to imaging blood flow, Tc99m and 1-123 labeled SPECT brain perfusion agents have been used in conjunction with Tc99m labeled red blood cells in order to determine the

Status of S PECT brain perfusion agents

27

ratio of blood flow to blood volume [2,18]. This ratio is an indicator of cerebral autoregulatory reserves and appears to be important for risk stratification of CVD patients. A more common method of measuring autoregulatory capacity is to perform a rest/ activation study with CO2 or intravenous administration of acetazolamide (Diamox® [7, 8,18]. Both CO2 and acetazolamide produce cerebral vasodilation and increase rCBF diffusely. Typically, vascular reserve is normal in patients with primary neuronal degeneration but decreased in patients with vascular disease [8]. Brain regions with vascular disease which have normal rCBF during the baseline study will often demonstrate decreases in rCBF during a brain activation test [4], In the past, rest and activation studies were performed on different days using the same radiopharmaceutical, however, recently these studies have been performed on the same day with both imaging studies being performed within hours of each other or occurring simultaneously [7,13,36,37], Simultaneous imaging studies are possible if two different radionuclides are used for the rest and activation studies and if the administration of the radionuclides can be staggered so that one radionuclide is administered before the activator (i.e., Diamox® or CO2) and the other after [7-8]. Although these studies seem very promising, quantification is problematic due to differences in the physics of the radionuclides and the brain pharmacokinetics (i.e., brain extraction and retention) of the agents during high flow conditions. In conclusion the development of Tc99m brain perfusion imaging agents has renewed interest in the use of nuclear medicine imaging of the brain, allowing the practitioner to go beyond non-invasive assessment of brain diseases based on anatomic information alone. Their excellent dosimetry and good photon flux of the Tc99m perfusion agents may make it possible to routinely perform brain stress studies that may prove to be of great value in early detection of psychiatric and neurologic diseases. Accompanying and, in many cases, preceding the development of new imaging agents has been improvements in imaging equipment which allows for the acquisition of high-quality SPECT images. As the technology expands, indications for SPECT brain perfusion imaging can be expected to increase dramatically with the understanding of its role in clinical medicine.

R. C.Walovitch

28

Most importantly since physiologic changes in tissue almost always precede anatomic changes, SPECT brain imaging promises to be most valuable as a screening tool in many neurologic and some psychiatric conditions. Increasingly, successful treatment of these disorders will depend on early detection. ACKNOWLEDGEMENT I would like to thank Joseph Biegel for his image processing technical support and Donna Hulub for her invaluable secretarial assistance in the preparation of this manuscript.

Status of S PECT brain perfusion agents

29

[1]

Andersen AR, Friberg H, Lassen NA, et al.: Assessment of the arterial input curve for [99mTc]-d-l-HM-PAO by rapid octanol extraction. J Cereb Blood How Metab 8 (1988) 23 - 30.

[2]

Buell U, Braun H, Ferbert A, et al.: Combined SPECT imaging of regional cerebral blood flow (99mrc-Hexamethyl-Propyleneamine Oxime, HMPAO) and blood volume (99mTc-RBC) t 0 assess regional cerebral perfusion reserve in patients with cerebrovascular disease. Nucl Med 27 (1988) 51 -56.

[3]

Castagnoli A, Borsato N, Bruno A, et al.: SPECT brain imaging in chronic stroke and dementia: a comparison of 99mxc-ECD and "mTc-HMPAO. In: Hartmann A, Kuschinsky W, Hoyer S, eds. Cerebral Ischemia and Dementia. Berlin: SpringerVerlag, (1991) 327 - 333.

[4]

Chollet F, Celsis P, Clanet M, et al.: SPECT study of cerebral blood flow reactivity after acetazolamide in patients with transient ischemic attacks. Stroke 20 (1989) 458 - 464.

[5]

Creutzig H, Schober O, Gielow P, et al.: Cerebral dynamics of N-isopropyl-(1123)piodoamphetamine. J Nucl Med 27 (1986) 178 - 183.

[6]

Devous MD Sr., Leroy RF: Comparison of interictal and ictal regional cerebral blood flow findings with scalp and depth electrode seizure focus localization. J Cereb Blood How Metab 9 (1) (1989) 91.

[7]

Devous MD, Sr., Lowe JL, Payne JK: Dual-isotope brain SPECT imaging with 99mx c and 123 I. Validation by phantom studies. J Nucl Med 33 (1992) 2030 - 2035.

[8]

Devous MD Sr, Payne JK, Lowe JL: Dual-isotope brain SPECT imaging with 9 9 m T c and 123i. Clinical validation using 133x e SPECT. J Nucl Med 33 (1992) 1919 - 1924.

[9]

Ell PJ, Janitt PH, Costa DC, et al.: Functional imaging of the brain. Sem Nucl Med 17 (1987) 214 - 229.

[10] Ell PJ: Mapping cerebral blood flow. J Nucl Med 33 (10) (1992) 1843 - 1845.

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[11] Garrett K, Villanueva J, Kuperus J, et al.: A comparison of regional cerebral blood flow with Xe-133 to SPECT Tc99m-ECD. J Nucl Med 29 (1988) 913. [12] Gemmell HG, Evans NTS, Besson JAO: Regional cerebral blood flow imaging: a quantitative comparison of technetium-99m-HMPAO SPECT with C 1 5 02 PET. J Nucl Med 31 (1990) 1595-1600. [13] Holm S, Madsen PL, Rubin P, et al.: Tc99m HMPAO activation studies: validation of the split-dose, image subtraction approach. J Cereb Blood Flow Metab 11(2) (1991) 766. [14] Holman BL, Lee RGL, Hill TD, et al.: A comparison of two cerebral perfusion tracers, AMsopropyl 1-123 p-iodoamphetamine and 1-123 HIPDM in the human. J Nucl Med 25 (1984) 25 - 30. [15] Holman BL, Devous MD, Sr.: Functional brain SPECT: The emergence of a powerful clinical method. J Nucl Med 33 (1992) 1888 - 1904. [16] Inugami A, Iwao K, Kazuo U, et al.: Linearization correction of 99m-r c _i a 5 e i e( j hexamethyl-propylene amine oxime (HM-PAO) image in terms of regional CBF distribution: comparison to C^5o2 inhalation steady-state method measured by positron emission tomography. J Cereb Blood Flow Metab 8 (1988) 52 - 60. [17] Kety SS: The theory and applications of the exchange of inert gas at the lungs and tissues. Pharm Rev 3 (1951) 1 - 41. [18] Knapp WH, von Kummer R, Kubler W: Imaging of cerebral blood flow-to-volume distribution using SPECT. J Nucl Med 27 (1986) 465 - 470. [19] LaFrance ND, Wagner HN, Whitehouse P, et al.: Decreased accumulation of isopropyliodoamphetamine (1-123) in brain tumors. J Nucl Med 22 (1981) 1081 - 1083. [20] Lagriize HL, Levine RL: Quantitative positron emission tomography and single photon emission computed tomography measurements of human cerebral blood flow. Am J Physiol Imag 2 (1987) 208 - 215.

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[21] Lassen NA, Ingvar DH, Skinh0j E: Brain function and blood flow. Sei Amer 239(4) (1978) 62 - 71. [22] Lassen NA, Holm S: Single photon emission computed tomography. In: Mazziotta JC, Gilman S, eds. Clinical brain imaging: Principles and application. Philadelphia: F.A. Davis Company, (1992) 108 - 134. [23] Lee BI, Markand ON, Wellman HN, et al.r HIPDM single-photon emission computed tomography brain imaging in partial onset secondarily generalized tonic-clonic seizures. Epilepsia 28 (1987) 305 - 311. [24] Lee BI, Markand ON, Wellman HN, et al.: HIPDM-SPECT in patients with medically intractable complex partial seizures. Ictal study. Arch Neurol 45 (1988) 397 - 402. [25] L6veill6 J, Demonceau G, De Roo M, et al.: Biodistribution and brain SPECT imaging with Tc99m-ECD in humans: a new radiochemically stable brain perfusion agent. J Nucl MediO (1989) 1902- 1910. [26] L£veill6 J, Demonceau G, Walovitch RC: Intra subject comparison between Tc99mECD and Tc99m-HMPAO in healthy human subjects. J Nucl Med 55(4) (1992) 480484. [27] Magistretti PL, Uren RF: Cerebral blood flow patterns in epilepsy. In: Nistico G, Di Perri R, Merinardi H, eds. Epilepsy: An update on research and therapy. New York: Liss, (1983) 241 - 247. [28] Maurer AH: Nuclear Medicine: SPECT comparisons to PET. Radio Clin N Am 26(5) (1988) 1059 - 1074. [29] Moretti JL, Defer G, Cesaro P, et al.: Early and delayed IMP 1-123 SPECT as a prognostic index for clinical recovery in cerebral ischemia. J Nucl Med 28 1987 623. [30] Moretti JL, Defer G, Cinotti L, et al.: Comparative tomoscintigraphic study of stokes using ECD Tc-99m, HMPAO Tc-99m and IMP 1-123, preliminary results. Eur J Nucl Med 14(5/6) (1988) 311.

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[31] Mori H, Shiba K, Matsuda H, et al.: Characteristics of the binding of N-isopropyliodoamphetamineP^I] in rat brain synaptosomal membranes. Nucl Med Commun 11 (1990) 327. [32] Murase K, Tanada S, Fujita H, et al.: Kinetic behavior of technetium-99m-HMPAO in the human brain and quantification of cerebral blood flow using dynamic SPECT. J Nucl Med 33 (1992) 135 -143. [33] Nakagawara J, Nakamura J, Takeda R, et al.: Clinical comparison between Tc-99m ECD and 123I-IMP SPECT images in patients with cerebrovascular disease. J Cereb Blood How Metab 77(2) (1991) 31. [34] Neirinckx RD, Burke JF, Harrison RC, et al.: The retention mechanism of technetium99m-HM-PAO: intracellular reaction with glutathione. J Cereb Blood Flow Metab 8 (1988) 4 - 12. [35] Oldendorf WH: Need for new radiopharmaceuticals. J Nucl Med 19 (1978) 1182. [36] Pantano AP, Lenzi GL, Di Piero V, et al.: CBF-SPECT activation study by Tc-99mHM-PAO split-dose method. J Cereb Blood How Metab 77(2) (1991) 767. [37] Ring HA, George M, Costa DC, et al.: The use of cerebral activation procedures with single photon emission tomography. Eur J Nucl Med 18 (1991) 133 - 141. [38] Roy and Sherrington: J Physiol (London) 77 (1890) 85 - 108. [39] Shiba K, Mori H, Matsuda H, et al.: Technetium-99m p-Iodophenethyldiaminodithiol (DADT-IPE): potential brain perfusion imaging agent for SPECT. Nucl Med Biol 79(3) (1992) 303 - 310. [40] Shishido F, Uemura K, Murakami M, et al.: Arterial clearance and cerebral uptake of Tc-99m-ECD in patients with cerebrovascular disease compared with PET. Jpn J Nucl Med 29(1) (1992) 27 - 35.

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[41] Sperling B, Lassen NA: Hyperfixation of HMPAO in subacute ischemic stroke leading to spuriously high estimates of cerebral blood flow by SPECT. Stroke 24(2) (1993) 193 - 194. [42] Suzuki S, Sakai F, Akutsu T, et al.: Tracer kinetics of 123I-IMP, Tc-99m-HM-PAO and Tc-99m-ECD: Measurements of temporal changes in arterial and jugular venous radioactivity. J Cereb Blood Flow Metab 11(2) (1991) 774. [43] Verhoeff NPL, Buell U, Costa DC et a:. Basics and recommendations for brain SPECT. NuclMed 31 (1992) 114- 131. [44] Walovitch RC, Hill TC, Garrity ST: Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, Part 1: Pharmacology of technetium-99m ECD in nonhuman primates. J Nucl Med 30 (1989) 1892 - 1901. [45] Walovitch RC, Williams SJ, LaFrance ND: Radiolabeled agents for SPECT imaging of brain perfusion. Nucl Med Biol 17 (1990) 77 - 83. [46] Walovitch RC, Franceschi M, Picard M, et al.: Tc99m-ECD metabolism in healthy volunteers. Neuropharmacology 3 (1991) 283 - 292. [47] Walovitch RC, Sakowski R, Dorian SM: Intra subject comparison of Neurolite® to Ceretec™ in patients with stroke and dementia. J Nucl Med (1993) 34(5) 199. [48] Winchell HS, Baldwin RM, Lin TH: Development of I-123-labeled amines for brain studies: localisation of I-123-iodophenylalkyl amines in rat brain. J Nucl Med 21 (1980) 947.

SPECT BRAIN IMAGING IN PSYCHIATRIC DISORDERS: CURRENT CLINICAL STATUS

Ralph A. O'Connell, M.D. Clinical Director, Department of Psychiatry St. Vincent's Hospital and Medical Center Of New York Professor of Psychiatry, New York Medical College

Introduction New brain imaging technologies which permit direct and nontraumatic assessment of the living brain are naturally of interest to psychiatry.

Computed tomography (CT) and nuclear

magnetic resonance imaging (MRI) provide structural information.

Positron emission tomography (PET) and single

photon emission computed tomography (SPECT) measure functional aspects of cerebral blood flow and metabolism. All of these have current and potential applications in psychiatry (1). Single photon emission computed tomography (SPECT) has been available for over 10 years.

