Head motion during positron emission tomography: is it significant?

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Psychiatry Research: Neuroimaging 61 (1995) 43-51

Head motion during positron emission tomography: is it significant? Urs E. Ruttimann*, Paul J. Andreason, Daniel Rio Laboratory of Clinical Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes o f Health, 10 Center Drive MSC 1256, Bethesda, MD 20892-1256, USA Received 4 November 1993; revision received 31 May 1994; accepted 8 August 1994

Abstract

High sensitivity for detecting local brain function differences from subsequent PET images acquired at different cerebral stimulation states requires interscan head motion to be minimized. This motion was measured by an optical lever system during scanning (130 min) of 15 subjects in a dual-dose injection study. Despite motion restriction by a face-mask restraint system, rotations in the sagittal and coronal planes (up to 4.1 ° and 2.4°, respectively) significantly influenced the measured means and variances of local metabolic differences between states. Hence, adjustments for head movement by retrospective, digital slice realignment or, better, real-time corrections are important.

Keywords: Functional imaging; PET methodology; Face-mask restraint; Cerebral glucose utilization

1. Introduction

With the continuing improvement of resolution in medical images, the ability to control head movement becomes increasingly important. Spatial registration errors are detrimental in functional studies, when the effect of pharmacological or other stimuli on regional cerebral metabolism is measured by the pixelwise difference of positron emission tomographic (PET) images acquired from the same subject in two different states of cerebral stimulation (Brooks et al., 1987). The sen* Corresponding author, Tel: +i 301 496-5228; Fax: +1 301 402-0445. Elsevier Science Ireland Ltd. SSDI 0925-4927(95)02565-F

sitivity of this technique for the detection of regional differences is limited by the amount of misregistration artifact generated by head motion between acquisition of the respective scans. Hence, the purpose of this study was to measure head motion during the acquisition of PET images and assess its impact on measurement of local brain function. 2. Methods

A total of 15 male subjects (mean age = 31.8, SD = 8.9) who were participating in an ongoing study on the effects of meta-chlorophenylpiperazine (mCPP) on cerebral glucose utilization.were

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U.E. Ruttimann et al./ Psychiatry Research: Neuroimaging 61 (1995) 43-51

studied (Andreason et al., 1992). All subjects gave informed consent after receiving information about the hazards and benefits of the study. The subjects were free of medication and were evaluated before admission to the protocol with a comprehensive physical examination, psychiatric assessment, and laboratory tests. Two volume stacks of 21 images each were acquired on a Scanditronix PC 1024-7B PET scanner (Scanditronix AB, Uppsala, Sweden) in a sequential, two-dose injection protocol (3 and 5 mCi) using the tracer 2-[lSF]fluoro-2-deoxy-D-glucose (FDG). The volume stacks comprised three sets of seven interleaved slices. The scanner has an interslice distance of 3.8 mm, in-plane spatial resolution of 7.5 mm full-width at half maximum (FWHM), and axial resolution of 10.5 mm FWHM (Daube-Witherspoon et al., 1987). The collection time for one set of slices was 10 min. A filtered back-projection method yielded image matrices of 128 x 128 pixels with 2 x 2 nun size. Subject head motion was restricted during the entire time course of the two-dose injection study (transmission scans, uptake periods, and emission scans) by an individually molded thermoplastic face mask (Tru-Scan Imaging, Inc., Annapolis, MD) that was clamped to the scanner table. This head-holding device is routinely used for virtually all PET scans performed at the Clinical Center of the National Institutes of Health and at many other PET facilities worldwide. To improve comfort, which is essential to minimize movement, 1.5inch foam padding was tucked behind the subjects' heads for support, large pillows were placed under their knees to reduce lower back strain, and their arms were supported in a slightly flexed position by small pillows. Head movements were monitored by an optical lever system, consisting of a laser pointer mounted on the scanner table that directed its beam onto a mirror, which was rigidly coupled to the subject's dentition by a dental mold (Fig. 1). This mold had been prefabricated from each subject's occlusal impression in a fast-setting dental material (Reprosil®, Caulk/Dentsply, Milford, DE). The specular reflection of the beam to the opposite wall of the scanner room produced a light spot (approximately 5 mm in diameter) whose vertical (Ay) and horizontal displacements

