Use of Functional Magnetic Resonance Imaging

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CEREBRAL BLOOD FLOW

USE OF FUNCTIONAL MAGNETIC RESONANCE IMAGING Christine C. Lee, MSc, Clifford R. Jack, Jr, MD, and Stephen J. Riederer, PhD

Functional magnetic resonance imaging (fMRI) of the brain shares all the appealing features of diagnostic noncontrast MR imaging scans in that it is entirely noninvasive and nonionizing. Rather than emphasizing purely structural information, fMRI uses scanning techniques to sensitize image acquisition to the local metabolic and hemodynamic changes that occur when the brain is activated or stimulated. The ability to image such local areas of function is what makes fMRI a u seful technique. In some ways, perfusion imaging with magnetic resonance in the mid-1980s16• 33-35 was a precursor to fMRI. In perfusion imaging, as in fMRI, signal intensity from a specialized MR imaging sequence is sensitized to reveal local areas of altered brain perfusion. In 1991, a group at the Massachusetts General Hospital (Boston, MA) generated functional magnetic resonance maps of the brain using visual stimulation on a 1.5-T MR imaging system.5 These studies were performed with two separate magnetic resonance contrast media injections and employed a first-pass contrast bolus tracking technique to reveal increased cerebral blood volume (CBV) during task activation. Shortly thereafter, several groups, extrapolating from the pioneering work of Ogawa et al,42 demonstrated task activation with MR imaging using intrinsic contrast- the blood oxy-

genation level dependent or BOLD mechanism.4· 31 · 43 Since then, fMRI has flourished to join the ranks of positron emission tomography (PET), magnetoencephalography (MEG), and electroencephalography (EEG) as a useful technique for noninvasive mapping of brain function. EEG, MEG, and PET employ different means of localizing regional brain activity. EEG and MEG are sensitive to cerebral electromagnetic activity. PET employs an injected radioactive tracer to provide a direct measure of a variety of local hemodynamic and metabolic parameters, including regional cerebral blood flow (CBF), CBV, cerebral metabolic rate of oxygen (CMR02), and cerebral metabolic rate of glucose (CMRgiu). Systematic comparison of the spatial and temporal resolutions of these functional imaging systems with fMRI will provide a better understanding of the emerging clinical significance of fMRI. PET images have a spatial resolution typically around 5 to 10 mm9• 44· 51 and a temporal resolution on the order of minutes. The spatial resolution for MEG is 2 to 3 mm for sources at the cortical surface, and the temporal resolution is on the order of milliseconds.20 The spatial resolution of EEG is more coarse due to the blurring effect of the skull and scalp on electrical conduction. Although MEG has better swface spatial resolution than PET, MEG suffers from poorer

From the Magnetic Resonance Research Laboratory (CCL, CRJ, SJR), and the Department of Diagnostic Radiology (CRJ, SJR), Mayo Clinic, Rochester, Minnesota

NEUROSURGERY CLINICS OF NORTH AMERICA VOLUME 7 • NUMBER 4 • OCTOBER 1996

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depth spatial resolution leading to ambiguity of sources of electrical activity in deep cortical structures. In comparison, fMRI can achieve spatial resolutions as good or better than PET with superior temporal resolution-on the order of seconds. With no need to rely on radioactive tracers or to perform invasive procedures, fMRI allows for unlimited repeatability. Such flexibility and safety, in addition to good spatial and temporal resolutions, make fMRI desirable in the clinical setting. Although the need for more extensive experimental corroboration of fMRI with goldstandard clinical tests is warranted, excellent correlation of fMRI data to known functional cortical organization has already been shown for visual stimuli50 and sensorimotor stimuli (Fig. 1, Color Plate 1). 27, 46, 57 The breadth of its potential utility, including fMRI of deeper brain structures,7 higher cognitive function,28, 39 and the cerebellum,13' 14' 21 has already been explored by many groups. Some groups have tried to follow the effects of drug administration26 as well as the effects of alcohol37 and pain8 on cerebral activity. Neurophysiologic studies have been explored.22,54 The immediate applications of fMRI in neurosurgery, neuropsychiatry, neurophysiology, and neurology include its use in presurgical mapping, language lateralization, memory studies, seizure studies, and drug studies. This article provides a brief description of the science and techniques of fMRI. It then discusses its potential use in the clinical setting.

