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Neuroscience Tutorial

By Debbie Gomez,2014-05-05 21:18
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Neuroscience Tutorial

    Brain Imaging

(This page is currently under development.)

Introduction

    Non-invasive examination of the brain is crucial in performing medical diagnoses of brain disorders and damage, and for researchers studying its cognitive functions. A number of imaging techniques have been developed, and the field is growing steadily.

    Some of the techniques available, each with its own set of advantages and disadvantages, are covered in this tutorial:

    ; CT

    ; MRI

    ; SPECT/PET

    ; FMRI

    ; EEG/ERP

    ; EROS

    ; TMS

    ; MEG

Computer Tomography (CT)

    ; Used to be called CAT scanning, short for Computer Aided Tomography

    ; An X-ray tube projects X-rays through the head

    ; As the X-rays get projected, the intervening tissue absorbs some of them.

    Receptors on the other side of the head detect the those attenuated X-rays

    that passed through.

    ; The more dense the tissue, the more attenuation takes place

    ; By rotating the X-rays a full 180? around, a computer can use algorithms to

    reconstruct the image:

    ; Though it provides good anatomical information, no information is provided

    on cognitive function

    ; Spatial resolution is not great: between 5 to 10 mm, which takes the average

    of a point and 1 mm of the tissue around it

    ; Because it uses X-rays, it may be harmful (especially for pregnant women

    and children)

    ; It is a relatively less expensive method than others such as MRI (see below)

    ; Below is a sample CT image. Notice the bone is white, and there is very little

    difference between the brain's gray and white matter

    ; In summary, the color relationship between the amount of attenuation and

    the density of the tissue is as follows:

    Computer Aided Tomography (CAT) later got shortened to Computer Tomography (CT). These devices (used to) consist of an X-Ray source and a sensor opposite each other and separated by enough space to fit a human body.

    An object is scanned by shooting a tightly focused beam of low intensity X-Rays through it from the source and sensing the strength of the remainder beam after it goes through the object. The whole contraption then rotates a little bit (say, one degree) and the process repeats. Once the scanner collects a bunch of these readings a computer munches on them and eventually it spits out a graphical representation of the “slice”. The object is then moved up a little bit (say, one centimeter) and the whole thing starts all over again. Once the procedure is done and all the slices have been computed, you have a stack of slices that can be used to “view” the insides of people without ever invading their bodies (’cept for the radiation, of course but

    even that represents a much lower dose than is normally dispensed via traditional X-ray procedures). The name tomography refers to the fact that the scanner computes a “slice” of the scanned object, not just a flat image. Each slice really is a volumetric (tomo-) image (-graphy) made up of “voxels.” Each voxel

    represents a three-dimensional cube of the slice.

MRI

    MRI uses magnetic fields and radio waves to produce high-quality two- or three dimensional images of brain structures without injecting radioactive tracers.

    In the procedure, a large cylindrical magnet creates a magnetic field around the research volunteer's head, and radio waves are sent through the magnetic field. Sensors read the signals and a computer uses the information to construct an image. Using MRI, scientists can image both surface and deep brain structures with a high degree of anatomical detail, and they can detect minute changes in these structures that occur over time. Within the last few years, scientists have developed techniques that enable them to use MRI to image the brain as it functions. Functional MRI (fMRI) relies on the magnetic properties of blood to enable scientists to see images of blood flow in the brain as it is occurring. Thus researchers can make "movies" of changes in brain activity as patients perform various tasks or are exposed to various stimuli. An fMRI scan can produce images of brain activity as fast as every second, whereas PET usually takes 40 seconds or much longer to image brain activity. Thus, with fMRI, scientists can determine with greater precision when brain regions become active and how long they remain active. As a result, they can see whether brain activity occurs simultaneously or sequentially in different brain regions as a patient thinks, feels, or reacts to experimental conditions.

    An fMRI scan can also produce high-quality images that can pinpoint exactly which areas of the brain are being activated. For example, fMRI can produce an image that distinguishes structures less than a millimeter apart, whereas the latest commercial PET scanners can resolve images of structures within 4 millimeters of each other.

    In summary, fMRI provides superior image clarity along with the ability to assess blood flow and brain function in seconds. To date, however, PET retains the significant advantage of being able to identify which brain receptors are being activated by neurotransmitters, abused drugs, and potential treatment compounds.

