Editorial

Functional brain imaging celebrates 30thanniversary

The year 1977 was a turning point in the history ofbrain imaging. Two conferences, both in Copen-hagen, marked the event. The Sixth BiennialMeeting of the International Society of Neuro-chemistry was held at the Danish TechnicalUniversity in the Copenhagen suburb of Lundt-ofte. Hosted by biochemist Jørgen Clausen (1931–2004), the participants learned of the multitude offindings obtained with Sokoloff�s method of deter-mining regional glucose metabolism in the brain ofanimals by autoradiography of 14C-labeled2-deoxyglucose (2DG) uptake but also tentativelyin the human brain by positron emission tomog-raphy of 18F-labeled fluorodeoxyglucose (FDG)uptake. Sokoloff�s magnum opus had appearedthat same year in the Journal of Neurochemistry,after at least 3–4 years of tantalizingly complexpresentations and publications of foreshortenedabstracts (1). The results of animal studies con-firmed the regional differences of brain activitythat were expected from measures of blood flow tothe brain, and the preliminary findings in humansconfirmed the regional changes expected whenregionally specific brain functions are executed.These changes in the mammalian brain formed thebasis for the formulation of a theory of functionalflow–metabolism coupling, which much later hadto be abandoned, in part or in whole, whenregional measurements of cerebral oxygen con-sumption came of age.The other side of the coin, the cerebral blood

flow, was the topic of the Eighth InternationalCBF symposium at the Scandinavia Hotel inCopenhagen in June 1977, which later becameknown as Brain77. The hosts were clinical neuro-physiologists N. A. Lassen (1926–1997) and D. H.Ingvar (1924–2000) from Copenhagen and Lundrespectively. As vascular physiologists, at 51 and53 years of age, Lassen and Ingvar were theundisputed stars of regional brain blood flowstudies in humans. The first CBF symposium inLund in 1965 had 35 participants, but the roster ofactive participants had now grown to 500 who

presented 100 posters and gave 100 oral presenta-tions of 10-min duration, the majority in Ingvar�sand Lassen�s honor. The vascular physiologistswere honored for their contributions to the under-standing of circulation in the brain, and only bydefault for their contributions to cognitive neuro-science, �default� because the professional psychol-ogists had ignored the brain as an organ during theentire preceding half-century and would only bedragged half-heartedly into the functional imagingfield in the ensuing 30 years.The keynote lecturers were the American Julius

Axelrod (1912–2004), the 1970 Nobel laureate inmedicine or physiology, and the Swede AndersBjorklund. Axelrod spoke of the neurochemistry ofcatecholamines, the topic for which he was hon-ored by the Nobel committee, and Bjorklund spokeof the anatomy and tentatively the physiology ofthe catecholaminergic neurotransmitter systems,but neither topic was as yet foremost in the mindsof the attendees at the symposium. At previousmeetings, the free communications concentratedon technical aspects of the intracarotid bolusinjection and clearance method of cortical bloodflow measurement and on its clinical applications,but now the focus turned towards the functionalorganization of the human brain, for the purposeof evaluating and interpreting the regional changesin blood flow obtained with intracarotid bolusinjection method in terms of the ways the humanmind works.Ingvar had obtained his medical degree in 1950

and then spent the years 1951–1953 as researchfellow at the Montreal Neurological Institute inQuebec. Under the tutelage of Wilder Penfield andHerbert Jasper, he explored the foundations of theelectroencephalogram in cats as a test of therelationship between brain function and bloodflow to the brain (2) that was first deduced by Royand Sherrington (3) 60 years earlier. In 1974,Ingvar used the new method of functional brainimaging to observe for the first time the regionalcortical patterns related to language perception

Acta Neurol Scand 2008: 117: 219–223 DOI: 10.1111/j.1600-0404.2007.00981.x Copyright � 2008 The AuthorJournal compilation � 2008 Blackwell Munksgaard

ACTA NEUROLOGICASCANDINAVICA

219

and production. These observations prompted thestill ongoing revision of the understanding ofBroca�s and Wernicke�s areas as specific sites ofcortical language and speech functions. In 1977, atBrain77, Ingvar reported that normal conscious-ness depends on a relatively high resting blood flowto the frontal lobes.Lassen had obtained his medical degree from the

