Magnetic Resonance Imaging - Federation of American Societies for

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INSIDEthis issue

MRI: From AtomicPhysics to

Visualization,Understanding andTreatment of Brain

Disorders3

How MRI Works4

Medical Applications

6

Functional MRI8

Change in BrainDuring Adolescence

10Anticipated

Applications inMedical Practice

11

Breakthroughs in Bioscience 2 www.faseb.org/opar

COVER IMAGE: An 3-D reconstructed MRI image of the human head highlighting the location of a brain tumor (green) and associated

vasculature (red). The brain ventricles are highlighted in blue. The three-dimensional localization of the tumor is visualized in rela-

tion to sections of the brain in two different planes. This figure provided courtesy of Dr. Ferenc Jolesz, Brigham & Women’s

Hospital, MA.

Acknowledgments David Holzman, Lexington, MA, authored the article and

David Lester, PhD, US Food and Drug Administration, was

the scientific advisor. They are grateful to the FASEB

Breakthroughs in Bioscience Committee members for their

guidance in developing the article as well as to the scien-

tists who reviewed it.

BREAKTHROUGHS IN BIOSCIENCE COMMITTEE

Fred Naider, PhD, Chair, College of Staten Island, CUNY

Tony Hugli, PhD, The Scripps Research Institute

Richard Lynch, MD, University of Iowa College of Medicine

Margaret Saha, PhD, College of William and Mary

SCIENTIFIC REVIEWERS

Cecil Charles, MD, Duke University

Kimberlee Potter, PhD, National Institute of Aging, National

Institutes of Health

The Breakthroughs in Bioscience series is directed by

Tamara R. Zemlo, PhD, MPH, Senior Science Policy

Analyst, Office of Public Affairs, FASEB.

The following people were very helpful in providing infor-

mation for the preparation of this article.

Herbert Abrams, Stanford University

Michael Bernstein, American College of Radiology

Cecil Charles, Duke University

John Crues, Radnet Management, Los Angeles

John A. Detre, University of Pennsylvania, Philadelphia

Joseph M. Eskridge, University of Washington

David Fisher, University of Washington

Jay N. Giedd, National Institute of Mental Health

Isaac Halpern, University of Washington

Steven E. Harms, University of Arkansas for Medical

Sciences

Joseph Hornak, Rochester Institute of Technology

Keith Johnson, Brigham and Women’s Hospital, Harvard

Medical School

Ferenc Jolesz, Brigham and Women’s Hospital, Boston, MA

Marcel Just, Carnegie Mellon University

Chelsea Kidwell, University of California, Los Angeles

Steven Larson, Memorial Sloan Kettering Cancer Center

Paul Lauterbur, University of Illinois

Henry McFarland, National Institute of Neurological

Disorders and Stroke

Barry Pressman, Cedars-Sinai Medical Center, Los Angeles

Richard Rudick, Cleveland Clinic Foundation

Steven Seltzer, Brigham & Women’s Hospital, Harvard

Medical School

Deborah Yurgelun-Todd, McLean Hospital, Belmont, MA


She was watching TV whenshe was struck by a sud-den, terrible headache, a fit

of nausea, and powerful feelingsof deja vu. Two days later, doc-tors at Boston’s Brigham andWomen’s Hospital scanned thisyoung college student’s brain,using a technology called mag-netic resonance imaging (MRI).The MRI revealed a tumor thesize of a child’s fist embedded inher temporal lobe that was begin-ning to cause seizures, and hereerie sense of deja vu was a signof that. Left untreated, it likelywould also have interfered withher speech and movementbecause circuitry controllingthose functions is within thefrontal lobe.

Before neurosurgeons began usingMRI, standard procedures fortreating such tumors were consid-ered very risky for patients, andoutcomes often proved as bad asthe disease. Although slicingthrough brain tissue can kill neu-rons, which do not regenerate,redundancy in critical areas of thiscircuitry may spare speech if cut-ting is kept to a minimum. MRInow helps neurosurgeons meet acritical challenge, namely, doingthe least possible damage during avital procedure.

MRI does so by providing theclearest pictures of brain anatomyof any available imaging technol-ogy. By other means, the type of

tumor growing within the youngwoman’s temporal lobe is indis-tinguishable from healthy braintissue. But MRI reveals suchtumors with precision, and alsoshows blood vessels as well asother key landmarks within thebrain, enabling neurosurgeons tonavigate carefully through its del-icate landscape. Thesurgeons, led by Dr.Peter Black, thus avoid-ed inadvertent, poten-tially life-threateningdamage as they cutthrough to the tumorand removed it.

