1 Imaging Brain Function in Humans at 7 Tesla Magnetic Resonance in Medicine 45: (2001) Essa Yacoub, Amir Shmuel, Josef Pfeuffer, Pierre-Francois Van De Moortele, Gregor Adriany, Peter Andersen, J. Thomas Vaughan, Hellmut Merkle, Kamil Ugurbil, and Xiaoping Hu* This article describes experimental studies performed to demonstrate the feasibility of BOLD fmri using echo-planar imaging (EPI) at 7 T and to characterize the BOLD response in humans at this ultrahigh magnetic field. Visual stimulation studies were performed in normal subjects using high-resolution multishot EPI sequences. Changes in R* 2 arising from visual stimulation were experimentally determined using fmri measurements obtained at multiple echo times. The results obtained at 7 T were compared to those at 4 T. Experimental data indicate that fmri can be reliably performed at 7 T and that at this field strength both the sensitivity and spatial specificity of the BOLD response are increased. This study suggests that ultrahigh field MR systems are advantageous for functional mapping in humans. Magn Reson Med 45: , Wiley-Liss, Inc. Key words: cerebral function; functional imaging; MRI; fmri; BOLD; ultrahigh field Since its initial demonstration in 1992 (1 3), functional magnetic resonance imaging (fmri) has evolved into a widely used methodology for mapping neuronal function. The basis of most fmri studies is the blood oxygenation MATERIALS AND METHODS level dependent (BOLD) contrast (4 6), which is derived Data Acquisition from the fact that the magnetic property of hemoglobin Normal subjects were enrolled for this study, which was depends on its oxygenation state (7). Because deoxygenated hemoglobin is paramagnetic, deoxygenated blood sity of Minnesota. All subjects provided written consent. approved by the institutional review board at the Univer- leads to a local decrease in T* 2 and T 2. Neural activity Functional imaging studies were performed using a visual causes a local increase in blood flow, which overcompensates any increase in oxygenation utilization (8) and leads by red LED goggles flashing at 10 Hz (Grass Instruments, stimulation paradigm where the stimulus was generated to a reduction in local deoxyhemoglobin concentration. Quincy, MA). A block design was used for all studies. Consequently, neural activity leads to an elevation in T 2 - A 90-cm bore 7 T magnet (Magnex Scientific, Abingdon, or T* 2 -weighted images. Based on this principle, the majority of fmri experiments are performed by acquiring a was used. For all studies, a quadrature transmit and re- UK) coupled with a Varian INOVA console (Palo Alto, CA) series of T* 2 -weighted images while a subject performs a ceive surface coil, designed for covering the occipital cortex (23), was used. Scout images were first obtained with certain task or experiences some type of stimulation. As a susceptibility phenomenon, the BOLD contrast can an inversion-recovery (IR) prepared TurboFLASH (24) sequence (TI: 1.4 s, TR/TE: 8/3 ms, matrix: , slice be imaged with MRI at various magnetic field strengths. The development of fmri methodology coincided with the thickness: 5 mm) for identifying the slice of interest. A introduction of high magnetic fields, and one of the seminal studies describing fmri in the human brain for the IR-prepared segmented TurboFLASH (TI: 1.4 s, TR/TE: 8/3 sagittal slice, 6 mm from the midline, was selected. An first time was performed at 4 T (1). However, due to their ms, two segments, two averages, matrix: , slice wide availability, 1.5 T systems are currently used for the thickness: 5 mm) image was obtained over the selected majority of fmri studies in humans. In animal models, slice as an anatomic reference. Functional imaging studies higher magnetic fields (4.7 T and 9.4 T) have been widely were performed using a T* 2 -weighted EPI sequence. The used (9 11). Theoretical considerations (12 14) and ex- EPI sequence was implemented with a readout gradient consisting of alternating trapezoidal gradient lobes. For Nyquist ghost removal, a reference scan in the fmri series Center for Magnetic Resonance Research and Department of Radiology, was obtained and used to correct for discrepancy between University of Minnesota, Minneapolis, Minnesota. the odd and even echoes (25). Note that the algorithm as Grant sponsor: National Institutes of Health; Grant numbers: P41RR08079 (a