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Images of Brain Function

THE LANCET

THE first technique allowing measurement ofneuronal function in the intact brain was the

electroencephalogram. In fifty years the limitationsof clinical electroencephalography have becomevery obvious. The scalp electrodes sample onlyabout a quarter of the convoluted outer surface ofthe brain "globe". The underside and mesial

aspects of the hemispheres are not assessed; nor isthe brainstem. Furthermore, there is still great un-certainty about the nature and location of thegenerators of EEG rhythms. Elaborate supplemen-tary techniques-notably, the recording of evokedresponses-have yielded little reliable informationon the localisation of function in the human brain.The past fifteen years, however, have seen theadvent of new techniques for measuring, directly inthe brain, in unanaesthetised man, the functionalactivity of defined parts of the organ. Radioisotopemethods give quantitative regional values for cere-bral blood-flow (rCBF) and for various metabolicindices (notably, regional glucose uptake). And, bymeans of two-dimensional and three-dimensionaldevices, it is possible to "see" brain function in acompletely new fashion. Detailed maps, in colour,can thus be made of the topographic distribution offunction in normal and diseased brain.The principle behind these new methods was laid

down in 1890 by Roy and SHERRINGTON.l Theysuggested that enhanced activity in one part of thebrain results in a regional hyperaemia which parallelsthe increase in neuronal activity and local metabo-lism. This has been confirmed many times, andregional blood-flow measurements are now used ex-tensively to localise brain functions in animals andman. Today’s techniques for regional measurementof blood-flow and metabolism are founded on thework of KETY who in 1945, with SCHMIDT, de-scribed, the nitrous-oxide method for measuringaverage cerebral blood-flow and oxygen uptake.2KETY’S group subsequently devised the first quanti-tative autoradiographic technique for recordingregional cerebral blood-flow (rCBF) in animals.3Then, some years later, LASSEN and INGVAR4,5 in-troduced a method employing intra-arterial injec-tion of radioactive inert gas: recording of krypton-

1. Roy CS, Sherrington CS. On the regulation of the blood supply to the brain.J Physiol 1890; 11: 85-108.

2. Kety SS, Schmidt CF. The determination of cerebral blood flow in man bythe use of nitrous oxide in low concentrations. Am J Physiol 1945; 143:53-66.

3. Landau WM, Freygang WH Jr, Rowland LP, Sokoloff L, Kety SS. The localcirculation of the living brain, values in the unanesthetized and anesthe-tized cat. Trans Am Neurol Ass 1955; 80: 125-29.

4. Lassen NA, Ingvar DH. The blood flow of the cerebral cortex determined byradioactive 85krypton. Experientia 1961; 17:42-43.

5. Lassen NA, Høedt-Rasmussen K, Sørensen SC, Skinhøj E, Cronqvist S, Bod-forss B, Ingvar DH. Regional cerebral blood flow in man determined bykrypton. Neurology 1963; 13: 719-27.

85 or xenon-133 clearance permitted simultaneousmeasurement of rCBF in many areas of the human

brain, without anaesthesia. Because of the trauma,this method has largely been restricted to patientshaving intracarotid injections for cerebral angio-graphy. High-resolution instruments have providedan abundance of two-dimensional images reflectingcortical function in health and disease. Thexenon-133 injection method shows where thehuman brain cortex receives sensory messages,where it generates motor responses, and what re- gions participate in cognitive tasks. The observa-tions of OLESEN6 are especially noteworthy. Hereported in 1971 that movements of the right handwere associated with a substantial increase ofblood-flow in the left rolandic hand area; further-

more, higher functions such as speech, reading, cal-culation, and problem-solving yielded "functionallandscapes" in the cortex with specific features per-taining to the function in question.7 The intra-arterial rCBF technique also revealed that eventsin the brain underlying pure mental activity—cog-nitive activity unrelated to sensory input and unac-companied by any overt motor or behavioural res-ponse-were associated with increased blood-flow,mainly in the prefrontal cortex.8