During this period there have

been significant advances in instrumentation.

Multihead

gamma camera systems now permit spatial resolution in the range of 6-8 mm, allowing good differentiation of cortical and subcortical structures.

A number of radiopharmaceuticals

are available which provide measures of regional cerebral blood flow (rCBF).

The inert gas Xenon 133 can be used with

SPECT to measure cerebral blood flow, but has limited spatial resolution.

Iodine 123 iofetamine (IMP) was the first

available radiopharamaceutical to measure regional cerebral

R. A. O'Connell

36

blood flow (rCBF).

More recently technetium-99m compounds

have been developed which measure rCBF.

Tc-99m

hexamethylpropyleneamine oxime (HMPAO) is currently available and Tc-99m ethyl cysteinate dimer (ECD) is in clinical trials.

Radiotracers which serve as neuroreceptor ligands

are also under development. SPECT has been found to be useful in the differential diagnosis and management of stroke, dementia and epilepsy (2).

There is a growing experience using cerebral SPECT in

psychiatric disorders (3,4).

SPECT technology has potential

in differential diagnosis, in understanding pathophysiology, and in predicting and monitoring treatment outcome.

However,

when a new technology becomes available careful evaluation of its evolving role in clinical practice is required.

Usually

this involves an accumulation of clinical experience followed by controlled trials. must be determined.

Diagnostic sensitivity and specificity The complexity of determining the

predictive power of diagnostic tests was illustrated in our experience with the dexamethasone suppression test (5). Besides differences in instrumentation and radiopharmaceuticals, several potentially confounding variables must be considered when comparing data from different brain imaging studies.

These include age, sex,

handedness, previous trauma or substance abuse, concurrent medical conditions, the length of the illness and exposure to treatments, especially antipsychotic medications.

The

possible effects of caffeine and nicotine have to be considered (6,7).

The state of the study subjects during the

SPECT brain imaging in psychiatric disorders radiotracer uptake is also a consideration.

Some studies

involve patients in the resting state, others while performing a cognitive task.

This paper will review the

recent literature on SPECT brain imaging in psychiatric disorders, with reference to relevant PET findings, and attempt to assess the current place of SPECT in clinical psychiatry.

Dementia Brain SPECT was studied initially in cerebrovascular disease, and since has been extensively evaluated in several types of dementia.

In Alzheimer's disease 1-123 IMP SPECT shows a

pattern of bilateral perfusion defects in posterior temporal and parietal regions which has been found to be accurate in diagnosis

(8).

Similar findings have been reported using Tc-

99m HMPAO

(9).

The SPECT pattern of multiple focal perfusion

defects in multi-infarct dementia

(MID) is distinguishable

from that seen in Alzheimer's disease (10).

SPECT scans have

demonstrated frontal and temporal hypoperfusion consistent with clinical and neuropsychological findings in patients with frontal lobe dementia (11).

Decreased rCBF to the

caudate has been demonstrated in patients with Huntington's chorea prior to evidence of atrophy with MRI

(12-14).

Neuropsychiatric symptoms are so common in AIDS that the condition has become an important consideration in the differential diagnosis of dementia.

In early HIV

encephalopathy, or AIDS Dementia Complex (ADC), CT and MRI scans are often normal.

In a study with IMP, 30 of 32

37

R. A. O'Connell

38

patients with HIV encephalopathy could be blindly distinguished from 15 non-HIV patients and 6 controls (15) . The SPECT scans in HIV patients showed multifocal cortical and subcortical areas of hypoperfusion.

In another study of

40 patients using HMPAO in early and advanced stages of HIV infection, all patients with HIV encephalopathy had pathological SPECT scans, 50% of whom had negative CT or MRI scans (16).

In a double-tracer study IMP and HMPAO were

compared in 25 patients with different clinical stages of AIDS (17).

HMPAO showed uptake defects to a greater extent

than IMP in patients in the earlier stages of AIDS.

One

group compared brain SPECT with HMPAO in ADC and chronic cocaine abusers (18).

These authors found cortical defects

in 100% of AIDS patients and 90% of cocaine abusers.

They

concluded that the patterns in the two populations could not be distinguished.

As IV drug abuse is a risk factor for

AIDS, they advised caution in arriving at a specific diagnosis based on SPECT pattern alone.

Partial complex Seizures Partial complex seizures can present as a psychiatric disorder, especially when the seizure focus is in the temporal lobe.

The focus may not always be evident on EEG

and SPECT has been helpful in localization (19-22).

The area

of the seizure focus is hypoperfused interictally, and hyperperfused during a seizure.

SPECT studies have

correlated well with EEG localization.

In complex partial

seizures refractory to medical treatment temporal lobectomy is an option.

SPECT imaging is now an accepted part of the

evaluation in these patients.

39

SPECT brain imaging in psychiatric disorders

Schizophrenia The most consistent functional brain imaging finding in schizophrenia, both PET and SPECT, has been diminished regional cerebral blood flow (rCBF) or metabolism in the prefrontal cortex (hypofrontality).

Increased basal ganglia

activity has been inconsistently noted and may be due to exposure to antipsychotic medications.

There are also

reports of abnormalities in temporal lobe rCBF. Recent well controlled PET studies (23,24) using 18-Fflurodeoxyglucose (FDG) have confirmed a relative hypofrontality in schizophrenia which is not due to previous treatment, age or cortical atrophy.

The hypofrontality is

associated with the negative symptoms of schizophrenia. Cognitive tasks specific to frontal lobe functions bring out the relative hypofrontality when compared to normal controls. In never medicated patients, basal ganglia metabolism is reported to be low compared to controls. SPECT brain imaging studies have generally been consistent with PET findings.

An earlier study using the 1-123 IMP

SPECT method (25) did not find hypofrontality in schizophrenic patients compared to controls, but did report increased caudate blood flow.

However, patients were scanned

at rest and medications were not controlled for.

Another

study (26), also with 1-123 IMP, did not observe hypofrontality in schizophrenics.

Recent controlled SPECT

studies using Xenon 133 have found hypofrontality in schizophrenics.

In monozygotic twins discordant for

R. A. O'Connell

40

schizophrenia scanned with Xenon 133 while doing the Wisconsin Card Sorting Test, a task which stimulates prefrontal function, all of the schizophrenic twins were hypofrontal

(27).

In another study using Xenon 133 (28),

decreased frontal lobe activation was noted in schizophrenics given the Tower of London test, a stimulant of left mesial frontal cortex.

The results suggested that the

hypofrontality is related to negative symptoms and not due to long-term neuroleptics or chronicity of illness.

There are now a number of reports using Tc 99m HMPAO in schizophrenia.

A pilot study reported significantly reduced

rCBF in the left anterior frontal region in schizophrenics compared to depressives (29).

Hypofrontality was not found

in a study of 10 medicated schizophrenics, but a relative increase in rCBF in the left hippocampus and basal ganglia was noted in the patients compared to controls (30).

A study

of 25 schizophrenics and matched controls found increased rCBF in caudate and thalamus in patients, thought to be secondary to neuroleptics (31).

Patients also showed

decreased rCBF in left frontal cortical regions, inversely correlated with negative symptoms, and increased rCBF in left posterior cortical regions.

In a study comparing newly

diagnosed, drug naive, schizophrenics (32), a significant deficit in left inferior prefrontal region rCBF in patients on activation with the Wisconsin Card Sorting Test and impaired striatal repression on the left side during the task were reported, which the authors hypothesized may be due to a lack of corticostriatal feedback.

Acute administration of

haloperidol has been found to reduce hypofrontality and

S P E C T brain imaging in psychiatric disorders

41

suppress hyperactivity in the dominant temporo-occipitalparietal regions in schizophrenics (33).

A study of 28

female schizophrenics and 11 controls (34) found that patients with predominantly positive symptoms had relatively normal and homogeneous cerebral blood flow, but that patients with negative symptoms, and chronic patients, showed inhomogeneous tracer uptake and multiple regions of hypoperfusion.

Temporal lobe abnormalities have also been reported in functional brain imaging studies of schizophrenics

(35).

Several groups have studied hallucinating schizophrenic patients.

One reported on a patient scanned with IMP while

hallucinating who had increased uptake in the left temporal region (36).

Another found significantly lower

frontal/occipital ratios and lower frontal/whole slice ratios using HMPAO in schizophrenics experiencing auditory hallucinations compared to normal controls (37).

SPECT

studies with HMPAO have reported temporal lobe asymmetries associated with auditory hallucinations in schizophrenic patients

(38,39).

At this stage, with increasing sophistication of technique and better resolution, SPECT studies are confirming the hypofrontality observed in PET studies of schizophrenics. This hypofrontality may be seen at rest, but is brought out more consistently by a cognitive challenges of frontal lobe function, and is related to the negative symptoms of the disorder.

At this time there are insufficient data available

on the sensitivity or specificity of these findings for the

R. A. O'Connell

42

diagnosis of schizophrenia.

The originally observed basal

ganglia findings were probably related to exposure to antipsychotic medications.

The relationship of temporal lobe

changes to acute psychosis needs further study. Affectiv* Disorders Several PET studies have demonstrated abnormalities in cerebral metabolism in depression.

Reduction in prefrontal

cortex glucose metabolism in unipolar depression, bipolar depression, and obsessive compulsive disorder with secondary depression has been reported (40).

The scores on the

Hamilton Rating Scale for Depression correlated negatively with the glucose metabolic rates in the left dorsal anterolateral prefrontal cortex.

The metabolic rates and

depression rating scores improved with antidepressant medication.

Ten severely depressed patients were studied

using FDG PET (41).

Left prefrontal glucose hypometabolism

was confirmed in the depressed state.

Another PET study of

33 patients with primary depression found a decrease in left anterior cingulate and left dorsolateral prefrontal cortex (42).

The authors also described a pattern peculiar to

depressed patients with reversible cognitive impairment.

A

brain metabolic pattern of globally lower metabolic rates, relatively lower superior medial frontal cortex rates, and somewhat higher rates in basal ganglia has been described in patients with seasonal affective disorder (43).

There have been few PET studies of patients in the manic state.

Unipolar depressives could be differentiated from

bipolar depressives in the depressed state using PET (44).

S P E C T brain imaging in psychiatric disorders

43

In all 9 cases in which a bipolar was scanned in both a depressed mood, and later in a normal or hypomanic state, the cerebral metabolic rate increased during the more euphoric mood.

SPECT studies of depression using the Xenon 133 method confirm the observations of reduced cerebral blood flow. A marked reduction in global cortical blood flow was found in 41 patients with major depressive disorder compared to 40 controls (45).

Cortical blood flow has been noted to be

significantly decreased in the left hemisphere of bipolar depressive compared to unipolars and controls (46).

In an

early SPECT study with 1-123 IMP decreased cortical and subcortical rCBF was reported in 22 major depressives (25). There were significant inverse correlations with the Hamilton depression score and the rCBF in all regions measured. Several manic patients were noted to have increased temporal lobe activity, but this finding was also noted in other acute psychoses.

In another IMP study (47), 12 out of 19 depressed

patients had increased uptake in the right temporal lobe, compared to only one of 12 medical controls. cortical rCBF was not reported.

Decreased

These authors suggested that

the asymmetry of temporal lobe activity may be of diagnostic utility.

IMP was also used to scan 32 patients with

endogenous depression and 10 normal controls (48).

The

depressed patients showed a generalized decrease in rCBF, greater in the left hemisphere, which was negatively correlated with the severity of depressive symptoms.

One

study using 99mTc-exametrazime (49) also showed reduced uptake in cortical and subcortical regions of depressed patients compared to controls.

44

R. A. O'Connell

Functional brain imaging studies generally confirm decreased cerebral blood flow in depression, more so in the left frontal cortex.

These findings, initially seen in PET

studies, have been replicated with SPECT.

The decrease in

rCBF seems to be related to depression as a symptom or syndrome, rather than to a specific depressive disorder, although it may be more evident in bipolar depression.

The

decreased rCBF is reversible to some extent on clinical improvement.

In a review of the dementia spectrum of

depression (50), the authors point out that in functional neuroimaging, primary degenerative dementia has a characteristic pattern involving the posterior parietal cortex, and extending into adjacent temporal and occipital lobes, sparing the sensory motor cortex.

This pattern is not

found in patients with primary depression and this difference can be helpful in differential diagnosis. Anxiety Disorders There are few functional brain imaging studies in anxiety disorders.

PET studies have demonstrated increased rates of

glucose metabolism in the frontal lobes (hyperfrontality) of patients with obsessive compulsive disorder (OCD).

In a

controlled study (51), significantly elevated metabolic rates in both cerebral hemispheres, the heads of the caudate nuclei and orbital gyri were found in OCD patients.

Eighteen adults

with childhood onset of OCD were scanned with FDG PET (52). Patients had increased metabolic rates in the left orbital frontal, right sensorimotor, and bilateral prefrontal and anterior cingulate regions compared to controls.

SPECT brain imaging in psychiatric disorders

45

Similar findings have been reported using SPECT. In a pilot study of 10 OCD patients using HMPAO (53), a relative increase in rCBF in basal ganglia and the anterior cingulate gyrus was found.

In another study

(54) also using

HMPAO, OCD patients had significantly higher ratios of medial-frontal to whole cortex CBF than controls.