National Centers for Research Resources (NCRR) grant); RO1MH55346; described by Bruder et al. (25) also removes to a large Grant sponsors: W.M. Keck Foundation; National Foundation for Brain Imaging (NFFBI). providing a reasonable registration between the fmri data extent off-resonance induced distortions in the EPI images, *Correspondence to: Xiaoping Hu, Ph.D., CMRR, th Street SE, Minneapolis, MN and the anatomic scan. Received 12 June 2000; revised 19 September 2000; accepted 16 October fmri experiments were performed using a segmented T* 2 -weighted EPI sequence (matrix: matrix, eight 2001 Wiley-Liss, Inc. 588 perimental data (10,11,15,16) have consistently revealed that the specificity, sensitivity, and contrast of the BOLD response to neural activity increases with the field strength (also see 17 21). This field strength dependence has led to a recent surge in the number of high field (3 and 4 T) MRI systems available. Recently, two human systems operating at fields higher than 4 T became available. The 8 T system has generated a great deal of interesting data (22), mostly in anatomic imaging. With the 7 T whole-body system in our laboratory, we have begun experimental fmri studies in humans for the first time at magnetic field strengths that significantly exceed 4 T. The experiments were conducted using a surface coil with a visual stimulation paradigm. Functional mapping of the visual cortex using echo-planar imaging (EPI) at 7 T was demonstrated and activationrelated R* 2 changes ( R* 2 ) were quantified. This article presents the experimental details and results.
2 fmri at 7 Tesla 589 segments, cm 2 FOV, 5 mm slice, half-fourier acquisition with eight additional lines). Due to the relatively short T* 2 at 7 T, k-space segmentation was needed for high-resolution EPI. The EPI images were acquired with a TR of 0.37 s per segment (corresponding to an acquisition time per image of 3 s) and an average flip angle of 40 (averaged over the Calcarine sulcus). During the acquisition of fmri data, the subject s respiration and heartbeat were monitored for subsequent removal of physiological noise. The study was performed in five normal volunteers. The fmri protocol consisted of acquiring 81 images consecutively, during which the stimulus was turned off for nine images and on for nine images in an alternating manner. The same protocol was run for TEs of 10, 15, 22.5, 34, and 51 msec. A study was performed in the same group of subjects at 4 T using the same stimulation protocol. The images at 4 T were acquired on the same sagittal slice using identical parameters except the TEs and a surface coil based on an equivalent design. The TEs used at 4 T were 15, 22.5, 34, 51, and 76 msec. At both fields, field homogeneity was optimized with shimming, achieving a typical slice linewidth of 15 Hz at 4 T and 20 Hz at 7 T. Data Processing The acquired k-space data of the T* 2 -weighted EPI time series were preprocessed using a retrospective technique (26) to remove physiological fluctuations before the application of a Fourier transform to convert the raw data into images. The first seven images in each time series were discarded to avoid intensity variations during the transition to steady state. The four epochs in the fmri time series were averaged to generate a single epoch for further analysis. The T* 2 -weighted EPI images obtained at different TEs were first analyzed separately using cross-correlation (27) using a correlation template generated by convolving the boxcar function of the stimulation paradigm with a hemodynamic response described by Friston et al. (28). Crosscorrelation maps were thresholded with a single threshold (0.7; P 0.001) to generate maps at corresponding TEs. In the second part of the data analysis, regions of interest (ROIs) over gray matter and draining veins, detectable at the image resolution employed, were identified. Veins were recognized from the anatomic image and the T* 2 - weighted images in which they appeared dark (5,15). The ROIs for the two field strengths were matched by selecting the same sagittal slice for the studies at both fields and using anatomic landmarks for the location of the ROIs (see Fig. 2a). Within each ROI, the average intensity for the activation period, defined as the average of images 4 9 in the nine-image stimulation period (the first three images skipped to account for