SPECT

    Similar to PET, this imaging procedure also uses radioactive tracers and a scanner to record data that a computer uses to construct two- or three-dimensional images of active brain regions.

    Generally, SPECT tracers are more limited than PET tracers in the kinds of brain activity they can monitor. SPECT tracers also deteriorate more slowly than many PET tracers, which means that SPECT studies require longer test and retest periods than PET studies do. However, because SPECT tracers are longer lasting, they do not require an onsite cyclotron to produce them. SPECT studies also require less technical and medical staff support than PET studies do. While PET is more versatile than SPECT and produces more detailed images with a higher degree of resolution, particularly of deeper brain structures, SPECT is much less expensive than PET and can address many of the same drug abuse research questions that PET can.

PET

    Positron emission tomography (PET) is a nuclear imaging modality that provides investigators with data on biochemical and physiologic functions in vivo. PET is based on the detection of gamma radiation that is produced when a positron emitted by an unstable radionuclide collides with an orbital electron surrounding matter which causes an annihilation reaction. Each annihilation reaction results in the conversion of a positron/electron pair of two kiloelectron-volt gamma rays that travel outward in directly opposing paths.

    Positron emission tomography combines the expertise of medicine, chemistry, physics, and physiology with computer technology to study the function of organs such as the heart and brain. When you have a PET scan, small amounts of common substances that your body uses -such as water or sugar- are made radioactive and injected into your blood stream through an intravenous (IV) tube that is placed in a vein in your arm. You should not experience any discomfort from this material. The way these radioactive substances are distributed throughout your body depends on how your different organs are functioning. The slight radioactivity in the substances is there to provide a way to trace where the substances move. The PET scanner's sensitive radiation detectors measure the location of the radioactive substances in your body. A computer translates the information into pictures that provide information on an organ's function.

    The method of using small amounts of radiactive material is often preferable in cases where organ function must be measured. Other tests, such as x-ray or contrast dye, show the outline of the organ but not its function.

    PET measures emissions from radioactively labeled chemicals that have been injected into the bloodstream and uses the data to produce two- or three-dimensional images of the distribution of the chemicals throughout the brain and body.

    PET studies involve use of a machine called a cyclotron to "label" specific drugs or analogues of natural body compounds, such as glucose, with small amounts of radioactivity. The labeled compound, which is called a radiotracer, is then injected into the bloodstream, which carries it to the brain. Sensors in the PET scanner detect the radioactivity as the compound accumulates in different regions of the brain. A computer uses the data gathered by the sensors to construct multicolored two- or three-dimensional images that show where the compound acts in the brain.

    Using different compounds, PET can show blood flow, oxygen and glucose metabolism, and drug concentrations in the tissues of the working brain. Blood flow and oxygen and glucose metabolism reflect the amount of brain activity in different regions and enable scientists to learn more about the physiology and neurochemistry of the working brain.

    In drug abuse research, PET scans are being used to identify the brain sites where drugs and naturally occurring neurotransmitters act, to show how quickly drugs reach and activate a neural receptor, and to determine how long drugs occupy these receptors and how long they take to leave the brain. PET is also being used to show brain changes following chronic drug abuse, during withdrawal from drugs, and while the research volunteer is experiencing drug craving. In addition, PET can be used to assess the brain effects of pharmacological and behavioral therapies for drug abuse.

EEG

    Electroencephalography uses electrodes placed on the scalp to detect and measure patterns of electrical activity emanating from the brain.

    In recent years, EEG has undergone technological advances that have increased its ability to read brain activity data from the entire head simultaneously.

    EEG can determine the relative strengths and positions of electrical activity in different brain regions. By tracking changes in this activity during such drug abuse-related phenomena as euphoria and craving, scientists can determine brain areas and patterns of activity that mark these phenomena. The greatest advantage of EEG is speed-it can record complex patterns of neural activity occurring within fractions of a second after a stimulus has been administered. The biggest drawback to EEG is that it provides less spatial resolution than fMRI and PET do. As a result, researchers often combine EEG images of brain electrical activity with MRI scans to better pinpoint the location of the activity within the brain.

    ; Rostral/Caudal or Anterior/Posterior: Used to locate coronal sections.

    ; Dorsal/Ventral or Superior/Inferior: Used to locate horizontal sections.

