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Patient inside a CT scanner.

The ambulance arrives at thehospital, blue light flashing.

Speed is of the essence now. The pa-tient is admitted with a suspectedstroke. The doctors must make a di-agnosis as quickly as possible. Oneof the most pressing questions:which parts of the brain have beendamaged by inadequate circulationor bleeding? The result determineswhich initial rehabilitation measuresare introduced. Today, in an increas-ing number of hospitals, MRI (mag-netic resonance imaging) is helpingdoctors make their diagnosis. Withinminutes it provides medical staffwith information on whether the pa-tient has suffered a stroke and whichregion of the brain is affected.

The benefits of MRI cannot beoveremphasised: the faster the doc-tors respond, the greater the area ofthe brain they can rescue. Strokesare the third most common cause ofdeath in western industrialised na-tions after cardiovascular diseaseand cancer. Approximately 250,000people suffer a stroke in Germanyeach year. Around ten percent ofthose affected are under 40. What iseven more significant: strokes areone of the main causes of seriousdisability; one in four disabled peo-ple in Germany owes their conditionto a stroke. Over one million strokevictims are unfit to work or are un-able to look after themselves.

The big advantage of MRI is that itdoes not require major surgical in-tervention. It is what is known as anon-invasive method, in which elec-tromagnetic waves act on the humanbody. Although the magnetic fieldproduced by MRI apparatus is ex-tremely intense – around one milliontimes greater than the earth’s naturalmagnetic field -, there is no risk of

The development of magnetic resonance imaging (MRI) is one

of basic research’s success stories. Nowadays it is a fundamen-

tal part of medical diagnostics. Yet this research has been a

lengthy process – it is over fifty years since physicists first began investigating so-called nuclear

magnetic resonance. By adopting new methods, NIKOS K. LOGOTHETIS and his colleagues

at the MAX PLANCK INSTITUTE FOR BIOLOGICAL CYBERNETICS in Tübingen

have succeeded in considerably extending their understanding

of the basic principles of functional MRI, thereby

advancing cognitive neurobiology.

Inside the Chamber

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injury, according to the current stateof knowledge. The physical phenom-enon underlying MRI is so-callednuclear magnetic resonance. Thepath to its discovery is lined withnumerous Nobel prizes and beginsback in the first half of the 20th cen-tury when the properties of atomswere described: Planck, Rutherford,Bohr, Schrödinger and Heisenberg,these were the physicists who drew

University were investigating themagnetic properties of atoms andmolecules. Physicists already knewthat the nucleus of an atom is madeup of two types of particle: positive-ly charged protons and unchargedneutrons. Negatively charged elec-trons circulate around the nucleus.All these particles have “spin” or in-trinsic angular momentum. In otherwords, they spin around their own

axis like a little top,thereby producing amagnetic moment.When no external mag-netic field is present, theaxes of rotation are dis-tributed arbitrarily withthe result that the mag-netisation is balancedout. However, if anatomic nucleus is intro-duced into an externalmagnetic field, the mag-netic moment of the nu-cleus aligns itself in thisfield – in much thesame way as the dipolemoment of a small barmagnet aligns itselfwith the north andsouth pole. The align-ment may be parallel orantiparallel to the exter-nal magnetic field,whereby parallel align-ment is accompanied bya low energy level, an-tiparallel by a higherenergy level.

Rabi and his col-leagues wanted to dis-cover the conditions

needed to reverse the magnetic mo-ment of an atomic nucleus andthereby its alignment. They weresuccessful in the late thirties whenthey sent a stream of lithium chlo-ride molecules through a magneticfield, thereby releasing radio waves.At a certain frequency, known as the

resonance frequency, the radiowaves produced precisely the energyneeded by the nuclei to jump to ahigher energy level and to realign inthe magnetic field. The resultingweakening in the radio waves pro-vided the scientists with a test sig-nal. So Rabi found a way of demon-strating this transfer. The researchersdescribed this new technique as“molecular beam magnetic reso-nance”. Rabi’s research group usedthis technique primarily to discoverhitherto completely unknown factsabout interactions between mole-cules. The researchers were now vir-tually able to “see” how individualatoms bonded to one another, andhow their nuclei were affected byneighbouring atoms. In 1944 thiswork brought Rabi the Nobel prizefor physics.

PLAIN HYDROGEN

After the Second World War, thephysicists Edward Purcell of HarvardUniversity and Felix Bloch of Stan-ford University were engaged in sep-arate attempts to find a simplermethod to allow nuclear magneticresonance to be measured in liquidsand solids, as well as in gases. Bothscientists decided to investigate hy-drogen, firstly, because it is the sim-plest atomic nucleus with spin, andsecondly, because it occurs most fre-quently in the human body (thebody consists of 70 percent water,each drop of water containingaround 1024 hydrogen nuclei).