(Ax) enabled determination of head rotations in the sagittal and coronal planes, corresponding to "nodding" and "tilting" motions, respectively. The distance from the dental mirror to the opposite wall of d = 360 cm yielded a measurement sensitivity of 12.6 cm/°, which was at a level to notice even slight movements associated with blood pulsations. The dental mold was inserted only during periodic positional measurements and then removed for better comfort. To avoid the gagging reflex, it did not extend over the subject's palate. The possible error associated with this practice was assessed with the optical lever in a short run of subsequent removals and reinsertions of the molds for each patient at the beginning of the study, and was found to be less than 0.1 °. Head-motion measurements were made during acquisition of the transmission scan at the beginning of the study, after injection of FDG, and during the acquisition of each set of emission images (Fig. 2). For each measurement, the light spot positions were visually averaged over approximately 1 min and then recorded relative to the position determined during the transmission scan. To demonstrate visually the impact of head motion on drug-effect assessment, corresponding slices from the two emission scans (before and after injection of mCPP) were digitally subtracted. Since the resulting images represented a combination of possible true glucose utilization differences along with artifacts due to interscan motion, it was of interest to investigate whether a retrospective realignment of the slices by digital means could reduce misregistration artifacts. This imageprocessing step would also verify indirectly the rotation angles measured by the optical lever system. Hence, the stack of slices comprising second-dose images was virtually positioned into the stack of first-dose images by digitally rotating it by the negative amounts of the optically measured rotational movements. This was achieved by applying appropriate three-dimensional homogeneous matrix transformations (Rogers and Adams, 1976) to the volume stack and using linear interpolation between slices to synthesize the new set of slices (Mintun et al., 1989). However, the interpolations involved in applying these transformations, as well

U.E. Ruttimann et al./ Psychiatry Research: Neuroimaging 61 (1995) 43-51

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Fig. 1. Schematic of optical lever system. (A) Laser pointer, (B) mirror coupled to subject's teeth by a dental impression mold, and (C) light spot. Rotations are determined within coronal plane: a = tan-I[Ax/(2d)l, within sagittal plane: a = tan-I[Ay/(2d)], (a <: 1).

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Fig. 2. Group average (connected points)and range of head rotationin the sagittalplane ("nodding") measured in 15 subjects over the time course of two-dose P E T scanning.

as slice interpolation, per se, cause blurring, resulting in an additional loss of image resolution. To assess the consequences of head motion between scans on the measures of regional glucose utilization rate (rag glucose/100 ml tissue/min), selected sites were sampled by 11 regions of interest (ROIs) as shown in Fig. 3. The position of this slice (slice D) and the ROI sizes (square: 6 x 6 pixels; circle: 5-pixel diameter) have been defined and used in previous studies (Cohen et al., 1988; Andreason et al., 1994) to match structures illustrated in the Matsui-Hirano (1978) atlas of the human brain. This particular slice level represented both cortical and subeortical structures, so that the motion effects across a variety of ROIs could be studied. Since mCPP was always given before the second scan, a possible drug effect on the measurements could he canceled by the following study design. The optical measerements of head motion in the sagittal plane (considered as the most relevant) served to sort the slices retrospectively into two groups: those that had

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U.E. Ruttimann et al./ Psychiatry Research: Neuroimaging 61 (1995) 43-51

Fig. 3. Placement of regions of interest for the measurement of regional glucose utilization rates.

undergone only positive rotations and those that had undergone only negative rotations. Difference images between first- and second-dose images were produced for each group, and the sign of these differences inverted in the group with negative rotations. Selection of an equal number of difference images from each group then constituted a sample where image artifacts were associated with apparent positive rotations only, while possible drug effects were canceled due to either their addition or subtraction in equal halves of the sample. To compare local measures of glucose utilization when derived from digitally realigned versus unaligned slices, the ROIs from the three frontal, two tempo-

ral, two occipital, and four subcortical areas were each combined to represent four different anatomical regions, and the corresponding measurements analyzed with repeated measures analysis of variance (ANOVA) (program 4V, BMDP Statistical Software, Inc., Los Angeles, CA). 3. Results

Fig. 2 displays the average and the range of the absolute rotational motion within the sagittal plane ("nodding"), relative to the start of the procedure, over the scanning time course. A similar,