The

findings were unrelated to scores on the Yale-Brown Obsessive Compulsive Scale but correlated negatively with anxiety. Using discriminant function analysis 80% of the patients were correctly identified.

This same group found that the

hyperfrontality was significantly reduced on treatment with fluoxetine

(55).

OCD patients were scanned with both Xenon 133 and Tc 99m HMPAO

(56).

The Xenon method did not detect significant

differences in cortical or basal ganglia blood flow between OCD patients and controls.

Using HMPAO the patients were

noted to have significantly increased uptake in dorsal parietal cortex bilaterally, in left posterior frontal cortex, and in bilateral orbital frontal cortex.

There was

also significantly reduced uptake in the head of the caudate in the OCD patients.

The pattern of increased frontal rCBF

seems to be associated with obsessive compulsive disorder.

PET has also been used in panic disorder.

Patients

vulnerable to lactate induced panic attacks showed an abnormal hemispheric asymmetry of parahippocampal blood flow, blood volume, and oxygen metabolism; and an abnormally high whole brain metabolism in the resting, non-panic state

(57).

Hippocampal asymmetry has also been noted in patients with

46

R. A. O'Connell panic disorder (58) .

Metabolic decreases in the left

inferior parietal lobe and the anterior cingulate gyrus and medial orbital frontal cortex during a task of auditory discrimination were also seen.

However, these studies must

be considered with caution as readings of increased temporal lobe metabolism have been shown to be due to extracranial muscle blood flow associated with arousal (59). been few SPECT studies of panic disorder.

There have

One group (60),

using HMPAO SPECT noted that yohimbine consistently reduces frontal rCBF in patients with panic disorder, but not controls.

They interpret this as a possible abnormality in

the projection from the locus ceruleus in panic disorder patients.

Generalized anxiety disorder is a difficult diagnosis to study because of the somewhat fluid diagnostic criteria. Eighteen patients with generalized anxiety disorder and 15 controls were studied using PET (61).

In a passive viewing

task, off medications, patients had lower absolute brain 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 in the right precentral frontal gyrus.

Significant left-right

asymmetry of the parahippocampal gyri was not found.

An

active vigilance task caused increased basal ganglia metabolism in patients.

Benzodiazepine medication reduced

absolute metabolic rates.

In an other study CBF was measured

with 133 Xenon in patients with generalized anxiety disorder compared to controls (62).

Significant inverse correlations

with CBF and state anxiety were found in most brain regions.

47

SPECT brain imaging in psychiatric disorders Functional brain imaging studies of the anxiety disorders are complicated by problems of diagnostic reliability and confounding variables.

SPECT studies of OCD generally

confirm PET findings of hyperfrontality. panic disorder with SPECT are needed.

Further studies of

It will be important

to differentiate SPECT patterns which are specific to an anxiety disorder from patterns which are related to state anxiety.

The relationship between CBF and anxiety is

complicated (63).

The former can be influenced by such

anxiety-related changes as catecholamines, blood viscosity and CO2 levels.

Psychoactive Substance Use Disorders There have been a number of both PET and SPECT studies of patients with alcohol and cocaine abuse.

Both of these

disorders have a high incidence and are often comorbid with other psychiatric disorders.

FDG PET was used to study 22

neurologically intact healthy alcoholics compared to controls (64).

Alcoholics had significantly lower whole

brain metabolism, more marked in the left parietal and right frontal regions.

The patients had no neurological symptoms

and minimal or no brain morphological changes.

The authors

attributed the findings to the direct effect of alcohol as well as alcohol withdrawal on brain metabolism.

Evidence of

functional disruption of right-sided and frontal brain regions and hyperactivity of cerebellar-cortical connections in alcoholic chronic organic mental disorders has also been noted (65) .

Similar findings are seen with SPECT.

In a

study of chronic alcoholic men with Xenon 133 (66), reduced mean CBF was noted in patients.

The low flow rates seen were

R. A. O'Connell

48

associated with the severity of the alcoholism, cerebral atrophy and mental impairment.

Decreased CBF in 24 out of 26

alcoholic patients scanned with HMPAO has been reported, the frontal region and left hemisphere being more affected

(67).

The SPECT patterns of Alzheimer's disease could be distinguished from that of Korsakoff's psychosis using TcHMPAO (68) .

Impaired flow in frontal regions was correlated

with poor performance on tests of memory and orientation.

At least 2 centers have used FDG PET to study the effects of cocaine on cerebral metabolism.

One examined the acute

effects of cocaine hydrochloride vs. saline placebo in 8 polydrug abusers (69).

Cocaine induced euphoria and reduced

glucose metabolism globally in 26 of 29 brain regions.

No

significant effects were seen in the pons, cerebellar cortex or vermis.

However the authors note that decreases in

cerebral metabolism are seen in human subjects given other euphoriants including benzodiazepines, barbiturates and amphetamines.

Another group investigated changes in brain

function associated with cocaine dependence and withdrawal (70) .

Patients studied within 1 week of last cocaine use had

higher levels of global brain metabolism, as well as higher levels of regional metabolism in basal ganglia and orbitofrontal areas than controls.

This was not true of

patients studied 2 to 4 weeks after withdrawal.

The authors

concluded that the time-dependent fall in metabolic activity represented a function of drug withdrawal related to dopamine activity.

Scattered focal cortical deficits in 12 habitual

cocaine abusers have been noted in an IMP SPECT study (71). The deficits ranged from small and few to multiple and large

SPECT brain imaging in psychiatric disorders

49

and had a predilection for frontal and temporal lobes. However, as cited above (18), these authors cautioned that this pattern did not be distinguish AIDS dementia complex from chronic cocaine abuse.

Discussion The assessment of the appropriate clinical role of any new medical technology is a challenge, particularly for psychiatry, where the technology is presumed to measure functional brain mechanisms related to psychopathology.

The

history of medicine documents the "uncritical acceptance of medical innovation"

(72).

The poor quality of the early

evaluation of MRI is an illustrative case (73) .

More recent

prospective studies of the accuracy of MRI have used methodologically rigorous designs to determine diagnostic specificity and sensitivity

(74) .

The evaluation of SPECT

studies of psychiatric disorders is complicated for at least three reasons: 1) the general lack of etiologically based diagnoses in psychiatry, 2) the probable heterogeneity of most psychiatric disorders, and 3) the many potential confounding variables inherent to the studies.

The ideal diagnosis is etiologically based.

Robins and Guze

(75), following the medical model, proposed four criteria for establishing the diagnostic validity of a psychiatric disorder: clinical outcome, family loading, treatment response and laboratory tests.

This model, which has had

significant influence on psychiatric research, assumes that a specific psychiatric disorder has a single etiology, with a

R. A. O'Connell

50

predictable course of illness and response to treatment.

At

present SPECT has a more established clinical role in disorders such as cerebrovascular disease, dementia and epilepsy where the etiopathogenesis is better understood. The SPECT patterns in these disorders are understandable in conjunction with the known pathophysiology and in the context of the clinical picture SPECT is helpful in diagnosis.

This

is not the case in the "functional" psychiatric disorders, e.g. schizophrenia, for which there are no known single etiologies or validated biological markers.

It is now

generally assumed that the major psychiatric disorders are heterogeneous.

They are clinical syndromes, with somewhat

fuzzy boundaries, which most likely subsume different etiologies.

Consequently different brain image patterns

should be expected when subjects are grouped solely on diagnosis.

The field has become more aware of this issue in

studies of schizophrenia and bipolar disorder (76).

PET

studies have shown evidence for common alterations of glucose metabolism in schizophrenia and affective disorders (77).

No

matter how rigorous the diagnostic criteria used to select subjects, it is unlikey that SPECT studies based on diagnosis alone will be sufficient.

Another approach, complimentary to and not exclusive of diagnosis, is to include dimensions of psychopathology and clinical history as variables.

Andreasen et al (78) have

developed a good instrument along these lines.

An example

where this has been productive is the correlation of negative symptoms with hypofrontality in schizophrenia.

Another

example is the relationship of left temporal abnormalities to

SPECT brain imaging in psychiatric disorders

51

thought disorder reported in a computerized, quantitative MRI study of schizophrenics

(79).

Future SPECT studies should

include measures such as cognitive functions, positive or negative symptoms, affect or anxiety.

Reliable rating scales

are available for these dimensions of psychopathology.

It is

probable that specific SPECT patterns will be more strongly correlated with a dimension than a specific diagnosis. patterns need to be compared across diagnoses.

SPECT

An increased

ventricular brain ratios (VBR) was first described in schizophrenia but has since been described in other psychoses.

Potentially confounding variables which affect cerebral blood flow have to be controlled for in SPECT studies.

These

include age, sex, exposure to medications, smoking, alcohol and substance abuse, head trauma and the subject's psychological state at the time of the study among others.

A

history of childhood developmental disorders must also be considered.

It would be advantageous to develop some

uniformity of protocols so studies can be compared. Standardization of cognitive tasks may be required.

SPECT is a powerful technology with a great potential for diagnosis and research in psychiatry.

As the first

generation of studies evolved over the past ten years its value has become more evident.

As with MRI and PET, the next

phase should incorporate rigorous methods to insure comparability of diagnosis, dimensions of psychopathology, subject variables and scanning protocols.

R. A. O'Connell

52

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53

54

R. A. O'Connell 29. Sauer H, Schroder J, Henningesen H et al: R e g i o n a l c e r e b r a l b l o o d flow in endogenous p s y c h o s e s m e a s u r e d b y 99m T c H M P A O SPECT. Eur N e u r o p s y c h o p h a r m a c o l o g y 1 9 9 0 ; 1 : 7 1 - 7 3 . 30. K a w a s a k i Y, Suzuki M { Maeda Y e t al: R e g i o n a l c e r e b r a l b l o o d flow in p a t i e n t s w i t h schizophrenia: A p r e l i m i n a r y r e p o r t . Eur A r c h P s y c h i a t r y 1992;241:195-200. 31. L e w i s SW, F o r d RA, S y e d GM et al: A c o n t r o l l e d s t u d y of 9 9 m T c - H M P A O s i n g l e - p h o t o n emission imaging in c h r o n i c s c h i z o p h r e n i a . P s y c h o l M e d 1992;22:27-35. 32. R u b i n P, H o l m S, Friberg L et al: A l t e r e d m o d u l a t i o n of p r e f r o n t a l a n d s u b c o r t i c a l brain a c t i v i t y in n e w l y d i a g n o s e d s c h i z o p h r e n i a a n d schizophreniform disorder. A r c h G e n Psychiatry 1991;48:987-995. 33. M a t s u d a H, Jibiki I, Kinuya K e t al: Tc-99 H M P A O SPECT a n a l y s i s of n e u r o l e p t i c effects o n r e g i o n a l b r a i n function. C l i n N u c l M e d 1991;16:660-664. 34. B a j c M, M e d v e d V, B a s i c M e t al: C e r e b r a l p e r f u s i o n i n h o m o g e n e i t i e s in schizophrenia d e m o n s t r a t e d w i t h s i n g l e p h o t o n e m i s s i o n c o m p u t e d tomography a n d Tc 9 9 m hexamethylpropyleneamineoxime. Acta Psychaitr Scand 1989;80:427-433. 35. Gur, RE, P e a r l s o n { GD: Neuroimaging in s c h i z o p h r e n i a r e s e a r c h . S c h i z o p h r e n i a Bulletin 1993; 19:337-352. 36. M a t s u d a H, G y o b u T, II M e t al: I n c r e a s e d a c c u m u l a t i o n of N - i s o p r o p y l - ( 1 - 1 2 3 ) p - i o d o a m p h e t a m i n e in t h e l e f t a u d i t o r y a r e a in a s c h i z o p h r e n i c patient w i t h a u d i t o r y h a l l u c i n a t i o n s . Clin Nucl M e d 1988;13:53. 37. E r b a s B, K u m b a s a r H, Erbengi G, B e k d i k C: T c - 9 9 m H M P A O / S P E C T d e t e r m i n a t i o n of regional c e r e b r a l b l o o d flow c h a n g e s in s c h i z o p h r e n i c s . Clin Nucl M e d 1 9 9 0 ; 1 5 : 9 0 4 - 9 0 7 . 38. A n d e r s o n J, Fawdry R, Gordon E et al: S P E C T a s y m m e t r y of l e f t t e m p o r a l lobe in h a l l u c i n a t e d s c h i z o p h r e n i c s . Biol Psychiatry 1991;29:291. 39. M u s a l e k M, P o d r e k a I, Walter H et al: R e g i o n a l b r a i n f u n c t i o n in h a l l u c i n a t i o n s : A study of r e g i o n a l c e r e b r a l b l o o d flow w i t h 99m-Tc-HMPAO-SPECT in p a t i e n t s w i t h a u d i t o r y h a l l u c i n a t i o n s , t a c t i l e hallucinations and n o r m a l c o n t r o l s . C o m p r P s y c h i a t r y 1989;30:99-108. 40. B a x t e r L R Jr, S c h w a r t z JM, Phelps M E e t al: R e d u c t i o n of p r e f r o n t a l c o r t e x g l u c o s e metabolism c o m m o n t o t h r e e t y p e s of d e p r e s s i o n . A r c h G e n Psychiatry 1989; 4 6 : 2 4 3 - 2 5 0 . 41. M a r t i n o t J - L , H a r d y P, Feline A et al: L e f t p r e f r o n t a l g l u c o s e h y p o m e t a b o l i s m in the d e p r e s s e d state: A c o n f i r m a t i o n . A m J Psychiatry 1990; 1 4 7 : 1 3 1 3 - 1 3 1 7 . 42. B e n c h CJ, F r i s t o n KJ, Brown RG et al: T h e a n a t o m y of m e l a n c h o l i a : F o c a l a b n o r m a l i t i e s of c e r e b r a l b l o o d flow in m a j o r d e p r e s s i o n . P s y c h o l Med 1 9 9 2 ; 2 2 : 6 0 7 - 6 1 5 .

