.Vmuopsycholoyia. Vol. 24. No. 1. pp. 135-140. 1986. Printed m Great Britain

@X&393?. 86 53.W~O.00 Pergamon Press Ltd.

REGIONAL CEREBRAL BLOOD FLOW IN NEUROPSYCHOLOGY

J. RISBERC

Department of Psychiatry, University Hospital, S-221 85 Lund, Sweden

Abstract--iMeasurements of regional cerebral blood flow (rCBF) provide information about the metabolic and functional level of the cortex. Difierent techniques for measurement of rCBF are described and their potentials and limitations are outlined. Typical results from measurements in normals during performance of mental tasks are shown and as well as clinical measurements in patients with organic dementia. Future improvements of the techniques regarding spatial as well as temporal resolution are outlined. It is concluded that measurements of rCBF are likely to be of great value in the future exploration of brain-behaviour relationships.

INTRODUCTION

THE FIRST empirical observation which linked regional cerebral blood flow (rCBF) to mental processes was made by FULTON in 1928 [I]. He reported an increased bruit over an arterio- venous malformation in the occipital lobe of a patient who was reading. However, several decades would pass before further evidence of the coupling between rCBF and mental functions was presented. Meanwhile, it was generally believed that the cerebral circulation was unaffected by normal mental activity. This conclusion was based on the results from only one study [14], which had showed unchanged total brain blood flow during mental arithmetic. Evidence supporting Fulton’s observation has accumulated since the introduc- tion of regional measurement techniques in the middle of the ‘sixties [2, 61. Since then the sensitivity of rCBF to cortical functional changes during mental processes has been documented in numerous studies. This sensitivity is due to an intrinsic mechanism, which regulates local blood flow in accordance with the functional and metabolic level of the neuronal tissue [73. These changes of flow and function are narrowly localized, possibly down to the columnar level [133. As will be further discussed in this paper, present rCBF methods for studies in humans have limited spatial resolution, giving a fairly coarse image of the flow pattern. Improvements of spatial, and to some extent also temporal, resolution are, however, in sight. It will be concluded that rCBF measurements are likely to be an important aid in the future exploration of brain-behaviour relationships in health and disease.

THE INTRA-ARTERIAL 133Xe INJECTION TECHNIQUE

The first regional CBF technique was introduced in the early ‘sixties by LASSEN and INGVAR [33. It was based on the injection of an inert, diffusible (penetrating the blood-brain barrier) radioactive tracer, ‘33xenon (133Xe), into the internal carotid artery. The instantaneous arrival and subsequent clearance of the tracer was followed by multiple external scintillation detectors. The rate of disappearence of Xe from the region recorded is proportional to the level of perfusion and absolute flow values (in ml blood/100 g brain

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tissueimin) can be calculated from the curves. Several different flow measures might be calculated, but of greatest interest are those describing the blood flow in the grey matter.

The intra-arterial i3jXe method was the preferred technique during the ‘sixties and early ‘seventies. An instrument with high spatial resolution (about 10 mm) was used with success by LASSEN and his group [4] in the study of rCBF changes during mental processes. The technique has, however, severe drawbacks due to the risk and discomfort involved in the puncture of the carotid artery. No normal volunteers and only restricted patient populations can be studied. The measurements can generally be performed on one occasion only, and in only one hemisphere. From the middle of the ‘seventies, the intra-arterial method has gradually been replaced by non-invasive and bilateral technology. Today, close to all rCBF research in neuropsychology utilizes the ‘33Xe inhalation technique.

Methodology THE L33Xe INHALATION TECHNIQUE

The L33Xe inhalation technique had been suggested in the ‘sixties but methodological problems related to extracranial contamination, recirculation of the isotope and other complicating factors were not properly solved until the middle of the ‘seventies [5, 1 l]. A standard rCBF recording consists of 1 min of breathing of a mixture of ‘33Xe and air followed by 10 min of normal air breathing. The arrival and disappearance of the tracer is followed by bilaterally placed scintillation detectors. Present commercially available systems have 16 or 32 detectors which give a spatial resolution of 3-5 cm. As for the intra-arterial technique, different measures of grey matter blood flow are calculated from the recorded curves.