USING THE SCIENCE OF MR IMAGING TO CAPTURE PHYSIOLOGIC BEHAVIOR

Neuronal activation is closely coupled with local hemodynamic and metabolic changes. Although the "brain versus vein" issue which questions whether fMRI actually captures function at the neuronal (brain) level or at the vascular (vein) level is debated, the spatial proximity of both the electrical and hemodynamic responses provides sufficient specificity needed to use fMRI for brain mapping. Two physiologic phenomena have been exploited to provide contrast for fMRI scans. The most common fMRI technique relies on a relatively small (2%-5%) signal change that occurs due to uncoupling of CBF and oxidative

metabolism following neural activity. Increased local neural activity resulting from specific tasks produces increases of about 50% in CBF and CMRgiu but only minimal increases of about 5% in CMR02 and about 7% in CBV.17,18The key phenomenon is that during neural activation, oxidative metabolism does not increase proportionally (about 5%); in fact, the cerebral oxygen extraction fraction decreases about 31 %. Accordingly, this physiologic response to neural activity sets up a local environment, where there is a transient increase in the concentration of oxyhemoglobin or, equivalently, a decrease in the concentration of deoxyhemoglobin. It is specifically the decrease in the deoxyhemoglobin species that is of interest. The diamagnetic property of oxyhemoglobin stands in contrast to the larger paramagnetic45 feature of deoxyhemoglobin arising from its four unpaired electrons. By imparting susceptibility effects or local field inhomogeneities, protons in the region of paramagnetic species such as deoxyhemoglobin w ill experience greater dephasing in the presence of a magnetic field. This ultimately affects the signal amplitude that is sampled at the time of a gradient refocused echo in MR imaging. Generally, the signal obtained in the presence of deoxyhemoglobin will be smaller than that obtained in the presence of oxyhemoglobin. As described above, activated cerebral tissue causes a decrease in local deoxyhemoglobin concentration, resulting in a relative drop in local field susceptibilities w hich produces a stronger signal (Fig. 2). This forms the basis of image contrast in fMRI. The beauty of this technique is that the contrast is entirely intrinsic. This form of contrast has been termed BOLD contrast.42 Sensitivity to differences in magnetic inhomogeneities is best captured by gradient recalled echo (GRE) scans, and the change in signal amplitude is represented by the change in T2* relaxation rates of the resting brain versus the active brain. Another source of signal in functional imaging arises from regional blood flow. Blood flow-based fMRI has been p erformed with12 and without31 saturating the blood flowing into the imaging slice. By suppressing the signal from static tissue within an imaging plane, inflow of unsaturated blood appears bright relative to the stationary tissue. This change in blood flow is directly related to a change in signal amplitude, but rather than manifesting

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Figure 1. FMRI - Neurosurgical corre lation. lntraoperative photograph of the cortical surface prior to placement of the recording strips (A) and strips on the cortical surface for comparison (B). Four recording strips are seen through burr hole. Three (A, B, and C) are oriented vertically. They have been placed beneath the intact bone with only the inferior-most contact showing through the burr hole. Dis a horizontally oriented T-strip with three middle contacts showing. The patient's nose is on the reader's left, the top of the image is the superior part of the head, and the electrodes in strip D overlie the sylvian fissure and the inferior part of the frontoparietal operculum . The central sulcus was shown by means of cortical stimulation to lie between strips A and B. Therefore, the tumor straddles the inferior portion of the central sulcus. See also Color Plate 1 for Figure 1C, 10.

itself as changes in T2* relaxation rate as is the case in BOLD contrast, inflow contrast is reflected in changes in Tl relaxation rate. Tlweighted MR imaging scans can be used to estimate this change in blood flow . The scanning technique is based on the same general principles as two-dimensional time-of-flight

MR angiography. 29 The initial fMRI studies which were based on this inflow contrast used spin-echo inversion recovery to acquire the functional images.31 A more recent method uses echo-planar imaging (EPI) and signal targeting with alternating radio frequency . This method has been called EPISTAR. 12

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Time Figure 2. In the activated state, the concentration of deoxyhemoglobin (deoxyHb) effectively decreases because of the disparate increase in cerebral blood flow (CBF) compared to the cerebral metabolic rate of oxygen (CMR02 ). This decrease in deoxyHb means that there are less paramagnetic effects from the unpaired electrons in deoxyHb; the transverse magnetization during the activation state is therefore largerthan in the baseline state. Examples of images that one may acquire for both the activated and baseline states are shown. The gross similarity of the two images serves to emphasize the small percent signal change (2% to 5%) that actually creates the contrast. The actual areas of activation are not grossly visible; the local, high signal-intensity in the left hemisphere is caused by a tumor.