S P E C T brain imaging in psychiatric disorders

55

43. C o h e n RM, G r o s s M, Nordahl T E et al: P r e l i m i n a r y d a t a on t h e m e t a b o l i c b r a i n p a t t e r n of p a t i e n t s w i t h s e a s o n a l affective disorder. Arch Gen Psychiatry 1992;49:545-552. 44. S c h w a r t z JM, Baxter L R Jr, M a z z i o t t a J C et al: T h e d i f f e r e n t i a l d i a g n o s i s of depression: R e l e v a n c e of p o s i t r o n e m i s s i o n c o m p u t e d tomography s t u d i e s of cerebral g l u c o s e m e t a b o l i s m t o t h e b i p o l a r - u n i p o l a r dichotomy. J A M A 1987;258:1368-1374. 45. S a c k e i m HA, P r o h o v n i k I, M o e l l e r J R et al: R e g i o n a l c e r e b r a l b l o o d flow in m o o d disorders: I. C o m p a r i s o n of m a j o r d e p r e s s i v e s a n d normal controls a t rest. A r c h G e n P s y c h i a t r y 1990;47:60-70. 46. D e l v e n n e V, D e l e c l u s e F, H u b a i n PhP e t al: R e g i o n a l c e r e b r a l b l o o d flow in p a t i e n t s w i t h affective d i s o r d e r s . J P s y c h i a t r y 1990;157:359-365.

Br

47. A m s t e r d a m JD, Mozley PD: T e m p o r a l lobe a s y m m e t r y w i t h i o f e t a m i n e (IMP) SPECT imaging in p a t i e n t s w i t h m a j o r d e p r e s s i o n . J A f f e c t Disorder 1992;24:43-53. 48. K a n a y a T, Y o n e k a w a M: R e g i o n a l cerebral b l o o d flow d e p r e s s i o n . J p n J Psychiatry N e u r o l 1990;44:571-576.

in

49. A u s t i n MP, Dougall N, R o s s M et al: Single p h o t o n e m i s s i o n t o m o g r a p h y w i t h 9 9 m T c - e x a m e t a z i m e in m a j o r d e p r e s s i o n a n d t h e p a t t e r n of b r a i n activity u n d e r l y i n g the p s y c h o t i c / n e u r o t i c continuum. J A f f e c t D i s o r d e r 1 9 9 2 ; 2 6 : 3 1 43. 50. Emery VO, O x m a n TE: U p d a t e o n t h e d e m e n t i a s p e c t r u m of d e p r e s s i o n . A m J Psychiatry 1992;149:305-317. 51. B a x t e r LR Jr, Schwartz JM, M a z z i o t t a J C et al: C e r e b r a l g l u c o s e m e t a b o l i c rates in n o n d e p r e s s e d p a t i e n t s w i t h o b s e s s i v e - c o m p u l s i v e disorder. A m J Psychiatry 1988; 145:1560-1563. 52. S w e d o SE, Schapiro MB, Grady C L et al: C e r e b r a l g l u c o s e m e t a b o l i s m in c h i l d h o o d - o n s e t o b s e s s i v e c o m p u l s i v e d i s o r d e r . A r c h G e n P s y c h i a t r y 1988;46:518-523. 53. G o o d m a n W K , M c D o u g l e CJ, Price LH e t al: S P E C T i m a g i n g of obsessive-compulsive disorder with Tc99m d,l-HMPAO. J Nucl M e d 1990 ; 31: 750 54. M a c h l i n SR, H a r r i s GJ, P e a r s l s o n GD e t al: E l e v a t e d m e d i a l - f r o n t a l cerebral b l o o d flow in o b s e s s i v e - c o m p u l s i v e p a t i e n t s : A S P E C T study. A m J Psychiatry 1 9 9 1 ; 1 4 8 : 1 2 4 0 - 1 2 4 2 . 55. H o e h n - S a r i c R { P e a r l s o n GD, H a r r i s GJ: E f f e c t s of f l u o x e t i n e o n r e g i o n a l cerebral b l o o d flow in o b s e s s i v e c o m p u l s i v e p a t i e n t s . A m J Psychiatry 1 9 9 1 ; 1 4 8 : 1 2 4 3 - 1 2 4 5 .

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56. Rubin RT, Villanueva-Meyer J, Ananth J: Regional Xenon 133 cerebral blood flow and cerebral technetium 99m HMPAO uptake in unmedicated patients with obsessive-compulsive disorder and matched normal control subjects. Arch Gen Psychiatry 1992;49:695-702. 57. Reiman EM, Raichle ME, Robins E et als Neuroanatomical correlates of a lactate-induced panic attack. Arch Gen Psychiatry 1989;46:493-500. 58. Nordahl TE, Semple WE, Gross M et al: Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacolgy 1990;3:261-272. 59. Drevets WC, Videen TO, MacLeod AK et al: PET images of blood flow changes during anxiety: Correction. Science 1992;256:1696. 60. Woods SW: Regional cerebral blood flow imaging with SPECT in psychiatric disease: Focus on schizophrenia, anxiety disorders, and substance abuse. J Clin Psychiatry 1992; 53:(suppl)20-25. 61. Wu JC< Buchsbaum MS, Hershey TG et al: PET in generalized anxiety disorder. Biol Psychiatry 1991;29:1181-1199. 62. Mathew RJ, Weinman ML, Claghorn JL: Anxiety and cerebral blood flow. In Mathew RJ (Ed): The Biology of Anxiety. Bruner Mazel, New York, 1982. 63. Wilson WH, Mathew RJ: Cerebral blood flow and metabolism in anxiety disorders. In Hoehn-Saric R, McLeod DR: Biology of Anxiety Disorders. American Psychiatric Press, Washington, DC, 1993. 64. Volkow ND, Hitzemann R, Wang GJ et al: Decreased brain metabolism in neurologically intact healthy alcoholics. Am J Psychiatry 1992;149:1016-1022. 65. Martin PR, Rio D, Adinoff B et al: Regional cerebral glucose utilization in chronic organic mental disorders associated with alcoholism. J Neuropsychiatry Clin Neurosci 1992;4:159-167. 66. Melgaard B, Henriksen L, Ahlgren P et al: Regional cerebral blood flow in chronic alcoholics measured by single photon emission computerized tomography. Acta Neurol Scand 1990;82:87-93. 67. Erbas B, Bekdik C, Erbengi G et al: Regional cerebral blood flow changes in chronic alcoholism using Tc-99m HMPAO SPECT: Comparison with CT parameters. Clin Nucl Med 1992;17:123-127. 68. Hunter R, McKluskie R, Wyper D et al: The pattern of function-related regional cerebral blood flow investigated by single photon emission tomography with 99m Tc-HMPAO in patients with presenile Alzheimer's disease and Korsakoff's psychosis. Psychol Med 1989;19:847-855.

SPECT brain imaging in psychiatric disorders 69. London ED, Cascella NG, Wong DF et al: Cocaine-induced reduction of glucose utilization in human brain. A r c h G e n Psychiatry 1990;47:567-574. 70. Volkow ND, Fowler JS, Wolf A P et al: Changes in b r a i n glucose metabolism in cocaine dependence and withdrawal. Am J Psychiatry 1991;148:1759-1760. 71. Tumeh SS, Nagel JS, English R J et al: Cerebral abnormalities in cocaine abusers: Demonstration by SPECT perfusion brain scintigraphy. Work in progress. Radiology 1990;176:821-824. 72. Grimes DA: Technology follies: The uncritical acceptance of medical innovation. JAMA 1993;269:3030-3033. 73. Cooper LS, Chalmers TC, McCally M et al: The poor guality of early evaluations of magnetic resonance imaging. JAMA 1988;259:3277-3280. 74. M u s h l i n AI, Detsky AS, Phelps CE et al: The accuracy of m a g n e t i c resonance imaging in patients with suspected multiple sclerosis. JAMA 1993;269:3146-3151. 75. Robins E, Guze SB: Establishment of diagnostic validity in psychiatric illness: Its application to scizophrenia. A m J Psychiatry 1970;126:983-987. 76. Blacker D, Tsuang MT: Contested boundaries of bipolar disorder and the limits of categorical diagnosis in psychiatry. A m J Psychiatry 1992;149:1473-1483. 77. Cohen R M { Semple WE, Gross M et al: Evidence for common alterations in cerebral glucose metabolism in schizophrenia and major affective disorders. Neuropsychopharmacology 1989; 2:241-254. 78. Andreasen NC, Flaum M, Arndt S: The Comprehensive Assessment of Symptoms and History (CASH): A n instrument for assessing psychopathology and diagnosis. Arch Gen Psychiatry 1992;49:615-623. 79. Shenton ME, Kikinis R, Jolesz FA et al: Left-lateralized temporal lobe abnormalities in schizophrenia and their relationship to thought disorder: A computerized, quantitative MRI study. N Eng J Med 1992;327:604-612.

57

HMPAO-SPECT results P. Danos, Broich, G. Department Clinic for University Department Austria

findings in opioid polydrug users

- preliminary

S. Kasper, E. Klemm, F. Grunwald, C. Krappel, K. Höflich, B. Overbeck, H.-J. Biersack, H.-J. Moller of Psychiatry (P.D., G.H., C.K, H.J.M.) and the Nuclear Medicine (E.K., F.G., B.O., H.J.B.) of the of Bonn, Germany of Psychiatry (S.K.) of the University of Vienna,

Department of Psychiatry Germany

(K.B.) of the University of Halle,

Introduction Substance abuse disorders constitute a special challenge to psychiatric research today [12]. There are reports which revealed atrophic brain changes in heroin addicts [15, 26] . Animal studies support these findings by showing that endogenous opioids [14] and morphine [25] can directly modify neural growth. However, other CT and MRI-studies did not replicate pathological morphological,findings in opioid dependents [1, 7, 34] . There are just a few studies exploring the changes of the cerebral blood flow in opioid dependency. Single case reports indicated that heroin can induce cerebro-vascular accidents [5], the neurobiological substrate being not yet conclusive. Animal studies have suggested that heroin (3,6-diacetylmorphine) and it's metabolites (6-acteylmorphine and morphine) [16] have a significant effect on the glucose consumption or blood flow. Except for one study [28] most of the studies [3, 9] found a decrease of the blood flow in the limbic and cortical regions of the rat as an effect of opioids. As a result of the study by Volkow et al. [32] it is hypothesized that the main toxic

60

P. Danos et al.

effect of drug abuse is due to a disturbed cerebral tion.

The metabolic

effects

of one

dose of morphine

cerebral blood flow were described by London et al. have

found significant

reduced blood

circulaon

the

[18], who

flow in whole brain and

six cortical areas in a Fluorodeoxyglucose-PET-study. However, the effects of the chronic heroin uptake on regional cerebral blood flow have not yet been investigated. Human studies have shown that cannabis [35], barbiturates

[33], cocaine

[27] or tranquilizer

[31], amphetamines

[6] are known to have

an influence on cerebral blood flow. We also wanted to relate the

findings

additional

of

the blood

consumption

amphetamines,

flow measurements

of

barbiturates,

other

drugs

data

(cannabis,

tranquilizer),

(age, sex) and clinical variables

with with

about

cocaine,

demographic

(duration of the consumption

of opioids, detoxification data) .

Methods

Subjects We

performed

40

SPECT-studies

in

37

(19

females,

18

males)

patients who were opioid addicted and fulfilled the DSM-III-R criteria for opioid dependence (304.00). All the patients gave their patient

informed group

consent consisted

to

participate

of

19 women

in

and

this 18 men

study.

The

whose

ages

ranged from 17 to 40 years (mean=27.0 years, SD=4.7). The average height was

173.9 cm

(SD=8.8) and the average weight

was

64.2 kg (SD=10.4). Thirty-two patients (86%) were right-handed, 5

(13%) patients were

left-handed. All

HIV-negative. Thirty-four

of

the patients

were

(92%) patients were addicted to her-

oin, 3 (8%) patients were substituted with levomethadone before they were included in the study. The mean duration of the heroin use was

5.7 years

(SD=4.3) , the average amount

of

daily

HMPAO-SPECT findings in opioid polydrug users street-heroin was 1056 mg/day patients

who

were

only

(SD=465). There w e r e just 5 (13%)

heroin-dependent:

patients w e r e also dependent Twenty-two also Two

were

(5%)

(DSM-III-R:

also dependent

on

(62%)

304.30).

tranquilizer

(DSM-III-R: 304.10). Eleven (29%) patients w e r e

dependent

patients

Twenty-three

o n cannabis

(59%) patients w e r e

or barbiturates

61

on

cocaine

also

(DSM-III-R:

304.20)

amphetamine-dependent

patients

were

also

and

9

(DSM-III-R:

alcohol-dependent

(24%)

304.40).