University of Copenhagen in 1951. During thefollowing years, he specialized in internal medicineand increasingly sought answers to questions of thephysiology of circulation, particularly as it pertainsto the perfusion of the brain. Lassen spent the year1957–1958 as a post-doctoral fellow with SeymourKety (1915–2000) at the National Institutes ofHealth (NIH) in Bethesda, MD. Under the super-vision of Kety, Sokoloff and Freygang had workedout a method of measuring regional blood flowrates in the living animal brain (4), and Lassensummarized these and other findings in a muchquoted monograph in Physiological Reviews, �Cere-bral blood flow and oxygen consumption in mandetermined by the inert gas diffusion method� (5),the writing of which Kety had assigned to Lassen.Upon Lassen�s return from the NIH, he and

Ingvar devised the intracarotid bolus injectionmethod that records the clearance of a flowtracer with banks of stationary, collimated, singleNaI detectors covering a whole hemisphere, ulti-mately with as many as 254 single detectors, eachtargeting less than 1 cm2 of brain surface (6). Thiswas the method for which Lassen and Ingvarinstantly became famous. With this method, in themid-1970s, Lassen and his co-workers obtained thefirst color-coded maps of the activation of discretefunctional centers of the intact and resting orworking human brain. The presentation of func-tional maps in no less than 16 pages of color platesin the Brain77 volume of abstracts became Lassen�smajor contribution to the conference, and theimages in turn formed the basis for the following30 years of functional mapping of the humanbrain. The Brain77 volume of abstracts appearedas a separate hardcover volume to which theabstract citations below refer (7), and Ingvar andLassen wrote a commentary that appeared in thisjournal in 1978 (8). Ominously, the cover of thevolume of abstracts featured the outline of aphrenology bust.The titles of the majority of the sessions at the

Brain77 symposium would not have surprised atime-traveling visitor from 2007. The topics ofNeurogenic Control and Autoregulation (now �neu-rovascular coupling�), Biogenic Amines (now�monoaminergic neurotransmission�), Activation,Deactivation (now �default mode�), Metabolic Con-

trol (now �flow–metabolism coupling�), Blood–Brain Barrier, New and Atraumatic Methods(now �MEG, PET ⁄MEG, PET ⁄MR, NIRS, fMRI,phMRI,MRS, andDTI�), Ischemia, Recovery (now�neuroinformatics�), Stroke, Epilepsy and Migrainewould raise no eyebrows in 2007, although Barbi-turate Therapy has an odd ring to it. Nor wouldmany of the names of speakers at Brain77 be out ofplace in 2007: Alpert, Baron, Bolwig, Chance,Edvinsson, Eichling, Fahrenkrug, Fazio, Feindel,Ginsburg, Greenberg, Heiss, Heistad, Hossmann,Ido, Jones (Terry), Kuschinsky, Lenzi, Lou,McCul-loch, MacKenzie, Nemoto, Ojeman, Paulson,Phelps, Pickard, Quistorff, Raichle, Reivich, Re-hncrona, Risberg, Rosenblum, Siesjo, Sokoloff,Thompson (C.J.), Tomita, Traystman, Vannucci(R.C.), Welsh and many others have remainedfixtures at the CBF symposia until this day.Quite a few of the speakers and poster presenters

at Brain77 are no longer with us, of course, and ithas been said that once the historical core ofparticipants dies out, there will be no more CBFsymposia. This could happen in part because of thegrowth of the subject matter, as the CBF symposiaevolved into �No-Flow� or �Low-Flow� meetingsfocused on oligemia and hypoxia of the brain, incompetition with the �High-Flow� meetings orga-nized by the more recent Human Brain MappingOrganization that focused on the increased flowrates of functional activation. The Human BrainMapping meetings originally were conceived tomeet the requirements of one of these separatedirections, although this particular direction inturn can be said to be in danger of being trappedinto a single-minded pursuit of a new phrenology(9, 10). The origin of this trap may be the verymethods available to the vascular physiologists asthey rushed into places where psychologists fearedto tread.To be sure, the seeds of a new phrenology were

evident at Brain77. The tools of Functional BrainImaging include the measurements of neurotrans-mission as well as flow and metabolism in the livingbrain. At Brain77, however, mapping of neuro-transmission in vivo was not yet possible, with afew notable exceptions; so, sessions on �activation�(a term not coined until much later) focusedexclusively on changes in flow observed underspecific experimental circumstances. In Figure 1,Ingvar et al. (#14.2) presented the average flowmaps that revealed the relatively high flow infrontal cortex which proved to the authors the keyrole of this part of the brain in normal unperturbedconsciousness. The significance of the finding mayor may not have been lost on the audience in 1977,but this �default� mode of brain function does not