The two research groups succeededin creating the conditions for mag-netic resonance at virtually the sametime. Their experiments provided theunderstanding for the methodknown today as NMR spectroscopy.This allowed, amongst other things,“relaxation times” to be measured, inother words the time needed by asystem to return to a state of equilib-rium – a matter of seconds or frac-

tions of a second. In 1952 Purcelland Bloch were also awarded theNoble prize for physics.

If, in the early fifties, nuclear mag-netic resonance was considered pri-marily as a physical method formeasuring the magnetic propertiesof nuclei, the observation that theNMR signal was influenced by itschemical environment led to an al-most explosive spread. For thechemical environment of atomic nu-clei produces a shift in the resonancefrequency compared with the freenucleus (at the same frequency theprotected nucleus resonates at ahigher external magnetic field). This“chemical shift” is a characteristicvalue for the different groups of amolecule. It can be used to charac-terise substances.

Today NMR spectroscopy is an in-tegral part of chemical analysis andno industrial or university laborato-ry could manage without NMR appa-ratus. However, in the early sixties,NMR technology was still relativelyunsophisticated: a decisive step for-ward came with the use of pulsed ra-dio waves in place of a single con-tinuous wave. The pulse was madeup of a number of frequencies, suchthat, the shorter the pulsed radiowave, the broader its frequencyspectrum. Scientists no longer hadlaboriously to test radio waves ofdifferent wavelength to determineresonance frequency. The pulsemethod became the instrument ofchoice for physicists and chemistswhen investigating atoms and mole-cules. However, analysing the testsignal remained extremely time-con-suming. To speed up the process, thehelp of a mathematical tool wasneeded.

By the late sixties, the develop-ment of the computer had advancedsufficiently to enable complex NMRspectra to be analysed using a calcu-lation (known as a Fourier trans-

form) which was still complicated forthe lay mathematician. Richard Ernstand Weston Anderson succeeded incombining the pulse method with acomputational tool. The new methodwas not only a thousand times fasterthan its predecessor, researcherscould now also observe signals onetenth of the size of those studied ear-lier. In 1991 Richard Ernst receivedthe Nobel prize for chemistry for hiscontribution to the further advance-ment of NMR spectroscopy.

The idea of using NMR as a diag-nostic tool also emerged back in thefifties. But further developments,particularly in computer technology,were required before magnetic reso-nance imaging (MRI) became reality.In 1971 the British engineer GodfreyHounsfield combined an X-ray unitwith a computer and used variousalgebraic methods to scan a bodyoptically from different sides and fi-nally produce cross-sectional im-ages. This laid the foundation forcomputed tomography (CT). Just un-der two years later, the chemist PaulLauterbur developed a mathematicalprocess which enabled images to becreated using nuclear magnetic reso-nance. It was preceded by delibera-tions as to how the recorded NMRsignal could be located within asample. If the point of origin of asignal could be determined accurate-ly, then, according to Lauterbur, akind of “map” could be drawn of theobject being investigated. In his ex-periments he therefore superimposeda second weaker magnetic field gra-dient over the spatially uniform stat-ic magnetic field gradients.

IN THE PICTURE

Since the resonance frequency ofthe atomic nuclei in an externalmagnetic field is proportional to thestrength of the field, only at onepoint does the magnetic field gradi-ent for the various parts of the object

provide the conditions for reso-nance, enabling the position of themolecules to be determined and anappropriate image to be constructed(nowadays three electromagneticgradients are applied to producemagnetic resonance images). It wasleft to the Englishman Peter Mans-field and his colleagues to publishthe first NMR image of part of a hu-man body in 1976: a finger in whichthe bones, nerves, and arteries wereall visible.

TENSE STATE

So what happens under the condi-tions just described? When a patientis introduced into the powerful mag-netic field of a nuclear magnetic ormagnetic resonance scanner, the nu-merous small “hydrogen magnets” inthe body partially align themselves.This arrangement of aligned particlemagnets is then exposed to a highfrequency magnetic transmitter. This“interference” knocks the small par-ticle magnets out of their orderedposition. They are now in a tense(high-energy) state since they actu-ally want to realign themselves inthe large magnetic field. Conse-quently, the moment the interferenceis switched off, the particle magnetsquickly return to their initial, low-energy state. In doing so, they emit acertain quantity of energy, corre-sponding to a radio signal of a cer-tain wavelength (this is the reso-nance frequency mentioned at thebeginning). The signals from theparticle magnets can be collected by“rinsing” in the magnetic resonancescanner. The number and immediateenvironment of the particle magnetsdetermine the strength of the signaland the time it takes the particlemagnets to return to their initialstate (a few milliseconds or severalseconds). The patient is unaware ofall this. Based on the tissue-specificbehaviour of particle magnets, doc-

