Computerized Medml imaging and Graphrcs. Vol. 16. No. 5, PP. 31 l-322, Printed in the U.S.A. All rights reserved.

0895-61 I l/92 IS.00 + .I0 Copyright 8 1992 Pergamon Press Ltd.

1992

VARIABILITY OF THE REGIONAL CEREBRAL BLOOD FLOW PATTERN STUDIED WITH [“Cl-FLUOROMETHANE AND POSITION EMISSION TOMOGRAPHY (PET)

R. J. Seitz* and P. E. Roland Laboratory of Brain Research and PET, Karolinska Institute, Box 60400, S- 1040 I -Stockholm, Sweden (Received 29 April 1992)

Abstract-The mean regional cerebral blood flow (rCBF) pattern measured with [“Cj-fluoromethane and positron emission tomography (PET) in 26 healthy subjects was heterogenous throughout the brain showing the highest rCBF in the medial prefrontal cortex and the lowest rCBF in the inferior temporal cortex. Right/left asymmetry of the mean rCBF was not significant. The variability of the rCBF pattern was assessed by dividing the subjects into one group of naive subjects and one group of subjects who had habituated to the scanning procedure. Naive subjects had a significantly higher mean rCBF (p < 0.05) in defined areas of the higher order association cortices predominantly in the right cerebral hemisphere, but a virtually identical mean rCBF in the primary cortical input and output areas. These findings suggest a raised level of mental activity in subjects undergoing the first PET measurement. Key Words: Regional

cerebral

blood flow, Positron

emission

tomography,

Rest, Habituation

ments ( 13- 15). Prominent task-related mean rCBF decreases in the prefrontal cortex resulted from a lower rCBF during stimulation compared to a higher rCBF at rest. A high rCBF in the prefrontal cortex has been shown earlier to be characteristic for resting wakefulness and referred to as “hyperfrontality” ( 16). The resting state (rest) has been defined as a state in which the awake subjects lie relaxed in supine position on the examination bed, do not move, and do not receive any kind of sensory stimulation (17, 18). At rest the electroencephalogram (EEG) shows a regular alpha-activity in the posterior leads, and the PaCO* should be close to 40 mmHg (17). In spite of this clear definition, PET measurements at rest revealed a considerable variability of the rCBF, rCMRGlu and rCMR02 for gray and white matter structures and of the CBF, CMRGlu, and CMRO* for the whole brain among different subjects and in repeated measurements in the same individuals (4, 19-24). This variability expressed as standard deviation ranges between 12 and 23% tending to be the largest for glucose metabolism (4, 19, 2 l-24). In this study we examined, whether the notable variability of the global CBF at rest is possibly due to subgroups of subjects with different rCBF patterns. In particular, we asked if the variability of the rCBF pattern is influenced by habituation of the subjects to the

INTRODUCTION

The regional cerebral blood flow (rCBF) and regional cerebral metabolism of glucose (rCMRGlu) are indicators for synaptic activity within neuronal populations (l-3). The advent of positron emission tomography (PET) made it possible to demonstrate in man that rCBF or rCMRGlu are specifically increased in the primary visual cortex by visual stimulation, in the primary auditory cortex by acoustic stimulation, in the primary somatosensory cortex by tactile stimulation, and in the primary motor cortex by finger movements (4-8). Such studies revealed that the stimulation induced rCBF and rCMRGlu increases are coupled ( 1,8,9). Probably due to the small size of areas increasing the rCBF or rCMRGlu during stimulation, however, the mean global CBF and CMRGlu did not change compared to the resting control state ( lo- 12). Recent PET studies using intersubject averaging revealed, moreover, that task-related mean rCBF increases were balanced by large areas of mean rCBF decreases elsewhere in the brain during visual stimulation, right hand vibratory stimulation, and unilateral sequential finger move-

* Correspondence should be addressed to Dr. R. J. Seitz, Department of Neurology, Heinrich-Heine-University Diisseldorf. MoorenstraBe 5. 4000 Diisseldorf I, Germany.