Recent improvementsin MRI provide addi-tional means for neuro-surgeons such as Dr.Black to avoid otherpotentially catastrophicmishaps. For instance,“functional” MRIenables them to picturecritical centers of the brain as anindividual responds to questionsor other stimuli. Thus, when theyoung woman responded to arecited list of words such as“heat”, “light”, “fast”, and “sky”,her brain’s language center“glowed” brightly in the function-al MRI pictures, whereas hermotor cortex was most activewhen she wiggled her fingers ortoes. Those responses helped Dr.Ferenc Jolesz map those andother critical functions and advise

Dr. Black on how not to damagethe vital circuitry through whichthey act.

Meanwhile, the surgeons tookadvantage of yet another recentMRI wonder, a system developedjointly by researchers at Brighamand Women’s Hospital andGeneral Electric Medical

Systems, called image-guidedsurgery. It permits them to workinside the magnetic coils of theMRI instrument, which furnishesupdated 3-D images of apatient’s brain every few min-utes, and thus to track theirprogress in detail on a monitorthat hangs above the surgicalfield (Fig.1). The successful surgery enabled the youngwoman to return to normal lifewhere she ultimately resumedher class work, says Dr. Jolesz.

MRIMagnetic Resonance Imaging:From Atomic Physics to Visualization! Understanding and Treatment of Brain Disorders

Figure 1. Using image-guided surgery, the surgeon is oper-

ating on the patient, who lies within the coils of the MRI.

The screen, showing the patient’s brain, is visible above

the surgeon. This figure provided courtesy of Dr. Ferenc

Jolesz, Brigham & Women’s Hospital, MA.


MRI began to come into generaluse in the mid-1980s. But mostof the tools Jolesz used to extractthe temporal lobe tumor wereunavailable before the mid-1990s.Until then, MRI had been veryslow, like taking photographs inthe days of the Civil War. Apatient had to lie stock-still for10–30 minutes for each picture.The slow image acquisition madeit difficult to use MRI in much ofthe body, where the rhythms oflife never cease. The beating ofthe heart, the pulsation of thelungs, and the peristalsis of thegastrointestinal tract inevitablyblurred these slowly acquiredimages, making it impractical touse MRI throughout much of thebody. But the MRI equivalent ofshutter speed has risen exponen-tially, and image acquisition cantake as little as one twentieth of asecond.

The core of a magnetic resonanceimaging machine is a magnet sopowerful that it could drive apen-sized piece of metal with theforce of a bullet. Generally, itconsists of a tubular structurelarge enough for the patient to lieinside while images are being

made, although, specializedsmaller magnets sometimes areused to image a patient’s extremi-ties, such as wrists, knees, or fin-gers. People approaching thesepowerful electromagnets mustdivest themselves of materialsthat are sensitive to magnets,such as any metal, and creditcards. Similarly, patients withmetal plates, pacemakers, orother prostheses are not eligiblefor MRI tests. The electricity cir-culating in the coils of an MRImachine is roughly one-twelfththat produced by a typical com-mercial nuclear power plant.

One big advantage to MRI is thatit is a non-invasive medical pro-cedure. Nothing is inserted in apatient’s body, no dyes are swal-lowed, and no contrast agents areinjected, except under special cir-cumstances. Moreover, patientsare not exposed to ionizing radia-tion, as is the case with X-rayComputed Tomography (CT)imaging.

For medical purposes, the mag-netic resonance imager usually istuned to “see” hydrogen, which isthe most abundant element within

the body. The magnet first alignshydrogen atoms that come withinits field, and then a radio-fre-quency pulse is applied to jostlethem momentarily. As theyrealign, special receivers pick uptheir signals and transmit thatinformation into computers inwhich special programs convertthose signals into vivid images.The various tissues and fluids aredistinguishable from one-anotherlargely because the concentrationof hydrogen varies within differ-ent tissues and bodily fluids.

The images from MRI are crosssections of the brain or body, thinslices of tissue, like slices ofbread from a loaf. Computer pro-grams can be used to assemblethese image slices into three-dimensional datasets. The com-puter power needed for this fastanalysis, which was unavailable afew years ago, now fits on adesktop. Most of the time, how-ever, doctors analyze thoseimages slice by slice.