The main reasons that most research groups perform £MRI with emphasis on BOLD contrast rather than on inflow contrast are because BOLD effects generally dominate in £MRI scans3' 30 and a priori knowledge of temporal features of the activation-induced CBF change is required in order to capture inflow contrast. In addition, rigorous spatial relationships between the direction of arterial inflow and the brain section being imaged must be maintained in inflow-based fMRI. EPISTAR imaging, for example, is constrained to singleslice data acquisitions. Therefore, BOLD contrast is more commonly used than inflow contrast for practical and logistic reasons. As hardware and software for magnetic resonance systems improve, it is almost certain that sensitivity to both BOLD and inflow contrasts will also improve. fMRI CONSIDERATIONS

logical impetus for fMRI at higher field strengths (B In magnetic resonance physics, Faraday's law would predict that the susceptibility-based signal increases proportionally with (B0 ) 2, and, indeed, increased signal has been observed at higher field strengths.53 Modeling studies and in vivo experimentation reveal an increase in £MRI signal-to-noise ratio (SNR) with increasing field strength. 2, 3z, 40 A number of groups have performed £MRI with good results on MR imaging scanners, ranging from 1.5 T to 4 T. Research continues to explore possible field strength-dependent sensitivity for identification of activation in different brain regions. Until conclusive evidence dictates performing fMRI at a particular field strength, the choice of magnetic field strengths (1.5-4 T) is currently based primarily on cost and availability . The superior sensitivity of high-field systems is balanced against their substantially greater cost and increased sensitivity to susceptibility-related image distortion. 0 ).

Magnetic Field Strength Issues MR Imaging Data Acquisition

The low contrast-to-noise ratio of fMRI (roughly 2%-5% signal change between active and resting brain states at 1.5 T) provides a

The use of EPI has proven to be very useful in fMRI. EPI is a fast data acquisition technique

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whereby multiple lines of the information needed to reconstruct a single cross-sectional image are acquired in one repetition time (TR). (Fig. 3). In single-shot EPI (ssEPI), all the necessary data to reconstruct a cross-sectional image are acquired in a single TR, and in multipleshot EPI, several TRs are needed to acquire the same desired data set. The advantages of EPI arise largely as a result of its speed in data acquisition. It is possible to acquire an entire image data set in less than 50 milliseconds. At this speed, EPI becomes less sensitive to motion because in essence, it provides a "snapshot" of the imaging plane. With careful design of the timing sequence, EPI can be used to acquire multiple slices of data, providing better coverage of the brain during an fMRI study. The advantages of multiple-slice acquisitions will be discussed in the section on fMRI in presurgical mapping. Running EPI based on GRE formation allows for sensitivity to susceptibility or T2* effects, thereby tuning data acquisition to BOLDbased changes that occur. Many groups have employed ssEPI for fMRI scanning. Using ssEPI for fMRI does not come without hardware demands. Even though data for an entire image must be acquired in one TR, it is more important to acquire these data with sufficient SNR. Although the signal of interest decays at an exponential rate of T2*, the gradients used to encode spatial information must rapidly switch between opposite polarities to completely sample and encode the signal. Figure 3 illustrates this gradient switching in the schematic of the frequency-encoding gradients. To do this with acceptable SNR, gradient coils with fast enough slew rates are needed. Investigators have addressed this need by choosing high-performance whole-body gradients10 or inserts. 52• 55 As is the case in many imaging systems, there are trade-offs. The primary trade-offs in running ssEPI are limited spatial resolution (around 3- 4 mm) and lower SNR due to higher bandwidth.15