    ; Medial/Lateral: Used specifically to locate saggital sections, but in general to

    differentiate between the center and the edge. The half-way saggital section is

    known as the midsaggital cut.

    MEG is a completely noninvasive, non-hazardous technology allowing for functional imaging of the brain's electrophysiology at a millisecond temporal resolution. Localization of electrical activity has an accuracy of approximately 2 mm. MEG measures the intercellular currents of the neurons in the brain giving a direct information about the brains activity, spontaneously or to a given stimulus. Measurement preparation and collection times are relatively short and can be performed by a technician with a minimum of training.

    Other brain imaging technologies include EEG, x-ray computed tomography (CT), MRI, PET, and SPECT, which generally measure anatomy or blood flow, neither of which gives direct information about brain function. EEG, which shares MEG's fine temporal resolution, cannot accurately localize sources, unless electrodes are placed on the cortex itself. For comparison, the following is a list of imaging techniques contrasted to MEG:

Magnetic Resonance Imaging (MRI)

    ; Gives anatomical information, no information about function.

    ; Possible hazard, especially to children or pregnant women, due to high RF and magnetic fields.

    ; Cost of equipment comparable to MEG.

    ; Cost of procedure comparable to MEG.

    Computed Tomography (CT)

    CT has a limited role in the investigation of partial epilepsy because MRI is superior to CT in demonstrating brain tumors, vascular malformations, and focal brain atrophy. The diagnostic value of MRI in visualizing mesial temporal sclerosis and atrophy is under study. MRI is useful postoperatively to assess the extent of surgical resection.

    ; Gives anatomical information, no information about function.

    ; Possible hazard, especially to children or pregnant women, due to x-rays.

    ; Cost of equipment comparable to MEG.

    ; Cost of procedure comparable to MEG.

    Electroencephalography (EEG)

    EEG displays the electrical activity of the brain. Nerve cells in the brain are constantly creating very small electrical signals, whether a patient is waking or sleeping. EEG techniques such as depth or subdual

    electrode recordings, which are used at present to locate the seizure-provoking area.These invasive methods carry some risk, their use requires considerable expertise and, above all, they cause discomfort and inconvenience to the patient.

    ; Measures electrophysiology of extracellular currents. The patten of extracellular current flow is

    affected singnificantly by he differing electrical conductivity properties of the brain, cerebrospinal

    fluid, skull, and scalp.

    ; Localization accuracy is impaired by distortions created by the conductivity of the scalp and

    inhomogeneous tissue conductivity.

    ; Time consuming to place and localize large numbers of electrodes. Compared with EEG, MEG is

    a much faster technique: instead of first pasting a set of electrodes on the scalp, requiring at least

    half an hour, the subject's head is just put inside the helmet.

    ; Sensitive to both radial and tangential current sources. MEG signals reflect current flow in the

    apical dendrites of pyramidal cells oriented tangential to the skull surface, EEG reflects both

    tangential and radial activity.

    ; Cost of equipment much less than MEG.

    ; Cost of procedure more than MEG (long preparation time).

    Subdural Electrocorticography (ECoG)

    ; Measures electrophysiology of extracellular currents.

    ; Highly invasive technique suitable for clinical cases only.

    ; Possible hazard due to need for general anesthetic and surgical procedure.

    ; Sensitive to both radial and tangential current sources.

    ; Cost of equipment less than MEG.

    ; Cost of procedure much more than MEG (craniotomy required).

    Stereotactic Electroencephalograph Potentials (SEEP)

    ; Measures electrophysiology of extracellular currents.

    ; Highly invasive technique suitable for clinical cases only.

    ; Possible hazard due to need for general anesthetic and surgical procedure.

    ; Sensitive to both radial and tangential current sources.

    ; Cost of equipment less than MEG.

    ; Cost of procedure much more than MEG (craniotomy required).

    Functional Magnetic Resonance Imaging (fMRI) fMRI is a new application of MRI technology that allows the study of functional activity in the brain. Localized intrinsic signal changes that correlate with increases in neuronal activity are non-invasively detected allowing the acquisition of high resolution images that are dependent on brain activity rather than anatomy.

    ; Measures blood flow or blood volume, rather than electrophysiology.

    ; Does not allow for spontaneous measurements of Alpha rhythms etc.

    ; Does not allow for millisecond time resolution.