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scanning procedure. We, therefore, selected one group of naive subjects who had no previous experience with PET scanning when they were exposed to the first PET measurement at rest (first group). For comparison, served a group of subjects who were habituated to the PET scanning procedure when undergoing the same PET measurement at rest (second group). Quantitative data analysis and localization of the rCBF to anatomical structures were done on mean images after spatial standardization of the individual PET images by use of the computerized brain atlas program (25,26). Our observations show that in the first group the mean rCBF was significantly higher in cortical higher order association areas. METHODS The rCBF was measured in 26 healthy male righthanded volunteers (age range 19-38 years) with [“Clfluoromethane and the SCANDITRONIX 384-7B PET camera (27). Fluoromethane is a volatile inert and freely diffusible tracer with a high Oswald solubility coefficient of 1.0 to 1.2 (28). A bolus of 60 mCi was administered through an oral tube and inhaled by the subjects, while their nose was closed by a nose clamp. For this [’'Cl-labelled inhaled gas, the highest absorbed dose (approximately 30 mSv) was delivered to the lung and liver. A catheter in the left brachial artery, for measurements of the arterial tracer concentration and the PaCO*, was inserted under local anaesthesia. During the 4-min PET scan, the arterial tracer concentration was continuously measured with a time window of 1 s using the automatic blood sampling device (29). Two blood samples were taken for the measurement of the PaCO*. PET images were reconstructed using the contour-finding algorithm described by Bergstrom et al. (30). Since [“Cl-fluoromethane is an inert and freely diffusible tracer, it is possible to calculate the absolute rCBF from the mean tracer uptake in the brain per time interval (PET,) and the time activity curve of the arterial tracer concentration (Ck-,r) according to

where tj is the time interval, k the clearance, and * means convolution. As detailed elsewhere, this computation is performed for the first 90 s after tracer administration, pixel-by-pixel, using a maximum likelihood approach (3 1). The subjects denied a history of neurologic, psychiatric, or medical disorders. The subjects were informed that the purpose of the study was to investigate the internal brain activity when they were at rest. They

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1992, Volume 16, Number 5

had no previous experience with PET scanning. However, they had been trained to breathe smoothly through an oral tube at least 1 day before the examination. The subjects were informed that they could withdraw from the study at any time. Written informed consent was obtained in accordance with guidelines approved by the Ethic’s Committee of the Karolinska Institute and the Declaration of Human Rights, Helsinki 1975. The subjects were equipped with the fixation helmet (32) to provide an accurate positioning in the PET camera and to prevent head movements during the PET scan. Ten minutes before the rCBF measurement, the subjects were placed comfortably and supine on the bed of the PET-scanner, supported by soft pillows. Their eyes were closed with cotton wool pads and a mask to exclude light and their ears were covered by the fixation helmet (32). The subjects were not allowed to move, to tense their muscles, or to say anything. The subjects were instructed not to think of anything particular. To control that the subjects were awake during the PET scan, eight needle electrodes were inserted into the scalp for recording of the surface EEG. The temperature in the examination room was kept at 23°C. The light was slightly dimmed, there was only ambient noise originating from the cooling fans of the PET camera and the wobbling mechanics. All personnel had fixed positions and speech was prohibited. The first group comprised nine and the second group 17 subjects. The subjects of the second group had two to three preceding rCBF measurements under stimulation conditions. In these preceding rCBF measurements, the subjects performed a right-hand movement sequence ( 14), a right-hand somatosensory discrimination task (33), or underwent visual stimulation with coloured standardized geometric patterns ( 13). The order of the PET scans assigning the subjects to the first group or second group was random. The global CBF of each subject was calculated from manually drawn regions of interest (ROI) covering the whole slice of each of the seven PET image slices. The comparison between the first and second group was done on absolute rCBF values in ml/ 100 g/ min and after normalization of the original PET images to a global CBF level of 5 1.5 ml/ 100 g/min. This value was the mean global CBF of the subjects in the second group and considered as baseline. Normalization is a widely used method to reduce intersubject variability (4,34). Normalization was performed according to pi/ gCBF X 5 1.5, where pi is the individual pixel and gCBF the global CBF of that subject. For evaluation of the absolute mean rCBF differences between the first and second group and of the relative mean rCBF differences after normalization, the

Variability of regional cerebral blood flow pattern

computerized brain atlas program was used. It has recently been demonstrated that this program uses linear and nonlinear transformation parameters that allow to spatially standardize the PET images of different subjects with high accuracy and precision (25). These transformation parameters were determined in each subject on high-resolution magnetic resonance (MR) images (spatial resolution 1.O mm) taken by a 0.5-Tesla SIEMENS MAGNETOM (Siemens-Elema, Solna, Sweden). Although the subjects wore the fixation helmet (32) during the MR scan. residual misalignments between the MR and PET images were corrected by angulations and translations. The product of the three linear transformation parameters (x, y, and z direction) was called “brain size index.” Out of the spatially standardized PET images, mean images (X = sum of each voxel value in ml/ 100 g/min / number of subjects) and corresponding images of the standard error of mean (SEM) for each voxel were created. A voxel-by-voxel subtraction of the mean PET image of the second group from the average PET image of the first group demonstrated the differences of the mean rCBF in ml/ 100 g/min between both examination groups. The differences of the mean rCBF were accepted as significant, if they reached the following four criteria. First, from the average images and corresponding images of the SEM, t-maps for the mean rCBF differences were calculated voxel-by-voxel according to:

%nt

+

%econd

’ becond

(hst

313

RESULTS The absolute mean global CBF of all 26 subjects was 54.0 f 9.2 (SD) ml/100 g/min. This value is in excellent agreement with the CBF of whole brain of 54.2 ml/100 g/min as determined with the KetySchmidt technique (reviewed in 37). As evident from the EEG recordings, the subjects were awake and relaxed showing a good expression (on average 90%) of a regular 10/s alpha-activity with an occipito-parietal maximum. There was no difference (p > 0.05, twotailed t-test) in the duration of the alpha-activity in the first and second group. The PaC02 was in all subjects 40 f 2 (SD) mm Hg. The pattern of the mean rCBF varied considerably among the different brain structures. By far the highest mean rCBF occurred in a large area bilaterally in the medial part of the prefrontal cortex localized to the superior frontal and anterior cingular gyrus (Table 1). The next highest mean rCBF values were observed in the insular cortex, followed by moderate mean rCBF values in the thalamus, the basal ganglia and the occipital cortex. The lowest mean rCBF occurred in the inferior temporal cortex. Since the regional differences occurred in anatomical structures far larger than the resolution of the PET scanner used, they cannot be explained by the partial volume effect that depresses the image values in small anatomical structures (38). Rather, they are likely to reflect different

x first hrst

E. ROLAND

Only mean differences with a t > 2.3 1 (8 degrees of freedom, corresponding to p < 0.05 [35]) were accepted. This procedure minimizes the error of the first type in this comparison of two mean populations. Fourth, the ROIs had to have a minimal spatial dimension of 7.6 X 7.6 mm2 in plane and an axial extension of 13.5 mm [FWHM and slice distance of the used PC 384-7B PET camera (27)]. This is a robust procedure that does not take the greatest rCBF differences of individual voxels but renders ROIs as large as possible. The resulting mean ROI values tend to underestimate the differences because of the partial volume effect at the border of the ROIs (36) but have a favourable statistics compared to single voxel values (25). The rCBF differences were anatomically localized by interactive overlay of the anatomical structures retrieved from the data base of the computerized brain atlas (26).

The rCBF differences were thresholded at an isocontour oft > 2.06. This numerical value would correspond to p < 0.05 in a two-tailed t-test with 24 degrees of freedom (35). Regions of interest representing the differences of the mean rCBF between the first and second group were outlined on the t-maps along an isocontour oft > 2.06. Since the tirst group consisted of nine subjects only, it was investigated thereafter, if the SEM of each ROI in the first group was equal to the SEM of the corresponding ROIs in the second group, since a t-test requires the equality of the variances of the mean values to be compared. Third, t-values for the mean differences taking the different number of subjects (n) in the two groups into account was calculated according to:

t=-

R. J. SEITZand P.

??

-

&cond

1 W&s, &irst +

+

(%econd %econd -

-

1 )S#econd 2

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Table 1. Mean rCBF values (+/-

September-October

1992. Volume

16, Number

5

SD) in ml/100 g/min for 26 healthy male volunteers Measured

Mean

Anatomical structure in the computerized brain atlas (Greitz et al. I99 1) Superior frontal gyrus Midfrontal gyrus Inferior frontal gyrus Lateral orbital gyrus Rectal gyrus Precentral gyrus Postcentral gyrus Superior parietal lobule Precuneus Angular gyrus Calcarine cortex Insular gyrus Anterior cingular gyrus Posterior cingular gyrus Superior temporal gyrus Inferior temporal gyrus Hippocampus Cerebral white matter Caudate nucleus Putamen/Pallidum Thalamus Pons Cerebellar cortex

Right

First group Left

77.0 (19.6) 74.2 (24.3) 64.2 (12.2) 60.9 (20.6) 61.9(11.4) 63.7 (18.3) 58.9 (13.8) 56.3 (12.5) 60.5 (13.1) 63.3 (9.8) 62.5 (24.6) 55.5 (14.5) 57.5 (6.2) 56.7 (5.2) 56.4 (10.0) 56.3 (12.4) 65.4(11.3) 63.3 (12.3) 58.4 (14.6) 58.4 (15.7) 56.4 ( 12.4) 55.3 (15.0) 75.6 (18.1) 76.9 (14.2) 81.1 (25.8) 80.9 (24.0) 57.5 (17.4) 58.7 (15.2) 55.3 (8.0) 50.5 (11.4) 44.6 (8.2) 49.1 (9.0) 53.5 (8.5) 51.7 (8.2) 30.3 (8.6) 28.8 (8.8) 59.3 (20.3) 56.7 (12.1) 65.3 (17.2) 66.0 (I 3.7) 62.4 (17.2) 61.9 (18.3) 51.5 (8.6) 51.4 (10.0) 51.6 (10.9)