data acquisition. In addition to developing a specific stimulus for language, memory, sensory, or motor areas, the design of the stimulus paradigm must ensure that the stimulus is delivered at a set frequency so that correlation with the physiologic response can later be extracted from the image set. When repeated cycling of baseline and activated states occurs, a periodic change in cerebral physiologic response with respect to time also occurs, as schematically shown in Figure 4 (top). The length of time from the onset of stimulus to 90% peak BOLD response is about 5 to 8 seconds, and the time from the cessation of stimulus to 10% above baseline response is about 5 to 9 seconds. 1 During an fMRI scan, a stimulus generally occurs in on-off cycles, where the" off" interval usually lasts longer than 5 seconds, during which time the cerebral hemodynamics return to some baseline state of either no stimulus or some baseline stimulus. The "on" interval lasts the same amount of time and reflects an activated brain state, where the patient receives a stimulus or executes a task. This "on-off" cycle is repeated a predetermined number of times. The timing of a stimulus paradigm is schematically illustrated in Figure 4 along with the hemodynamic response to show that the periodicity of the stimulus is coupled to the actual cycling of the hemodynamic response (also shown). During this cycling of the hemodynamic response which typically lasts on the order of minutes, snapshot images are acquired. During execution of such a stimulus paradigm, hundreds of images are usually acquired. The logistics of a stimulus paradigm generally means that there often must be active patient participation during the scan, whether it be to execute some task or to be alert to visual stimulation. In fact, patient participation is actually more involved when the necessity to maintain head immobility during the fMRI scan is considered. This is further addressed below.

What Makes fMRI Scans Different from Other MR Imaging Scans?

Extraction of Functionally Correlated Data

The biggest difference between an fMRI scan and a standard clinical MR imaging scan is the activation or stimulus paradigm. The stimulus paradigm describes the nature of the stimulus as well as its timing during

Estimation of the functionally activated area from an fMRI image set is a critical step in thefMRI imaging process. Many methods have been used to determine which pixels (individual picture elements in a cross-sectional dis-

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play) in an imaging plane have time-varying signal intensity values that are tightly correlated with the physiologic response. 30• 36 Figure 5 illustrates two methods that can be used to extract the functional data. Although the first of these, subtraction, is useful for providing an initial result of a functional study, it is sensitive to noise, particularly motion. Correlation methods extract pixels having a signal profile over time that is specifically correlated with the frequency of the stimulus. Because most sources of noise due to physiologic motion such as cardiac pulsatility and respiration are likely to occur at a different frequency than that of the stimulus paradigm, the pixels associated with motion will drop out. This assertion, however, is predicated on the existence of a set of perfectly registered images. Misregistered images arising from interimage motion are responsible for a source of error in fMRI studies.

Problems to be Addressed

Bulk head motion, resulting in misregistered images in the functional image set, can compromise or, at worst, invalidate the determination of activated areas. Even though ssEPI allows for "snapshot" imaging and hence minimizes errors due to intraimage motion, it still cannot resolve the problems of interimage motion. Artifacts arising from stimulus-correlated motion have been studied, 23 and various approaches have been taken to minimize motion artifacts. One method relies on physical restraints, including such devices as bite bars, vacuum-pack head molds, and face masks. This method does a reasonable job at restricting bulk head motion, but it is still inadequate for clinical fMRI studies. Signal fluctuations from physiologic processes such as cardiac pulsations, respiration, and cerebral pulsations can still lead to artifactual changes that

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Figure 5. Two methods that have been used for extracting functional data. Many other analytical techniques are available. A, Subtraction method. Here, the average of the "OFF" images are subtracted from the average of the "ON" images. This particular method is sensitive to motion artifacts. Note the thin rim of signal outside the skull ove r the left hemisphere owing to a side-to-side head motion that occurred during the series of fMR images. B, Correlation method. Here, in a subject with a right frontal vascular malformation, the signal from all the images are cross-correlated with a sinusoid that has the same frequency as the stimulus frequency. The activation detected by th is approach is indicated by arrows.

