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Experimental Brain Research 5, 72--78 (1968). Regional Changes in Cerebral Blood Volume. During Mental Activity. JARL RISBERO and DAVID H. I~OVAI~.
Experimental Brain Research 5, 72--78 (1968)

Regional Changes in Cerebral Blood Volume During Mental Activity JARL RISBERO and DAVID H. I~OVAI~ Department of Clinical Neurophysiology, University Hospital, Lund, Sweden Received September 1, 1967 Summary. Ten human subjects were injected intravenously with a non-diffusible gamma-emitting isotope. At steady state, 8 collimated scintillation detectors, placed laterally to the subject's head, measured the activity in 8 hemisphere regions. During various types of psychological tests, regional variations in the g a m m a radiation were recorded. Different patterns of changes were seen during reception of visual impulses, and during various cognitive tasks. These patterns probably represent changes in cerebral blood volume, which are caused b y regional metabolic and circulatory events, mainly in the cerebral cortex, and which have a relation to mental activity. Previously demonstrated changes in regional cerebral blood flow during mentation highly support this interpretation. The untraumatie method usedin the present study permits, for the first time, continuous extracranial measurements of regional cerebral circulatory events related to mentation. Key Words: Mental activity in m a n - - tZegional cerebral blood volume - - Isotope measurements Introduction

We have recently demonstrated t h a t small, but significant, and to some extent localized, changes take place in the cerebral blood flow during increased mental activity (INGvAI~and RISB~G 1967). These results were taken to show t h a t mental activity gives rise to regional changes in the cerebral metabolism which cause secondary changes of the regional cerebral blood flow. The isotope clearance method permitted differential flow measurements in the grey and white matter within circumscribed parts of the hemisphere studied (LAssv, N et al. 1963, HOWDT-RASMUSSEN et al. 1966). I t was established that the flow increase in mentation took place almost exclusively in the grey matter compartment. The method was, however, discontinuous and involved an isotope injection into the internal carotid artery. Furthermore, a constant flow was required during the 15 min of measurement. I t was therefore not suited for studies of rapid flow changes, for large scale studies, or for measurements in normals. In order to investigate the regional pattern of cerebral circulatory changes in mental activity in normals, a new, harmless and continuous technique would be necessary for regional measurements in the brain during longer periods. Since there are no quantitative blood flow methods which can be used for such a purpose in man, we have had to rely on an indirect technique b y means of which the regional cerebral blood volume (rCBV) in eight different parts of the brain is measured simultaneously following administration of an intravaseular non-diffusible gamma-

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emitting indicator (radioactive iodinated serum albumine, RISA). This method will b e d e s c r i b e d i n d e t a i l e ] s e w h e r e , t o g e t h e r w i t h a r e p o r t o n r C B V c h a n g e s i n a l a r g e r g r o u p o f n o r m a l s d u r i n g m e n t a t i o n (I~ISBERG i n p r e p a r a t i o n ) . T h i s is a b r i e f summary of our first findings on rCBV changes during mental activity in ten human subjects.