U.E. Ruttimann et al./ Psychiatry Research: Neuroimaging 61 (1995) 43-51

but smaller trend of increasing deviation from the original position over time was observed for head rotation in the coronal plane (maximum after 130 min = 2.4°). Judged from the uniformity of these trends, it is unlikely that mCPP administration (given just before injection of the second dose of FDG) contributed to increased head motion. Of relevance to the application in a dual-dose injection protocol is the motion that occurred between the acquisition of corresponding sets of slices in the two emission scans. Table 1 summarizes these rotations under the heading Between subsequent dose scan. Although the average discrepancies may not be of particular concern, maximal individual rotations in the sagittal plane of up to 4.1 o and in the coronal plane of up to 2.4° occurred. With anteroposterior and lateral diameters of the human skull of 180 mm and 140 mm and if one assumes, in the worst case, the fulcrum for rotations in the sagittal and coronal planes to be located at the back or to the side of the head, respectively, these maximal rotations may result in axial displacements at extreme frontal and lateral borders of the brain of 180° • tan(4.1 °) = 12.9 mm and 140° • tan(2.4°) = 5.9 mm. Under the same assumptions, critical angles, ac, can be derived such that resulting axial displacements at the frontal or lateral brain borders are limited to lie within the interslice distance of 3.8 mm. The last column in Table 1 shows that 14 out of 45 paired sets of slices (31.1%) displayed rotation discrepancies in the sagittal plane larger than a~ = 1.21°. The cor-

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responding limit of Otc = 1.55° for rotations in the coronal plane was exceeded by only one pair

(2.20/0). Since on this particular PET scanner, the collection of each volume stack of slices is achieved in three sequentially obtained sets, the motion during the acquisition of one complete emission scan is also of importance. Head rotation within that time period will result in an assembly of nonparallel slices, which are assumed to be parallel and equidistant in subsequent image-processing steps that generate three-dimensional data representations. Table 1 summarizes the corresponding rotation measurements under the heading Within same dose scans. Due to the shorter time interval, these rotations are generally smaller than those observed between subsequent dose scans. However, notable extremes of about 1.5° occurred, and while the impact of within-scan rotations in the coronal plane was small, still 5 out of 30 (16.6%) slice sets exceeded ccc for rotation in the sagittal plane. The top two images of Fig. 4 show equivalent PET slices obtained before (left) and after (right) injection of mCPP. This subject rotated his head between the two acquisitions by 2.4 ° in the coronal plane and by and 4.1 ° in the sagittal plane. Identical contrast settings have been used for the bottom images. The bottom-left image shows the corresponding subtraction, displaying strong, crescent-shaped misalignment artifacts. When the second emission image was retrospectively realigned to the first by three-dimensional homogeneous

Table 1 Head rotations (°) in coronal and sagittal planes between subsequent and within same emission scans Rotation

n

Mean

SD

Maximum

% Rotation > %

Between subsequent dose scan Sagittal 45 1.0 Coronal 45 0.5

0.9 0.5

4.1 2.4

31.1 (% -- 1.21 °) 2.2 (% = 1.55°)

Within same dose scans Sagittal 30 Coronal 30

0.4 0.3

1.6 1.5

16.6 (ctc = 1.21°) 0.0 (orc = 1.55°)

0.7 0.5

Note. t~c is the "critical" angle such that resulting axial displacements are within the interslice distance of 3.8 mm. For anteroposterior and lateral diameters of the skull of 180 mm and 140 ram, and the fulcrum of motion at the back or to the side of the head: sagittal plane - ac = tan -I (3.8/180) = 1.21°, coronal plane - c~c = tan -I (3.8/140) = 1.55°.