Advantages

The basic advantage in neuropsychological research is the fact that a physiologic phenomenon, which mirrors the functional state of the brain is measured with high accuracy. The spatial resolution is better than for most other measures of brain function, e.g. electrophysiological recordings, and will be further improved in the future (approaching 10 mm, see paragraph “Future technical development”). Repeated measurements can be made in normal healthy volunteers as well as in patients. Up to 1000 measurements per yr might be made by one technician using one rCBF machine. The cost is U.S. $100, or less, per study.

Features and limitations

Applicability. Although the ‘33Xe inhalation technique is non-invasive, it still gives added radiation to the subjects studied. The critical organ is the lung and the exposure is in the order of 100 mRad per measurement. Compared to most other investigative methods in nuclear medicine and radiology, this dose is quite low-due to the very fast elimination of the gas following the 1-min breathing period. For clinical rCBF studies this exposure is accepted by radiation safety and human ethics committees in, to the author’s knowledge, all countries. The situation is, however, different regarding healthy volunteers. Measurements in normals are not permitted in some central European countries, while they are allowed in, for example, the U.S.A. and in the Scandinavian countries. The rCBF researcher has to consult the local radiation safety and human ethics committees before starting a study and might have to

REGIONAL CEREBRAL BLOOD FLOW IN SEUROPSYCHOLOGY 137

modify his protocol regarding selection and size of the sample and the number of measurements made in each subject.

The experimental situation. Baseline measurements are commonly made during a ‘resting’ state with the subject laying on a comfortable bed with minimal visual and auditory stimulation and with the instruction to be relaxed without falling asleep. The subject has been infol-md about the measurement procedure and allowed some minutes to adapt to the breathing system and the face mask. The mental state of the subject is, however, poorly standardized since different emotional, attentional and cognitive reactions to the measure- ment situation can be expected. As an alternative reference, many researchers prefer a state when the subject is performing some simple sensory-motor control task. Numerous studies have compared rCBF during a baseline state with that of an activated state. A variety of visual, auditory and tactile stimulations with verbal or motor responses have been successfully tried [S, lo]. The principle of the clearance method and the measurement situation has put some restraints on the design of such activation studies. Only the average blood flow level during the recording period can be calculated from the curves. No transient changes related to processing of shortlasting stimulation can be measured. The activation task has thus to consist of a series of similar items presented continuously, which start a couple of minutes before the registration and continue for at least the first 5 min of the measurement (during which period the grey matter blood flow is determined). The supine and rather fixed position of the subject and the face mask also impose some practical limitations on possible language and motor responses. Since an rCBF study, with present methodology, can be repeated with a minimal time interval of about 20 min [S], there are also limitations regarding the number of different activation tasks which can be utilized during a recording session. Our experience is that it is difficult to do more than four consecutive measurements without the subject being uncomfortable and tired. In mentally disturbed patients often only one or two measurements are possible because of distress caused by the face mask, the breathing system and the fixed position of the head.

Spatial resolution

Until now nearly all rCBF research in neuropsychology has utilized two-dimensional recording systems. With such systems the region of measurement for each detector has the shape of a truncated cone. The tissues in this cone have successively less influence on the recorded curve the deeper their position. This is due to the absorption of the emitted photons in the brain tissue. The low energy of the ‘33Xe photons (80 keV) is the reason why two out of three photons emitted in medial brain regions will be absorbed. The two-dimensional recordings are thus heavily dominated by radiation from super&al cortical layers. The more diffuse influence from deeper, including contralateral, structures will, however, cause an underestimation of the true hemispheric and regional differences in flow by a factor of about two [lo].

It is possible to measure rCBF in deeper brain structures by using three-dimensional (tomographic) recording equipment. This technique, called single photon emission computed tomography (SPECT), has so far been used very little in neuropsychology. When ‘33Xe is used as an indicator in such measurements the flow maps will unfortunately have rather poor spatial resolution (20-25 mm). This resolution is inferior to that of most other tomographic techniques (e.g. position emission tomography, PET), and is not good enough for accurately relating the recorded flow values to any smaller anatomically-defined brain regions. More resolute pictures are obtained by using newer tracer substances like iodo-

138 J. RISBERG

amphetamine and technetium-iabelled Iipophilic compounds. The use of such tracers for neuropsychological studies is, however, prohibited by high radiation exposure and very limited repeatability.