hemodynamic response), and that for the resting period, defined to be the average of the three images prior to stimulus onset, were calculated. The T* 2 for the resting and active conditions were derived using exponential fitting of the average image intensity vs. TE. The R* 2 of these ROIs was calculated for the two field strengths and all subjects. T 2 Measurements of Human Venous Blood Venous blood was drawn from volunteers from the arm into a standard, evacuated, 10 cc vial that contained an appropriate amount of solid heparin to prevent clotting. The tube was quickly wrapped to insulate it and inserted into a specially constructed RF coil. T 2 values were measured with a spin echo sequence with different TEs. Each measurement was performed within a minute and the first measurement was performed no later than a minute or two after the blood was drawn. The sample tube was then removed from the coil, shaken, reinserted, and the measurement repeated. Three or four such measurements were performed with highly reproducible T 2 values in each case. The reported data for each volunteer is the average of these measurements. Blood O 2 saturation was measured with a blood gas analyzer before and after the T 2 measurements and found to be the same. RESULTS Figure 1a displays activation maps obtained from one subject at all TEs for both 7 and 4 T. Similar maps were generated from data of the other subjects. At the same statistical threshold, the 7 T maps exhibited a considerably larger activated area at all TEs except the last one, particularly in the gray matter regions. A paired t-test for the number of activated pixels (averaged over all TEs) between the 7 T and 4 T data showed that the 7 T maps were significantly (P 0.008) larger than those of the 4 T data. To illustrate the quality of the functional data, the time course of the activated regions are shown for TE of 22 msec at 7 T and compared with that of TE of 30 msec at 4Tin Fig. 1b. Activation correlated changes exhibit a higher CNR at 7 T. As expected, the activation maps in Fig. 1a varied with TE and became most prominent at a certain TE, depending on the field strength. This is more clearly demonstrated in Fig. 2b, which plots the signal change S (average signal during activation average signal during rest) as a function of TE for gray matter and vessel ROIs indicated in Fig. 2a. In the gray matter, S had a maximum at a TE of 25 msec at 7 T, and 35 msec at 4 T, consistent with the theoretical prediction that there is a maximum for activation-induced signal change which occurs when TE T* 2 (29). At 4 T, S in regions associated with vessels showed an approximate plateau that persisted until a TE of 35 msec. In the ROI surrounding large vessels, a monotonic decrease was seen with the TE values of 10 msec or more employed in the 7 T experiments; presumably, this is because the venous blood T* 2 is 10 msec or less at 7 T, consistent with the rapid decrease in venous blood T 2 and T* 2 with increasing magnetic field (11). The shortened venous blood T* 2 at the higher magnetic field is also evident in the T* 2 -weighted images (Fig. 2a); the large venous vessel contributions (see arrow in Fig. 1a) disappeared in the 7 T activation maps at long TEs, while the same vascular contributions remained prominent with increasing TE at 4T. Figure 3 plots the logarithm of the signal with respect to TE during rest and activation, respectively. Although the signals mostly follow an exponential decay, this
3 590 Yacoub et al. FIG. 1. a: Activation maps obtained at different TEs in one subject at 4 T (top) and 7 T (bottom). TEs in msec are marked in the maps. b: Timecourses for TE of 22 msec at 7 T (left) and TE of 34 msec at 4 T (right). exponential behavior is not so well maintained by the signals from large blood vessel regions. This is most likely due to the fact that there is more signal fluctuation in the vascular area from cardiac pulsation. In addition, pixels that contain both tissue and relatively large venous blood volume fraction (e.g., due to the presence of large blood vessels) may also exhibit an oscillatory behavior (17 20). This oscillatory behavior arises because the deoxyhemoglobin containing blood has a different resonance frequency compared to surrounding tissue (17 20). The T* 2 during the rest condition for the ROIs considered were as follows. Averaged over all