Materials and Methods The method was first tested on a group of three patients (56, 59 and 60 years old), and later a group of seven healthy male students (20--25 years old) was studied. The patients were brain t u m o u r suspects and underwent gamma-encephalography with 400/~C of RISA in two of the cases, a n d 500/2C of l~THg Chlormerodrine (Neohydrin) in one case. I n all patients the present measurements were made on the healthy side. I n the normals, 100/~C of RISA was administered intravenously. This corresponds to a total body radiation dose of 0.2 fads and a blood radiation dose of 0.6--0.7 fads (SMIT~ 1965). The time interval between the injection and the start of the rCBV measurement was 2 0 ~ 3 0 rain for the normals and about 1 h for the patients. G a m m a radiation was recorded from eight regions of the brain b y eight scintillation detectors (1 • 1 inch thallium activated sodium iodide crystals) shielded b y at least 13 m m of lead. The detectors were mounted in parallel cylindrical holes (diameter 35 ram) within a block of lead, at right angle to the lateral surface of the subject's head. The normals (all right-handed except one) were measured on the left side and the patients on the right. The measuring fields corresponded roughly to two "frontal", one "precentral", one "central", one "postcentral", one "parietal", and two "occipital" parts of the hemisphere. Each field comprised, of course, a conical p a r t of the whole head, b u t calculations showed t h a t a b o u t 75 ~ of the radiation recorded e m a n a t e d from the hemisphere closest to the detectors. The position of the head in relation to the block of lead was made as uniform as possible in all the subjects b y means of an adjustable head-holder, which minimized movements during the studies. The central axis of each measuring field was marked with a small piece of lead on the skin, and a lateral x-ray of the skull enabled a gross localization of the measuring fields. W i t h the doses used, counting rates of a b o u t 500 cpm were recorded from each detector in the normals, and a b o u t 2000 cpm in the patients. The background activity was 15--30 cpm. The eight scintillation detectors were coupled via amplifiers and pulse height analysers to an eight channel tape recorder. For measurements with RISA the windows of the analysers were adjusted to energies between 180 and 450 keV (and 60--100 keV for the patient in which the 197Hg isotope was used). I n the normals recordings were usually made for 3 h and 15 min. I n the patients the measurements periods did not exceed 60 rain. Each channel on the tape was analysed b y means of a counter which yielded the absolute n u m b e r of impulses for each minute. Measurements of the clearance rate of R I S A showed t h a t the radiation recorded over the head diminishes a b o u t 8 % in 24 h. This means t h a t during the 3 h of measurement the baseline decrease was negligible and, thus, no correction was made for the I~ISA clearance. However, 197Hg Chlormerodrine has a much shorter half time in blood (about 100 rain). The changes in rCBV measured with 197Hg were therefore superimposed upon a mono-exponential clearance function (Fig. 3).

Psychometric Methods rCBV measurements were made during rest and during the following psychometric tests. 1. Thurstone's Picture Memory Test (T~u~sToz~ 1938). This test consisted of a series of simple meaningful pictures, which were memorized in silence during 3 - - 5 rain. Each picture was shown during 5 sec. Later, usually following a brief rest period, the memorized pictures were to be recognized b y naming the respective number, amongst several other pictures looking similarly. 2. Reasoning Test (THv'RSTO~E 1938, DU~EMAZ~and S~L1)E 1959). Each item consisted of five geometrical figures, four of which h a d a common feature. The subject was to tell which of the five which was in some respect different from the others. 3. Spatial Test (WEsTRI~, personal communication). The task consisted of telling the investigator which geometric figure, from a choice of five, which would fit a given incomplete square.

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J. R ISBEBG and D.H. INGYAB:

4. Digit-Span-Backward Test (W~e~SLEB 1959, INGYABand RISBERG 1967). Series of 4--9 digits were given orally to the subject (who had closed eyes) and the subject was asked to repeat them backwards. He was forced to repeat as many digits as possible. In addition, intermittent photic stimulation with about 20 flashes/sec was made in each case during 4 min. The influence of cranial muscular activity was investigated by letting the subject chew candy vigorously for some minutes. The EEG was also recorded during rest and test epochs of the measurement periods. The results of the EEG studies will be dealt with elsewhere (RISBERG, in preparation). Controls of the systolic blood pressure did not show any substantial changes during the tests. They were less than 5 mm Hg.

Results Patients. I n t h e t h r e e p a t i e n t s o n l y a l i m i t e d t e s t p r o g r a m conld be carried out. H e r e o n l y t h e results from t h e p i c t u r e m e m o r y t e s t will be d e a l t with. Fig. 1 shows t h e results from one of t h e p a t i e n t s s t u d i e d w i t h I~ISA. D u r i n g learning when t h e ~ cpl

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Fig. 1. Changes of regional cerebral blood volume (rCBV) measured by R I S A during the picture memory test in a patient. Note the occipital increase and the frontal decrease durRest Recoil Rest ing "learning". A large increase of rCBV is seen during "recall", especially in the eentralI r r r i , p r 10 15 rain 20 postcentral parts of the hemisphere