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may be incorrectly interpreted as functional activation. Also, the use of some physical restraints may be contraindicated in certain patient populations such as epileptic patients. Another approach uses registration algorithms to align the images prior to functional data extraction. One registration algorithm described by Woods et al, 56 has produced aligned images and resulted in more accurate functional interpretation. The approach of using navigator echoes has also been recently explored.25

POTENTIAL CLINICAL APPLICATIONS Neurosurgery-Correlating fMRI with Invasive Cortical Mapping

Twenty-two clinical fMRI studies have been performed to date at the Mayo Clinic in patients ranging in age from 10 to 53 years (mean, 30 years; 12 female and 10 male patients). A chronological assessment of the fMRI patient studies so far is presented in Table 1. fMRI exams were evaluated using two levels of clinical criteria stated as the following questions: (1) Was functional identification of the central sulcus achieved? (2) In patients who proceeded to surgery, did independent invasive tests corroborate fMRI results? Clinically adequate identification of the central sulcus was possible in only 11 (50%) of the 22 fMRI patient studies. There were 11 cases (50%) in which there was inadequate identification of the central sulcus; the predominant cause was ultimately attributed to the effects of motion. Although physiologic brain and cerebrospinal fluid (CSF) motion from cardiac systole and respiration is expected, the most damaging of the artifacts was due to bulk head motion. In general, when compared to volunteer controls, patients are unable to voluntarily immobilize their heads for the length of time required for an fMRI exam. Corroboration of functional data with operative somatosensory evoked potential (SEP) recordings and extraoperative stimulation mapping following subdural grid implantation has been studied in five patients. The goal of this work was to use fMRI techniques to evaluate patients who had become potential surgical candidates because of medically refractory epilepsy. The specific purpose of fMRI was to

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determine the sites of somatosensory activation in the perirolandic region. Neurosurgery-Presurgical Mapping Using Single-slice fMRI (Case Study 1: Patient No. 12 in Table 1) Patient History

A 27-year-old woman presented with a history of partial complex seizures since the age of 3 years. Recently, her seizures had become medically intractable. Diagnostic MR imaging studies revealed that a focal lesion consistent with a cavernous hemangioma was located in the right paracentral hemisphere and, more specifically, near the expected hand region of the somatotopic homunculus. An fMRI scan was performed to ascertain the location of the central sulcus and thus to determine the location of the lesion with respect to eloquent tissue. Neurosurgical resection of the lesion was planned. Methods

The fMRI study was performed on a 1.5-T system (Signa; General Electric Medical Systems, Milwaukee, WI) using the standard birdcage head coil. A single, oblique slice was selected parallel to the anterior-commissureposterior-commissure line and roughly through the somatotopic region of interest. GRE-based multiple-shot EPI was performed with the following scanning parameters: echo time, 60 milliseconds; repetition time, 250 milliseconds; field of view, 24 cm; section thickness, 4 mm; bandwidth, 64 kHz; one signal averaged; a 128 X 128 data matrix; and echo-train length, 16. Acquisition time per image was 2 seconds. Physical head restraint was achieved by a custom-molded face mask. The stimulus paradigm was unilateral hand brushing and bilateral finger tapping. Twelve (12) images were acquired during each activated ("on") state and resting ("off") state. Four "on-off" cycles elapsed per run, with each run lasting about 3.5 minutes. A complete fMRI study required six runs to accommodate different slice locations or different stimuli. These parameters were typical for the single-slice clinical fMRI studies that we initially employed at the Mayo Clinic. An immediate preliminary outcome of each fMRI run achieved by real-time computer integration made tailoring an fMRI

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Table 1. CHRONOLOGICAL SUMMARY AND ASSESSMENT OF !MRI EXAMS OF PATIENTS WITH MEDICALLY REFRACTORY EPILEPSY

Patient No. Single-slice !MRI 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Multiple-slice !MRI 21 22

Age and Sex

Clinically Adequate Identification of Functional Sensory or Motor Cortex? Pathology

Yes

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Tumor Tumor FL sz; no lesion Tumor Gliosis FL sz; no lesion Tuber FL sz; no lesion Encephalomalaciat Encephalomalacia§ Cav hemangioma Cav hemangioma Gliosis Tumor FL sz; no lesion FL sz; no lesion Porencephalic cyst Tuberous sclerosis Unknown ?Encephalomalacia

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study possible while the patient was in the magnet. Functional analysis was based on cross-correlation techniques. Results

The fMRI results are shown in Figure 6. Based on the fMRI results, it was determined that the central sulcus was the sulcus located just posterior to the cavernous hemangioma. SEP recordings provided corroboration of the results obtained from the fMRI study (Fig. 7). Additional diagnostic CT and MR imaging scans included an angiogram which localized the cavernous hemangioma between two veins (Fig. 8).