The non-invasive nature of MRIhas opened new areas of research.Investigators learn much of whatthey know about human maladies

How MRI works Medical imaging was far from the minds of Dr. Felix Bloch and Dr. Edward Purcell in 1946, when each independently dis-covered how to measure magnetic resonance, the breakthrough that led several decades later to MRI. Scientists alreadyknew that the nucleus of an atom can absorb energy (i.e., resonate) from radio waves when placed in a magnetic field andthat different atoms absorb different amounts of such energy. But until the two of them independently determined how todo so, no one could measure the phenomenon. For their analytic efforts, they shared the 1952 Nobel Prize in physics.“There was no idea that hidden inside this phenomenon was the possibility of making pictures,” says Dr. Paul Lauterbur, achemist at the University of Illinois, Champaign-Urbana, who has contributed significantly to this field of research.

Unfortunately for physicists, atoms usually are contained in molecules, which skew the signals and play havoc withthe measurements that typically interest physicists. However, chemists seized upon the technique as a way of analyzingthe structure of molecules, says Dr. Lauterbur. Nuclear magnetic resonance (NMR), as the technique was then called,


by studying animal models. Thesemay be animals that are bred toexpress particular genetic diseaseslike those in humans or animalsin which specific diseases, suchas cancer, HIV infection or otherconditions are induced. Studiesusing MRI in these animal mod-els may lead to similar applica-tions in clinical investigations.For example, when the MRI tech-nique called diffusion-weightedimaging was being developed foruse in humans with strokes,researchers used the technique toperform imaging studies in ani-mal models of stroke and thendissected the animals’ brains. Thedissections showed theresearchers how to interpret thediffusion-weighted images so thatthey would understand what theywere seeing when they performeddiffusion-weighted MRI in humanstroke victims.

However, even without good ani-mal models for many psychiatricmaladies, including depression,dementia and schizophrenia, MRIprovides a powerful means forvisualizing how the brains ofindividuals with such disordersdiffer from those of others—

without medical researchersresorting to surgery or other inva-sive procedures. For example,researchers from theMassachusetts General Hospitalreported early in 2000, that cer-tain regions of the brain aresmaller than normal in individu-als during the early stages ofAlzheimer’s Disease. Indeed,these differences can be detectedthree years before other symp-toms appear. Other researchers atDuke University are using mag-netic resonance spectroscopy,which is closely related to MRI,to view direct brain responses todrugs among individuals beingtreated for this same disease. Aswith much of the basic and clini-cal research involving MRI, theNational Institutes of Health(NIH) supports this work directlyas well as through focused train-ing and education programs.

Ever more powerful magnets andsteady improvements in comput-ers are raising the speed andincreasing the precision of MRIimaging. Seven million MRI scanswere performed on patients in1998, up from virtually nonebefore the mid-1980s. MRI is

making brain surgery far moresuccessful than it ever was, andonce-impossible operations arenow considered routine and canbe finished faster with less harmto patients.

MRI arose following an obscurediscovery in 1921 by physicistsOtto Stern and Walther Gerlach,who found that magnetic fieldscan perturb the energy state ofthe nucleus within an atom. In1946, physicists Felix Bloch andEdward Purcell figured out howto measure the energy required todrive those changes from oneenergy state to another.

“Through very esoteric research,with no apparent applications,physicists discovered the magnet-ic resonance phenomena, andchemists used it to learn aboutthe structure and conformation ofmolecules,” says RepresentativeVern Ehlers from Michigan, whodeals with science-related issuesin Congress. “Doing similarlyesoteric research on elementaryparticles, physicists developedvery rapid computerized datagathering and analysis tech-niques. Combining these two,

can distinguish among different types of chemicals because the nuclei of each chemical element resonates to a particu-lar frequency of radio wave and then emits signals at a characteristic frequency. Furthermore, and this is what both-ered physicists, but pleased chemists, the electrons surrounding each nucleus slightly distort the resonant frequency.The technique soon proved powerful for determining structures of organic chemicals, the carbon-containing moleculesfound throughout living systems, as well as of many commercially useful chemicals, including drugs, plastics, andfibers. NMR is almost universally used in chemistry laboratories, and it is required for advanced chemical studies.