subjects and all resting period images, the gray matter T* 2 was msec at 7 T and msec at 4 T. Note that this measurement should be minimally affected by the shimming because they are voxel-specific and the linewidth of each voxel should be negligible compared to the T* 2. These measured values are in good agreement with the optimum TEs corresponding to the largest S. In the vessel regions, the T* 2 was found to be msec at 7 T and msec at 4 T. However, these values can be regarded as approximations because of complications associated with partial volume effects with surrounding tissue. A separate measurement of ex vivo venous blood found the T 2 to be approximately 7 msec for blood with a normal O 2 saturation (Y) of 60% (subject 1: T msec, Y 38%; subject 2: T msec, Y 39%; subject 3: T msec, Y 59%). Table 1 lists the R* 2 for ROIs in gray matter and venous vessel regions for each subject at both field strengths. For gray matter, the average R* 2 was found to be s 1 at 7 T and s 1 at 4 T. The ratio between the R* 2 changes at the two fields is , which represents a supralinear increase with the field strength. The vessel ROI (Table 1) at 4 T shows a larger intersubject variation than the gray matter ROI, presumably due to more contributions from the vascular signal at 4 T. In the vessel ROI, the R* 2 change increased only slightly with the field strength.
4 fmri at 7 Tesla 591 FIG. 3. a: Plot of signal intensity vs. TE for gray matter ROI and vessel ROI at 7 T. b: Plot of signal intensity vs. TE for gray matter ROI and vessel ROI at 4 T. FIG. 2. a: ROIs for data (4 T: top; 7 T: bottom) shown in Figs. 3b, 2b, and 4. The gray matter ROI is shown in blue and vessel regions are indicated in green. b: Plots of S vs. TE for gray matter ROI (top) and vessel ROI (bottom). DISCUSSION Functional mapping in the visual cortex in humans at 7 T is demonstrated in this work. Experimental results indicate that fmri can be robustly performed at 7 T using ultrafast imaging techniques such as EPI. The study based on multiple TEs reveals that at 7 T, in the human visual cortex, T* 2 is 25 msec and that this is also the optimal TE to be used in BOLD based fmri studies. Despite the concerns with the high magnetic field, the only side effect reported by the subjects was a slight dizziness if they were pushed into the magnet too fast. This effect is similar to what has been reported at 4 T. Prior to the present fmri study, we have conducted a behavior study at 7 T using a mental rotation paradigm that was previously employed to evaluate the effects of 4 T (30). The behavior data (to be reported separately elsewhere) showed that there was no difference in subject performance in and outside the magnet. The studies presented here demonstrate that bloodrelated mechanisms that contribute to the BOLD effect (see discussion in 17 21) are virtually inoperative at 7 T for TEs equal to or exceeding the optimum TE of 25 msec, while they are still significant at the optimum TE of 35 msec at 4 T (see Fig. 2, 34 msec and 22 msec images for 4T and 7T, respectively). This has significant implications with respect to the specificity of the functional images at 7 T since such blood-related effects are mostly associated with large blood vessels. Previous studies (13,17 21,31,32) based on eliminating blood contributions to BOLD mechanism using Stejskal-Tan-
5 592 Yacoub et al. Table 1 R* 2 Change Arising From Visual Stimulation Subject 4T R* 2 Gray matter R* 2 Vessel region R* 2 7T R* 2 Ratio 4T R* 2 7T R* 2 kb sc pa rg dc Mean STD The negative sign in front of the R* 2 is ignored for clarity. Ratio ner gradients (33) have demonstrated that most if not all of the signal changes induced by neuronal activation originate from intravascular or blood-related effects at 1.5 T. The same conclusion was shown to be applicable, albeit to a lesser extent, even to 4 T at TE values of msec that are often used at this field strength (17 20,34). At these field strengths, the fractional BOLD signal changes induced by activation substantially exceed the 2% microvascular blood volume fraction in the brain (35). Therefore, these blood-related effects are thought to arise from blood within the large vessels (17) (i.e., with diameters comparable or larger than voxel dimensions) or voxels that are occupied by both tissue and venous blood with comparable partial volumes (i.e., voxels