EDITORIALS

Magnetic Resonance Imaging of Brain Function

There is increasing interest among neurologists, psy- chologists, and psychiatrists in a group of new methods for mapping brain function deriving from magnetic res- onance imaging (MRI), which has been so successful during the last decade in the depiction of brain anat- omy and pathology. The new methods promise an un- paralleled combination of spatial and temporal resolu- tion, together with freedom from radiation hazard and the opportunity to study single subjects as often as desired. As with any new technology, however, the claims must be examined with care, the limitations must be fully understood, and standards of good prac- tice need to be established.

MRI of brain function, variously known as functional MRI (fMRI) or magnetic resonance functional neuro- imaging (MRFN), has been an attractive possibility for perhaps a decade. Because, by contrast with x rays, MRI mainly “sees” soft tissue, specifically the water content of tissue, it is in principle sensitive to any changes in the environment of cerebral water mole- cules that may arise from neural activity. However, the major source for such changes is variations in blood flow and because the blood volume in brain is less than 5%, it was clear from an early stage that functionally related changes in MR images of the brain were likely to be small.

The earliest successful fMRI study [ 11 used an intra- vascular tracer, in this case a paramagnetic chelate of gadolinium (Gd-DTPA), which creates nonuniformity in the magnetic field surrounding the vessels, and hence reduces the MR image intensity obtained with imaging sequences sensitive to field inhomogeneity. The loss of signal is roughly proportional to the quan- tity of contrast agent. Typically, a bolus of contrast agent is rapidly injected into a leg vein. Images of the brain are subsequently acquired at 1-second intervals as the bolus passes through, using the ultrafast echo- planar imaging technique (EPI) 12, 31. Integration of .he attenuation versus time in a given pixel allows itimation of the relative blood volume in that pixel, , tissue with larger blood volume shows a greater :ening. Comparison between a blood volume map 1 with the brain at rest and one where the subject 1 a flickering array of light-emitting diodes re- ie expected increase in blood volume in the

that deoxyhemoglobin is also more paramag- tissue or oxygenated blood [4}, Ogawa and

(51, and Turner and associates {bl made iimals using trials affecting blood oxygen-

visual cortex.

ation, such as anoxia, and found that gradient-echo MR images showed very clear changes in intensity, corre- lating well with the overall concentration of deoxyhe- moglobin, which acts as a natural MRI contrast agent. Because the magnetic field inhomogeneity surrounding deoxygenated vessels extends well beyond the vessel radius, the magnitude of this blood oxygenation level- dependent (BOLD) contrast can be a good deal larger than the small blood volume might suggest, and in this way a robust method for observing blood oxygenation changes came into being.

Kwong and colleagues [7] were the first to demon- strate that the oxygenation changes in cerebral blood concomitant with human brain functional activity could be detected with this technique. The observed tran- sient hyperoxemia results from the not yet fully under- stood propensity for regional changes in cerebral blood flow (CBF) to greatly outweigh local changes in oxygen uptake {8}, a fact observed directly by neurosurgeons who have watched the blood locally flush pink in the superficial cerebral vasculature of conscious open-skull patients engaged in brain tasks during surgical plan- ning. Functionally induced oxygenation changes appear as “intrinsic signals,” which have been studied optically through cranial windows in animal models 191. In hu- man brain, it appears to take between 5 and 10 seconds for the blood flow and oxygen uptake to reach new equilibria after initiation of a brain task. This represents an inherent limitation on temporal resolution for fMRI.

In Kwong’s {7] initial experiment human subjects were given visual stimulation for intervals of 30 sec- onds, alternating with 30-second rest periods, while a slice of brain passing through the calcarine cortex was imaged at 3-second intervals, using gradient-echo EPI. He observed a rise in signal, nicely synchronized with the periods of visual stimulation and restricted spatially to gray matter regions expected to lie within primary visual cortex. Similar experiments were performed at about the same time by Ogawa and colleagues {lo] at the University of Minnesota, using a slower imaging technique (Turbo-FLASH) but an MRI system op- erating at the higher magnetic field of 4.0 T. Their results amply confirmed those of Kwong and col- leagues [7].

Since then there has been a flood of experimental work. It has been demonstrated that neither EPI nor the use of unusually high magnetic fields is essential for the effect to be observable, although both of these assist considerably in obtaining large volumes of data

Copyright 0 1994 by the American Neurological Association 637

rapidly and with good functionally related contrast 111). Simple [12) and complex {13] motor tasks, audi- tory stimulation, cognitive tasks in the form of word generation 1141, and visual imagery 115) have been added to the repertoire of fMRI-observable brain acti- vations. The time for superficial demonstrations of the efficacy of the technique is now over, however, and serious, novel, neuroscientific investigations have be- gun. As an example, the role of the supplementary motor area in motor ideation is examined in an article 116) in this issue of the Annals. A second article in this issue [ 17) has applied fMRI to the study of the human auditory cortex.

Intensive studies of possible artifacts and errors are also underway. The most serious practical problem arises from a virtue of fMRI, i.e., its excellent spatial resolution. Even a tiny, 0.5-mm movement of the head can change the intensity of a boundary pixel by as much as 4096. Because it is not yet quantitative, the technique currently relies on difference experiments, in which the large baseline MR image intensity is sub- tracted out as two conditions are compared. Head mo- tion between conditions results in confusing structure in the difference image, which should be featureless except where blood oxygenation changes have taken place. Fortunately, such misregistration can be cor- rected by comparing the image details, especially if vol- ume information (a set of image slices) is collected at each scan. If there is no out-of-plane motion, single slices can even be reregistered. Tyszka and co-workers 116) are the first to use the powerful and elegant dgo- rithm of Woods and associates [17} to realign their data, greatly enhancing the credibility of their findings.

A further desideratum is correct statistical treatment of fMRI data. In the article of Tyszka and co-workers [16), the F ratio is used, which is appropriate for spoiled gradient-echo images with acquisition times relatively long compared with CBF rise time. For more rapid EPI acquisition, correctly thresholded correlo- grams have been presented by Friston et al{19), which include the effect of temporal smoothness resulting from the slow rise of CBF in response to neural activ- ity. Correct statistical treatment also excludes artifacts due to large cardiac cycle-related changes in major veins {20], which may appear as activation on simple difference images due only to their magnitude.

When used with care, fMRI has a bright future in fundamental neurological research, in surgical planning for epilepsy and tumor excision, in studies of pediatric cognitive development, and in investigation of psychi- atric disorders, including monitoring effects of drug therapy on brain function.

Robert Turner Institute of Neurology, Queen Square University of London, London, UK

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