U.E. Ruttimann et al./ Psychiatry Research: Neuroimaging 61 (1995) 43-51

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Fig. 4. PET slices obtained before and after injectionof metachlorophenylpiperazine. Top: First (left) and second (right) dose emission images, with measuredinterscan head rotations of 2.4° in the coronal plane and 4.1° in the sagittal plane. Bottom: Subtractionof the imagesabove,before(left)and after (fight) retrospectivedigital realignment.

matrix transformations applied in the opposite directions of the measured motions, the artifacts were substantially reduced (bottom right). The effects of head motion between subsequent scans on the measurement of regional glucose utilization rates and, in particular, their differences between first and second dose images (called

Table 2 Repeated measuresanalysis of variance in combinedregionsof interest (ROIs) for corrected versus uncorrected differences between subsequent dose scans

"metabolic changes" below, to avoid confusion) were analyzed in a repeated measures design. Specifically, paired differences between the scans in a set of predefined ROIs were investigated with and without retrospective digital slice realignment designed to correct for head motion. To summarize the effects on different locations in the brain, the 11 ROIs of Fig. 3 were combined accordingly into frontal, temporal, occipital, and subcortical areas (Table 2). Only in 9 out of 45 pairs of slices was the rotation in the sagittal plane in the negative direction (chin down). Hence, 18 slice pairs (9 each for positive and negative rotations) were available for analysis in the design to counterbalance drug effects (Methods). Multivariate ANOVA (MANOVA) of the four areas indicated that uncorrected metabolic changes were statistically significantly different from zero (H0: the null vector, T 2 = 15.16; F = 3.15; dr= 4, 14, P < 0.05), while those obtained from corrected slices were not (T: = 9.58; F = 1.97; df= 4, 14; P > 0.15). Hence, it is likely that by assuming the motion effects to be negligible, one may falsely conclude that there is a drug effect, when none exists. The results above are consistent with those of a repeated measures MANOVA (Table 2) that tests directly for differences between corrected and uncorrected regional metabolic changes (T 2 = 25.70; F = 5 . 2 9 , dr=4, 14; P = 0 . 0 0 8 ) . The measurements in all brain regions, except the occipital area, were affected by digital realignment (P values not corrected for multiple testing). Of importance to note is the substantial decrease in the variance of the measurements of metabolic changes (estimated from 11 ROIs in 18 slices) from 4.81 for uncorrected slices to 1.10 for corrected slices ( F = 4.38; df= 197, 197, P < 0.0001). 4. D i s c u s s i o n

ROI Frontal Temporal Occipital Subcortical

MS (ROI)

MS (error)

F

16.32 6.52 0.03 38.75

1.10 0.44 !.04 2.28

14.82 14.81 0.02 16.97

P

(dr= 1, 17) 0.001 0.001 0.876 0.001

Note. n = 18 slices,9 positive and 9 negativerotations in the sagittal plane. Multivariate analysis of variance: Hotelling's T2 = 25.70; F= 5.29; dr= 4, 14; P = 0.008.

The optical measurements show that movement restrictions by a face-mask restraint system result in a group average of the head rotations < 1°. Based on this relatively small value, one might be tempted to argue that the impact on glucose utilization measures is small, and that the motion effects will average out to zero. The expectation for the latter to happen is overly optimistic, as in

U.E. Ruttimann et al./ Psychiatry Research: Neuroimaging 61 (1995) 43-51

our sample only 9 out of the 45 slices (20%) underwent negative rotations in the sagittal plane. Indeed, the majority of subjects displayed systematic postural changes ("back arching," probably arising from efforts to alleviate lumbar pain developing over the course of the procedure, causing a slowly increasing backward rotation in the sagittal plane (Fig. 2). Furthermore, in some subjects, even if they are cooperative, much larger than average rotations may occur (Table 1). Due to the usually small sample sizes in PET studies, a few extreme rotations may have a large impact on the variance of the glucose measurements and thus significantly limit the detection of subtle functional differences between subsequent scans. By applying a criterion for angular motion to restrict axial displacements at the borders of the brain to within the interslice distance of 3.8 mm, 31% of the between-dose scans were found to exceed that critical angle for rotation in the sagittal plane. Rotations in the coronal plane are less of a problem because the lateral head dimensions are smaller and the face masks restrain head tilting better than they restrain nodding (maximum rotations of 2.4° vs. 4.1 ° in coronal vs. sagittal planes). Rotations similar in magnitude to those displayed in Table 1 have been measured by an electromagnetic tracking device (which cannot be used in the metallic environment of a scanner) in five subjects placed into a mock setup using the same face-mask restraint system. The group average of each subject's maximum rotation over 45 min was 2 ° and 1° in the sagittal and coronal planes, respectively (Kempner et al., 1987). Motion between sets of scans obtained from the same dose is somewhat less problematic because of the shorter time intervals involved. However, about 17% of the slice sets were still found to exceed the critical-angle limit for sagittal rotations. Since head position discrepancies tend to increase with scanning time (Fig. 2), the use of faster decaying radionuclides, such as 150 (half-life, 123 s) for blood flow studies (Fox and Mintun, 1989) may present an advantage. From 8 to 10 such scans can be acquired within a single PET session lasting about 100 rain. But, if scans collected earlier in the session are to be compared with scans acquired later, or images from equivalent experimental conditions (replications) are averaged to improve the