    ; Possible hazard, especially to children or pregnant women, due to very high RF and high magnetic

    fields.

    ; Cost of equipment comparable to MEG.

    ; Cost of procedure comparable to MEG.

    Positron Emission Tomography (PET)

    PET measures regional cerebral metabolism and blood flow. PET imaging has been quite successful in identifying the focus as an area of hypometabolism between attacks. This observation may be used in selecting patients with partial and secondarily generalized seizures for resective surgery. Because of the high costs and complexities of PET, this technology has been confined to a limited number of centers.

    ; Measures metabolism of oxygen or sugar, rather than electrophysiology.

    ; Does not allow for spontaneous measurements of Alpha rhythms etc.

    ; Does not allow for millisecond time resolution.

    ; Possible hazard, especially to children or pregnant women, due to ionizing radiation from ingested

    radionuclides.

    ; Measurements cannot be repeated, after annual maximum dose is reached (generally one

    examination)

    ; Cost of equipment much greater than MEG (to perform PET a cyclotron or other accelerator is

    required).

    ; Cost of procedure much greater to MEG (five or more Ph.D. level staff are required to operate

    cyclotron, make radiopharmaceuticals and measure patients).

Single Photon Emission Computed Tomography

    (SPECT)

    SPECT can also be used for functional imaging of the brain because it demonstrates regional cerebral blood flow, which is linked to cerebral metabolism and can therefore be used to identify the epileptic focus. SPECT uses conventional and readily available equipment and radiopharmaceuticals. These compounds can be used to study both ictal and interictal states. In the past decade, this relatively affordable technology has become widely available. More work is needed to determine whether SPECT is as sensitive as PET in localizing the epileptic regions.

    ; Measures blood flow, rather than electrophysiology.

    ; Does not allow for spontaneous measurements of Alpha rhythms etc.

    ; Does not allow for millisecond time resolution.

    ; Possible hazard, especially to children or pregnant women, due to ionizing radiation from ingested

    radionuclides.

    ; Cost of equipment less than MEG.

    ; Cost of procedure comparable to MEG.

    Regional Cerebral Blood Flow (rCBF)

    ; Measures blood flow, rather than electrophysiology.

    ; Does not allow for spontaneous measurements of Alpha rhythms etc.

    ; Does not allow for millisecond time resolution.

    ; Possible hazard, especially to children or pregnant women, due to ionizing radiation from ingested

    radionuclides.

    ; Cost of equipment less than MEG.

    ; Cost of procedure comparable to MEG.

    Mind-reading, that staple of science fiction, is inching closer to science fact, thanks to steady progress in the field of brain imaging. In the last few years, neuroimagers have established a new technology while fine-tuning an older one. They are now building more powerful machines and beginning to make headway against their ultimate challenge--determining the order in which brain regions become activated as a person thinks, moves, senses, and learns. Until now, brain scans have been subject to the neural equivalent of physics' Heisenberg uncertainty principle: They could detect the areas or the timing of neural activation, but not both.

    "It's a really exciting field," says Stephen Koslow, director of the division of basic and clinical

    neuroscience at the National Institute of Mental Health. While cautioning that "we're not going to get some early definitive answers," he adds, "We all believe there's great potential and are quite happy to fund" grant proposals involving brain-imaging technology. Purchases of brain scanners, which cost more than $1 million apiece, are not covered by federal grants, but the National Institutes of Health's National Center for Research Resources has funded up to $400,000 worth of improvements to existing machines. The two main technologies used in brain-imaging research are positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI) with blood-oxygen-level- dependent (BOLD) contrast. PET machines first appeared in 1974. There are now about 360 worldwide, most of which are used clinically, according to Ronald Nutt, technology director of CTI Inc. in Knoxville, Tenn., which produces such units. Seiji Ogawa, a biophysicist at AT&T Bell Laboratories in Murray Hill, N.J., discovered fMRI-BOLD in 1988 (S. Ogawa et al., Magnetic Resonance in Medicine, 14:68-78, 1990). The current prevalence of this

    technology is impossible to gauge, but Diar Shipman, a marketing manager at General Electric Medical

    Systems-Americas in Waukesha, Wis., says that about 800 of the MRI machines installed by his firm in the last three years had BOLD capability.