Discussion

This case study provided convincing verification of the fMRI results. Running one entire study, including all the scouts, required about 2 hours. This was due, in part, to the fact that the fMRI was performed in a single-slice mode. Another limitation due to single-slice acquisition is that such a view is not what is seen at the time of surgery. A more helpful image would be a three-dimensional rendering that would clearly depict sulci and gyri relative to the locations of functional activity. Multipleslice fMRI acquisitions as described in the following case study provide more complete anatomic coverage of the functional sensorimotor area than single-slice acquisitions.

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Neurosurgery-Presurgical Mapping Using Multiple-slice fMRI (Case Study 2: Patient No. 21 in Table 1)

Because of its inefficiency, it is unlikely that single-slice acquisition will find extensive use in the clinical setting. Multiple-slice acquisition lends itself to increased spatial coverage per functional run which, in tum, leads to more revealing three-dimensional displays of the brain plus activated regions. To date, we have performed two multiple-slice ssEPI fMRI studies for presurgical mapping (patients no. 21 and 22 in Table 1). Both were successful in identifying activation expected in the anatomic location of the central sulcus and preliminarily indicated the superiority of this technique over the single-slice approach. The following illustrates the results that can be achieved by using multiple-slice acquisitions. Patient History

In this case study, a 32-year-old woman presented with a left temporal-parietal tumor. The goal of fMRI was to ascertain the locations of the hand and face parts of the homunculus in the primary motor and sensory gyri in relation to the tumor. Methods

The fMRI study was performed on a 1.5T system using a high-performance three-axis local gradient coil (Medical Advances, Milwaukee, WI) . GRE-based ssEPI was used to acquire the data with the following scanning parameters: echo time, 35 milliseconds; repetition time, 1328 milliseconds; field of view, 24 cm; section thickness, 5 mm; bandwidth, 125 kHz; one signal averaged; flip angle, 60 degrees; a 64 X 64 data matrix; eight slices. The elapsed time between image acquisitions was 166 milliseconds. Sponges were used for head restraint. The stimulus paradigm involved air puffs on the lips and bilateral hand squeezing. Nine images per slice were acquired for each "on" interval and each "off" interval. Three "on-off' cycles were specified. Four hundred thirty-two images were acquired in about 72 seconds. Again, real-time computer integration allowed for monitoring of head motion and initial inspection of the areas of activation. Cross-correlation was used for data extraction.

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Results

Figure 9; Color Plate 2 illustrates the threedimensional renderings of the brain depicting the tumor and the hand and face regions. Because the surgical field did not expose the regions of the motor strip, corroboration of the fMRI data with awake cortical mapping could not be directly determined. Discussion

The three-dimensional display shown in Figure 9; Color Plate 2 suggests the potential benefits that such a view could provide for neurosurgeons. Multiple-slice acquisitions also provide the additional advantage that, in general, 10 contiguous slices, each 5 mm thick, are sufficient coverage for determining activation areas for several paradigms without the need to represcribe a different slice or set of slices. For example, it is possible to perform an fMRI hand-motor study immediately followed by a language study without the need to redefine the slice acquisitions. Although no language or cognitive studies were performed for this patient, functional exams involving language-related cognitive activities have been done.24 Language lateralization using fMRI is discussed more fully later. Neurosurgery-Presurgical Mapping Using Multiple-Slice fMRI and the Effects of Prior Craniotomy (Case Study 3: Patient No. 22 in Table 1)

Performing fMRI on patients is usually quite different than performing fMRI on highly motivated normal volunteers. Artifacts from prior cranial surgery can pose a significant barrier for fMRI. This case study describes such an example. Patient History

A 40-year-old woman presented with a right parietal tumor suspected to be an oligodendroglioma. Past surgeries included a craniotomy for an SEP exam with subdural electrodes. Her diagnostic MR imaging scan revealed susceptibility artifacts in the region of the craniotomy. The goal of this fMRI study was to localize the somatotopic hand region. Methods

The fMRI study was performed as described in the previous section (case study 2), except