(DSM-III-R:

303.90). All patients were

clinically a s s e s s e d daily w i t h the

Global

scale

Impression

measured

daily

[21].

The

degree

of

w i t h the Opiate Withdrawal

Clinical

withdrawals

Scale

[4,

was

modified

version by Kasper/Danos]. Five

(13%)

study.

patients

received n o m e d i c a t i o n

Thirty-two

(80%)

patients

during

received

the

SPECT-

levomethadone

(mean=19.5 mg/day, SD=2.6) on the day of the SPECT-study a n d 11 (28%) patients also received diazepam in addition to the levomethadone mg/day;

(mean=9.2 mg/day; SD=4.8), or clorazepate SD=10.8).

prothixen

Fourteen

(35%)

(mean=115.5 mg/day;

patients

(mean=17.8

received

chlor-

SD=71.4).

SPECT Imaging For

studying

cerebral

perfusion,

w e used

technetium-99m-HMPAO

as a tracer for cerebral b l o o d flow. This imaging technique has been previously described in detail

[13]. Brain SPECT w a s per-

formed 30 min. after i.v. injection of 555 M B q (15 mCi)

techne-

tium- 99m-HMPAO. During the injection, subjects lay quietly w i t h their

eyes

(Genesys, n=10)

open.

ADAC,

rotating

SPECT

n=30) gamma

matrix. Transaxial,

or

was

performed

a

double-head

camera.

Data

were

using

a

single-head

(DYNA-SCAN, stored

in

coronal a n d sagittal slices w e r e

(2 pixels thick). For the transaxial

Picker, a

64x64

generated

images w e u s e d a

special

P. Danos et al.

62

cut

parallel

to

the

longitudinal

axis

of

the

temporal

lobe

[13] . The spatial resolution was about 15 mm with the Picker-camera and 12 mm for the ADAC-camera, respectively. The spatial resolution of both systems is in the same range, some minor differences due to the different systems used must be considered, but major alterations of the values are not expected. The SPECT-studies (mean=7.4;

(n=40) were performed during the first

SD=4.3)

of

detoxification.

In

one

days

patient

we

assessed 2 SPECT-studies and in one patient 3 SPECT-studies.

Data analysis Forty

SPECT-scans

were

analyzed

qualitatively

by

experienced

nuclear medicine physicians blind to the patients drug status. For the Quantitative

analysis,

14 square regions of

interest

were placed in both frontal lobes, lateral and medial temporal lobes, parietal lobes, occipital lobes, basal ganglia and both sides of the cerebellum. We used the average counts/pixel of a transaxial slice and in addition a coronal or sagittal slice for each region. An angle of 90° between the transaxial and the coronal or sagittal slice was

chosen.

ganglia,

Transaxial

cerebellum,

slices were

and

the

placed

temporal

through

lobes.

the

Coronal

were placed through the temporal lobes and the basal

basal slices

ganglia.

Sagittal slices were located 4 pixel right and left lateral to the median slice. For evaluating regional cerebral blood

flow

(rCBF), we calculated a regional index as a ratio between the averaged counts/pixel of two slices'(transaxial and coronal or sagittal,

respectively) of one region and the total count of

all regions.

HMPAO-SPECT findings in opioid polydrug users

63

Quantitative calculations were performed by an experienced nuclear medical physician (E.K.) who was blind to the qualitative assessment. The relative rCBF of areas with qualitatively described decreases was compared with relative rCBF of normal areas of the same localization. For statistical reasons we selected areas with a decrease of perfusion in at least 5 SPECT-studies. Relative regional cerebral blood flow was measured by indices which show the ratio between counts/pixel of one region of interest and mean counts/pixel of all regions of interest.

Statistical analysis All results are reported with means and standard deviations. We compared the indices of the regions of interest with the qualitative observations using two-tailed t-test procedures. A significance level of p 97%. After administration of Na-perchlorate to block the ligand absorption in the thyroid, the subjects received 5 mCi (185 MBq) [123J]G(_)JBZM as an intravenous bolus injection. A rotating dual-head gamma camera (Siemens Dual Rota ZLC37) was used for the SPECT examination. This was connected, on-line, to a computer (Nodecrest Micas 2000). The camera heads were equipped with low-energy, all purpose (LEAP) collimators. The precise details of the data collection and processing, the image reconstruction and attenuation correction are described elsewhere in detail (24). Reconstructed, transversal slices (15.6 mm thick) were used for the evaluation. These slices overlapped and were shifted 3.1 mm in an axial direction from

150

Ch.Wober et al.

one another. Those slices in which the striatum was best visible were selected. Regions were then drawn in the left and right striatum and the left and right frontal cortex and the counts/pixels calculated. This procedure was repeated in adjacent slices and the maximum values used for further calculations to exclude tilting effects. The values in the striatum (total binding) and in the frontal cortex (non-specific binding) were each determined between left and right and then a ratio between striatal and frontal count-rate was formed. This ratio reduced by 1 is the ratio specific/non-specific binding. Under equilibrium conditions and if non-specific binding in the frontal reference region and on the striatum is equal, this corresponds to the binding potential B^x/K^ of striatal D2 receptors and is directly proportional to the receptor density Bjnax- Because there is a clear age-dependency of the D2 receptor binding with decreasing binding in increasing age (5, 7), the binding potential of patients treated was compared with age-matched controls and the values expressed in % control value. Student's t-test for unpaired values (two-sided) was used for statistical analysis. Results

Effect of typical receptors

and atypical neuroleptics

on dopamine D2

The D2 receptor binding potential (=specific/non-specific binding) under therapy with typical neuroleptics was 0.30 ± 0.15; under therapy with the atypical neuroleptic clozapine it was 0.68 ± 0.18. In comparison, a value of 0.73 ± 0.09 was measured in the medication-free, healthy control group. In percent of the age-matched normal value, the mean receptor blockade under typical neuroleptics was 59.7 ± 21.0; under clozapine 20.3 ± 16.2. With typical neuroleptics the receptor blockade increased

The pharmacological influence on striatal dopamine D2 receptor

151

in accordance to an exponential function with increasing chlorpromazine-units. Under clozapine such a relationship could not be detected despite a sufficient antipsychotic effect. In some patients the receptor blockade was totally lacking (tabs. 1, 2; fig. 1, 2). In 2 patients under therapy with 300 mg remoxipride daily, the receptor blockade was 67% and 69% (fig. 3). Effect of calcium channel-blockers on dopamine D2 receptors Under therapy with flunarizine or cinnarizine the D2 receptor binding potential was reduced in all patients compared to the age-matched normal value (0.45 ± 0.14 vs. 0.73 ± 0.09; tab. 3; fig. 4). This difference corresponds to an average D2 receptor blockade of 38.0 ± 14.6% and was statistically highly significant (p 5

> 10

. 15

- -H 20

25

, 30

Chlorpromazin equivalents

Fig. 1: Dosage of classical neuroleptics in chlorpromazine equivalents (mg/kg BW) and dopamine D2 receptor binding potential (logarithmic scale)

0.1

-

0

'

'

5

10

1

15

Chlorpromazin equivalents

Fig. 2: Clozapine dosage in chlorpromazine equivalents (mg/kg BW) and dopamine D2 receptor binding potential (logarithmic scale)

154

Ch. Wöber et al.

73 •a c 500

mg

in

two

medications, non-responders 6-8 weeks

of

chlorpromazine

equivalents per day; calculated according to Wressell et al [35] at some point during their illness. Patients were permitted to continue w i t h routine anti-cholinergic treatment. The following operational responders following severe

criteria were applied to the patient had

to

have

a BPRS

score

indicators of poor social

residual

positive

and

of

45 or more,

and clinical

negative

group. and

Nonthe

performance:

symptoms

affecting

behaviour, high dependency o n others for most of the activities of daily living (eg shopping, cooking, cleaning), marked social isolation and poor self care [31]. By applying these criteria 10 responders and 8 non-responders were identified. There were no significant differences between groups in terms of age, illness duration, treatment duration or type of treatment.

123

BPRS and GAS groups.

I-IBZM SPECT brain imaging in schizophrenia

183

scores were significantly different between both

The m e a n BPRS

score

for responders was

lower than that of the non-responders

significantly

(P= 0.001). The mean GAS

scores pre and post treatment showed a significant

improvement

only

significant

in

the

responders

group

(P=0.002).

No

differences in D2 receptor availability were found in the patient groups in the right or the left striata with either the ratio or the subtraction indices. M e a n ratios o n the right for responders and non-responders were 1.24 (S.E. 0.045) and 1.16 (S.E. 0.024) respectively. responders

Mean

were

ratios on the left for

1.29

(S.E.

0.048)

and

responders and n o n 1,15

(S.E.

0.021)

respectively. Mean subtraction indices for responders and nonresponders o n the right w e r e 24.87 1.78).

Mean

subtraction

indices

(S.E. 5.13) and 13 .4 (S.E. for

the

responders

and

non

responders o n the left were 30.6 (S.E. 5.6) and 15.4 (S.E. 2.4). M e a n ratios for the controls in the right and left striata were 1.68 (SE 0.029) and 1.7 (SE 0.033) respectively. Mean subtraction indices were 67.7 (S.E. 2.9) and 79.4 (S.E. 3.27) in the right and left respectively. Thus

in

this

study

we

demonstrated

a

marked

degree

of

antipsychotic blockade of central D2 receptors in both responders and

non-responders.

We

applied

standard

ratings

of

specific

psychopathology as well as global outcome measures to patients on routine clinical treatment; an accepted method of

assigning

response or non-response in groups of patients on antipsychotics [31, 36]. In addition to account for possible selection biases, group comparisons of specific D2 binding estimates were made on duration of treatment

illness (oral

and treatment

vs.

depot)

(weeks vs. years),

presence

and

type of

severity

of

extrapyramidal side effects a n d use of additional medication (eg, anticholinergics,

antidepressants). No significant

differences

on these parameters were found. All the non-responders

in our

trial had received an adequate trial of typical antipsychotic at some time in their illness. All but two had been on maximal doses of

at

least

two

distinct

chemical

antipsychotics for longer than 6-8 weeks.

classes

of

typical

184

J.V. Lucey et al.

Farde et al [5] were the first to demonstrate that clinical doses of typical antipsychotics were associated with high degree of D2 blockade in vivo, but Farde"s group did not correlate this with clinical response. We now show similar levels of D2 receptor availability in responders as non-responders on typical antipsychotics. This substantiates the findings of two preliminary PET studies performed on smaller samples [32, 33]. Clinical improvement appears to occur in the responsive group even at relatively low D2 occupancy whereas non-responders do not respond even at maximal D2 blockade. Thus mega-dose antipsychotic therapy for non-responders would appear to expose patients to drug toxicities without increasing the likelihood of additional clinical benefits [37, 38]. There is no doubt that D2 blockade is generally high for typical antipsychotics. The decreased availability for D2 receptor binding in our group of nonresponders (which was not significant) relates to the fact that this group was maintained on non-significantly higher levels of medication at the time of scanning. Clinicians titrate antipsychotic dosage against improvement. Various in vivo PET and SPET studies have demonstrated a close relationship between typical antipsychotic dosage and striatal D2 receptor blockade [39, 40]. Thus the relationship with therapeutic efficacy may be more complex than a simple linear D2 receptor action. The development of the atypical antipsychotic clozapine suggests that a second related hypothesis needed to be tested; that a high degree of D2 receptor occupancy is necessary for clinical response to antipsychotics T301. First introduced in the 1960"s clozapine was withdrawn 10 years later due to agranulocytosis [41]. However clozapine has a high antipsychotic efficacy even in the most resistant patients [36]. In animal studies the drug is a modest D2 antagonist and its mechanism of action may reside elsewhere. In the past the assessment of this therapy in patients has not been possible in patients. Some investigators have proposed that either modest D2 receptor occupancy or a combined effect at both D1 and D2 receptors is responsible for the antipsychotic effect. We have directly evaluated the role of D2

123

I-IBZM SPECT brain imaging in schizophrenia

185

receptors in the antipsychotic effect of clozapine in two groups of

patients.

One

group

was

receiving

typical

antipschotics without clinical improvement

high

potency

(N=6) and the other

(patients who, under the special licensing restrictions applied to clozapine, were considered poorly responsive to traditional compounds)

was

receiving

clozapine

with

good

effect

(N=10,

including 2 from the first group). Patients whether on typical antipsychotics or clozapine were similar in demographic details, disease duration and functional improvement. Non-responders

to

treatment w e r e defined

on

clozapine

had

in the same way as above.

significantly

lower

BPRS

scores

Patients

than

those

on

typical antipsychotics (p=0.001) Before clozapine treatment there was no

significant

groups.