    With its longer history, PET boasts the richer scientific literature, but fMRI has prompted much of the recent buzz in the imaging field. Nurtured by researchers at a handful of institutions in the early 1990s, it has become a common tool only since 1995. "Just about every major medical center is trying to come up to speed," says Joy Hirsch, an fMRI pioneer at Memorial Sloan-Kettering Cancer Center in New York. A

    major reason for the spread of fMRI is that it can be run on the magnetic resonance imagers already owned

    by hospitals. But additional hardware and software are needed, and the expertise to run these systems is not yet widely available.

    In addition to neuroscientists, physicists and computer professionals are being tapped as more federal dollars pour into fMRI research. Opportunities in the smaller PET field are expected to grow as a result of recent federal legislation. The Food and Drug Administration (FDA) Modernization Act of 1997 incorporates provisions (sections 121 and 122) prompting FDA to "come up with less burdensome [PET] regulations," says Jane Axelrad, associate director for policy at FDA's Center for Drug Evaluation and

    Research.

    Both fMRI and PET rely on the fact that more blood is routed to brain regions where neurons are active. The signals triggering increased blood flow are unknown, and reasons for the increase are hotly debated. It is still unclear, for example, whether active neurons need more blood-delivered oxygen (M. Barinaga, Science, 276:196-8, 1997).

    Researchers using PET typically inject water or butanol containing oxygen-15 into the bloodstream. In the blood, the isotope ejects positrons that collide with their anti-particles, electrons, creating high-energy photons. These travel to radiation detectors placed around the head, and the resulting images, color-coded by computers, indicate areas of increased blood flow.

    A more convoluted process generates the fMRI signal. In areas of neural activity, blood levels of oxyhemoglobin increase since active neurons use little if any of the extra oxygen available to them from heavier blood flow. A corresponding drop in deoxyhemoglobin levels, however, weakens an effect that a strong magnetic field has on the "spin" of hydrogen protons in and around the blood vessel. A magnetic resonance imager detects a higher resonance signal that results from the weakening of that effect. The outcome of fMRI "is not an image that relates in any way--at least, in any direct way--to a physiological parameter" like blood flow, says Peter Fox, director of the Research Imaging Center at the

    University of Texas Health Science Center at San Antonio. Other neuroimagers note the artifacts that can afflict fMRI studies. For example, some brain areas, such as those at air-tissue interfaces, don't generate signals.

    Nevertheless, Fox, a veteran PET researcher, concedes that "the more that we can move work onto fMRI, the better. It's more widely available, and it doesn't require radiation." He himself uses fMRI to identify "task-induced" changes in the brain.

    Unlike Fox, a number of former PET researchers have switched their allegiances entirely to fMRI. Though scientists in academia and industry agree that PET is the best imaging tool for examining metabolism and drug binding in the brain, some of its drawbacks are unavoidable. The use of short-lived radioisotopes is expensive (an on- site cyclotron is needed), and experiments are cramped because subjects can be injected with only limited amounts of radioactive tracer.

    Super-Scanners

    PET is less sensitive than fMRI, meaning that its signal-to-noise ratio is lower--there's more static--and that its images suffer from poorer spatial resolution--they're blurrier. Newer PET scanners and techniques exhibit improved sensitivity, and a machine making its debut this summer may largely erase present imaging deficiencies.

    Developed by CTI and Siemens Medical Systems Inc. of Iselin, N.J., the High Resolution Research Tomograph (HRRT) should be shipped to a European laboratory this June, according to CTI's Nutt. This noncommercial system will have 119,808 detectors, far more than the 18,000 found in PET machines now in common use. Each detector will harbor a crystal of lutetium orthooxysilicate, a fast-acting, high-output scintillator. Current scanners have 4 mm resolution, but HRRT should be able to distinguish active brain areas that are 2 mm apart. Compared with current machines, HRRT should be four times more sensitive to radioactivity, and its signal-to-noise ratio should double.

    To achieve super-scanning, fMRI researchers have been steadily boosting the strength of the magnetic fields to which they expose their human subjects. Most fMRI systems generate a 1.5-tesla (T) field, but Kamil Ugurbil, a radiology professor at the University of Minnesota in Minneapolis, notes that many 3-T systems and a handful of 4-T setups are already in operation. The sensitivity afforded by a 4-T system allowed a team, including Ugurbil, to see thin columns in the visual cortex that respond to one eye or the other (R.S. Menon et al., Journal of Neurophysiology, 77:2780-7, 1997).