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Figure 6. Figures 6, 7, and 8 belong to the same patient (patient 12 in Table 1). In this particular patient study, single-slice acquisitions were obtained for the fMRI runs (right in each figure). In each of the images, a T1-weighted spin-echo image is included on the left for anatomical reference. This particular study was confirmed by intraoperative somatosensory evoked potential (SEP) recording. A, fMRI of the most inferior of the three slices where functional activation was detected. This is a bilateral motor study whereby the patient (the same patient illustrated in Figure 58) executed bilateral finger-tapping during the "ON" intervals. 8, C, Middle slice. During the unilateral sensory exam (8), the patient's left palm and fingertips were brushed during the "ON" intervals. During the bilateral motor exam (C), the patient again executed bilateral finger-tapping during the "ON" intervals. 0, Most superior slice. A unilateral sensory exam. In all the fMR images, the apparent enlargement of the lesion compared to that in the T1 -weighted spin-echo image is because of the sensitivity of the scanning sequence to deoxyhemoglobin. Tliese results (A, 8, C, 0) suggest that the ipsilateral precentral gyrus is located just posterior to the cavernous hemangioma, and the central sulcus (arrows) is immediately posterior to that. Illustration continued on opposite page

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Figure 6 (Continued).

for the following: echo time, 45 milliseconds; repetition time, 1200 milliseconds; 10 slices. The elapsed time between each image acquisition was 120 milliseconds and inflatable pads were used for head restraint. The stimulus paradigm invoked alternating finger tapping, alternating hand squeezing, and alternating hand brushing. Seven fMRI runs were performed. Cross-correlation techniques were used for the data extraction. Intersections of activation maps for repeated paradigm studies were performed to exclude pixels which w ere uncorrelated with the frequency of the stimulus. Results

The fMRI results as shown in Figure lOA; Color Plate 2 (left, right) depict sensorimotor ac-

tivation anterior to the lesion. We concluded on the basis of the fMRI that the functional sensorimotor area is located along the anterosuperior margin of the tumor, thus placing the tumor in the parietal lobe. This makes intuitive sense because the patient's seizures begin with sensory symptoms and she had no motor deficits at this time. An operative view (Figure lOB) is also shown to demonstrate the relation of the tumor to the motor hand area as documented by intraoperative direct cortical stimulation mapping. Discussion

Two things are of interest in this case. First, prior craniotomies may produce image artifacts that are due to bulk susceptibility effects, (Fig. lOC) . This makes interpretation of fMRI results

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Figure 7. lntraoperative photographs of the same patient as in Figure 6. The patient's left is up and her right is down. A , Surgical field. Note the position of the AVM between two cortical veins, for correlation with Figure 8. B, Surgical field with the numbered electrode strip contacts in place. The eight-contact T-strip for the SEP recordings was placed so that contacts 3 through 5 were placed over the vascular malformation area. Note that contact 4 is placed on the posterior border of the cavernous hemangioma. C, SEP obtained with referential recording. The phase reversal occurring at contact 5 indicates that the central sulcus is located just under contact 5. The SEP study was interpreted to indicate that contact 5 was over the central sulcus, and the precentral gyrus was located between contacts 4 and 5. This matched the location of the functional precentral gyrus and central sulcus as determined by the fMRI study. Illustration continued on opposite page

in the region of the craniotomy difficult. Fortu-

nately, in this patient, the susceptibility artifacts did not obscure the relevant functional area. Nevertheless, that may not always be the case, and artifacts from prior craniotomies will likely preclude the effective application of £MRI in a small number of otherwise suitable candidates. Second, the ability to perform a functional run

in 72 seconds allows for rep eatability w hich, in turn, means that extraction of highly correlated pixels can be obtained by intersection of two or more fMRl runs of the same paradigm. This method of data extraction excludes those pixels that are not correlated with the frequency of the stimulus such as those arising from motion. This procedure preserves those pixels that are

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Figure 7 (Continued) .

truly correlated with the stimulus frequency and excludes those that are not. Language Lateralization with fMRI

Minimization of damage to eloquent brain, particularly the areas subserving memory and

language, is a primary goal in resective surgery. Language-related deficits may be produced when surgery is performed on the hemisphere responsible for speech production.11 An accurate test in determining language lateralization, or which hemisphere controls speech production, is the Wada test, or the intracarotid sodium amobarbital test.