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signal-to-noise ratio, interscan intervals as long as those arising with the FDG tracer could occur. The analysis of the influence of interscan motion on the assessment of local changes of glucose metabolism (Table 2) supports two major conclusions. First, subject motion occurring despite the head restraint system may significantly affect the estimates of metabolic changes in certain ROIs. This conclusion rests on the assumption of a linear model for drug and motion effects (i.e., absence of "interactions"), which is believed to be realistic for the small rotation angles observed. Specifically, symmetry of the effects with respect to positive and negative rotations was required, which enabled the cancellation of drug effects in the analysis by matching. Under this assumption then, the effects of rotation in one direction caused by subject motion can, to a first order of approximation, be reversed by retrospective digital slice realignment in the opposite direction. Fig. 4 makes it plausible that the restriction to "small" angles required for linearity of the effects is indeed satisfied for the largest angular discrepancies observed in this sample. The fact that the crescent-shaped differences in the subtraction of the uncorrected slices could be largely removed by digital realignment in accordance with the measured head rotations indicates that these differences were mainly due to misregistration and not to drug effects. Since possible drug effects were on the average counterbalanced by design, the differences between "corrected" and "uncorrected" measures of regional glucose utilization change (Table 2) can be considered principally as arising from subject motion. The table also shows that ROIs along the frontal brain border were more affected by motion than ROIs in the occipital lobes. This finding is consistent with the notion that, in general, the fulcrum of the rotations was located at the back of the skull (rolling over the back of the head). The large motion sensitivity of the measurements from ROIs located in the thalamus and the basal ganglia is due to the small sizes of these structures, causing relatively small displacements to have significant impact. The second major conclusion pertains to the increased variance of the uncorrected relative to the corrected measures of metabolic change. Even if

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U.E. Ruttimann et al./Psychiatry Research: Neuroimaging 61 (1995) 43-51

the motion effects were not introducing any statistically significant bias on these estimates of change (i.e., the average of the motion effects is zero due to mutual cancellations), the increased variance would be of concern because of the concomitant reduction of statistical power. With the observed fourfold increase of variance, and assuming conservatively that the variance increased by that amount in only 30% of the slices with rotation angles exceeding otc (Table 1), the standard deviation (SD) in the total sample is estimated to be enlarged by a factor of 1.38. For a typical PET study size of n = 10 subjects and desired power of 0.8 for detecting true changes at the significance level of P = 0.05, that increase of the SD by a factor of 1.38 would cause the power to drop to about 0.52, and require an enlargement of the sample size to n = 18 to restore the original power. Hence, failure to account in some way for interscan motion may incur a substantial loss of statistical power or, alternatively, necessitate almost a doubling of the sample size. A limitation of the present study is that only measurements of rotation about two axes were feasible, and the third rotation and the three linear displacements could not be obtained. Since the linear displacement in the axial direction superposes to the axial displacements arising from sagittal and coronal rotations, the total axial misregistration of some brain regions may even exceed the values reported here. The measurement method used in this study was only developed to obtain some realistic estimates of the magnitude and relevance of the problem, and we do not advocate its routine application. However, a more refined, optoelectronic measurement system is currently under development, capable of real-time measurement of all six motion parameters. With the use of these measurements, "on-the-fly" corrections could be achieved, such as instantaneous position control of the scanner detector ring to follow head movements and produce a virtually stationary emission image. While such data could also be used for retrospective realignment as shown in Fig. 4, realtime motion correction is preferable because it is not restricted by the assumption of a linear effects model. Furthermore, the practice of linear slice interpolation to synthesize "corrected" slices is fraught with problems on its own. The commonly