To analyze a compound, researchers would place it in a tube, which then was put inside a magnet. The nuclei in thecompound line up with the magnetic field in the same way that the needle of a compass points north in the earth’smagnetic field. Once in the magnet, the compound is zapped with a range of radio-frequency pulses, some of whichcause the various nuclei in the chemical compound to resonate. The resonating nuclei then release energy, each atcharacteristic frequencies, which are displayed as peaks and valleys that vary with frequency. Chemists use such infor-mation to determine molecular structures.


MRI was developed, providingarguably the best medical diag-nostic tool ever made, as well asan excellent biomedical researchinstrument. The point is simplebut important: seemingly imprac-tical research yields huge divi-dends and deserves substantialand stable funding.” Whileapplied research typically extendsexisting knowledge, basicresearch lays foundations fromwhich truly novel technologiesmay arise.

Medical ApplicationsMultiple SclerosisMRI is providing scientists with aclear view of the circuitry of thebrain, and it is showing them howthe brain works, as well as howdisease causes it to malfunction.For example, multiple sclerosis(MS) is a chronic, progressivedisease that afflicts roughly aquarter-million Americans.Typical symptoms include loss ofbalance, paralysis, numbness,visual disturbances, incontinence,and even dementia. These symp-toms, resulting when componentsof the immune system misguid-edly attack specialized sheaths

that insulate connections betweennerve cells, vary greatly, makingdiagnosis difficult. But MRI canovercome such diagnostic uncer-tainties because it readily showsthose damaged sheaths as small,whitish spots.

MRI also can help doctors deter-mine whether or when a patientwith early-stage MS needs treat-ment. Even when a patientappears clinically stable, the dis-ease can be stealthily ravagingthe brain, and such early-stageMS patients usually should betreated, whereas those whoseMRIs show few active lesionsmay safely delay treatment.

Researchers are developing other,potentially more accurate ways tomonitor MS with MRI. Dr.Richard Rudick and Dr. ElizabethFisher of the Cleveland ClinicFoundation use MRI to measurebrain volumes with precision.Among healthy men and women20-50 years old, 87 percent of thebrain volume is tissue and theremaining 13 percent is water,with less than one percent vari-ability. However, among individ-uals with MS, the tissue fractiondeclines by about 0.7 percent

annually. Measuring these declin-ing tissue volumes may enablephysicians to determine how longindividual patients have had MSand to more accurately predictthe course of the disease. “Itlooks as if the atrophy severityand the change in atrophy scorepredict the patient’s status 6-8years down the line,” says Dr.Rudick. This use of MRI alsomight help determine whether apatient’s treatment is working, aswell as the effectiveness of newdrugs being tested in clinical trials.

StrokeAnother devastating brain dis-ease, stroke, is the third leadingcause of death in the U.S. About550,000 strokes occur annually,killing roughly 100,000 peopleand leaving many others severelydisabled. One such patient, aretired college professor who waswriting a book when stricken,was left paralyzed and with so lit-tle short-term memory that shewas usually unable to recallwhich close friend had visited heras recently as an hour earlier.

Although chemists quickly embraced this useful technology, applying it to medicine proved more challenging. For onething, radio-frequency waves could not be captured on photographic film, or its equivalent. Thus, a quarter centurypassed before Dr. Lauterbur figured out how to apply this technology to imaging. In 1971, he saw some experimentswhich showed that different tissues, in this case, from a rat, produced different magnetic resonance signals. “Peoplesaid, maybe we will be able to detect and diagnose cancer using biopsy specimens,” says Lauterbur. At first, themethod required removing tissue from the body, putting it into a tube like ordinary chemicals, and then placing thetest tube within the magnet of then-available instruments. “I asked myself, is there any way one can tell where anNMR signal is coming from inside a complex object, for example, an animal?” he recalls. The answer was a resound-ing “Yes!”

MRI images used in medicine are based predominantly upon information from hydrogen nuclei, which are by far the mostabundant element in the body, accounting for 63 percent of the atoms, including those in the water that bathes living tissue.Magnetic resonance is sensitive to signals that differ from one tissue to another as well as to relative concentrations of


Most strokes occur when a brainartery is blocked, either by a clotgrowing on the vessel wall, or,as in the case of this college pro-fessor, by one that the bloodswept into the brain from else-where in the body. Less often, inabout 20-25 percent of cases, astroke may result from a rup-tured blood vessel. In both cases,brain tissue that becomesdeprived of oxygen quickly dies.However, knowing the cause ofstroke is critical for determininghow stroke patients are treated.Strokes caused by clots are treat-ed with clot-busting thrombolyt-ic drugs, provided the patientreaches the hospital within threeto six hours of onset. However,if the stroke arises from a hem-orrhage such drugs need to beresolutely avoided because theycan make matters worse.