Editorial

220

appear to have aroused the interest of the commu-nity at large until the advent of the new millen-nium.The attention of the audience instead turned

towards the decrements and increments in circula-tion, as Risberg et al. (#14.16) revealed the focalchanges observed when subjects engaged in mentaltesting, and Risberg�s associates Nilsson et al.(#25.18) and Berglund (#25.20) presented thechanges seen in paranoia and alcoholism. Lassenet al. (#14.12) presented the changes evoked bybasic sensory and motor activity, and Lassen�sassociates Larsen et al. (#14.18), Soh et al.(#14.20), Melamed & Larsen (#29.4) and Rolandet al. (#29.14 and #29.16) presented the localchanges evoked by listening and speech, shown inFigure 2, as well as the changes associated withdisturbed speech in aphasia, conjugate eye move-ments, cognitive interpretation of somatosensoryand auditory information, and voluntary move-ments, executed repetitively or in the direction of agoal. The general map of speaking, reading aloudand listening closely resembles the much morerecent and better known map obtained with posi-tron emission tomography by Petersen et al. (11).When Roland et al. presented the posters of the

flow maps associated with higher cognitivefunctions, the authors had no doubt that the flowchanges were reliable measures of the changes in

Figure 1. Average cerebral blood flow distribution after smoothing, recorded twice with a 12-detector system in left hemisphere in 12neurologically normal adult humans by means of intracarotid bolus injection of radioactive xenon and subsequent calculations ofrates of washout from assumed tissue compartments of gray and white matter, as well as initial washout rate. Washout rates arenormalized to whole brain average. From abstract #14.2: Ingvar DH, Philipson L, Torlof P, Ardo A, Average rCBF pattern ofresting consciousness studied with new color display system. In: Cerebral Function, Metabolism, and Circulation (Ingvar DH, LassenNA, eds), Acta Neurologica Scandinavia supplementum 64, volume 56. Copenhagen: Munksgaard 1977, pp. 252–253.

Figure 2. Normalized blood flow distribution maps oflanguage processing in the left or right hemisphere of 36 right-handed adult humans, calculated as initial washout rates ofxenon-133 activity recorded by computerized 254-channelsystem after intracarotid injection. From abstract #14.18:Larsen B, Skinhøj E, Soh K, Endo H, Lassen NA, The patternof cortical activity provoked by listening and speech revealedby rCBF measurements. In: Cerebral Function, Metabolism,and Circulation (Ingvar DH, Lassen NA, eds), Acta Neuro-logica Scandinavia supplementum 64, volume 56. Copenhagen:Munksgaard 1977, pp. 268–269.

Editorial

221

regional cortical metabolism and probably in thelocal neuronal activity as well. In making this claimin the abstracts, the authors specifically quotedfindings reported the year before, according towhich �rCBF correlated well with rCMRO2� innormal subjects and patients with chronic, stablediseases of the brain, including one individual withmild dementia, in whom �appropriate parallelchanges occurred in both rCBF and rCMRO2

during hand exercise� (12). Later this proved not tobe the case when Raichle�s associates Fox et al. atthe Brain85 symposium in Lund-Ronneby pre-sented evidence of complete dissociation betweenflow and oxygen consumption changes duringsomatosensory stimulation in awake humans (13),a finding which became the foundation of BOLDsignal imaging by MR and forever changed thefield of Functional Brain Imaging.Seeds of other controversies were also evident at

the Brain77 symposium. Regional measures ofbrain glucose and oxygen metabolic rates withpositron-emitting tracers and variously constructedcoincidence detecting devices became possible inthe early 1970s (14). Three more or less conflictingmethods were discussed at the symposium: partic-ipants reported determinations of glucose con-sumption with 11C-labeled glucose or 18F-labeledFDG, and determination of oxygen consumptionwith 15O-labeled oxygen gas. In a provocativelytitled abstract, Hawkins et al. (#24.4) arguedstrongly in favor of determining glucose consump-tion in the rat brain with injections of labeledglucose. The method was used in primates andhumans by Raichle et al. (#9.12) and in rats byJones (S.C.) et al. (#24.18) and the results in factare very close to current regional values of thebrains of the respective species, although an obvi-ous issue was the loss of labeled metabolites fromthe brain. The image obtained in a single adulthuman in shown in Figure 3. To circumvent thisproblem, Reivich et al. (#9.14), Kuhl et al. (#9.16)and Phelps et al. (#24.14) instead used Sokoloff�smethod based on the irreversible trapping of FDG-6-phosphate, which in turn requires that research-ers know the value of the deceptively named�lumped constant�. An example of this approachwas presented by Kuhl et al. in Figure 4. Interest-ingly, in subsequent years, the value of this constanthas grown from 0.5 in 1977 to 0.8 in 2002 (15), withthe unintended consequence that it no longer is ingood taste to ask about the correct value.The students of regional oxygen metabolism in