Apart from confirming several classic conceptsabout functional localisation in the cerebral cortex,the observations in normal brain have yielded newdata on the distribution of brain activity at rest,during mental effort, during pain, and so on. Incertain patients the resting functional landscape ofthe cortex has been found to differ from normal. In

organic dementia the landscape is flatter and tendsto be lower, owing to the reduced level of activity;such changes are often seen predominantly in thefrontal lobes. When demented patients are givenpsychometric tests, activation of frontal-lobe or

cortical association areas seems subnormal. In cere-brovascular disorders rCBF studies have clarifiedthe pathophysiology of occlusive lesions and, alas,have also revealed the futility of most therapeuticendeavours including administration of vasoactivedrugs.9 Two further observations with the rCBFtechnique deserve mention. INGVAR and FRANZÉNIOexamined chronic schizophrenics and found abnor-mal "hypofrontal" cortical landscapes, notably inthose with pronounced autistic symptoms. And, in

6. Olesen J. Contralateral focal increase of cerebral blood flow in man duringarm work. Brain 1971; 94: 635-46.

7. Lassen NA, Ingvar DH, Skinhø) E. Brain function and blood flow. Changesin the amount of blood flowing in areas of the human cerebral cortex, re-flecting changes in the activity of those areas, are graphically revealedwith the aid of radioactive isotope. Scient Am 1978; 239:62-71.

8. Ingvar DH. Brain work in presenile dementia and in chronic schizophrenia.In: Brain Work (Alfred Benzon Symp VIII) Copenhagen: Munksgaard.1975: 478-92.

9. Olesen J. Cerebral blood flow methods for measurement regulation, effectsof drugs and changes in disease. Thesis, University of Copenhagen.Copenhagen: Munksgaard. 1974.

10. Ingvar DH, Franzén G. Distribution of cerebral activity in chronic schizo-phrenia. Lancet 1974; ii: 1484-85.

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a patient with focal cortical epilepsy, HouGAARD etal. 11 recorded hyperæmia in the active focus pro-ducing paroxysmal EEG discharges. rCBFmeasurement may well prove more accurate thanEEG for localising epileptogenic zones in the cor-tex. If so, there will doubtless be renewed interestin neurosurgical treatment of focal epilepsy.An important further step in the imaging of

brain function was taken by SOKOLOFF, with histechnique for measuring regional glucose uptake. 12This method, which employs radioactive deoxyglu-cose, has a resolution so high that functional

changes (i.e., altered glucose uptake) can bedetected in single cortical neuronal columns about200 µm wide. The original method was suitable onlyfor animals, but a version using the positron-emittingradioisotope 18F-fluoro-2-deoxyglucose was soon

devised for man.13 Many other labelled compoundsare being tried-including transmitter substancesand neurotropic drugs. Thanks to the workofKuHL,TER-POGOSSIAN, ERIKSSON, PHELPS, and their as-sociates, radioisotope detection instruments havekept pace with these developments: the so-calledemission tomographs today have a fairly high reso-lution of about 1 cm. Thus, it is now possible tomeasure, without anaesthesia, both blood-flow andmetabolic activity in small defined parts of thehuman brain. Three-dimensional positron emissiontomography employs computer methods akin tothose developed for computerised tomography (CT)of the brain.

Emission tomography demands not only accessto a cyclotron, for manufacture of the short-livedpositron-emitting isotopes, but also a team of highlytrained doctors, engineers, chemists, physicists, andtechnicians. So far, few research centres are yetengaged in it. The staggering costs have indeed in-spired a search for simpler alternatives. Mapping ofelectromagnetic resonance, of magnetic fields, andof infra-red absorbance has been tried, but the resultsfall far short of those obtained with positron emissiontomography. An interesting transmission tomogra-phy technique employs cold non-radioactivexenon-a heavy isotope which, if given in concen-trations of 50-80%, can be seen in CT scans.14However, at these levels xenon has a distinct anoes-thetic effect, which means that the technique is un-suitable for measuring variations of brain function.Lastly, there is the three-dimensional rCBF

11. Hougaard K, Oikawa T, Sveinsdottir E, Skinhøj E, Ingvar DH, Lassen NA.Regional cerebral blood flow in focal cortical epilepsy. Arch Neurol 1976;33:527-35.