Most patients with an acute strokereceive a CT scan before MRI,because CT is particularly sensi-tive to bleeding in the brain andalso because such instruments arecheaper and thus more widelyavailable than MRI. While CTshows bleeding, MRI can revealthe size and location of the stroke

far more accurately and preciselythan CT. This more detailed infor-mation can be vital when makingtreatment decisions.

A recently developed MRI tech-nique, called diffusion imaging(Fig.2), can diagnose strokeswithin minutes, revealing thelocation and size of damage.Diffusion imaging highlights therandom movement, or diffusion,of water, which decreases when astroke kills nerve cells. Thus,

where neurons are dying, there isa net flow of water from the extra-cellular spaces into the cells.Since water diffuses relativelyfreely outside cells, while itsmovement is constrained insidecells by all the cellular machinery,there is less than ordinary diffu-sion in the vicinity of the stroke,and this difference shows upclearly on diffusion MRI. Thatmovement of water from theextracellular spaces into the dying

Figure 2. Three different MRI imaging protocols of a patient 20 min after a stroke event.The T2 weighted image in the first panel shows some structural information about thepatient’s brain but no evidence of the site of the stroke. The diffusion weighted image,which monitors the random movement of water, shows a distinct lesion on the right sideof the patient (right side of middle panel). This is representative of decreased water dif-fusion in the area of the stroke, where there are dead neurons. The third panel shows aperfusion image, which demonstrates regions of the brain where there is reduced bloodflow. The region of reduced blood flow in this patient (dark areas) is identifiable by thelower contrast and structural detail. This is larger than the area highlighted in the diffu-sion-weighted image, which may indicate that there may be additional neuronal cell loss.Courtesy of Drs. Steven Warach and Lawrence Lautor, National Institutes of NeurologicalDisorders and Stroke, National Institutes of Health, MD.

hydrogen in tissues and fluids. As with conventional NMR, tissues are placed within a magnetic field, and then subjectedto a radio-frequency pulse. That momentary pulse quickly aligns the hydrogen nuclei within it, but then they realign moreslowly with the constant magnetic field within the magnetic resonance device. This realignment, or relaxation, takes sever-al hundred milliseconds to a few seconds, depending on the environment surrounding the hydrogen atoms. For instance,hydrogen nuclei in water have a long relaxation time, as they do in blood and in cerebrospinal fluid. In tissues, their relax-ation time is much shorter, and it is shortest in fat — around 300 milliseconds. These differences in relaxation timesappear as degrees of brightness within the MRI image. In scientific shorthand, relaxation time is called T1.

Yet another phenomenon, called T2, makes MRI still more versatile when it comes to distinguishing one tissue fromanother. To understand T2, imagine nuclei behaving like tops, says Dr. David Fisher of the University of Washington.Tops spin around their axes, but as they spin, they also lean. That leaning constantly shifts direction, from north towest to south to east and north again, tracing circles. Nuclei have a property, called spin, which resembles this direc-tional leaning of tops. Now imagine many tops all leaning in the same direction, all shifting direction together. This


neurons takes place because nor-mal, healthy cells, including neu-rons have a lower concentrationof salt than the surroundingextracellular fluids. Therefore saltleaks into the neurons, like waterseeping into a boat through tinyholes in the gunwales, and so theneurons have to bail it. They havespecial pumps just for this task.But as a clot chokes off theblood, the bailing pumps losetheir energy supply and stopworking, and the cell dies. Saltflows inward and water follows.

One challenge in treating strokesis that most victims do not reachthe hospital quickly enough to becandidates for thrombolytic drugs,which ordinarily are effective onlywhen used within about threehours of onset. But Dr. Chelsea S.Kidwell of the University ofCalifornia, Los Angeles and hercolleagues are developing a meansfor using MRI imaging informa-tion to predict whether particularpatients might benefit from suchthrombolytic treatments at timesfollowing that usual three-hourwindow. “We believe that theinformation we are obtaining fromthe MRI will indicate if there isstill salvageable tissue beyondthese absolute time windows, andthat this information could then beused to make treatment decisions,”says Dr. Kidwell.

