Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198 & 2012 ISCBFM All rights reserved 0271-678X/12 $32.00 www.jcbfm.com
Statistical parametric mapping demonstrates asymmetric uptake with Tc-99m ECD and Tc-99m HMPAO SPECT in normal brain Benjamin H Brinkmann1,2,7, David T Jones3,7, Matt Stead1,3, Noojan Kazemi4, Terence J O’Brien4, Elson L So3, Hal Blumenfeld5, Brian P Mullan6 and Gregory A Worrell1,3 1
Mayo Systems Electrophysiology Laboratory, Mayo Clinic, Rochester, Minnesota, USA; 23D Medical Imaging, LLC, Byron, Minnesota, USA; 3Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA; 4 Departments of Medicine and Neurology, The Royal Melbourne Hospital, Victoria, Australia; 5 Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA; 6 Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198; doi:10.1038/jcbfm.2011.123; published online 21 September 2011 Keywords: brain asymmetry; brain imaging; SPECT
Introduction Cerebral perfusion is commonly studied using a variety of isotopes and tracer molecules in singlephoton emission computed tomography (SPECT), including Tc-99m ethyl cysteinate diethylester (ECD), Tc-99m hexamethyl propylene amine oxime (HMPAO), I-123 isopropyl n-iodoamphetamine. These radiotracers are absorbed and bound in cortical tissues with a limited amount of back-
Correspondence: Dr BH Brinkmann, Mayo Systems Electrophysiology Laboratory, 200 First Street SW, Rochester, MN 55905, USA. E-mail:
[email protected] 7 These authors contributed equally to the study. This work was supported by the National Institiutes of Health (Grant R01-NS63039) and by an intramural Novel Methodology Development Award from Mayo Clinic. Received 6 January 2011; revised 16 July 2011; accepted 18 July 2011; published online 21 September 2011
diffusion, providing the advantage that a highquality image can be acquired of the cerebral blood flow patterns even after a delay of several hours after the tracer injection. This is particularly advantageous for obtaining images of the blood flow patterns during a seizure, i.e., ‘ictal SPECT’. Positron emission tomography (PET) is capable of mapping cerebral perfusion with higher spatial resolution than SPECT using O-15-labeled water, although PET isotopes are expensive, not available to many centers, and have short half-lives. O-15 PET images represent the immediate perfusion state of the brain at the time of image acquisition and are essentially limited to interictal (between seizures) studies because of the logistical challenge of injecting and immediately scanning the patient during a seizure. Cerebral blood flow is an important diagnostic metric in stroke (Liebeskind, 2009), neurodegenerative disease (Josephs et al, 2006), movement disorders (Takahashi et al, 2010), and epilepsy (Duncan, 2009; O’Brien et al, 2000; Kazemi et al, 2009), and is
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 191
frequently used as a surrogate estimation of neural activity in clinical neurology and research studies of cerebral function. In many cerebral perfusion studies, the homologous contralateral brain region is used as a reference to estimate the magnitude of perfusion abnormalities, or brain regions are laterally averaged to reduce noise and increase statistical sensitivity. Lateral differences in SPECT tracer uptake have been used to identify the abnormal brain regions in temporal lobe epilepsy (Rowe et al, 1991; Newton et al, 1994; Devous et al, 1998), stroke (Mountz et al, 2003), and Parkinsons disease (Felicio et al, 2009). In many studies where activity changes are statistically analyzed or mapped, it is not uncommon for investigators to laterally mirror images to align the clinically affected side or effect of interest to increase statistical power (Chassagnon et al, 2009). This approach assumes that the normal pattern of cerebral perfusion is sufficiently symmetric that direct left–right comparisons offer a valid, unbiased estimate of deviation from normal resting perfusion. However, it is well known that the normal human brain exhibits significant asymmetry in structure and function (Toga and Thompson, 2003). The physical shape of brain exhibits a characteristic Yakovlevian torque (LeMay, 1976; Galaburda et al, 1978), or petalia, where the right frontal lobe is wider and protrudes more anteriorly than the left, whereas the left occipital lobe is wider and extends farther posteriorly than the right. Many structural asymmetries of the brain center around the perisylvian area and are correlated with handedness (Toga and Thompson, 2003). The superior curvature of Sylvian fissure occurs more anteriorly on the right side than on the left (LeMay, 1976), resulting in a more anterior and superior termination point for the Sylvian fissure on the right side. The planum temporale, a triangular region of cortex located just below the posterior Sylvian fissure involved in auditory and language perception, is up to 10 times greater in volume on the left side compared with the right, particularly in righthanded individuals (Geschwind and Levitsky, 1968; Pieniadz and Naeser, 1984; Steinmetz et al, 1991; Shapleske et al, 1999; Watkins, 2001), although one study found an overall increase in gray matter density on the right side (Good et al, 2001). Hippocampal volumes have also been shown to be asymmetric, with the right side larger (Jack et al, 1989). Functional lateralization is one of the foundations of brain organization, and is well documented through lesion studies (Brain, 1941; Rasmussen and Milner, 1977), direct electrical stimulation of cortex (Penfield and Jasper, 1954), and intracarotid sodium amytal testing (Wada et al, 1975), with language functions typically residing in the left hemisphere and showing a strong correlation with planum temporale size and right handedness (Foundas et al, 1995). Prior studies investigating lateral asymmetry in SPECT images of normal brain have used visual comparison (Aubert-Broche et al, 2005), manually
placed or drawn region of interest (ROI) measurements (Markus et al, 1993; Catafau et al, 1996; Baird et al, 1999; Grova et al, 2003; Aubert-Broche et al, 2005), template-based ROI measurements (Krausz et al, 1998; Van Laere et al, 2001) or a two-compartment model (Risberg et al, 1975) to assess asymmetry. Prior studies have not, however, provided a comprehensive picture of the patterns of SPECT asymmetry. Although differences have been shown between perfusion tracers (Koulibaly et al, 2003; Ito et al, 2006; Inoue et al, 2003), prior studies of normal resting asymmetry have not directly addressed the influence of the tracer. This information is important in providing a context for perfusion asymmetry measured in pathologic states, as well as in assessing the validity of left–right averaging in perfusion experiments. The purpose of the present study was to measure and analyze asymmetries in baseline SPECT tracer uptake patterns in normal volunteers using semiautomated ROI analysis and statistical parametric mapping (SPM; Frackowiak et al, 1997). The two methods are complementary, as the ROI approach lends itself to a quantitative presentation of statistical results, whereas the SPM analysis provides a spatial map of statistically significant asymmetry.