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Figure 10. Another multislice !MRI patient study (Patient 22 in Table 1). (A, left and right) Threedimensional renderings that illustrate both the sensory (red) and motor ( green) regions at different viewing angles. An arrow depicts the interhemispheric fissure. In the image on the right, the nose is pointed to the reader's right and the top of the image and head is slightly turned down. Sensory and motor activation is located in the anterior-superior margin of the tumor. B, Operative field. A black + is placed in the center of the surface of the tumor that spans a roughly circular region encompassing the paler-looking tumor tissue. Here, again, the nose is pointed to the reader's right, the back of the head to the reader's left, and the top of the head is the top of the image. 1 indicates the location of the thumb jerk produced by cortical stimulation, so that 1 should lie over the motor strip. 7 lies over the central sulcus vein, and 6 lies over the sensory strip. Because the operative view is oriented as in A (right), one can note the parallel of the mappings obtained by cortical stimulation with that by !MRI. C, This patient had a prior craniotomy, which introduced artifacts that are not usually encountered in !MRI scans of normal subjects. The artifacts are substantially worse on ssEPI (left, straight arrows) than on the corresponding T1-weighted anatomic image (middle, curved arrows). This !MRI study (right) overlaying a T1-weighted image was successful, but in a case with activation in areas of susceptibility artifacts, the interpretation of !MRI becomes more questionable. See also Color Plate 2 for Figure 1OA.

Although the Wada test yields accurate results, it is invasive. Some groups have used fMRI to determine language lateralization,6• 24• 38• 47• 48 but variations in setup, including differences in field

strengths and stimulus paradigms, have resulted in only preliminary findings which have differed in some instances. 6• 38 Some groups have used covert w ord generation,24• 47 as opposed to physical vocalization,38• 41 in order to

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minimize the effects of head motion. Support of covert word generation is provided by the suggestion that lateralization may be more prominent with internal speech generation than with active speech localization. 49 • 58 Despite these variations, all language studies thus far have been able to demonstrate local activation in one or more of the following Brodmann's areas: 44 (Broca's area) 24 • 38• 47 and homologous areas of activation in the right hemisphere. Head motion, intersubject variability, the design of the stimulus paradigm, and susceptibility artifacts at tissue-air interfaces near the orbits and frontal sinuses, 19 for example, are critical areas that still need to be investigated. It remains to be explored just how far fMRI can be used to provide definitive, reliable results in language and speech mapping.

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SUMMARY It has been the goal of this article to provide the reader with a brief background of fMRI, a basic understanding of the techniques of fMRI, and, more importantly, the potential for clinical and experimental studies using fMRI. In contrast to the limited number of installed PET and MEG units, the large installed base of MR imaging scanners (over 1000 installed at least at 1.5 T in the United States) makes fMRI potentially widely available. Initial studies (both clinical and experimental) have been validated and are reproducible in mapping the sensorimotor and visual cortices. The areas of language lateralization and memory are still preliminary at best. As methods to reduce the effects of head motion (due to both bulk head motion and physiologically induced motion) arise, the reliability of fMRI should improve, allowing for more definitive identification of task activation. ACKNOWLEDGMENT

Preliminary investigations on the use of fMRI in localizing the effects of learning and memory have encountered similar variations as those described above for language lateralization. Spatial working memory 39 and the learning of a sequence of finger movements 28 are just two examples of studies that have used fMRI for mapping of these cognitive regions. In one study where spatial working memory was examined, local activation was discernible in the prefrontal cortex. 39 This particular study involved a stimulus paradigm whereby working memory was evaluated by asking the subject to signal the repeated occurrence of a white, irregular object during a functional run. Positive identification was made by asking the subject to raise an index finger. The baseline condition was defined by asking the subject to identify instances when either a colored configuration or a dot occurred in the stimuli. The advantage of repeatability in fMRI is exemplified in its applications to localize and follow the aspects of learning over time. Problematic issues that arise are primarily head motion and susceptibility artifacts at tissue-air interfaces. With more research and definitive results, it may be that fMRI will eventually be a preferable way to obtain preoperative and follow-up results in patients who have undergone resections of brain subserving memory and learning.

We would like to thank Dr Fredric Meyer, Dr Corey Raffel, Dr Richard Marsh, Dr Frank Sharbrough, Dr Gregory Cascino, Dr Elson So, Dr Mary Zupanc, and Dr Yue-Cheng Xu for their support and assistance in our efforts to further explore £MRI at the Mayo Clinic.

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