The central area of the stroke,

coordinated leaning is roughly what happens when whole bunches of nuclei are “in phase”. When a radio-frequencypulse is applied during MRI, the nuclei align and the spins come into phase. When the pulse ceases, the spins of thenuclei gradually “dephase”, and the signal weakens. The further out of alignment they fall, the weaker the signalbecomes. When the spins are entirely random, the signal disappears. The time required for the spins to fall completelydephase is T2.

Like relaxation, the rate of dephasing depends on characteristics of the tissue being imaged, but those characteristics

Functional MRIFunctional MRI (fMRI) enables researchers and physicians to visualize parts ofthe brain that are active during specific tasks" This technique highlights fast#moving blood! and blood moves fastest in those parts of the brain that areworking hardest" Active regions glow more brightly than inactive regions infunctional magnetic resonance images"

fMRI is fomenting a revolution ofsorts within the neurosciences"Throughout science and medicine!researchers typically address largeand complex questions by firstbreaking them into smaller! moremanageable components" Amongneuroscientists! for instance! oneparticularly important but alsohighly complex question! how doescommunication change betweenspecific nerve cells when anindividual learns a new skill and itsmemory becomes encoded! couldnot be addressed because theylacked the tools needed to get at itsinherent complexity" “Whilereductionism [the strategy ofasking small! manageablequestions] has done wonderfulthings for science! you need to putthe pieces together and see howthe whole thing works!” says Dr"Just" “In neuroscience! fMRI hasbeen one of the first tools to let you see how the parts work together"”

fMRI also is revolutionizing brain surgery! helping surgeons to avoid damagingareas of the brain that are critical to speech! movement! and other necessaryfunctions" Someday such information may enable researchers to developbetter teaching methods and to redesign work environments for thoseperforming complex jobs! such as air traffic controllers" Perhaps a new field ofbrain ergonomics$will emerge"

Functional MRI aids neurosurgeons so that they

can avoid damaging critical areas of the brain

when performing delicate brain surgery. It high-

lights regions of brain activity upon perform-

ance of some task, sensory or motor. A cutaway

of a three-dimensional reconstructed image of

a human head shows the location of an identi-

fied tumor (green) in relation to brain regions

of auditory (red), visual (blue) and motor (yel-

low) activities as identified using functional

MRI. This figure provided courtesy of Dave

Gering, Artificial Intelligence Laboratory, MIT.

© Dave Gering

1 Ergonomics is an applied science concerned with designing and arranging things people useso that they can be used efficiently and safely.


where the blood supply is chokedoff, may be surrounded by anarea where the blood flow ismerely restricted, stressing thestill-undamaged nerve cells. Arecently developed techniquecalled perfusion-weighted MRIcan measure this blood flow (Fig.2). Combined with diffusion-weighted images, it can providevaluable information about howthe stroke may progress. If anarea of low blood flow surroundsthe central area of the stroke, thestroke is likely to spread, unlessnormal blood flow is quicklyrestored. But if not, doctors canbe pretty sure that the stroke hasrun its course and that furthertreatment with thrombolyticdrugs offers no benefit.

Within hours following a stroke,the brain begins adapting to itsnew limitations, marshallingregions that normally have noth-ing to do with the tasks that thedamaged region had been per-forming. Sometimes, however,the damage overwhelms this lim-ited ability of other brain seg-

ments to adapt to performing newactivities. Using functional MRI(see box previous page), Dr.Marcel Just of Carnegie MellonUniversity is developing thera-pies that aim at improving thedamaged brain’s capacity to dealwith its changed circumstances.For instance, patients whose lan-guage networks are damaged bystroke often can no longer under-stand complex sentences. Basedon functional MRI studies, Dr.Just learned that the undamagedbrain sometimes enlists the pre-frontal cortex to reason throughunfamiliar tasks. To engage theprefrontal cortex to help lan-guage-impaired stroke patientsovercome some of their speech-associated difficulties, Dr. Justhas presented them with sen-tences, asking them to find theverb, and to explain the action.He finds that, over a month,some patients improve so muchthat they could again analyzecomplex sentences as quickly assubjects with normal brains.Functional MRI studies indicatethat the patients’ prefrontal cor-

tices again are active when thepatients converse.

Brain SurgeryIt is no accident that brain sur-geons use many, if not all, theMRI tools that are available.Operating on the brain is delicateand complex for many reasons.The skull is difficult to penetrate,nerve cells are easily damagedand slow or impossible to repair,and anatomic landmarks are diffi-cult to discern. Even with MRI tohelp in visualizing the functionalanatomy of the brain, brain sur-geons are afforded a view that ismore like that from a tiny port-hole rather than a picture window.