Right (32.8) (23.9) (23.6) (32.4) (21.3) (15.7) (8.3) (16.4) (15.0) (24.3) (17.5) (25.6) (30.6) (27.4) (14.3) (14.0) (14.1) (10.2) (18.0) (12.6) (25.0) 55.2 57.4 (15.1)

Left

84.0 65.0 69.3 70.4 65.5 61.4 64.8 66.2 73.5 69.8 63.6 84.5 92.9 66.7 62.3 57.0 54.8 32.0 61.5 73.2 73.7

levels of ongoing synaptic activity in the different cerebral structures. Right/left asymmetry of the mean rCBF was 10% at maximum and not significant. The right/left ratio was 1.01 k 0.05 (SD). The ratio of the mean rCBF in gray over white matter varied between 1.7 and 2.7 in the cerebral hemispheres. Thus, the gray matter/white matter ratio in the mean rCBF images averaged across numerous subjects is similar compared to the reported gray matter/white matter ratio of 2: 1 for ‘*FDG obtained in original PET images with the same camera type (22). In the naive subjects with no prior experience to PET scanning (first group) the mean global CBF (59.2 f 10.2 (SD) ml/100 g/min) was 14.9% higher than in the habituated subjects of the second group (5 1.5 + 8.2 (SD) ml/ 100 g/min). This difference was statistically significant (p < 0.05, two-tailed t-test for comparison of two population means). Figure 1 shows that the global CBF of the studied subjects was not correlated to their age, sizes of their brains, or to the PaC02. Neither in the first nor in the second group, was there a correlation of the global CBF and PaC02. Thus, the global CBF seemed to reflect an overall level of mental activity characteristic for each subject. The regional analysis demonstrated that the mean rCBF was largely symmetrical between the two cerebral hemispheres (Table 1). In the first group the right/left

Second group

(I

88. I 66.7 65.2 66.5 68.2 65.1 60.1 62.6 72.5 71.2 63.5 84.5 98.4 70.5 54.4 53.8 60.1 29.7 62.7 73.2 68.8 1.6) 58.0

(26.0) (I 5.4) (17.5) (32.1) (13.4) (15.7) (13.1) ( 16.9) (17.6) (28.0) (20.0) (19.3) (34.4) (23.1) (13.5) (I 1.8) (13.4) (12.0) (15.1) (20.3) (21.1) (16.0)

Right

volume Left

74.5 (23.0) 76.4 (2 1.O) 59.8 (19.8) 64.5 (12.0) 63.0 (18.4) 61.3 (10.9) 66.5 (22. I) 61.3 (20.4) 60.5 (12.4) 62.8 (10.5) 55.3 (14.8) 63.4 (20. I) 56.5 (6.4) 56.5 (4.8) 54.6(11.3) 55.8 (9.1) 64.0 (10.7) 61.6 (12.4) 56.9 (16.0) 56.6 (14.3) 55.6 (12.8) 53.9 (13.7) 75.9 (16.9) 76.6 ( 14.9) 80.4 (24.0) 79.4 (24.5) 57.8 (23.9) 55.4 (13.1) 54.4 (8.0) 50.4(11.8) 51.1 (11.5) 47.6 (9. I) 5 I .9 (8.2) 52.7 (8.6) 30.2 (8.7) 28.6 (8.7) 56.7 (13.3) 59.6 (19.7) 66.2 (19.3) 64.7 (16.5) 61.5 (18.0) 61.8 (17.9) 5 1.5 (6.9) 50.5 (9.9) 50.6 ( I I .O)

(mm’)

Right

Left

3403 6372 4237 5252 3318 2790 1881 4449 1860 4988 5019 3709 1543 1617 4110 4100 2673 5484 1257 2473 2430

2811 5918 3656 4819 3403 2494 1987 5040 2462 4734 4787 3846 1765 1839 3984 3941 3160 5991 1574 2335 2716 1913