12. Sokoloff L, Reivich M, Patlak CS, Pettigrew KD, Des Rosters M, KennedyC. The (14C)deoxyglucose method for the quantitative determination oflocal cerebral glucose consumption. Trans Am Soc Neurochem 1974; 5:85.

13. Reivich M, Kuhl D, Wolf A, et al. Measurement of local cerebral glucosemetabolism in man with 18F-2-fluoro-2-deoxy-D-glucose. Acta NeurolScand 1977; 56. Suppl. 64: 190-91.

14. Kelcz F, Hilal SK, Hartwell P. Computed tomographic measurement of thexenon brain blood partition coefficient and implication for regional cere-bral blood flow. A preliminary report. Radiology 1978; 127: 385-92.

method which detects single photon emission,tomographically, from xenon 127, 133, or 133."Positron emission tomography remains the clearleader. This development signals the advent of anew era in the neurosciences and probably in psy-chiatry too.

Scottish Hearts

THE past quarter-century has seen a big increasein deaths in Scotland attributable to ischxmicheart-disease (IHD), notably amongst men aged35-44. In 1976 a third of all deaths were fromheart-disease, 86% being designated IHD.1 Scot-land is top of the international table for total mor-

tality from IHD at all ages. The very high ratesapply to both men and women. Between 2.9% and3.5% of National Health Service expenditure inthat country is related to IHD.2

In 1977 the Chief Scientist to the Scottish Homeand Health Department established a workinggroup to review the research potential and require-ments relating to IHD in Scotland. The reportnow to hand,3 draws attention to the considerablediscrepancy between the IHD mortality-rate oScotland and that of England and Wales. Further-more, there are pronounced differences in IHDstandardised mortality ratios within Scotland4 (aalso within Finland, which has a similar high rateof IHD). Thus west-central Scotland has a mortality ratio considerably greater than either eastcentral or north-east Scotland, and probably hathe highest incidence in the world. Epidemiologicalcomparisons may therefore shed light upon xti

ology and pathogenesis; and the report favourselected small-group studies to identify risk factorin populations of high and low prevalence ratesRecognised risk factors such as hypertensionsmoking, and altered blood lipids are not encountered in every patient with IHD and other, as yeunidentified, factors are probably importantSerum cholesterol concentrations do not seem to b

greater in Scotland than in southern England.The working group wants to see comparisons odifferent socioeconomic groups, including infor

15. Lassen NA, Obrist W, Risberg J. Cerebral blood flow by Xe-133 inhalatioand single photon emission tomography. Contribution to the InternationaSymposium on Cerebral Circulation, Toulouse, September, 1979.

1. World Health Statistics Annual 1973-1976, vol. 1. Geneva: World HealtOrganisation. 1978.

2. Services for ischæmic heart disease 1. Scottish Health Service Planning UnitEdinburgh, 1978.

3. Scottish Home and Health Department. Research into coronary heart-diease in Scotland. Report to the chief scientist by the working group oischæmic heart-disease. Edinburgh, 1979.

4. Fulton M, Adams W, Lutz W, Oliver MF. Regional variations in mortalitfrom ischæmic heart and cerebrovascular disease in Britain. Br Hear1978; 40: 563-68.

5. Lewis B, Wootton IDP, Krikler DM, February A, Chait A, Oakley CMSigurrdson G, Maurer B, Birkhead J. Frequency of risk factors for isch&aelmic heart-disease in a healthy population: with particular reference to seum-lipoprotein levels. Lancet 1974; i:141-46.