Thus, despite their value, conven-tional MRI maps of the brainhave shortcomings. When tumorsor otherwise diseased tissues areextracted, the brain undergoesseismic-like shifts, rendering theoriginal map inaccurate. “Whenthe tumor comes out, it leavesthis hole,” says Dr. Jolesz ofBrigham and Women’s Hospital.“The remaining cortex is fallingin, and so there are deformations.

differ slightly from those that affect T1 relaxation times. In effect, tinkering with these two signal sources provides away of sharpening MRI images, much like adjusting contrast in a black-and-white TV picture. Moreover, certainagents, notably gadolinium, can be injected into a patient to increase contrast by reducing T1 values.

Dr. Lauterbur also figured out how to translate magnetic resonance signalsinto a two- and then a fully three-dimensional grid, no small feat. Spin raterises with the strength of a magnetic field. When a tissue slice is subjected totwo magnetic fields, parallel to the plane of the slice, but perpendicular toeach other, the spin will vary from lowest at one corner of the slice to highestat the opposite corner. Those differences enable the magnetic resonanceequipment to determine where in the slice each signal, whether T1 or T2, iscoming from. To produce a three-dimensional image, a series of consecutivetwo-dimensional slices is compiled one on top of the other, and a computerassembles all these two-dimensional images into a three-dimensional image.Beyond this basic MRI technology, improvements have involved ever moresophisticated developments in mathematics, engineering, and software.

The alignment of water nuclei are demon-strated for in phase (panel A) and out ofphase (panel B). The nuclei are “in phase”following a radio-frequency pulse, while theyare “out of phase” or dephased in their natu-ral relaxed state.

Panel A Panel B


You can’t use the original imageto guide the surgery.” Edema, orswelling that occurs during sur-gery may also shift the terrain. AtBrigham and Women’s, however,recent improvements being madeto conventional MRI mappingprocedures are changing all that.

Before surgeons ever scrub forsurgery, they review three-dimen-sional composites of various MRIimages of their patients’ respec-tive brains to plan the best path toa particular damaged area and toavoid causing incidental damage,such as “big bleeds.” First, con-ventional MRI provides a struc-tural map, pinpointing the tumorand major arteries in its vicinity.Additionally, functional MRImaps help to locate centers ofspeech, movement, and other crit-ical functions.

Typically during MRI-guidedbrain surgery, a patient lies upona platform that spans two mag-nets shaped like huge tires thatare spaced far enough apart formembers of the surgical team tostand between them. Initially, amonitor above the surgical fielddisplays the same image that thesurgeon studied, but aligned pre-cisely with the patient’s brain,providing the surgeon with thevirtual equivalent of X-rayvision. Throughout the operation,the MRI system provides a seriesof fresh images, each new oneoverlaying its predecessor on thescreen, thereby updating anyshifts within the anatomic terrain.Moreover, a special probeenables the surgeon to monitorspecific sites along the incisionwithin the brain, providing fresh

images that appear immediatelyupon the screen above.

Not only does this MRI-basedtechnology reduce the danger ofdamaging the brain, it alsoenables surgeons to remove more

of each tumor that theyencounter. Before this image-guided surgery became available,up to 80 percent of operationsultimately failed because they leftbits of low-grade tumor behind.

The Change in Brain During Adolescence is Plain Some researchers! including Dr" Deborah Yurgelun#Todd of McLean Hospitalin Belmont! Massachusetts! are investigating how the brain changes duringadolescence and into adulthood" Different centers of the brain! each withdistinctive roles! sometimes are at odds with one another" For instance! thethumb#sized piece of brain tissue called the amygdala! is a seat of emotionand impulse! whereas the frontal cortex is a center for executive functionssuch as planning! understanding the consequences of behaviors! andregulating emotions" Should one drive after drinking a six#pack of beer?Engage in sex with an unknown partner? Embark on an expedition to theSouth Pole? Start a new company? While the amygdala may be urgingaction! the frontal cortex is thinking through what the repercussions of thataction might be"