9553

9987

ratio was 1.O 14 + 0.056 (SD) with the greatest, still not significant difference in the superior temporal gyrus. In the second group the right/left ratio was 1.004 + 0.050 (SD) with the greatest, still not significant difference in the precentral gyrus. The mean rCBF in white matter was almost identical in the two cerebral hemispheres and in the two groups being on average 30.9 + 2.7 (SEM) ml/100 g/min in the first and 29.4 t- 2.5 (SEM) ml/100 g/min in the second group (Table 1). The significantly higher mean global CBF in the first group could, therefore, be attributed to a higher mean rCBF in the cortical and subcortical gray matter structures. A significantly higher mean rCBF in the first group compared to the second group occurred in six areas in the parietal, frontal, and temporal association cortices and in paralimbic structures including the posterior cingular cortex preferentially in the tight hemisphere (Fig. 2, Table 2). They did not follow the outline of the anatomical structures, but occupied only a small part of the entire anatomical structures of the computerized brain atlas (Table 1). The contribution of these regions was 3.5% of the difference of the mean global CBF between the first and second group. In addition to the regions with significantly higher mean rCBF values in the first group compared to the second group, there were 14 more structures that also

Variability of regional cerebral blood flow pattern

R. J. SEITZ and P. E. ROLAND

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30 40 50 60 70 Global CBF x brain size index

1

7

60

d

Fig. I. Lack of correlations between the global CBF values and the PaCOz, the brain size index determined by the linear transformation parameters of the computerized brain atlas programme, and the age of the 26 subjects d) R = 0.122. studied: a) R = 0.161, b) R = 0.077, c) R = 0.055,

showed a higher mean rCBF of about 18% to 21% in the first group, which was, however, not significant. Such areas were bilaterally the superior prefrontal cortex, the anterior cingular cortex, the fronto-orbital cortex, the Broca’s area, the right homologue of Broca’s area, the left angular and superior parietal gyrus, the mediodorsal thalamus, and the claustrum. Figure 3a shows that the absolute mean rCBF was in all these gray matter regions to almost the same degree higher in the first group than in the second group. Also, other cortical and subcortical gray matter regions including the primary motor cortex, the frontal eye fields, the primary somatosensory, visual, and auditory cortex showed differences of the absolute mean rCBF values between the first and second group. However, as evident from Table 1, these differences were considerably lower ( 1 to 8 ml/ 100 g/min). There were no gray matter

structures with a lower mean rCBF in the tirst than in the second group, Figure 3c shows the relation of the mean rCBF in white matter and 20 gray matter structures of the first and second group. It becomes evident that the differences of the mean rCBF between the first and second group were not due to a linear global factor, but were limited to a higher mean rCBF in gray matter structures. The relation was described at best with an exponential curve with a high correlation coefficient of R = 0.927. The SEM of the mean rCBF of the 21 regions shown in Fig. 3a and 3c was, except for two regions, far greater in the first than in the second group (Fig. 3b). Thus, the SEM of the mean rCBF of the gray matter structures in the first group was not correlated to the SEM of the mean rCBF in the second group (Fig.

316

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Left 14 12 10 8 8 4 2

Fig. 2. Localization of areas with a higher mean rCBF in the first group A on the lateral surface of the brain of the computerized brain atlas (26). The right posterior cingular cortex on the medial surfaces is depicted as A. The 14 axial image slices are indicated. The sulci shown are C = central, FI = inferior frontal, FS = superior frontal, L = lateral, IP = intraparietal, PO = postcentral, PR = precentral, TO = temporo-occipital, TS = superior temporal,

3b, d). These findings indicated regional differences of physiological activity between the two groups and predominantly among the subjects of the first group. Only gray matter regions with a relatively small SEM of the mean rCBF in the first group were significantly different from those in the second group. Figure 4 illustrates the relative mean rCBF values achieved by global linear scaling, normalization, for the 21 areas shown in Fig. 3. In this figure the PET images of the subjects were linearly scaled to a global value of 5 1.5 ml/ 100 g/min, which corresponded to the mean global CBF in the second group and was taken as baseline. It becomes evident that due to normalization, the differences of the relative mean rCBF between the first and second group decreased by about 50% compared to the differences of the absolute mean rCBF. Moreover, it can also be seen that after normalization the relative mean rCBF value in white matter in the first group was lower than in the second group. This was also the case for the other cortical areas with only little mean rCBF differences prior to normalization, such as the precentral gyrus and the primary visual cortex. That is, due to normalization, the highest absolute mean rCBF values in the first group were reduced and the lower absolute mean rCBF values of the first group were converted to smaller values in relation to the mean rCBF values in the second group. Thus, the differences between the two groups prior to normalization were no longer significant after normalization. Figure 4b demonstrates that normalization scales the mean rCBF in a linear fashion. In contrast, prior to normalization the mean rCBF in the first group was not linearly related to the mean rCBF in the second group (Fig. 3~). This comparison emphasizes that the