Scientists at the Max Planck Institute for Neurological Research in Cologne have tested methods involving magnetic resonance imaging and spectroscopy in experiments on animals. They provoked a 15-minute cardiac arrest in four different laboratory animals and tracked the re-suscitation of the brain. The pictorial representation permits assertionsas to the extent of brain damage and a precise analysis of the recoveryprocess. Here MR imaging illustrates changes in blood flow in the acti-vated brain area. The top three rows are examples of successful and thebottom row of unsuccessful resuscitation. Comparison with the images of ATP, glucose and lactate concentration shows that the MR images areactually closely linked with biochemical changes. On the basis of investi-gations such as these it is possible to document the progress of a braininfarction and the success of different therapeutic measures.

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the foundations for one of the mostsuccessful developments in basic re-search.

MAGNETIC MOMENTS

In 1929 Isaac Isidor Rabi and hiscolleagues at America’s Columbia

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tors and scientists can distinguishthe tissues of the human body in theMR image.

Today scanners not only provideimages from inside our bodiesthrough every imaginable plane ofsection, but also permit assertionsabout the functional state of certaintissues. The breakthrough for func-tional magnetic resonance imaging,fMRI, came in the eighties whenGeorge Radda and his colleagues atOxford discovered that MRI alsolends itself to detecting changes inthe oxygen content of blood. Theprinciple behind this method,known as BOLD (blood oxygen leveldependent), had already been de-scribed 40 years previously by LinusPauling und Charles D. Coryell. In apublication issued in 1936, they re-ported on the magnetic properties ofhaemoglobin, the pigment whichcarries oxygen and gives the redblood cells their colour.

RED OR BLUE BLOOD

The two chemists had discoveredthat the magnetic sensitivity of oxy-genated arterial blood differs by 20percent from oxygen-free venousblood. In 1990 Seiji Ogawa of At&TBell Laboratories demonstrated inexperiments on animals that, unlikeoxygenated haemoglobin, deoxy-genated haemoglobin increases thestrength of the magnetic field towhich it is exposed in its immediateenvironment. Consequently, regionscontaining large quantities of de-oxygenated haemoglobin alter themagnetic field around the blood ves-

sels and this, in turn, is reflected inthe MR image.

Since then, the use of fMRI has re-ally taken off – extending beyondthe clinical field. In neurobiologicalresearch, in particular, this techniquehas offered scientists new insightsinto the brain. As a result, fMRI hasbecome a tool for investigating thedevelopment of neuronal networksfor sight, speech, and hearing. Re-searchers can study activity patternsin the brain down to an accuracy ofless than a millimetre.

CAUGHT THINKING

After the initial euphoria, scepti-cism spread amongst scientists - howmeaningful really were the “prettypictures”. fMRI can certainly producehuge quantities of data, yet oftenthere is insufficient background in-formation or basis to allow measuredvalues to be interpreted correctly.Consequently, there was a huge gapbetween the spatially resolved viewof brain activity using fMRI and themany findings gained from electro-physiological measurements on ani-mal models. The reasons for thiswere largely technical: the interfer-ence between the scanner’s strongmagnetic field and the flow mea-sured at the electrodes prevented thetwo investigative methods beingused simultaneously and thus thegap between experiments on animalsand findings from human researchbeing bridged.

This obstacle has now been over-come by Nikos Logothetis and hiscolleagues at the Max Planck Insti-

surements were compared, a signifi-cant correlation was revealed be-tween the fMRI data and local fieldpotentials and less so with single celland so-called multi-unit measure-ments. “Our studies indicate thatchanges in the oxygen content of theblood are not necessarily accompa-nied by output signals, or neurons‘firing’. fMRI tends to reveal changesin local field potential and thus sig-nals arriving from other regions ofthe brain and their processing”, saysNikos Logothetis. And: “Imaging willreveal activity in a given area whichmay modulate the response sensitiv-ity of single neurons and even blocktheir firing; so we may now under-stand for the first time not only whatindividual neurons do – which canbe directly examined with micro-electrodes anyway – but also howthe neuronal network surroundingthem contributes to their activitypatterns underlying different func-tions and in the context of differentbehaviours.”