p a t i e n t looked a t t h e pictures, t h e r e was a h i g h l y significant rCBV increase (p < 0.001) of a b o u t 10% in t h e occipital area n u m b e r 8, as well as in t h e s u r r o u n d i n g areas 5 a n d 6. (S.D. for t h e rOBV-values d u r i n g t h e first 5 m i n rest periods was _+ 1.67%. Changes larger t h a n 3.4% are t h u s significant [p < 0.05]). A significant decrease of r C B V was, however, seen in t h e f r o n t a l areas 1 a n d 2, a n d also p a r i e t a l l y (area 7). D u r i n g " r e c a l l " , a m a r k e d increase of a b o u t 2 0 % was seen in t h e eentrM region (areas 3 a n d 6; c/. I~GVAB a n d I~ISBSRG 1967). Fig. 2 shows t h e results from a p a t i e n t in which t w o i d e n t i c a l studies with R I S A were m a d e w i t h a 24 h i n t e r v a l . M e a s u r e m e n t s from two f r o n t a l areas are shown (areas 1 a n d 2, Fig. 1) in which t h e r e was, like in t h e p a t i e n t of Fig. l, a m a r k e d a n d h i g h l y significant (p < 0.001) decrease of r C B V d u r i n g t h e m e m o r y test. I n t h e second m e a s u r e m e n t , 24 h later, t h e a m p l i t u d e of t h e changes was smaller, b u t t h e r e were striking similarities b e t w e e n t h e results from t h e two studies. There were no significant changes of rCBV in t h e o t h e r areas of m e a s u r e m e n t .

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I n t h e p a t i e n t shown in Fig. 3, lSiI-Ig Chlormerodrine was used as a tracer. Since this i s o t o p e h a s a h a l f t i m e in b l o o d of a b o u t 100 min, t h e changes of cerebral S.B.O ~ 56Y

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I~0 20 min 30 Fig. 2. Repeated rCBV studies with a 24 h interval in two frontal brain regions in a patient injected with RISA. Note the similarities in the decrease of activity in both regions in the two studies. In the second study the general amplitude was, however, smaller b l o o d v o l u m e d u r i n g m e n t a l a c t i v i t y m u s t be seen on t h e b a c k g r o u n d of a m o n o e x p o n e n t i a l w a s h o u t i u n c t i o n , which was d e t e r m i n e d for each a r e a d u r i n g t h e

control period. The results from this patient were very similar to those shown in Fig. 1 and 2. An occipital increase and a frontal decrease of rCBV was seen during the memory test. 5Tormals. F i g . 4 shows t h e mean rCB V changes for the whole group o f 7 n o r m a l s

during the reasoning test and the spatial thinking test. The S.I). of the rCBV-

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values d u r i n g t h e i n i t i a l 1O m i n r e s t period was + 1.59%. A n increase or decrease l a r g e r t h a n 3.2~o was t h u s s t a t i s t i c a l l y significant (p < 0.05). The reasoning test

" d_i Fig. 3. rCB V measurements with 197Hain oneof the patients. During rest the isotope disappeared with a halftime of aboug 100 min. The changes of rCBV during the picture memory test are seen superimposed on the monexponential clearance function of the baseline. Note the occipital increase, and the decrease in frontal and central parts of the hemisphere during the test

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J. RISBERGand D.H. INGrAte:

caused a significant increase of rCBV, especially in the frontal areas 1 and 2, the postcentral area 5. I n the occipital area 8 an increase of doubtful significance was seen. A slight decrease of rCBV was seen pre-centrally (area 3). During the period of rest which followed, the rCBV values returned to %cpm Reasoning'(est a n d spatial test. approximately the control 1 I I level (100%). iUtJi ~ \ / jw _ I V vi v I ~' The spatial test gave rise 2 1001-~/i -'v~v t v to rather similar rCBV I_ ] I I Ab,~ .A I I I I changes with an increase of 3 I v- - X ~ /I ~ \ / i ".I ~~ ~9 ~x_l!~ ~.--qI - - ~ ! J rCBV, especially in the fronA r t i A ~ | ,,~ ,~, I A L . _,. ja.a 9 _/ tal area 2. However, durIA ~ I i L ing this test areas 4 and 7, 5 IVUI -~ i "--' V v i ~ I located centrally and paI I I _I rietally, showed an increas6 lUUl~ ~ \/I " I x . ~ / I'-"'--J I X/~/ I L --~ i v I i ed rCBV while there was ~ , ~ A I A , . lk Ai_.~ I. no significant augmentaio5!I " I~ " ~A,~I I tion of rCBV in the post~,~,1 9 A. '-A,~,a~ ~ A -''L I 8 lUUl~ "~/ \1 ~ I I " I IV v . central area 5. ~,~L -i Reesoning I I Spatial I =~/ Rest i test I Rest test Rest There were also some I I I I I I I I 0 10 20 30 min 40 indications o f " after image" Fig. 4. Changes of rCBV in a group of 7 normals studied effects. This was especially with RISA. See text evident in the frontal areas I and 2 following the spatial test. I t m a y also be noted that an "anticipatory" effect was suggested in the seven normals with an increase of rCBV in the occipital area 8 preceding the spatial test. The digit-span-bac]cward test gave rise to only small changes of rCBV. There was a small increase ofrCBV frontally (peak value 4.8 %) while a decrease (maximal value 5.3 %) was found centrally in area 4. Intermittent photic stimulation did not only give the expected occipital increase of rCBV (peak value 3.8%), but also an augmentation in the frontal area 2 (peak value 5.0%). Vigorous chewing movements gave rise to an increase of radiation of about 3% in one frontal and one preeentral area (areas 1 and 3, Fig. 4). This would correspond to an increase of blood volume in the temporal muscles.