Dr" Yurgelun#Todd conductedfunctional MRI studies onadolescents ages $$#$% and onadults performing tasksmediated by the frontalcortex" Those studies indicatethat the frontal cortex is leastactive in the youngestadolescents! but that thisactivity rises steadily with ageuntil it reaches adult levels"Moreover! the amygdalaappears more active inteenagers than in adults"“That! in particular! made usthink that the likelihood forimpulsive behavior might begreater in adolescents than inadults!” says Dr" Yurgelun#Todd" Lower activity in thefrontal cortex of youths isconsistent with theirfrequently impulsive behavior!but MRI analysis by itselfcannot prove this explanation!she points out"

These images show the difference in brain activi-ty between healthy adolescents and adults whowere presented with pictures of faces displayingdifferent emotions, and asked to name the emo-tion being displayed on each face. The top twofigures show the lateral prefrontal cortex, whichis involved in planning, regulating emotions, andunderstanding the consequences of behavior, andthe bottom two figures show the amygdala, aseat of emotion and impulse. The adult prefontalcortex shows higher activity as represented bythe yellow color and larger colored area. (Thebrighter, more yellow colors indicate areas ofhigh activity, while red indicates areas of loweractivity.) This figure provided by DeborahYurgelun-Todd, McLean Hospital, Belmont, MA.


Anticipated Applications in Medical PracticeMRI-guided imagery soon mayhelp surgeons to substitutefocused beams of ultrasound orlasers for conventional scalpels asa way of removing brain tumors,essentially cooking them todeath. Ultrasound beams alreadycan be aimed and synchronizedelectronically, guided by MRI.Laser light can also be used tokill certain tumors, but applica-tions are still limited. Yet anotherrecently developed variety ofmagnetic resonance, which isheat sensitive, makes it possibleto monitor the temperature of atumor and its surroundings, toinsure that tumor, not healthy tis-sue, is being destroyed duringsuch procedures (Fig. 3).

Other MRI techniques are open-ing new windows into the brain.One approach involves using

MRI to detect changes in nucleiof elements other than the usualhydrogen. For example, MRI canbe used to detect changes in sodi-um ions, which move in and outof nerve cells when they transmitsignals throughout the brain. ThisMRI-based approach thus might

provide new insights aboutchanges to the brain following astroke or other diseases. It alsomight help in pinpointing brainareas involved in epilepsy thatsometimes need to be removed incases that cannot be controlled bydrugs. MRI analysis of nucleiother than hydrogen or sodium,within experimental or estab-lished psychiatric drugs may pro-vide insights about how suchdrugs are working and wherethey interact with the brain.

“Unlike other imaging modalities,which essentially have one tool,MRI is a big toolbox,” says Dr.Cecil Charles, head of radiologyat Duke University. Choosingwhat kind of MRI to use maydepend on whether a specific dis-ease involves changes in bloodflow, metabolism, structuralanomalies, or particular interac-tions with therapeutic drugs. “Theonly difficulty with MRI is decid-ing which tool to use,” he says.

Figure 3. Using a computer-assisted MRI three-dimensional reconstruction of apatient’s brain, a tumor (green) has beenidentified which can then be characterizedby taking a biopsy (first panel). This sameapproach can be utilized to kill the tumorwith heat by using a laser fiber (secondpanel). This innovative MRI-assisted tech-nique illuminates heated tissue (in red),guiding the surgeons so that they can avoidkilling normal tissue. The blue regions arethe ventricles of the brain. This figure pro-vided courtesy of Dr. Ferenc Jolesz,Brigham & Women’s Hospital, MA.

BiographiesDavid Holzman writes about science, medicine, and automobiles from Lexington,Massachusetts. He has written for Smithsonian, The Atlantic Monthly, the Journal ofthe National Cancer Institute, The Washington Post, the Boston Globe, Science, andnumerous other publications. He is a contributing editor to Physician’s Weekly and amedical correspondent for WebMD.

David Lester, Ph.D, is Team Leader of the Neural and Cellular PharmacologyTeam, at the Center for Drug Evaluation and Research, US Food and DrugAdministration (FDA). He has edited two books and published numerous researcharticles on imaging applications. He is Chair of the Public Affairs Committee of theAmerican Associations of Anatomists (AAA) and the AAA representative on theFASEB Science Policy Committee. He is also on the Board of Directors of theSociety for Nuclear Imaging in Drug Development. At the FDA, he is co-chair of theNeurotoxicity Assessment Subcommittee and a member of the CDER Committee forAdvancement of Science Education.

ReferencesInformation on NIH research activities on magnetic resonance technologies can befound at the National Center for Research Resources web page athttp://www.ncrr.nih.gov/ncrrprog/btdir/bt-c.htm.

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