differences of the absolute mean rCBF between the first and second group in the original, not normalized PET images were not due to global scaling. DISCUSSION In this study we have shown that the mean rCBF bilaterally in the inferior frontal cortex, in the right midfrontal, anterior parietal, and posterior cingular cortex, and in the right temporal lobe was significantly higher in subjects who had no previous experience with PET scanning compared to subjects who had habituated to the PET scanning procedure. Our results closely correspond to recent findings by Camargo et al. (39) showing that the intersubject variance of the cerebral glucose consumption preferentially originated from these cerebral structures. Moreover, our data indicate that the higher global CBF in the naive subjects was not due to a global factor such as the subjects’ age, the brain size, or the PaCOz . Similarly, no age effect could be demonstrated for the glucose utilization in resting subjects between the age of 21 and 83 years (40), whereas more recently the global glucose metabolism has been shown to decrease with age, but to be independent of brain size (41). The lack of relation of the global CBF and PaCOz suggests that mental activity at rest represents a specific behavioral state with a different intersubject variability, as that of pulmonary gas exchange. A repeat study in the same subjects should provide more direct evidence for this observation. The interpretation of our results has to take particular methodological aspects of this PET scanning procedure into consideration. The subjects were scanned while they were in an unstimulated state with

Variability of regional cerebral blood flow pattern Table 2. Regions with significant

of the absolute

Localization by the computerized brain atlas (Greitz et al. 199 I)

Functional area lntraparietal right (4) Posterior cingular right (9) Midfrontal anterior right (I Inferior frontal left ( 16) Inferior frontal right (I 7) Temporal pole right (I 8)

differences

I)

Angular gyrus Cingular gyrus Midfrontal gyrus Lateral orbital gyrus Lateral orbital gyrus Sup. temporal gyrus

Numbers in brackets behind the functional areas indicate * p < 0.05 (two-tailed f-test). + Calculated as: (Rest first - Rest later)/Rest first X 100.

the number

eyes and ears covered. They were in a relaxed and awake state as evident by the presence of a regular alpha-activity in the EEG records and the stable PaCOz values. Thus, they fulfilled the criteria of being at rest as described by Roland and Larsen ( 17) and Mazziotta et al. (18). This state is used as baseline control state for neurophysiological and neuropsychological stimulation tasks. For technical reasons, however, the subjects were equipped with an individually moulded fixation helmet, which prevented head movements during the examination (32). In addition, they had an arterial line in the left brachial artery, which was inevitable for recording the arterial input l‘unction of the tracer to be able to calculate the absolute rCBF (28, 31). Only the absolute rCBF, such as the absolute rCMRGlu, are related to synaptic activity of neuronal populations (1, 2). Moreover, the subjects had to breathe through an oral tube while the nostrils were blocked by a clamp. This clamp was necessary to prevent contamination of the air in the examination room due to expiration of the tracer by the subjects. Finally, the rCBF tracer was administered by cooperation of the subjects in that the subjects had to take a deep breath to quickly inhale as much of the [“Cl-fluoromethane as possible. Although certainly not being harmful and sham exercised several times before the actual PET scan with the subjects, this treatment might have stimulated the naive subjects during the first scan. Similar to our findings, a higher global CBF in the first examination compared to a lower global CBF in subsequent examinations has earlier been reported for ‘33Xe inhalation studies with the single photon technique (42-44). The work of Risberg et al. (42) demonstrated, moreover, that such a systematic decline of the global CBF was not only apparent in repeat rCBF measurements at rest, but slightly more pronounced in repeat rCBF measurements during internal problem solving. These authors assumed that the systematic decrease of the global CBF was inherent in the measuring

??

mean rCBF (ml/100

First group (n = 9)

ml SEM 78.7 88.4 81.7 54.4 65.3 70.0

R. J. SEITZ and P. E. ROLAND

(8.7) (9.9) (S.lj (7.9) (9.0) (6.3)

g/min) between

Second group (n = 17) ml SEM 59.5 68.1 62.2 35.7 45.6 51.3

317

(3.9) (4.5) (4.5 j (4.0) (4.3) (4.1)

the two groups Difference

ml 19.2* 20.3* 19.5* 18.7* 19.7* 18.7*

O/o+ 24.4 23.0 23.9 34.4 30.2 26.7

cm’ 3.16 2.99 2.78 2.62 3.85 2.87

of regions in Figs. 3 and 4.