After

significantly

difference

clozapine (p=0.003).

between GAS scores between

treatment, Mean

GAS

duration

scores

of

improved

treatment

clozapine w a s 4.5 months. M e d i a n signal ratios

the with

(BG/FC) for 14

normal subjects were 1.91 on the right (range 1.50-2.07) and 1.97 (1.66-2.15) patients

on

on

the

typical

left

at

60-80

min

antipsychotics,

after

median

injection.

ratios

were

For 1.18

(1.09-1.23) o n the right and 1.19 (1.09-1.27) on the left. For clozapine treated patients, the medians were 1.47 on the both sides (1.3-1.78 and 1.3-1.74 respectively). Differences between treatment

groups

on

the

right

and

left

were

significant

(p=0.001). The m e d i a n saturable binding component on the right for the group on typical

antipsychotics

and o n the

clozapine

group was 17 (9-22) and 42.5 (20-72), respectively (p=0.001). O n the left the median saturable binding component was 16.5 (9-25) for

the

typical

antipsychotic

group

and

42

(22-68)

for

the

clozapine treated group (p=0.0005). The median saturable binding component in the controls was 94.9 (72-146) and on the left 97.4. The higher ratios and increased saturable binding achieved

in

patients on clozapine compared w i t h typical antipsychotics were qualitatively obvious in every case. These results are similar to the less systematic PET and SPET studies w h i c h have not defined responses or clinical improvements using standardized measures [5, 40]. SPET can assess D2 dopamine

186

J.V. Lucey et al.

receptor availability in the basal ganglia and distinguish between groups on typical and atypical antipsychotics with high contrast and resolution. In animal studies 123I-IBZM is a highly specific D2 ligand with saturable, reversible and stereospecific binding; its in vivo binding accurately reflects the in-vitro kinetics [24]. The fact that receptor occupancy ratios differed significantly between groups reflects clozapines diminished ability to block D2 receptors. Clozapine has activity at a range of other receptors notably 5-HT-2 and 5-HT-3 and the D4 dopamine receptor [42]. The data suggest that the antipsychotic potency of clozapine resides in actions other than those at the D2 receptor. This is the first example of a potent antipsychotic whose effect does not lie primarily in D2 receptor blockade thus confirming doubts about a simple linear relationship between D2 receptor antagonism in vivo and clinical efficacy. Lastly we used the 1J3I-IBZM SPET neuroimaging technique to examine a third hypothesis: That disturbances in density, distribution and activity of the D2 receptors are the fundamental abnormalities underlying the genesis of schizophrenia T431. Crawley et al [11] performed the first in vivo study of D2 receptors in schizophrenic patients (many of whom had been treated with anti-psychotics). They reported an 11% increase in D2 receptors in 10 never treated patients using 'C,N-Methyl spiperone SPET. This finding was not replicated by a larger PET study using the specific D2 receptor ligand 'C raclopride [15] or by two other PET studies using different receptor ligands [16,17]. Nonetheless a large study by Farde et al [15] did show an intriguing asymmetry of binding in the patient group with higher D2 receptor densities in the left than in the right putamen of patients but not controls. To resolve these conflicting data we compared the D2 receptor occupancy in two groups of individuals; 20 antipsychotic free schizophrenics (17 never medicated and 3 antipsychotic free > 5 years) and 22 age, sex and handedness matched controls. The data were as follows. Mean ratios obtained in the patient

123

I-IBZM SPECT brain imaging in schizophrenia

g r o u p w e r e 1.65 95%

CI

(SE 0.027, 95% CI 1.6-1.7) a n d 1.71

1.65-1.75)

respectively.

187

on

the

right

In t h e control

and

on

the

(SE 0.024, left

group, m e a n ratios w e r e

sides

1.68

(SE

0.029, 95% CI 1.62-1.74) a n d (SE 0.033, 95% CI 1.64-1.76) on t h e right

and

left

sides

respectively.

Subtraction

p a t i e n t s o n t h e right a n d left s i d e s w e r e 66.11

indices

for

(SE 2.227, 95%

CI 61.8-70.4) a n d 70.86 (SE 2.354, 95% CI 66.1-75.5) a n d for t h e controls CI

(67.7 (SE 2.9, 95% CI 62-73.3) a n d 7 0 . 4 ( S E 3.27, 95%,

64-74.8).

No

significant

differences

were

shown

p a t i e n t a n d control g r o u p s o n e i t h e r sides w h e t h e r

between

subtraction

or ratio m e t h o d s w e r e u s e d . T h e r e w e r e n o s i g n i f i c a n t differences in

laterality

control

between

subjects

the

patient

(F=0.528,

group

p=0.357).

as

a

whole

However

and

there

the

was

a

s i g n i f i c a n t d i f f e r e n c e in the m e a n left l a t e r a l i t y index confined to

the

males

evidence

of

(5.57,95% a

case

by

CI

0.4-10.76,

sex

p=0.04)

interaction

ANOVA

(F=3.23,

showed p=0.08).

S c h i z o p h r e n i c m a l e s s h o w e d g r e a t l y i n c r e a s e d laterality c o m p a r e d w i t h t h e i r h e a l t h y c o u n t e r p a r t s . T h e r e w a s n o d i f f e r e n c e in m e a n left

laterality

controls

indices

(2.2, 95% CI

in f e m a l e p a t i e n t s c o m p a r e d to

female

5.029.53).

No s i g n i f i c a n t c o r r e l a t i o n w a s found b e t w e e n saturable D2 b i n d i n g a n d total B P R S scores, p o s i t i v e o r n e g a t i v e s y m p t o m s or d u r a t i o n of illness. L i n e a r r e g r e s s i o n in c o n t r o l s b e t w e e n D2 binding d a t a for the right a n d left s t r i a t a s h o w e d a n e g a t i v e c o r r e l a t i o n w i t h age; for t h e left

(r=0.561, p=0.01, 95% CI 0.8-0.15) a n d right

(r=0.653, 95% CI 0.79-0.11) r e s p e c t i v e l y .

P a t i e n t s D2 receptor

b i n d i n g d i d n o t show a s i g n i f i c a n t c o r r e l a t i o n w i t h age. These

results

overall

verify

elevations

smaller in

PET

striatal

studies D2

which

receptor

do

not

binding

show in

s c h i z o p h r e n i c p a t i e n t s c o m p a r e d to c o n t r o l s [15, 16,17]. However the left s i d e d D2 a s y m m e t r y n o t e d in t h e p a t i e n t group by Farde et

al

1990

is

confirmed

here

at

least

with

regard

to

male

p a t i e n t s c o m p a r e d to m a l e c o n t r o l s . In a d d i t i o n our d a t a supports e a r l i e r f i n d i n g s of a decline of striatal D2 receptors w i t h age in c o n t r o l s [17, 44, 45]. The w e i g h t of e v i d e n c e from the in v i v o

188 studies with

J.V. Lucey et al. four different

ligands used in three

different

centres (Karolinska, Orsay and London) [15, 16,17,43] suggests that overall striatal D2 receptor elevation cannot be regarded as a constant feature of schizophrenia. However Pilowsky et al [43] does provide data to substantive previous PET evidence of derangements

with

age

and

sex

in

striatal

D2

receptor

distribution [15,16,17]. Conclusions '"I-IBZM SPET has emerged as an increasingly useful tool

for

semiquantitative evaluation of central D2 status over the past five years. Studies have been performed in normal control groups [29,28,26] in differing disease states pharmacological

interventions

in

[28, 26] and following

humans

[25,33,

45].

High

resolution, brain dedicated SPET scanners provide similar data to PET images. With appropriate instrumentation, image analysis and research paradigms SPET is proving capable of substantiating and extending previous in vivo D2 receptor research.

123

I-IBZM SPECT brain imaging in schizophrenia

189

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IBZM-SPECT DURING NEUROLEPTIC TREATMENT K. Broich Department of Psychiatry, Martin-Luther-University of Halle-Wittenberg, Julius Kühn Str. 7, 06097 Halle, Germany S. Kasper, P. Danos, H.-J. Möller Department of Psychiatry, University of Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany F. Grünwald, E. Klemm, H.-J. Biersack Department of Nuclear Medicine, University of Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany A. Alavi Department of Nuclear Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA

Introduction: Recently significant progress has been made in the development of new central nervous system receptor imaging agents to visualize and measure in vivo preand p o s t s y n a p t i c structures of the d o p a m i n e r g i c system [4]. Several n e u r o p s y c h i a t r y diseases, such as schizophrenia, tardive dyskinesia, Parkinson's disease, Huntington's Chorea and drug addiction (particularly cocaine), involve changes of dopamine D2 receptor density in the brain [2, 5, 12, 16, 18-20]. Additionally dopamine and dopamine receptors play an important role in the action of antipsychotic agents: the antipsychotic effects as well as the extrapyramidal side effects of neuroleptics are considered to be mediated by a blockade of central postsynaptic dopamine D2 receptors [17]. The dopamine D2 receptor radioligands in conjunction with positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide a useful non-invasive tool in the evaluation of those various diseases and of antidopaminergic drug effects [1,3, 5, 13, 19].

K. Broich et al.

194

W e r e p o r t o u r r e s u l t s u s i n g 1 2 3 I-IBZM (S-(-)-N-[(l-ethyl-2-pyrrolidinyl)methyl]-2hydroxy-3-iodo-6-methoxybenzamide)-SPECT to study dopamine D2 receptor density and occupancy in healthy controls, after escalating doses of haloperidol and in 25 patients with schizophrenia.

Patients and methods: 5 healthy control subjects carefully screened by psychiatric and neurological examination were studied. After a baseline study two or three increasing doses of haloperidole (day 1: baseline study; day 2 , 3 and 4 blocking with 0.6 mg, 1.25 mg and 5 mg, respectively) were administered intravenously before the following SPECT studies. Informed consent was given by the control subjects. 3 to 4 mCi ( 1 1 1 - 1 4 8 MBq) 1 2 3 I-IBZM were injected intravenously. Data collection with a high-resolution three-head scintillation camera (Prism 3000, FWHM 7-8mm; 128 projections were acquired [128x128 matrix]) started 30 123 min after injection of I-IBZM and lasted for 60 min. Using a Butterworth filter (3.14) and attenuation correction, transaxial slices were reconstructed and coronal, sagittal and reorientated transaxial slices were calculated. Using a ROI technique, striatal uptake of I-IBZM was compared to other brain regions. In a semiquantitative approach, the counts/pixel of the basal ganglia region (BG) were normalized to the activity of the frontal cortex (BG/FC-ratio). In a another study 25 patients with schizophrenia according to DSM-III-R 123

criteria were studied after informed consent. I-IBZM-SPECT was performed using a double-head rotating scintillation camera (Siemens, FWHM 15 mm; 64 projections were acquired [64x64 matrix]. In this study data collection started 90 19Q min after the intravenous injection of 5 mCi (185 MBq) I-IBZM and lasted for 40 min. Using a Metz filter and filtered back-projection transaxial slices were reconstructed and coronal,193 sagittal and reorientated transaxial slices were calculated. Regional uptake of I-IBZM was calculated as described before. Both studies were approved by the local ethical committee.

IBZM-SPECT during neuroleptic treatment Results: Immediately after injection, significant uptake in the brain was observed in the planar images of the subjects examined. The SPECT images showed that the agent localized in the striatum. Although some uptake was noted in other structures (cerebral cortex and cerebellum), the striatum clearly appeared to be the primary site of concentration. Also dynamic data indicated that significant washout took place from the sites of nonspecific binding (cerebral cortex and cerebellum). Specific binding expressed as activity in the basal ganglia minus activity in various cerebral cortical parts or the cerebellum reached a plateau after 30 min and remained stable for two hours in the first study with the high resolution camera (Fig. 1). counts/pixel BASELINE

I T M

0

[ M I r | I I T I | I I M

J r T M | M I I | M M | I I 1 I | I I I



0.3 mg HALOPERIDOLE

-

1.2 mg HALOPERIDOLE

I

10 20 30 40 50 60 70 80 90

Time (min) Fig. 1: Specific activity (in counts/pixel) in basal ganglia calculated as the activity in basal ganglia minus activity in the frontal cortex in a healthy volunteer at baseline and after two escalating doses of haloperidol. In the control studies BG/FC ratios of 1.71±0.15 and BG/CB ratios of 1.73±0.17 were observed at baseline. Specific dopamine D2 receptor binding was markedly reduced by treatment with escalating doses of haloperidol. Dynamic data indicated that after treatment with 1.25 mg or 5 mg haloperidole significant

195

196

K. Broich et al. 193

washout of I-IBZM from the striatum was seen (Fig.l). After injection of 1.25 mg haloperidol a receptor blockade of up to 50% (mean: 29.3±15.1%) and after 5 mg of haloperidol of up to 80% (mean: 36.8±15.7) was detected [Fig. 2], 1 No side differences of the BG/FC-ratios of I-IBZM-uptake were found. The subject with a dopamine D2 receptor blockade of 80% after 5 mg haloperidole i.v. suffered from extrapyramidal side effects (rigidity, bradykinesia, akathisia).