    High magnetic fields offer another advantage. In studies using 1.5-T fields, subjects perform a task repeatedly so that researchers can detect a clear signal by averaging the faint signals from each trial. Yet

    subjects' performance may not remain consistent across trials, and the brain may respond differently after tasks are repeated. "We have demonstrated that you can see single events at high magnetic fields," says Ugurbil. "Subjects do one execution of a task, and you have a temporally resolved functional-imaging datum as a result of that [4-T trial]." Ugurbil is now installing a 7-T magnet at his research center. An 8-T scanner recently went online at Ohio State University College of Medicine. In October, Pierre-

    Marie Robitaille, the radiology professor who coordinates that facility, spent 10 minutes inside the 77,000-pound, liquid-helium-filled magnet when its field strength was 7.35 T. "I was fine," he recalls. "Once I was in the magnet, I couldn't sense that I was in it at all." In animal studies, high magnetic fields have not yet been found to pose a safety problem. According to Robitaille, the 8-T scanner contains the world's highest-field magnet for human scanning.

    All In The Timing

    Despite improvements in gadgetry, both fMRI and PET suffer from an intractable drawback. They depend on an increase in cerebral blood flow that starts within two seconds of stimulation and takes seven seconds to reach a peak, notes Mark Cohen, an associate professor in the brain mapping division of the University of California, Los Angeles, School of Medicine. Communication between neurons, however, occurs over tens of milliseconds, not seconds. Like long-exposure photographs, fMRI and PET consequently can't establish the order of the events that they depict.

    To sidestep this problem, neuroimagers have evolved strategies that involve existing technologies and combine the results through complex calculations. Using PET, George Mangun, a psychology professor at

    the University of California, Davis, and his colleagues localized brain activity associated with spatial attention. Then they clocked that activity at 80 to 130 milliseconds by recording event- related potentials, which are averaged from electroencephalograms (EEGs) taken from the scalps of subjects (H.J. Heinze et al., Nature, 372:543-6, 1994). Mangun is now trying the same strategy with fMRI instead of PET.

    EEGs promptly detect electrical currents in the brain, while magnetoencephalographs (MEGs) promptly register the magnetic effects of these currents. Recently, Anders Dale, a Harvard Medical School radiology

    professor, and his colleagues showed words to subjects and, using fMRI for localization and MEG for timing, found that brain activity in the visual cortex began 100 milliseconds after word presentation. The activity spread within 50 milli- seconds to frontal and temporal lobes of the cortex. "By combining the two methods, we get the movie, if you will, of activation," says Dale.

    Combining methods, however, does not strike Keith Thulborn, a radiology professor at the University of

    Pittsburgh Medical Center, as "an intrinsically elegant approach." Preferring to "get both spatial and temporal information out of a single signal," Thulborn has adapted fMRI so that it detects magnetic changes associated with sodium ions, not hydrogen protons. These ions generate signals almost immediately upon moving across the membranes of active neurons. Thulborn has gotten sodium imaging to work when subjects see an image repeatedly flashed for 10 minutes; he is now trying to show it works with brief stimuli. Last winter, his lab also succeeded in generating phosphocreatine images of the brain. To secure better temporal resolution, Gabriele Gratton and Monica Fabiani, assistant professors in the

    psychology department at the University of Missouri in Columbia, have dispensed with fMRI and PET altogether. Their $40,000 system shines near-infrared light on a subject's head. After the light has passed through the brain, it is detected by 16 optic fibers placed against the skull. Neural activity up to 1.5 centimeters below the surface of the cortex scatters the light, generating an immediate signal, according to Gratton. The spatial results yielded by his technique agree with those provided by fMRI, while its temporal findings are consistent with event-related potentials, the EEG-derived method (G. Gratton et al., NeuroImage, 6:169-80, 1997).

    "The major challenge for these techniques is to go beyond the idea that the brain has individual structures that do individual things," says Memorial Sloan-Kettering's Hirsch, who collaborated with Gratton. "We must look at the integration of those individual little functional departments in terms of coordinated assemblies that actually do complex tasks. That is the very exciting challenge of the next few years."