partially occupied by relatively large blood vessels). The partial volume effect in the latter case can lead to large signal modulations with activation due to the susceptibility-induced difference in the resonance frequencies of the two compartments (17 20). We have previously argued that these mechanisms should rapidly become inoperative at magnetic fields above 4 T (17 20) due to the rapidly decreasing T 2 of blood with increasing magnetic field (11) and we have experimentally demonstrated the absence of these mechanisms at 9.4 T (11). Similar results are also expected at 7Tin awake human subjects. While the field strength is somewhat lower relative to the animal studies, fractional oxyhemoglobin content in venous blood is also significantly higher in awake humans relative to anesthetized animals (60% vs. 80% in the animal model in the 9.4 T study (11)). Consistent with these expectations, blood T 2 at 7 T was found to be approximately 7 msec for 60% oxygenation level. This value is in remarkable agreement with the value of 6.7 msec predicted from the model based on 1.5 T data on human blood T 2 (36) if a quadratic dependence on magnetic field is assumed. In the absence of the above-described BOLD mechanism related to blood effects, macroscopic venous blood vessels can only contribute to T* 2 -weighted images at 7 T through the extravascular BOLD mechanism arising from static averaging of field gradients around these vessels (e.g., see discussions in 17 20,16-19). Such effects, however, are expected to be small at sites distant from the activated tissue because of dilution from vessels draining inactive areas. Therefore, they are not expected to be a major source of degradation of specificity of the fmri maps at 7 T. If only the extravascular BOLD effect associated with blood vessels larger than capillaries and postcapillary venules were to dominate the fmri signals at 4 and 7 T, then at best only a linear increase in activation related R* 2 is expected. If we consider the blood-related contributions to T* 2 -weighted fmri, then the linear dependence becomes an upper limit in the 4 T to 7 T comparison. Therefore, the supralinear increase observed in R* 2 in going from 4 to 7 T demonstrates the presence of a significant microvascular contribution which is expected to contribute supralinearly. Note that, although the anatomic landmarks used in ROI placement were clearly identifiable on both the 4T and 7T images, and the slices appear to be very similar in location, there may be some error in registering the ROIs across the different scans in an attempt to assess the field strength dependence. Increased microvascular contribution and diminishing large vessel contribution to fmri leads to increased specificity at the higher magnetic field of 7 T. It is possible that basal signal fluctuations increase at 7 T. This is currently being investigated separately. However, even if enhanced, such fluctuations will not necessarily degrade fmri studies at 7 T because they can be eliminated by a variety of methods (26,37,38). In fact, in this study, where the fluctuations associated with respiration and cardiac pulsation were removed, the temporal stability of the fmri time series was found to be comparable at the two field strengths and a clear gain in contrast-to-noise ratio for fmri was demonstrated in going from 4 to 7 T. This point is also illustrated by the timecourses shown in Fig. 1b. In addition, MR SNR also increases with field strength, as systematically demonstrated in a recent volume coil study (39), providing further gains for fmri studies. Therefore, we conclude that major advantages are realized in fmri studies of brain function at 7 T. A potential problem at 7TistheB 1 inhomogeneity and its potential degradation on SNR. While a full investigation of this issue is outside the scope of this article, we examined the SNR in the acquired images to get an idea on this issue. The SNR profiles in the raw images along a line perpendicular to the surface coil were obtained by smoothing the image profile and dividing by the noise estimated from a region outside the brain. The profiles for the two field strengths are plotted in Fig. 4 for one of the subjects. Evidently, the SNR at 7Tishigher for most of the ROI but falls off more quickly, probably due to increased dielectric
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