brain used inhalations of radioactive oxygen andcarbon dioxide gases, the latter labeled with 15O or11C. The quantitation presented by McKenzie(C.C.) et al. (#9.6) of Terry Jones� team at the

Hammersmith Hospital was still in its infancy andlimited to calculations of �metabolic� and �perfu-sion� ratios of normalized radioactivity counts inthe brain tissue. A ratio of ratios subsequentlyserved as an index of the oxygen extraction fraction(OER). Only Alpert et al. (#9.10) of GordonBrownell�s team at the Massachusetts GeneralHospital attempted a full kinetic analysis andobtained the rather inaccurate OER of 0.6. At theHammersmith Hospital, Lenzi et al. (#9.8, #13.12)observed selective cortical reductions in the OERin Parkinson�s disease and dementia, but it wasunclear then and is still uncertain now whetherdecreases are real or relative to increases else-where. In 2007, changes in cortical metabolism in

Figure 3. Accumulation of 11C-labeled glucose in the normaladult human brain after intravenous infusion of the tracer over6 min. Numbers indicate activity at the end of the infusionperiod, relative to whole brain average. A model of calculationof the glucose metabolic rate was presented in the abstracttogether with average values of the adult rhesus monkey brainbut the formula was not used in this illustration. From abstract#9.12: Raichle ME, Larson KB, Higgins CS, Grubb RL Jr,Eichling JO, Welch MJ, Ter-Pogossian MM, Three-dimen-sional in vivo mapping of brain metabolism and acid basestatus. In: Cerebral Function, Metabolism, and Circulation(Ingvar DH, Lassen NA, eds), Acta Neurologica Scandinaviasupplementum 64, volume 56. Copenhagen: Munksgaard 1977,pp. 188–189.

Figure 4. Development of blood flow and metabolism changesafter stroke. Note the large increase in perfusion 11 days afterthe stroke that matches the complete absence of glucose con-sumption in the same area of the right hemisphere 12 days afterthe stroke. From abstract #9.16: Kuhl DE, Phelps ME, Hoff-mann EJ, Robinson DE Jr, MacDonald NS: Initial clinicalexperience with local cerebral glucose utilization by emissioncomputed tomography, In: Cerebral Function, Metabolism, andCirculation (Ingvar DH, Lassen NA, eds), Acta NeurologicaScandinavia supplementum 64, volume 56. Copenhagen:Munksgaard 1977, pp. 192–193.

Editorial

222

Parkinson�s disease are still assessed by normali-zation against a global gray matter average, and itis still uncertain to what extent normalization candistort the regional patterns of change (16).Of course, Parkinson�s disease is primarily a

disorder of dopaminergic neurotransmission, butneurotransmitter and receptor imaging of the livingbrain had not been attempted yet in 1977. How-ever, Garnett et al. (#24.26) of Hamilton, ON,offered a tantalizing glimpse of the future use of18F-labeled fluoro-DOPA for the mapping of thedopaminergic neurotransmission in the livinghuman brain, which took several more years toreach its final form (17). With two simple sets ofcurves shown in Figure 5, Garnett et al. revealedthe kinetic behavior of a tracer that would later bethe basis for the diagnostic imaging of patientswith Parkinson�s disease. In baboons, he recordedthe absence of trapping in the cerebellum, theapparent irreversible trapping in the striatum, theinhibition of the trapping by reserpine and theelevated trapping evoked by pargyline, an inhibitorof monoamine oxidase, and by the acute adminis-tration of haloperidol, an antagonist of dopamineD2 receptors. This effect was subsequently ascribedto increased activity of DOPA decarboxylase, butthe claim was not tested in humans until 2006. Theresult remains inconclusive, but it does suggestincreased availability of the tracer (18). There isstill much work to do.