procedure indicating habituation of the subjects to the scanning situation. Indirect support for this explanation comes from repeat PET studies with intravenous tracer administration of Hz”0 for rCBF measurements and of j8FDG for measurements of rCMRGlu that did not show such systematic differences in subsequent measurements using intravenous tracer injection (10, 20, 23, 34, 45, 46). Recently, Tyler et al. (47) reported a tendency of the global CMRGlu to decline in repeat PET measurements. This tendency was, however, not significant. Significant effects of habituation on the rCBF are apparently caused by measuring techniques using active cooperation of the subjects for inhalation of the tracer. The accurate anatomical localization of the mean rCBF differences underlying the global CBF differences by use of the computerized brain atlas (25,26) revealed a higher mean rCBF in the first group in six areas of the prefrontal, parietal, and paralimbic cortex (Table 2). It should be emphasized, however, that all the regions with higher activity in the first group occupied only a small part of the entire anatomical structures, as retrieved from the data base of the computerized brain atlas. These cortical areas are remote from sensory and motor cortices and are presumed to subserve complex, integrative functions (5, 10, 48). In contrast, the primary cortical input and output areas (49) and the frontal eye fields ( 11) did not show rCBF differences between the first and second group. This was in accordance with that the subjects neither moved nor received any stimulation from the outside world. Similarly to our findings, Risberg and Ingvar (50), using the intraarterial ‘33Xe-technique, reported a more focalized rCBF pattern in gray matter during a second measurement. Also Mazziotta et al. (5 1) demonstrated with PET that the coefficient of variation of the mean rCBF differed considerably among various cortical areas in repeat measurements. More specifically, Lenzi et al. (52) reported that the rCBF and rCMR02 was

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Fig. 3. (a) Differences of the absolute mean rCBF values in the first group compared to the second group for the regions with the largest mean rCBF differences (I-18) the precentral cortex (19) the primary visual cortex (20) and the hemispheric white matter (21). The vertical bars indicate the corresponding SEM values. (b) The SEM of the first and second group for the 2 I regions. (c) Plot of the mean rCBF in gray matter regions and hemispheric white matter of the first and second group. The relation is nonlinear and can be fitted best to an exponential curve. (d) Lack of correlation of the SEM values of the regions of the first and second group (R = 0.235).

more variable in visual association areas than in motor and primary visual areas in repeat measurements. Taken these data together, the pattern of higher mean rCBF in the first group suggested that the subjects were fearing that something unpleasant may happen to them during the PET measurement. Anticipatory fear may have been the reason for the significantly higher mean rCBF in the right temporal pole (53). Moreover, anxiety has been reported to increase the rCMRGlu in the fronto-orbital and middle frontal regions (6), which also showed a higher mean rCBF in the first group. Another aspect of the internal mental activity may be related to raised attention and to the subjects’ attempts to cope with the scanning situation. Right parietal rCBF increases have recently been shown

subserve sustained attention (54). In the rhesus monkey, the posterior parietal cortex and the dorsolateral prefrontal cortex have recently been demonstrated to project to a large number of common cortical and subcortical neurons (55). This converging connectivity has been claimed to represent the basis of a neuronal network related to many aspects of behavior like the direction of motivation and attention (56, 57). Of these interconnected areas, the inferior and midfrontal cortices, the intraparietal cortex, the posterior cingular cortex, and the pole of the superior temporal cortex actually exhibited a higher mean rCBF in the first group in this study. Interestingly, the mean rCBF in the superior prefrontal cortex was not significantly different between the first and second group. This furto

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Fig. 4. (a) Plot of the mean rCBF for the 2 1 regions shown in Fig. 3 after normalization of the global CBF to 5 I .5 ml/100 g/min. The vertical bars indicate the corresponding SEM values. The normalized mean rCBF values of the first group are not significantly different from those in the second group. Note also that after normalization the mean rCBF of the first group is in some areas (19-20) below that of the second group. (b) Plot of the absolute mean rCBF versus the normalized mean rCBF of the first group. Note the linear relation compared to the exponential relation when plotting the regions of the first versus those of the second group (Fig. 3~).

ther

substantiates

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of the “hyperfrontality”

of the rCBF in resting wakefulness (58, 59) both before and after habituation to the scanning procedure. Finally, we would like to emphasize that the described differences of the absolute mean rCBF between the first and second group were abolished after linear scaling, normalization, of the global CBF to a common level. Normalization has been applied by different PET

laboratories (4, 9,60-62) and is used in the semiquantitative evaluation of qualitative rCBF images obtained with single photon emission tomography (SPECT). More recently, evidence is emerging that some neurobehavioral stimulation tasks, including cognitive aspects, significantly increase the global CBF compared to rest (3 1, 33,63,64). These global changes will remain undetected owing to the normalization process (5 I, 65).

