Functional Magnetic Resonance Imaging of the Brain

Dr. Denis Le Bihan (Diagnostic Radiology Department, The Warren G. Magnuson Clinical Center, National Institutes of Health [NIH], Bethesda, Maryland): We review the basic principles and potential applications of functional magnetic resonance imaging (fMRI) of the brain. In fMRI, scientists and clinicians from many disciplines have a new tool at their disposal that enables them to discover, in vivo and noninvasively, where in the brain normal or abnormal cognitive processes take place. Like positron emission tomography (PET), fMRI is based on the tight relation among neuronal synaptic activity, energy metabolism, and blood circulation, as was suggested at the end of the last century by Roy and Sherrington [1]. However, some of the limitations PET has for brain activation studies are overcome by MRI. First, MRI is completely noninvasive and does not use ionizing radiation; thus, it allows for repeated studies on individual persons. Second, PET facilities are few, but many MRI units are available for patient scanning. Finally, MRI can be used to obtain images with a resolution of better than 1 mm in less than one tenth of a second. Fast imaging methods, such as echoplanar imaging (EPI) [2], can now run on clinical MRI units and provide images of the working brain almost in real time. Activation images obtained with the Oxygen-15-labeled water PET technique take at least 40 seconds and have a resolution of better than 4 mm. Belliveau and colleagues [3] were the first to show that MRI could be used for activation studies. One can obtain images of blood volume by injecting a bolus of paramagnetic contrast agent, such as gadolinium diethylene triamine pentaacetic acid, into the bloodstream. Using this approach, Belliveau and colleagues obtained images of blood volume before and during stimulation with a flashing light and showed that the blood volume of the primary visual cortex increased during stimulation. This approach constituted a significant breakthrough but had several limitations, one of which was that it required the use of an external contrast agent. On the basis of earlier works describing the magnetic properties of hemoglobin [4] and the effect of these properties on the magnetic resonance signal [5], it was recently suggested that deoxyhemoglobin (which is paramagnetic, although oxyhemoglobin is not) in erythrocytes could be used as an endogenous source of contrast material [6, 7]. Kwong and colleagues [8], soon followed by others [9, 10], showed that MRI could be used to monitor in real time the local modulation of the level of blood oxygenation associated with brain activity. After a brief overview of the principles of MRI and fMRI, we review the first applications of fMRI in the visual and sensorimotor systems and in some cognitive tasks, such as language, memory, and behavior. Finally, we summarize the potential clinical applications of fMRI and review the current limitations of this technique and current issues in its research. Functional Magnetic Resonance Imaging of the Brain: Principles Dr. Peter Jezzard (Laboratory of Cardiac Energetics, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland): The nuclear magnetic resonance effect, first shown in the 1940s, is the result of the magnetic properties of some atomic nuclei, especially hydrogen nuclei from water molecules. When a person is placed in an MRI scanner, the magnetic fields from the hydrogen nuclei orient themselves along the strong magnetic field of the scanner. This orientation may be disturbed by exciting those nuclei with a burst of electromagnetic energy in the form of radiofrequency pulses. The nuclei then realign themselves by transmitting a radiofrequency signal that can be detected in a receiver coil placed around the patient's head. The frequency of the signal depends on the strength of the scanner's magnetic field; by causing the strength of this magnetic field to vary spatially, the resulting signal reflects the magnetization of water molecules at each point in space, thus producing an image [11]. An increasingly popular MRI technique, used extensively for brain scans, is EPI [2], which can efficiently sample the spatial information of the object after a single excitation of the water molecules. In this way, all data needed for an image can be obtained in less than 100 milliseconds, whereas a more conventional imaging sequence would take several tens of seconds (images resulting from the latter process would, however, have greater spatial resolution). This type of fast sequence is particularly useful for sampling large portions of the brain many times at short intervals to monitor brain activity. The most commonly used fMRI technique relies on a subtle increase in signal intensity in the regions activated during neuronal stimulation, which can be enhanced in a carefully designed experiment. The cause of this small increase in intensity is ascribed to a local change in the blood oxygenation