References

1. Sokoloff L, Reivich M, Kennedy C et al. The [14C]deoxy-glucose method for the measurement of local cerebralglucose utilization: theory, procedure, and normal valuesin the conscious and anesthetized albino rat. J Neurochem1977;28:897–916.

2. Ingvar DH, Soderberg U. A direct method for the mea-surement of cerebral blood-flow. Nature 1956;177:339–40.

3. Roy C, Sherrington C. On the regulation of the blood-supply of the brain. J Physiol 1890;11:85–108.

4. Freygang WH Jr, Sokoloff L. Quantitative measurement ofregional circulation in the central nervous system by theuse of radioactive inert gas. Adv Biol Med Phys1958;6:263–79.

5. Lassen NA. Cerebral blood flow and oxygen consumptionin man. Physiol Rev 1959;39:183–238.

6. Lassen NA, Ingvar DH. The blood flow of the cerebralcortex determined by radioactive krypton. Experientia1961;17:42–3.

7. Lassen NA, Ingvar DH (eds). Cerebral function, metabo-lism, and circulation (Ingvar DH, Lassen NA, eds. ActaNeurologica Scandinavia, supplementum 64, Vol. 56.Copenhagen: Munksgaard, 1977.

8. Ingvar DH, Lassen NA. Cerebral function, metabolism andblood flow. News and trends from the VIIIth internationalCBF symposium in Copenhagen, June 1977. Acta NeurolScand 1978;57:262–9.

9. Whishaw IQ. Locale and taxon systems: no place for neo-phrenology? Hippocampus 1991;1:272–4.

10. Uttal WR. The new phrenology. The limits of localizingcognitive processes in the brain. Cambridge, MA: TheMIT Press, 2001

11. Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME.

Positron emission tomographic studies of the corticalanatomy of single-word processing.Nature 2000;331:585–9.

12. Raichle ME, Grubb RL Jr, Gado MH, Eichling JO,

Ter-Pogossian MM. Correlation between regional cerebralblood flow and oxidative metabolism. In vivo studies inman. Arch Neurol 1976;33:523–6.

13. Fox PT, Raichle ME. Focal physiological uncoupling ofcerebral blood flow and oxidative metabolism duringsomatosensory stimulation in human subjects. Proc NatlAcad Sci U S A 1986;83:1140–4.

14. Plum F, Gjedde A, Samson F (eds). Neuroanatomicalfunctional mapping by the radioactive 2-deoxy-d-glucosemethod. Boston, MA: Neurosciences Research ProgramBulletin, 1976.

15. Hasselbalch SG, Holm S, Pedersen HS et al. The (18)F-fluorodeoxyglucose lumped constant determined in humanbrain from extraction fractions of (18)F-fluorodeoxyglu-cose and glucose. J Cereb Blood Flow Metab 2001;21:995–1002.

16. Huang C, Tang C, Feigin A et al. Changes in networkactivity with the progression of Parkinson�s disease. Brain2007;130:1834–46.

17. Garnett ES, Firnau G, Nahmias C. Dopamine visualized inthe basal ganglia of living man. Nature 1983;305:137–8.

18. Vernaleken I, Kumakura Y, Cumming P et al. Modulation of[18F]fluorodopa (FDOPA) kinetics in the brain of healthyvolunteers after acute haloperidol challenge. Neuroimage2006;30:1332–9.

A. Gjedde1,2,31Pathophysiology and Experimental Tomography

Center, Aarhus University Hospitals,Aarhus, Denmark;

2Montreal Neurological Institute, McGillUniversity, Montreal, QC, Canada;

3Department of Radiology, Johns HopkinsHospital, Baltimore, MD, USA

e-mail: albert@pet.auh.dk

Figure 5. Single-detector recording of radioactivity in thebrain tissue arising from uptake of 18F-labeled fluoro-DOPA(FDOPA). From abstract #24.26: Garnett ES, Firnau G, ChanPK, Belbeck LW, Intracerebral dopamine metabolism mea-sured with [18F]fluorodopa. In: Cerebral Function, Metabolism,and Circulation (Ingvar DH, Lassen NA, eds), Acta Neuro-logica Scandinavia supplementum 64, volume 56. Copenhagen:Munksgaard 1977, pp. 458–459.

Editorial

223