-10

-20

Reduction of BG/FC-Ratio (%)

H

II

0



0.6 mg HALOPERIDOLE

-30 -40

1.25 mg HALOPERIDOLE

-50 -60

r—I 5 mg LJ HALOPERIDOLE

-70 -80

Fig. 2: Reduction of IBZM binding after escalating doses of haloperidol in a healthy control subject. In untreated schizophrenic patients (n=4) a BG/FC-ratio of 1.29±0.04 was estimated. Schizophrenic patients (n=16) treated with typical neuroleptics as haloperidole or benperidole showed a significant reduction of BG/FC-ratio (1.04±0.03; p < 0.01). Patients of this group suffering from extrapyramidal side 123 effects revealed the lowest ratios of I-IBZM-uptake. No significant linear relationship between the dose of typical neuroleptics and BG/FC-ratio could be established. After treatment with clozapine no significant reduction of BG/FC-ratio was measured. No correlations between psychopathological subscores or clinical response to therapy and BG/FC-ratio were detected. One patient with acute exacerbation of

IBZM-SPECT during neuroleptic treatment

BG/FC-Ratio UNTREATED TYPICAL NL (with EPMS) r-, TYPICAL N L ( 0 LJ EPMS) CLOZAPINE

1 Fig. 3; BG/FC-ratios of I-IBZM-uptake in 25 patients with schizophrenia without treatment, after typical and atypical neuroleptics (NL). Patients with extrapyramidal side-effects after treatment with typical NL showed the lowest BG/FC-ratios. (*: p < 0.05; * * : p < 0.01)

BG/FC-Ratio 1,6 1,4 1,2 1

0,8

FLUPHENAZINEDEPOT (37.5 mg) FLUPHENAZINE (9 mg) CLOZAPINE (100 mg)

0,6 0,4

123 Fig. 4 : BG/FC ratio of I-IBZM-uptake in one patient with paranoid schizophrenia after treatment with typical and atypical neuroleptics. paranoid schizophrenia showed a marked reduction of BG/FC-ratio after oral and intramuscular injection of fluphenazine without satisfactory clinical response. After treatment with 100 mg clozapine there was complete clinical 1 recovery without reduction of the BG/FC-ratio of I-IBZM-uptake.

197

198

K. Broich et al.

Discussion and Conclusion: 193 With I-IBZM a highly selective CNS dopamine D2 receptor ligand has been introduced, which is suitable for SPECT imaging. IBZM is structurally a close analogue of raclopride, Biviax values are comparable to spiperone in the striatum and cortex of animals [10, 11]. Some preliminary clinical studies suggest that 1 I-IBZM-SPECT may be useful in various neuropsychiatric disorders [2, 5, 8, 9, 15]. In the present investigation the image quality and spatial resolution from the three-detector, dedicated SPECT camera was far superior to that obtained with the older rotating low resolution camera system. According to that the ratios measured with the high resolution camera are similar to those observed by other groups [2, 15]. Compared to the literature BG/FC-ratio was relatively low in the second study with the low resolution SPECT camera. In a recent study it was shown, that this ratio is based on the resolution of the camera system and only to a minor extent on the ROI technique [14]. Providing both faster scanning 193 time and excellent image quality with higher target-to-nontarget ratios of IIBZM-uptake, the dedicated SPECT system is preferred for imaging of central dopamine D2 receptors. 1 Our data show that I-IBZM-SPECT gives an estimation of dopamine D2 receptor density or occupancy by dopamine D2-antagonists like haloperidole. That low doses of haloperidole are followed by a relative high degree of receptor occupancy was found by other authors using PET or SPECT as well [6, 1 7, 15]. I-IBZM-SPECT was able to distinguish between schizophrenic patients treated with typical and atypical neuroleptics. No significant dopamine D2 receptor blockade was found after treatment with clozapine. Farde et al. [6, 7] and Pilowski et al. [15] reported a modest blockade of striatal dopamine D2 receptors after treatment with clozapine. However, they were still able to distinguish between patients on typical and atypical neuroleptics. One reason for the difference to our study may be that patients in our study were treated with lower doses of clozapine (100-300 mg). We found no relationship between dose of neuroleptics and blockade of dopamine D2 receptors nor were we able to establish a relationship between reduction of BG/FC-ratios and psychopathological subscores or clinical

IBZM-SPECT during neuroleptic treatment

199

response. Briicke et al. [2,3] described a curvilinear relationship between the dose of typical neuroleptics and receptor blockade measured by

I-IBZM-

SPECT. One reason that we did'nt find such a relationship may be the narrow range of the BG/FC-ratio between treated and untreated patients ensueing from the low resolution of our SPECT-system. On the otherhand the results indicate that the lack of therapeutic response cannot be attributed to an incomplete blockade of striatal dopamine D2 receptors and that the pathophysiological role of these dopamine receptors is questionable in therapy-resistant schizophrenic patients. With regard to the high incidence of extrapyramidal side effects in patients (treated with typical neuroleptics) with complete blockade of the striatal dopamine D2 receptors it can be hypothesized that the striatal dopamine D2 receptors play an important role in the pathogenesis of extrapyramidal side effects, but that in the pathogenesis of schizophrenia mesolimbic dopamine D2 receptors are more important than the striatal dopamine D2 receptors. However, the preliminary studies suggest that this method can be used to image and quantify striatal dopamine D2 receptors in vivo and may be of clinical value for the monitoring of neuroleptic treatment in schizophrenic patients. One major issue which remains unanswered is the more accurate quantitation of central 1

dopamine D2 receptors. A kinetic model of the uptake and retention

of IBZM in the striatum and other brain regions to obtain an accurate quantitative information on receptor density has not been established. Newer and faster SPECT equipment with the capability of dynamic scanning and additional progress in attenuation and scatter correction will improve the potential of SPECT to image and quantify central neuroreceptors.

References: 1.

Broich K, Alavi A, O'Brien C, Galloway S, Mozley D: SPECT

imaging of dopamine D2 receptors with 123I-IBZM in normal controls after escalating doses of haloperidol. J Nucl Med 33 (1992) 898

200

K. Broich et al. 2.

Brücke B, Podreka I, Angelberger P, et al.: Dopamine D - 2 receptor

imaging with SPECT: studies in different neuropsychiatry disorders. J Cereb Blood Flow Metab 11 (1991) 220-228 3.

Brücke T, Wenger S, Podreka I, Asenbaum S: Dopamine receptor

classification, neuroanatomic distribution and in vivo imaging. Wien Klin Wochenschr 103 (1991) 639-646 4.

Budinger T: Critical review of PET, SPECT and neuroreceptor

studies in schizophrenia. J Neural Transm 3 6 (1992) 3-12 5. Crawley J, Crow T, Johnstone E, et al.: Dopamine D2 receptors in schizophrenia studied in-vivo. Lancet II (1986) 224 6. Farde L, Wiesel F, Halldin C, Sedvall G: Central D 2 dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiat 4 5 (1988) 71-76 7.

Farde L, Wiesel F, Nordström A, Sedvall G: D l - and D2-dopamine

receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology 99 (1989) S28-S31 8. Geaney D, Ellis P, Soper N, Shepstone B, Cowen P: Single photon e m i s s i o n tomography assessment of cerebral dopamine D 2 receptor blockade in schizophrenia. Biol Psychiatry 32 (1992) 293-295 9.

König P, Benzer M, Fritzsche H: SPECT technique for visualization

of cerebral dopamine D 2 receptors. Am J Psychiatry 148 (1991) 1607-1608 10. Kung H, Alavi A, Chang W, et al.: In vivo SPECT imaging of D - 2 dopamine receptors: initial studies with [ 1 2 3 I ] I B Z M in humans. J Nucl Med 31 ( 1 9 9 0 ) 5 7 3 - 5 7 9

IBZM-SPECT during neuroleptic treatment 11. Kung H, Pan S, Kung M-P, et al.: In vitro and in vivo evaluation of [123I]IBZM: A potential CNS D-2 dopamine receptor imaging agent. J Nucl Med 30 (1989) 88-92 12. Leenders K, Frackowiak R, Quinn N, Marsden C: Brain energy metabolism and dopaminergic function in Huntington's disease measured in vivo using positron emission tomography. Mov Disord 1 (1986) 69-77 13. M a r t i n o t J, Huret J, P e r o n - M a g n a n P, et al.: Striatal D 2 dopaminergic receptors ascertained in v i v o by positron e m i s s i o n tomography and 76Br-bromospiperone in untreated schizophrencis. Am J Psychiatry 174 (1990) 44-50 14. Menzel C, Grünwald F, Klemm E, et al.: Hirn-SPECT mit 1 2 3 J markiertem Iodobenzamid (IBZM): Aspekte der semiquantitativen Auswertung. Nucl-Med 3 2 (1993) 227-230 15. Pilowski L, Costa D, Ell P, Murray R, Verhoeff N, Kerwin R: Clozapine, single photon emission tomography, and the D2 dopamine "receptor blockade hypothesis of schizophrenia. Lancet 340 (1992) 199-202 16.

Schwarz J, Tatsch K, Vogl T, et al.: Marked reduction of striatal 1 dopamine D 2 receptors as detected by IBZM-SPECT in a Wilson's disease patient with generalized dystonia. Mov Disord 7 (1991) 58-61 17. Seeman P: Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1 (1987) 133-152 18. Volkow N, Fowler J, Wolf A, et al.: Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 147 (1990) 719-724 19. Wagner H, Burns H, Dannais R, et al.: Imaging of dopamine receptors in the human brain by positron tomography. In: Greitz T. Ingvar DH. Widen, L (eds) The metabolism of the hujan brain studied with positron emission tomography. Raven Press, New York :251-267; 1985

K. Broich et al.

20.

Wienhard K, Coenen H, Pawlik G, et al.: PET studies of dopamine 18

receptor distribution using [ FJfluoroethylspiperone: findings in disorders related to the dopaminergic system. J Neural Transm [GenSect] 81 (1990) 195-213

lomazenil-SPECT imaging in psychiatric diseases

S.Schlegel, R. Schlosser, A.Hillert Department of Psychiatry, University of Mainz Untere Zahlbacher Str.8, 55131 Mainz, Germany 0.Nickel, A.Bockisch, K.Hahn Department of Nuclear Medicine, University of Mainz Langenbeckstr.1, 55101 Mainz, Germany

Introduction

By the development of IOMAZENIL ( 123 I-Ro 16-0154), the iodinated benzodiazepine antagonist flumazenil, the visualization of central benzodiazepine receptor (BZr) binding with single photon emission tomography (SPECT) became possible. Displacement experiments in humans [1] and in primates [2] have demonstrated that 90 - 110 min. following IOMAZENIL injection 80-90% of activity corresponds to specific binding. Our first study investigated whether IOMAZENIL is a suitable ligand in order to detect the BZr occupation during BZ treatment. The following studies were directed at the BZr binding in panic disorder and depression. This paper presents a short summary of our main IOMAZENIL-SPECT findings. Patients

All patients gave their informed consent. We investigated four groups of patients: 1) ten patients with epilepsy without psychiatric disorders were used as a reference group. All epileptic patients were treated with carbamazepine, which has no major influence on central BZr binding, since carbamazepine acts with

S. Schlegel et al.

204 the peripheral

type of

the BZr

[3] . 2) Ten depressed

with additional lorazepam treatment with diazepam dependence drawal

were

investigated.

patients

(0.5-5.0 mg) and one patient

(30 mg/die) and four weeks after with3)

Ten patients

with

panic

disorder

according to DSM-III-R. 4) Ten patients with a major depressive episode

according

drug-free

for

to DSM-III-R. The

at

least

two

weeks.

last

two

None

of

samples had the

patients had a history of neurological diseases, or

alcohol

abuse.

Thyroidal

uptake

of

been

psychiatric

epilepsy, drug 123

unbound

iodine

was

blocked by potassium iodide applied orally one day before to six days after the SPECT examination. Pregnancy was excluded in all female patients.

Methods The SPECT-scans were performed of 185 MBq (PICKER

(90-110 min.) after i.v. injection

IOMAZENIL using a double-head

rotating

International) . The total acquisition

Irregular

regions of interest were drawn

gamma

time was

three times

camera 25 min.

independ-

ently, considering the percentual isodense line of at least 50% of total activity;

the occipital cortex and the frontal

cortex

were measured at the level of the third ventricle, the right and left temporal regions at the same level as the pons and the cerebellum. The average counts per voxel (0.42 x 0.42 x 0.84 cm) were calculated from these three measurements. After

analyzing

described elsewhere

different

semiquantitative

approaches

as

[4] the average counts / voxel were normal-

ized for the injected counts of cm 2 of body surface.

Iomazenil-SPECT imaging in psychiatric diseases

205

Results The distribution of IOMAZENIL binding showed the highest activity in the occipital and frontal cortex in all samples, followed by both temporal regions and the cerebellum, and the lowest uptake in the pons. This Bzr distribution agrees with BZr binding postmortem

[5] and

PET

[6] or SPECT studies

[7] in healthy volun-

teers. BZ-treated regions

patients

compared

to

had

lower

the

BZ-free

group. Receptor occupancy compared

to

the mean

uptake

determined

values

of

values

depressives the

in and

all

as percentage BZ-free

cortical

the

sample

reference

of

activity

revealed

receptor occupation between 12-40% in lorazepam-treated

a

patients

(complete details will be presented separately). BZr occupation was

not

clearly

related

to

the

dosage

of

lorazepam.

In

one

patient with severe diazepam dependence, the intraindividual comparison after withdrawal revealed a BZr occupation of up to 80%. Supporting the involvement of the gamma-aminobutyric acid^ benzodiazepine receptor complex in the pathogenesis of anxiety 10,11] panic patients had

lower binding values

[8, 9,

compared to

the

reference group [12]. Depressed

patients

showed

significant

positive

correlation

between severity of depression - measured by the Bech-RafaelsenMelancholia-Scale

[13] and the frontal uptake values

[14]. This

result supports the postmortem findings of increased frontal BZrdensity in depression after suicide [15].

Conclusion Based on these preliminary

findings,

IOMAZENIL-SPECT provides a

powerful tool for the investigation of BZr binding in different

S. Schlegel et al.

206 psychiatric despite

disorders

and

BZr

occupation

under

the fact that only a semiquantification

BZ

treatment,

is possible

in

SPECT studies.