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Discussion

The present isotope technique measures the amount of an intravascnlar tracer within certain parts of the brain. Variations in blood volume within these cerebral regions are then reflected as changes in local radioactivity. Although the relationship between the volume of the cerebral vascular bed and its variation during regional changes in cerebral blood flow are not known, it seems reasonable to assume that the rCBV changes found in the present study are related to the regional blood flow changes in the brain during mentation which we have demonstrated previously (INGVA~ and I~ISBE~G 1967). This would mean that a regional blood

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flow increase, respectively decrease, is accompanied b y subtle changes of the volume of the cerebral vascular bed. Such a volume increase could either take place b y dilatation of the vascular bed or b y opening of new vascular channels. Although the first alternative seems more likely at present (OPITZ 1952), the second one remains to be excluded. Support for the first alternative was obtained b y letting the subjects inhale carbon dioxide, a powerful cerebral vasodilating agent (So~:oLOFF 1959), which gave rise to a significant increase of the rCBV values in all areas (RIsBERG, in preparation). Since there is a relationship between the volume of the capillary bed of the grey m a t t e r and the white matter, of about 4--1 (eft 0PITZ 1952), it also seems reasonable to conclude further t h a t the rCBV changes seen in the present study have mainly concerned the grey matter, i.e. the cerebral cortex. For the present method it is a prerequisite t h a t the major part of the R I S A injected will remain in the blood stream and not penetrate extravasally. I t is at present not known if such a penetration takes place, and, if so, how much will penetrate and become "immobile". However, if such a penetration had been substantial it had not been possible to carry out the present study. Furthermore, the CO ~inhalation test highly favours the view t h a t the regional t~ISA activity varies in parallel with the regional cerebral blood flow - - and blood volume. I t should also be stressed t h a t there was no indication t h a t active brain regions "absorbed" R I S A and made it "immobile", since the changes observed during mental activity usually were transient and the activity recorded returned to the baseline in the resting state (cf. I~ISBERG, in preparation). We find it justified to conclude t h a t the rCBV changes seen in the present study have a relation to regional alterations of blood flow in the brain which are known to take place during mentation (INGvAIr and I~ISBEnG 1967). Amongst the results reported, those from the occipital region seem least surprising. I t has been known for m a n y years t h a t an activation of the visual pathways gives rise to a local flow increase in the visual projection area (ScgMmT and HEND~IX 1937, SO~OLOFF 1961). SOKOLOFF (1961) found t h a t an increase of the blood flow in one region was sometimes accompanied b y a diminution of the flow in the surrounding. In this context it should be pointed out t h a t on some occasions a focal rCBV increase was also accompanied b y a "perifoeal" rCBV decrease (Fig. 1 and 3). Such a mechanism was also indicated in the results shown previously with rCBF measurements (I~GVAR and RISB~RG 1967). The main result of the present investigation is believed to be the demonstration of " p a t t e r n s " of rCBV changes which appear specific to certain forms of mental activity. The existence of such patterns was already indicated in our previous study (INGvAI~and RISBEn~ 1967) and they have here been confirmed and further elaborated. I t is at present too early to give a full interpretation for the patterns shown. I t should only be pointed out t h a t it has here for the first time been shown t h a t certain regions within the frontal lobes (the premotor region) appear to be selectively involved in complex intellectual functions which are a prerequisite for the performance of so-called reasoning tests and spatial thinking tests. The present method of localizing the measuring fields does not, however, permit one to assign these functions, or any other, to specific, cytoarchiteetonically well defined areas within the cerebral cortex.