used slice interpolation is performed under the assumption that all structures represented in a slice are actually located at the exact slice level, which introduces a bias in the direction toward the original slice positions, except at the halfway point (Mintun et al., 1989). This problem could possibly be alleviated by a more elaborate interpolation technique involving removal of scanner-induced blurring before interpolation, followed by appropriate reblurring (necessary for noise reduction) of the synthesized slice (Unser and Aldroubi, in press). Second, slice interpolation causes additional smoothing in the axial direction and concomitant loss of resolution. Based on the work by Worsley et al. (1992), the axial FWHM is expected to increase in the present context from 10.5 mm to at least 12.5 mm. However, we consider this to be a severe underestimation because the theory for this estimate requires the assumption of a Gaussian-shaped decay of the interpixel correlation function. While this is a good approximation for the correlation due to scanner-induced blurring, the correlation caused by anatomic structures decays at a much slower rate and extends over several slices (Ruttimann et al., 1993). Consequently, the resulting value of the axial FWHM due to interpolation is much larger, a finding congruant with visual inspection of the relevant images. Hence, head motion restriction by a face-mask restraint system is not sufficient and the resulting misregistration artifacts curtail the sensitivity of detecting real differences of local glucose utilization rates. While retrospective slice realignment offers some improvement, real-time correction during scan acquisition would be preferable. Since head motion already limits measurement accuracy in currently available scanners, further resolution improvements in next-generation machines should be accompanied by systems enabling the monitoring and correction of subject motion, if the potential advantages of better - - and more expensive - instruments are to be fully exploited. References Andreason, P.J., George, D.T., Szymanski, H., Momenan, R., Zametkin, A.J., Linnoila, M. and Eckardt, M.J. (1992) Cerebral glucose utilization in detoxified alcoholics ad-

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ministered the serotonin agonist mCPP. Alcohol Clin Exp Res 15, 367. Andreason, P.J., Zametkin, A.J., Guo, A.C., Baldwin, P. and Cohen, R.M. (1994) Gender-related PET differences in regional cerebral glucose metabolism in normal volunteers. Psychiatry Res 51, 175-183. Brooks, R.A., Di Chiro, G., Zukerberg, B.W., Bairamin, D. and Larson, S.M. (1987) Test-retest studies of cerebral glucose metabolism using fluorine-I8 deoxyglucose: validation of method. J Nucl Med 28, 53-59. Cohen, R.M., Semple, W.E., Gross, M., Holcomb, H.H., Dowling, M.S. and Nordahl, T.E. (1988) Functional localization of sustained attention: comparison to sensory stimulation in the absence of instruction. Neuropsychiatry, Neuropsychology, and Behavioral Neurology 1, 3-20. Daube-Witherspoon, M.E., Green, M.V. and Holte, S. (1987) Performance of Scanditronix PCI024-7B PET scanner. (Abstract 211) J Nucl Med 28, 607-608. Fox, P.T. and Mintun, M.A. (1989) Noninvasive functional brain mapping by change-distribution analysis of averaged PET images of H2150 tissue activity. J Nucl Med 30, 141-149. Kempner, K., Stein, S. and Green, M. (1987) An image inde-

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pendent method of evaluating the efficacy of head restraint devices used in brain imaging. (Abstract 1008) J Nucl Med Technol 15, Ab5. Matsui, T. and Hirano, A. (1978) An Atlas of the Human Brain for Computerized Tomography. Igaku-Shoin, Tokyo. Mintun, M.A., Fox, P.T. and Ralchle, M.E. (1989) A highly accurate method of localizing regions of neuronal activation in the human brain with positron emission tomography. J Cereb Blood Flow Metab 9, 96-103. Rogers, D.A. and Adams, J.A. 0976) Mathematical Elements for Computer Graphics. McGraw-Hill, New York, pp. 46-88. Ruttimann, U.E., Unser, M., Rio, D.E. and Rawlings, R.R. (1993) Use of wavelet transform to investigate differences in brain PET images between patient groups. Proc SPIE Math Methods Med Imaging 2035, 192-203. Unser, M. and Aldroubi, A. (1994) A general sampling theory for non-ideal acquisition devices. IEEE Tram Signal Processing 42, 2915-2925. Worsley, K.J., Evans, A.C., Marrett, S. and Neelin, P. (1992) A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab 12, 900-918.