COMBINED PERSPICACITY

An important discovery from ini-tial experimental investigations atTübingen is that the BOLD fMRI da-ta have a much lower signal-to-noise ratio than the electrophysio-logical measurements, probably dueto the considerable variability invascular response. According to Lo-gothetis, “this results in the spreadof neuron activity in the brain beingunderestimated when human fMRIdata are analysed using traditionalstatistical methods.” In other words:

tute for Biological Cybernetics inTübingen: using special electrodesand extensive data processing, theyhave not only succeeded in provingconclusively that BOLD fMRI actual-ly measures changes in neuron activity; the researchers have alsoestablished that the BOLD signal primarily reflects the input of neu-ronal information to the relevantarea of the brain and its processingthere rather than output signalstransmitted to other regions of thebrain.

With their new experimental tech-nique the Tübingen scientists canexamine various aspects of neuronactivity and also distinguish betweenso-called action potentials and localfield potentials. Action potentials areelectrical pulses generated by indi-vidual neurons or a relatively smallgroup of neurons. They are all-or-nothing signals which only occur ifthe triggering stimulus is sufficientlypowerful. In scientific jargon this isknown as “the neurons firing”. Ac-tion potentials therefore reflect theoutput. These signals are recorded bymicroelectrodes located right next tothe nerve cells. In contrast, localfield potentials are electrical poten-tials which change slowly and repro-duce the input signal to the synapsesand its continued processing in alarger neuron population.

The Max Planck researchers havenow examined the response to anoptical stimulus in the visual cortexof anaesthetised monkeys simultane-ously using these three differentmethods. When the series of mea-

the absence of an fMRIsignal does not neces-sarily mean that noneuronal informationprocessing is takingplace in this region ofthe brain – electrophys-iological measurementshave put us right. Cog-nition scientists will al-so have to preparethemselves for thiswhen interpreting theirfMRI data in future.

Moreover, the impor-tant contribution of lo-cal field potential to thefMRI signal is also con-sistent with investiga-tions into its bioener-getic basis. Scientistshave long known thatneuron activity and en-ergetic metabolism aredirectly linked. At rest,the human brain con-sumes 20 percent of theoxygen in the body although itmakes up less than two percent ofthe body mass. A short-term increasein brain activity (and thus in energyrequirement) is accompanied by anincreased blood flow (increased flowrate) and by a similarly increasedglucose requirement. The latter obvi-ously reflects synaptic activity. Forinvestigations using NMR spec-troscopy have revealed that 80 to 90percent of man’s entire cortical glu-cose consumption is attributable tothe energy requirement of so-calledglutamatergic neurons – that is to

say, neurons which make use of thetransmitter glutamine. Their activityis, in turn, recorded in field potentialmeasurements.

The facts about functional mag-netic resonance imaging have not allbeen told yet. One thing is certainhowever: fMRI is the result ofdecades of basic research, the impe-tus coming time and again from re-searchers who looked beyond theconfines of their own discipline. Leftto bureaucratic research planning, itwould probably never have comeabout. CHRISTINA BECK

Visual stimulus from a chequer-board pattern (left) triggers neuron activity in the brain which is recorded using single cell measurements(front) and functional magnetic resonance imaging (back). Scientists at the Max Planck Institute for Biological Cybernetics have developed a totally new experimental technique to enable different signals to berecorded at once. As a result, they have succeeded in demonstrating that changes in neuron activity really can be measured using BOLD fMRI. The BOLD signal primarily reflects the input of neuron informa-tion to the particular brain region and its processing there rather than output signals transmitted to other regions of the brain.

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1936Linus Pauling and Charles

D. Coryell discover that themagnetic behaviour of

haemoglobin alters according to its degree of

oxygenation.

Isaac Isidor Rabi and his colleagues develop the princi-

ples of nuclear magnetic resonance by sending lithiumchloride molecules through a

magnetic field, thereby releasing radio waves.

Independent of one another, Felix Bloch and

Edward Purcell succeed inidentifying the phenome-non of nuclear magneticresonance in liquids and

solids.

Using the so-called pulsetechnique and Fourier analysis, Richard Ernst

and Weston Anderson areable to advance NMR

technology significantly.

Godfrey Hounsfield builds the first CT scanner,thus laying the foundation

for virtually all imagingtechniques.

Paul Lauterbur links the development of CT with

deliberations on locating the NMR signal; the idea of

superimposing with a magneticfield gradient provides the basic

conditions for generating magnetic resonance images.

Peter Mansfield and his colleagues publish

the first image of part of the human body

– a finger – created byMRI.

1937 1945 1964 1971 1972 1976 1990 20011964 1971 1972 1976 1990 2001Seiji Ogawa discovers that

changes in the oxygen content ofspecific tissues can be identifiedin magnetic resonance images.

The so-called BOLD method thusenables the functional state of

tissue to be evaluated.

Using a new experimental technique, Nikos L. Logothetis and his colleagues succeed in recording electrophysiological

readings and fMRI data, thereby revealing function-specific

connections.