balance that results from the neuronal stimulation. It has been known for many years that deoxyhemoglobin is magnetically different from oxyhemoglobin [4, 5] and that, in the case of blood passing through tissue, the presence of deoxyhemoglobin creates point magnetic inhomogeneities within the blood vessels that result in microscopic field distortions around the vessels. The coherence of the signal from hydrogen nuclei in water in surrounding tissue is partially destroyed by those microscopic inhomogeneities, and, thus, the signal intensity is lower than it would be if they did not exist. During neuronal activity, local metabolism increases and local blood flow increases substantially, more than compensating for the demand for extra oxygen caused by the neuronal activity [12]. As a result, the local concentration of deoxyhemoglobin decreases, and the signal in those regions increases in intensity. Experiments have been done at various scanner field strengths (most clinical MRI systems range from 0.5 to 1.5 tesla). At NIH and numerous other sites, researchers have access to even higher field strengths for studies of humans (>3 tesla), which allows field strength to be compared. Because the MRI effect during neuronal stimulation has been shown to increase linearly and quadratically with field strength, high field strength is desirable, although it causes more technical difficulties. In a typical fMRI study, many images are collected at intervals of a few seconds over a period of several minutes to improve the statistical reliability of the data. An idealized time plot from a region of the brain in which signal changes occur is shown in Figure 1. The signal changes correspond to the applied stimulus but are somewhat delayed and smeared by the hemodynamic response of the patient. Figure 1 also shows an actual time course from a point located in the primary visual cortex during a visual stimulation study in which a flashing light stimulus was presented to the patient for periods of 30 seconds alternated with 30 seconds of rest. If statistical correlation or other statistical techniques are used, the data can be analyzed point by point to map regions of brain function. Figure 1. Time plots from a region of the brain in which signal changes occur. Top. Bottom. Functional Magnetic Resonance Imaging of the Human Brain: Visual Neuroanatomy Dr. James Haxby (Section on Functional Brain Imaging, Laboratory of Psychology and Psychopathology and Pathology, National Institute of Mental Health [NIMH], NIH, Bethesda, Maryland): An extensive body of literature on visual neuroanatomy and neurophysiology in nonhuman primates provides a detailed guide for directing functional brain imaging investigations of human vision [13, 14]. Functional brain imaging studies of the human visual cortex, done using PET, have shown it to have substantial homology with the visual cortex in nonhuman primates. Fox and colleagues [15] showed the retinotopic organization of receptive fields in the human primary visual cortex. In the extrastriate cortex, PET studies have identified an area in the lateral occipitotemporoparietal cortex that responds selectively to visual motion [16-18] and that may be the human homolog of the middle temporal/middle superior temporal complex (MT/MST, also called V5) in the macaque (Macaca mulatta). In the lingual gyrus, an area that is selectively activated by viewing colored stimuli or selectively attending to color has also been identified [16-18]. Many of the early fMRI studies were done on the human visual cortex [3-8]. More recent studies have taken advantage of superior spatial resolution to generate more detailed maps of the retinotopic organization of the primary visual cortex [19]. Additional representations of the visual field obtained by mapping retinotopy in individual brains have suggested the locations of early extrastriate regions. The area that responds selectively to visual motion has also been identified using fMRI [20]. This study showed that stimuli with low luminance contrast were as effective as high-contrast stimuli in activating this area; striate cortex, however, showed different responses to low- and high-contrast stimuli. This finding is consistent with the neurophysiology of area MT (middle temporal area) and further corroborates the homology between the human and nonhuman primate visual motion areas. This study also shows that MRI can continually measure the strength of response, thereby allowing studies of the effects of varying stimulus measures that may distinguish visual areas from one another. Studies with PET have also shown that the human visual extrastriate cortex, like that of the M. mulatta, appears to be organized into a ventral, occipitotemporal stream associated with the visual identification of objects and a dorsal, occipitoparietal stream associated with perception of the spatial relation among objects and with visual guidance of movements toward objects [21]. My colleagues and I have shown [22, 23]