References [1]

Beer H.F., Blaeuenstein P.A., Hasler P.H., Delaloye B., Riccabona G. ( Bangerl I., Hunkeler W., Bonetti E.P., Pieri L., Richards J.G., Schubiger P.A.: In vitro and in vivo evaluation of iodine-123-RO 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors. J. Nucl. Med. 31 (1990) 10071014.

[2]

Innis R.B., Al-Tikriti M.S., Zoghbi S.S., Baldwin R.M., Sybirska E.H., Laruelle M.A., Malison R.T., Seibyl J. P., Zimmermann R.C., Johnson E.W., Smith E.O., Charney D.S., Heninger G.R., Woods S.W., Hoffer P.B.: SPECT imgaging of the benzodiazepine receptor: Feasibility of in vivo potency measurements from stepwise displacement curves. J. Nucl. Med. 32 (1991) 1754-1761.

[3]

Post R.M., Uhde T.W., Ballenger J.C.: Efficacy of carbamazepine in affective disorders: Implications for underlying physiological and biochemical substrates. In: Emrich HM, Okuma T, Mueller AA (eds) Anticonvulsants in affective disorders. Elsevier Science Publishers, pp 93-115.1984

[4]

Schlegel S., Schlosser R. : Summary of benzodiazepine receptor binding studies measured by IOMAZENIL-SPECT. J Neural Transm (1994) Submitted

[5]

Mueller W.E.: The benzodiazepine receptor. Cambridge University Press. New York 1987.

[6]

Persson A., Pauli S., Halldin C., Stone-Elander S., Farde L., Sjo-ren I., Sedvall G. : Saturation analysis of specific 11C Ro 15-1788 binding to the human cortex using positron emission tomography. Hum. Psychopharmacol. 4 (1989) 21-31

[7]

Woods S.W., Seibyl J.P., Goddard A.W., Dey H.M., Zoghbi S., Germine M., Baldwin R.M., Smith E.O., Charney D.S., Heninger G.R., Hoffer P.B., Innis R.B. :• Dynamic SPECT imgaging after injection of the benzodiazepine receptor ligand

Iomazenil-SPECT imaging in psychiatric diseases

207

(1231)Iomazenil in healthy human subjects. J. Psychiat. Res. Neuroimaging 45 (1992) 67-77. [8]

N o r m a n T.R., Burrows G.D.: Anxiety a n d receptor. B r a i n Res. 65 (1986) 73-90.

the

benzodiazepine

[9]

Teicher M.H. Biology of Anxiety. M e d C l i n N o r t h A m 72 791-814.

(1988)

[10] Breier A., Paul S.M.: The G A B A a / b e n z o d i a z e p i n e receptor: Implications for the molecular basis of anxiety. J. Psychiat. Res. 24 (1990) 91-104 [11] Nutt D.J., G l u e P., Lawson C.: The neurochemistry of anxiety: a n update. Neuropsychopharmacol. Biol. Psychiatry 14 (1990) 737-752. [12] Schlegel S., Steinert H., Bockisch A., H a h n K., Schlosser R., Benkert O.: Decreased benzodiazepine receptor binding in p a n i c disorder measured b y IOMAZENIL-SPECT: A preliminary report. Eur A r c h Psychiatry Clin Neurosci. (1994) I n press. [13] B e c h P., R a f a e l s e n O.J.: The use of rating scales exemplified b y comparison of the Hamilton a n d the Bech-Rafaelsen Melancholia Scale. Acta Psychiatr Scand 62 Suppl. 285 (1980) 128-146. [14] Schlegel S., Schlosser R., Nickel 0., H a h n K. Association between increased benzodiazepine receptor binding and depression m e a s u r e d by IOMAZENIL-SPECT. Submitted.(1994) [15] C h e e t h a m S.C., Crompton M.R., Katona C.L.E., Parker S.J., Horton R.W.: B r a i n GABA^/benzodiazepine binding sites and glutamatic a c i d decarboxylase activity in depressed suicide victims. Brain Res 460 (1988) 114-123.

Clinical value of three-dimensional (3D) image presentation in single photon emission computed tomography

A. Bockisch Klinik für Nuklearmedizin, D - 55101 Mainz, Germany

Johannes

Gutenberg-Universität,

Introduction Single Photon Emission Computed Tomography (SPECT) has been found to be a necessary prerequisite for the detection of "cold" lesions located in extended organs like the brain. In addition to this application, SPECT has demonstrated its value in the more precise definition of the location of both "cold" and "hot" lesions. Computer systems have recently become available which allow the three-dimensional (3D), or more precisely pseudo 3D presentation of SPECT data [1,2]. This paper discusses the basics of 3D scintigram presentation and its applications in brain imaging.

Principle of 3D Data Presentation1 The 3D image presentation is based on conventional SPECT slices. A continuous stack of slices (arbitrary orientation) is chosen and an intensity level is defined. In the next step, isointensity lines are calculated in each of the slices for

3D images are usually presented in colour. The restriction to black and white

prints

in

this

book

results

in a

significant

loss. The

chosen

figures, nevertheless, should support the statements given in the text.

210

A. Bockisch

the chosen level and the outermost closed lines of neighboring slices are connected by small triangles forming an isointensity surface. In this manner a computed three-dimensional structure (object) is formed, which is illuminated by colored light of imaginary light sources, which are situated in the corners of a cube that encloses the object. The color and brightness values of each of the triangles are determined depending on the distance of the triangle and its angle in respect to the light source. In order to obtain a smoother appearance of the surface, there might be a continuous change of color on each triangle. In addition, shadows and highlights increase the three-dimensional impression. Figure 1 demonstrates the importance of shadows and highlights for the three-dimensional impression. The user can rotate the object around any of the three orthogonal axes and thus observe the object from any point of view. For maximal illustration of a defect or better spatial information, it might be helpful to present the images for different levels simultaneously. The lower level necessarily corresponds to an outer isointensity surface. Therefore, the surface of the lower level must be transparent, which is performed by only drawing the edges of the network of triangles. The surface of highest activity, which is the innermost, may be drawn as a solid. Usually the use of two levels is reasonable for clinical use; a grid defines an outer, lower isointensity surface, and a solid surface defines an inner, higher one. The lower level surface may be used to define the contours of the organ under investigation, whereas the inner surface delineates hot spots. The drawback of this method is the inability to demonstrate cold lesions that do not touch the surface of the organ. However, this problem can be overcome-in principle, as discussed later. Figure 2 (lower part) illustrates an example for two isointensity surfaces. The outer surface is fixed and demonstrates

Clinical value of 3D image presentation

211

Figure 1: 3D image - seen from right occipital oblique - of a patient after right hemispheric stroke with extended parietal perfusion defect. The highlights and especially the shadows generate the three-dimensional impression and allow a straight forward understanding of the pathological finding. 2

All 3D scintigrams shown in this paper were prepared with an Odyssey computer system, Picker Int..

212

A . Bockisch

Figure 2: 3D presentation of the bone scan of the head in a patient suffering from prostatic cancer with multiple bone metastases. Two isointensity surfaces are displayed. The outer transparent surface shows normal anatomy and is represented by a grid. The inner, solid surface demonstrates pathology. Upper row: Views from different angles are displayed. The real 3D impression is generated by observing the pseudo 3D images from many angles, preferably by on-line rotation. Lower row: Depending on the setting of the level of the inner surface, the number of detectable metastases is changed.

Clinical value of 3D image presentation

213

normal anatony, while the inner surface is modified in three steps. Depending on the setting of the level, defined as a percent of the maximal value, the number of hot spots decreases. This example visualizes the arbitrariness of 3D image presentation. To achieve the impression of the third spatial dimension, the intensity information in the scintigram is lost. Instead, spatial information about only one (or two) - arbitrarily chosen - intensities is displayed. Figure 2 (upper part) shows the same SPECT data, this time with fixed levels, but for different viewing angles.

Clinical Application for 3D Scintigraphy

Obviously, 3D images may be impressive - but are they of any additional value to traditional SPECT images? We found 3D imaging helpful for two indications; supporting the interpretation of SPECT images and for communication with referring physicians, especially with surgeons. In the context of this book, only examples related to brain imaging are given. In addition to brain imaging, there are other valuable applications established including DMSA scans of horse shoe kidneys and a variety of applications in bone scans. We prefer to utilize 3D applications for "internal reasons", which primarily are helpful for the film reader. They include acceleration of decision making for diagnosis and increasing sensitivity or specificity of findings. Cases, in which findings can only be established by 3D imaging, are rare and their number is dependent on the experience of the film reader. 3D images contain volume information and are therefore not sensitive to partial volume effects. Partial volume effects due to tilting or rotation may introduce an asymmetric appearance - of actually symmetric structures - into the SPECT

214

A. Bockisch

slice. These partial volume effects are reliably suspected by experienced film readers. However, on normal SPECT slices it is difficult to prove that asymmetry is only due to partial volume effects. By applying 3D reconstruction symmetry this can be proven or excluded, (fig. 3) . For this task the images have to be reconstructed repeatedly with varying levels, until finally a level is found that is just below the highest activity in the investigated structure. Symmetric activity distributions must result in about symmetric spatial extension of those activities under borderline conditions due to the characteristics of the point-spread function in SPECT reconstruction. Areas of higher activity will be visualized as spatially more extended due to th§ point-spread function characteristics of gamma cameras. Therefore^ the 3D images can prove or exclude symmetric activity ,distribution in smaller structures independent of the alignment of the patient. Figure 3 demonstrates a typical example for this effect. Three-dimensional ROI technique - a definite valuable help for the analysis in those cases - is not yet available. In addition to the examples given above, 3D images may be helpful for a quick orientation in complex structures. Other applications, in contrast, are called external indications and include all applications that are helpful for the referring physician. Referring physicians often are not experienced in reading SPECT slices, which differ as functional images considerably from the more common morphological c-CT slices. For these colleagues, the more suggestive 3D images may be valuable for communication . Figure 4 demonstrates an example of a patient following a stroke. The perfusion defect includes most of the left hemisphere and is obvious. However, the extent of the island of

Clinical value of 3 D image presentation

215

Figure 3: 123j_ibzm scan in a 63-year-old patient with suspicion of Parkinson's disease. Top: The transversal SPECT slices show an asymmetry of the basal ganglia which may be due to partial volume effects of the tilted head. Bottom: The 3D image demonstrates asymmetric activity distribution and proves reduced activity on the right side corresponding to a decreased density of free D2 - receptors.

216

A . Bockisch

Figure 4: "Tc^-HMPAO SPECT of a 58-year-old patient after stroke. The image on the right represents a conventional SPECT slice. Although most of the left hemisphere is lost, a small parietal area has survived. Precise location and spatial extent are understood much easier in the 3D image than on the SPECT slices. The 3D image is seen from left frontal oblique.

Figure 5: HMPAO-SPECT investigation of a patient suffering from temporal epilepsy. The 3D reconstruction is seen from right occipital and cranial. The cranial part of the brain is removed as described in the text. As the spectator is looking from inside, all structures with lower activity accumulation than the normal brain, are displayed. In that way the ventricles are nicely shown. In addition, the temporal horn appears to be enlarged. This is due to decreased perfusion of the temporal pole which is carrying an epileptic focus which was localized by this HMPAO investigation. 3D imaging allows very sensitive analysis of left - right asymmetry.

Clinical value of 3D image presentation

217

persistent viability and perfusion in the parietal lobe is understood with one glance on 3D images. Communication with the referring neurologist is thus significantly enhanced. As pointed out in the "Principles", 3D image presentation is primarily restricted to hot lesions at the present state. This restriction may be overcome, however, by Cunning technique in parenchymatous organs with quite homogeneous activity distribution. In those cases, the stack of reconstructed SPECT slices is chosen more narrowly than the organ, e.g. in transversal slices the top or the bottom part of the organ is missing. In that case, the 3D image permits looking into the organ that appears hollow and the outer contours of the organ, that are displayed, are observed from inside. 3D image appearance is inverted in these cases. As we look inside out, the displayed isointensity surfaces surround lower activity areas. Thus, cold lesions are visualized. Figure 5 demonstrates a patient with temporal epilepsy as an example. Despite the advantages, it must not be forgotten that the 3D images are based on data manipulation. 3D image processing necessarily includes a loss of information which is included in the SPECT slices. In order to achieve condensed 3D-information, one has to concentrate on the image of only one or two intensity levels. The image is significantly dependent on the choice of these - arbitrary - levels. Therefore data processing by experienced nuclear medicine specialists is mandatory.

Conclusion

In conclusion, benefits from 3D image presentation are at the present state mostly restricted to the interpretation of hot lesions. The image evaluation is enhanced concerning speed and reliability in anatomically complicated structures and in border line pathology, since 3D images are free of partial volume

A. Bockisch

218

effects.In

selected

cases

3D images are an

important

medium

for precise communication with surgeons.

References 1. Bockisch, A., S. Fischer, R. Piepenburg, K. Hahn: Indikationen fur die dreidimensionale Darstellung von Szintigrammen. Erfahrungen von einem Jahr klinischer Anwendung. Nucl.-Med. 32 (1993) A124 (Abstract) 2. Bockisch, A., H. Steinert, R. Piep«=nburg, J. Andreas: Clinical Application Of Single Photon Emission Computed Tomography And Three-Dimensional (3D) Image Presentation. Probl. Med. Nukl. 13 (1993) 71-74