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In addition, our data show that due to normalization, one may miss important rCBF changes that reflect changes of regional synaptic activity (l-3). In contrast, the rCBF in hemispheric white matter showed a high state-independent stability and low intersubject variability (Table 1, Fig. 3a and 3b). Therefore, normalization of semiquantitative count rate images taking white matter as reference appears possible to globally adjust different images without loss of significant physiological information. Low count rates in white matter may, however, preclude normalization of images of individual subjects. SUMMARY

The rCBF was measured in 26 healthy volunteers with bolus inhalation of [’‘Cl-fluoromethane and PET to study the variability of the global CBF and of the rCBF pattern at rest. Mean global CBF of all subjects was 54.0 f 9.2 ml/l00 g/min and identical to the CBF determined with the Kety-Schmidt technique. Regional analysis demonstrated that the highest mean rCBF occurred bilaterally in the medial parts of the prefrontal cortex, while the lowest gray matter values were observed in the inferior temporal cortex. This pattern supported the notion of the “hyperfrontality” of the rCBF at rest. As measure for the variability of the rCBF pattern, the PET scans were divided in one group of subjects who had the rCBF measurement at rest as first PET scan and in a second group of subjects who had the PET scan at rest after preceding PET scans with different physiological stimulation tasks. Subjects having the first PET scan had a significantly (p < 0.05) higher mean global CBF, which was due to a higher mean rCBF in cortical and subcortical gray matter structures. The significantly higher mean rCBF occurred in the parietal, prefrontal, cingular, and temporal association cortices whose functions have been related to higher order information processing. In contrast, the mean rCBF was not significantly higher in the primary motor and sensory areas. A “hyperfrontality” of the rCBF was present in both subgroups. Our results are in line with recent studies on the interindividual variability of the regional cerebral glucose consumption. The data suggest that the pattern of the rCBF at rest significantly varies due to differences in mental activity which may be related to habituation of the subjects to the scanning procedure.

Acknonledgmenls-This work was supported by the fellowship Se494 of the Deutsche Forschungsgemeinschaft. The authors thank Sharon Stone-Elander, Peter Johnstrom, Jan-Olov Thorell. and Goran Printz for providing the radioisotope. The expert help of Monica

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Serrander, Charlotta Lundmark, and B&t-Marie the experiments is gratefully acknowledged.

5 Berggren

during

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64. Cameron, O.G.; Modell, J.G.; Hichwa, R.D.; Agranoff, B.W.; Koeppe, R.A. Changes in sensory-cognitive input: Effects on cerebral blood flow. J. Cereb. Blood Flow Metab. 10:38-42; 1990. 65. Seitz, R.J.; Roland, P.E. Errors in quantification of rCBF-changes due to normalization. J. Cereb. Blood Flow Metab 9 (Suppl I): S432; 1989.

J. SEITZ studied medicine at the University of Hamburg and graduated in 198 1. In the same year he was promoted to Dr. med. at the University of Hamburg. From 1982 to 1987 he was a resident at the Departments of Neuropathology and Neurology at the University of Dusseldorf, Germany. From 1987 to I989 Dr. Seitz joined the PET-Laboratory, Department of Clinical Neurophysiology, Karolinska Institute and Hospital, Stockholm, Sweden, as a research fellow, under the guidance of Professor Dr. P. E. Roland. Since 1990 Dr. Seitz has been running the PET-Research group at the Department of Neurology, Heinrich-Heine-University of Dusseldorf, Germany. Since 199 I he is a consultant and lecturer for Neurology at the Heinrich-Heine-University of Diisseldorf. His scientific interest is directed towards the cerebral plasticity of motor functions in man.

About the Author-RODIGER

About the Author-PER

E. ROLAND, after having studied medicine, was a resident in the Departments of Neurology and Physiology at the University Hospital of Copenhagn from 1970 to 1979. Thereafter, he spent 2 yrs as a research fellow at the McGill Institute in Montreal, Canada. In 1987 Dr. Roland was promoted to Dr. med. at the University of Copenhagn, Denmark. Since 1986 Dr. Roland worked at the Department of Clinical Neurophysiology, Karolinska Hospital, Stockholm, Sweden. In 1988 he was appointed Professor at the Karolinska Institute and is head of the Laboratory for Brain Research and Positron Emission Tomography, Nobel Institute of Neurophysiology, Stockholm, Sweden. The scientific interest of Dr. Roland is directed towards the human somatosensory system, higher order movement control, and memory.