78 J. RISBEI~Gand D.H. IHGvA~: Regional Cerebral Blood Volume and Mental Activity It is obvious that the changes in rCBV recorded with the present technique during mentation may under certain conditions affect the results ofgamma-eneephalography. It seems indeed possible that concentrated mental activity during such a procedure may affect the brain scan. This interesting possibility would seem to merit further studies. F r o m the results it is clear t h a t the grey m a t t e r of the b r a i n does n o t work at a u n i f o r m f u n c t i o n a l level, b u t t h a t "islands" of a c t i v i t y can be identified b y techniques which are sensitive enough a n d measure regionally. The finding of rCBV changes d u r i n g m e n t a t i o n with opposite sign here again (el. INGVA~ a n d RISBE~G 1967) s u p p o r t the i n t e r p r e t a t i o n t h a t it is less likely to pick u p cerebral circulatory changes of the present t y p e with m e t h o d s like the K e t y t e c h n i q u e which only measure the total average cerebral oxygen u p t a k e a n d blood flow (SOKOLOFF et al. 1955). Finally, it should be stressed t h a t the t e c h n i q u e used here is simple a n d unt r a u m a t i c , a n d should be e m i n e n t l y suitable for large scale studies of regional f u n c t i o n a l events i n the b r a i n which a p p a r e n t l y have a relation to, a m o n g s t other things, m e n t a l activity. This investigation was aided by grants from the Swedish Medical Research Council (contracts No. B 67-21x-84-03) and fi'om the Wallenberg Foundation, Stockholm.

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Psychometric and experimental methods for the clinical evaluation of mental functioning. Stockholm: Almqvist and Wiksell 1959. HOEDT-RASMUSSEN, K., E. SVEINSDOTTIlaand N.A. LAss]~sr: The inert gas intra-arterial injection method for determining regional cerebral blood flow in man through the intact skull. Circular. Rec. 18, 237--247 (1966). I~Gvaa, D.H., and J. RISB]~G: Increase of regional cerebral blood flow during mental effort in normals and in patients with focal brain disorders. Exp. Brain Res. 3, 195--211 (1967). LASSEN, N.A., K. HOEDT-RASMUSSEN,S.C. SORENSEN, E. SKINnOJ, S. CEOHQVlST,B. BOD]rO~SS and D.H. INGVAR:Regional cerebral blood flow in man determined by Krypton sS. Neurology 13, 719--727 (1963). OPITZ, E. : Energieumsatz des Gehirns in situ unter aeroben und anaeroben Bedingungen. In: Die Chemie und der Stoffwechsel des Nervengewebes, pp. 66--108. Berlin-GSttingen-Heidelberg: Springer 1952. SCHMIDT,C.F., and J.P. H]~N])mx: The action of chemical substances on cerebral blood vessels. Res. Publ. Ass. nerv. merit. Dis. 18, 229--276 (1937). SMITH, E . M . : Internal dose calculation for 9~mTc. J. nucl. Med. 6, 231--251 (1965). SOKO~OFF, L.: The action of drugs on the cerebral circulation. Pharmaeo]. Rev. 11, 1--85 (1959). - - Local cerebral circulation at rest and during altered cerebral activity induced by anestesia or visual stimulation. In: Regional Neurochemistry, pp. 107--117. Ed. by S.S. KET:f and J. ELKES. New York: Pergamon Press 1961. --, R. MA~GOLD,R.L. W]~cnsLEI~and S. S. KETY: The effect of mental arithmetic on cerebral circulation and metabolism. J. clin. Invest. 34, 1101--1108 (1955). TnU~STO~P.,L.L. : Primary mental abilities. Psychometric monogr. 1. Chicago : University of Chicago Press 1938. WEe~ISL]~, D.: The measurement of adult intelligence. Baltimore: Williams and Wilkins 1956. JXRL RIS]3V.~G,F.K., and DAVID H. IHGVA~,M.D. Department of Clinical Neurophysiology University Hospital Lund, Sweden