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    When a patient is wheeled into the emergency room at Massachusetts General Hospital in Boston with partial paralysis or slurred speech--classic symptoms of a stroke--doctors waste no time. First stop is the magnetic-resonance-imaging machine on the second floor, a three-minute wheelchair ride away. Routine patients are yanked out of the scanner so the patient can get an urgent brain MRI. In 10 to 12 minutes, doctors know whether they are dealing with a stroke or another problem such as migraine or seizure. They also know which area of the brain is at risk. "Time is brain," says Lee Schwamm, a neurologist and assistant director of the acute-stroke service at the hospital. "The faster we can diagnose and start treatment, the more brain we save."

    Until very recently, that race to the scanner would have been fruitless. Neither CT scans (for computed tomography) nor regular MRI scans could reveal stroke quickly, and difficulty in diagnosis is one reason why stroke remains the third-leading cause of death and the primary cause of serious disability in the United States, leaving 3 million survivors unable to work or take care of themselves. Now a new MRI technique, recently approved by the Food and Drug Administration, "has really revolutionized how we take care of patients," Schwamm says. Known as diffusion-weighted imaging, it is the first major clinical application of functional magnetic resonance imaging, a technology that promises to transform our understanding of the workings of the human brain. "The technology is driving the science," says Alan Leshner, director of the National Institute on Drug Abuse, which funds functional MRI research. "That's different. Before, the questions didn't occur to us because we didn't have the technology to answer them. Now the technology is raising the questions."

    Picture perfect. Magnetic resonance imaging, which uses electromagnetic fields and radio waves to read minute shifts in the magnetic alignment of protons within the body, has been used in medicine since the early 1980s and has become indispensable thanks to its ability to picture soft tissues without subjecting patients to radiation or surgery. But those pictures reveal structures themselves--livers, brains, kidneys--and do not show how the structures work. Since disease is often an abnormality of function, regular MRIs can tell only so much.

    That lack of functional information has been particularly frustrating in observing the brain. Armored by the skull, it resists exploration and is so sensitive that poking into it can destroy speech, vision, and other key faculties. Neurologists often found out what was wrong only when they autopsied a patient. Other imaging techniques, such as PET (positron emission tomography) and SPECT (single photon emission-computed tomography), are limited because they take longer to produce a scan and can't be used repeatedly because they involve radioactivity.

    A better tool began to emerge in 1991, when Ken Kwong and Jack Belliveau at the imaging laboratory at Massachusetts General demonstrated that an MRI could be used to reveal not just structure but function as well. They did this by relying on a fact of physiology known since the 1880s: When a part of the brain is working, the blood flow to that area increases. By using a powerful MRI unit that could make a single-plane scan in 100 milliseconds, they could detect how oxygen levels changed with blood flow and track those changes over time. PET imaging had been used to track such changes before, but the new MRI techniques could assemble a functional brain image with better spatial resolution and do it much faster--a whole brain in two to six seconds, compared with one minute for a PET scan. And the MRI could be repeated within seconds; with PET, it takes nine minutes for the radiation to dissipate. It was as if scientists had been trying to see the brain through 1950s View-Masters and had just walked into a CinemaScope movie theater.

    Researchers quickly grasped the possibilities. Within a year of the publication of Belliveau and Kwong's findings, hundreds of scientists around the world were devising functional MRI experiments. The shift has been particularly abrupt in cognitive neuroscience, which explores the chemical underpinnings of mental activity. Before fMRI--medical shorthand for functional imaging--a cognitive neuroscientist might spend a year coaxing a monkey to perform a simple task, then record a smidgen of brain activity with an electrode. "I got so tired of killing monkeys for a living," says Roger Tootell, a neuroscientist who studies vision at Mass General. Now he mainly just slides human volunteers into "the magnet." There, subjects spend two hours staring at patterns projected on a tiny screen overhead, while the MRI records their brain activity, then spits out colorful 3-D pictures of the mind at work.

    Nothing to sneeze at. Of course, it's not quite that easy. An ultrapowerful MRI capable of functional imaging costs $2 million or more. Researchers pay $439 an hour to use one, and most researchers compete with clinical users for magnet time. Because correlation among the 3-millimeter-thick "slices" an MRI takes is crucial to create a 3-D image, a sneeze or a 1-millimeter twitch can wreck a whole session, so volunteers are packed in foam rubber or asked to chomp on custom-molded bite plates to minimize

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