Examples of results obtain by two-dimensional rCBF

Studies in normal subjects. As mentioned earlier, numerous studies have compared the rCBF of a baseline state (resting) with that of an activated state. Some typical results from the author’s laboratory are shown in Fig. 1. Thirty five normal healthy young volunteers ofboth sexes were studied during silent relaxation with closed eyes, as compared to activation by a test of word fluency and a test of verbal creativity (brick test; only 15 of the subjects). The

rCBF changer during mental activation

Word tluency

Il.35

Brick-test

n.15

Lt

iSl

FIG. 1. Changes of regional cerebral blood Bow (rCBF) in normal healthy young subjects during a word fluency test and a test of verbal creativity (brick test). The mean hemispheric difference to the resting measurement is shown in the boxes. Regional changes are denoted by clock symbols, black indicating higher flow during activation than during rest. Stars indicate significance (by t-test) of the

difference between rest and activation. (From WARKENTIN er al. in preparation).

rCBF measurements were made by standard ‘33Xe inhalation methodology in 32 regions of both hemispheres. The detectors were placed radially to the skull. During the word-fluency test the subject was asked to report aloud as many words as possible beginning with a given letter. In the brick test, the subject was asked to tell the investigator as many ways as possible of using a brick. The figure shows that both tests caused frontal and fronto-temporal increases in the left hemisphere with a tendency to more accentuated activation during the brick test. The results are thus in accordance with the hypothesis of left-hemisphere involvement in the production of speech. It is, however, evident from the figure that the limited spatial resolution of the present recording system gives in a rather coarse depiction of the flow changes.

Studies in patients. The rCBF methods have been widely used in clinical studies of patients with a variety of disorders affecting the brain [S]. The results have often added SignificantIy to the understanding of disease processes and the effects of different therapies. While the practical usefulness of the rCBF information in routine medical care still awaits definite proof in many neurologic disorders like stroke, one major clinical area of application seems

REGIONAL CEREBRAL BLOOD FLOW IN ~-EUROPSYCHOLOGY 139

very promising. This is the use of the technique for differential diagnosis of patients with dementia. It has been shown that fairly specific regional flow changes are seen in Alzheimer’s disease, dementia with fronto-temporal atrophy (Pick’s disease) and in multi-infarct dementia [12]. Comparison of diagnosis by rCBF with diagnosis at autopsy has shown agreement in about 90% of the cases [9]. An example of typical rCBF findings during clinical progress in a case of presenile Alzheimer’s disease is shown in Fig. 2. It has also been shown that rCBF is generally normal in pseudodementia caused by affective illness. The rCBF results can thus aid in the identification of treatable groups of demented patients. In our laboratory clinical routine evaluation of rCBF are made in about 1000 demented patients per year.

ALZHEIMER’S DISEASE F.T. d 68Y 781113 820422

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FIG. 2. Regional cerebral blood flow in a case of Alzheimer’s disease. The measurements are made during rest. The hemispheric mean is indicated in the boxes. Regional values are show as per cent of the hemispheric mean by means of clock symbols. Note the focal decreases in parietal and parieto- temporal areas, which are accentuated at the second investigation when the mental symptoms of the

patient had progressed.

Future technical development

Starting in autumn 1985, a new two-dimensional measurement system with 254 mini- detectors and ’ 33Xe inhalation technology will be evaluated in our laboratory. The system will provide maps of the cerebral blood flow with a resolution of about 10 mm for the superficial cortex, approaching the performance of the earlier high-resolution system for the intra-arterial ‘33Xe injection technique. This higher resolution is expected to markedly improve the accuracy of the flow maps, makin, a more definite conclusions about brain-behaviour relations possible. Further improvements in the methodology might also be obtained by utilizing tracers with very short physical half-lives, such as 195mAu (30 set). Such a tracer would make it possible to study rCBF with much better time resolution; flow determinations every minute seem not unrealistic. An improved time resolution would offer new possibilities for studying the dynamics of the activation response and the different steps in cortical information processing.

With the prospect of these improvements in the two-dimensional technique and with expected improvements of the tomographic technique, it seems likely that rCBF

140 J. RL%ERG

measurements will be of great value in the future exploration of brain-behaviour relationships in health and disease.

dcknowledyemenrs-Supported by the Swedish Medical Research Council (project No. 4969).

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