Materials and methods Volunteer Selection and SPECT Imaging For SPECT statistical analysis and mapping, a control group of SPECT images from 30 volunteers without any history of neurologic disease were acquired. The median age of the normal volunteers was 27.75 years (range 18.13 to 39.68 years). The group contained 15 males and 15 females, and 16 right-handed and 3 left-handed individuals, with hand preference unknown in 11 individuals. Volunteers were recruited through the Department of Nuclear Medicine at Mayo Clinic in accordance with an institutional review board-approved protocol, and all volunteers gave informed written consent to participate. The injected isotope, ambient conditions, and imaging protocol were identical to that used for a routine clinical SPECT brain imaging study. In the protocol, 20 mCi of Tc99m ECD were injected intravenously with ambient room lighting and the subject’s eyes open and ears unplugged. Isotope injections were performed in either the left or right arm, with the technologist delivering verbal instructions during the injection. Images were acquired on a dualheaded Elscint Helix gamma camera system (Elscint, Haifa, Israel) with ultrahigh-resolution fan beam collimators. Projections were acquired on a 128 128-pixel matrix over a 3601 circular orbit, with 120 views obtained at 31 intervals. For all studies, the gamma camera performed five 3601 orbits at 3 seconds per view at an energy setting of 140 keV with a 15% to 20% window. Images were reconstructed with ordered subset expectation maximization and a Metz filter (power, 3, full-width at halfmaximum (FWHM), 6 mm) rebinned into a 64 64 matrix with a 2 zoom. Chang attenuation correction (0.12 cm) Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 192
was applied (Chang, 1978), and a standard series of contiguous images was created in the transaxial, coronal, sagittal, and transtemporal planes.
Region of Interest Analysis Post-acquisition image processing for ROI analysis was performed using AnalyzeAVW 10.0 (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN, USA).
Cerebral pixels were identified in each subject’s SPECT by interactive thresholding. The anterior temporal lobes were segmented using a semi-automated seeded-regiongrowing algorithm using the global cerebral threshold value. Mean pixel intensities within each temporal ROI were measured and recorded, and the mean temporal pixel intensities were normalized to the cerebral extratemporal pixel mean. Hemispheric ROI’s were determined by dividing the thresholded brain along the
Figure 1 Lateral comparison performed in statistical parametric mapping (SPM) using a paired t-test between the original and mirrored normal ethyl cysteinate diethylester single-photon emission computed tomography (SPECT) images at a significance level of P < 0.001 shown (A) rendered on a standard atlas brain surface, (B) on an SPM glass brain display, and (C) on orthogonal sections through the T1 weighted MRI atlas brain image. Regions of increased SPECT signal relative to the contralateral hemisphere are shown in red, whereas regions of decreased signal are shown in green. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 193
interhemispheric fissure. A paired t-test was performed comparing the left and right normalized intensities for the temporal lobes and cerebral hemispheres using the statistics package in Matlab r2008a (The MathWorks, Natick, MA, USA). An asymmetry index was calculated using the following formula: ðRight LeftÞ AI ¼ 100% 1 2 ðRight þ LeftÞ
Unpaired t-tests were performed to compare the temporal and hemispheric asymmetry indices for the gender and handedness groups. The ECD and HMPAO images were spatially normalized to a high-resolution Montreal Neurological Institute (MNI) brain atlas (Montreal Neurological Institute, Montreal, Quebec, Canada), and SPECT signal intensity was measured in regions of interest defined by the anatomical automatic labeling template (Tzourio-Mazoyer
Figure 2 Lateral paired t-test result for the 14 hexamethyl propylene amine oxime normal single-photon emission computed tomography (SPECT). Analysis was performed at a significance level of P < 0.001 with a cluster-level threshold of 125, and are shown (A) rendered on a standard atlas brain surface, (B) on an statistical parametric mapping (SPM) glass brain display, and (C) on orthogonal sections through the T1 weighted MRI atlas brain image. Regions of increased SPECT signal relative to the contralateral hemisphere are shown in red, whereas regions of decreased signal are shown in green. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 194
et al, 2002) using the MarsBar toolbox (http://marsbar. sourceforge.net/).
Table 1 Asymmetry index values from ROI-measured pixel counts normalized to mean cerebral counts for the 30 normal volunteer Tc-99m ECD scans and the 14 normal volunteer Tc-99m HMPAO scans
Statistical Parametric Mapping
Asymmetry indices
Normal volunteer HMPAO SPECT images were obtained in Analyze 7.5 format, whereas volunteer ECD images were converted from Dicom to Analyze format for compatibility with SPM. Images were copied and flipped laterally using Analyze 10.0. The original and mirrored copy of each image were spatially normalized to a symmetric SPECT template using a nonlinear image registration algorithm implemented as part of the SPM-2 package (Wellcome Institute of Neurology, University of London, UK, http:// www.fil.ion.ucl.ac.uk/spm/) running under MATLAB 7.1 (Mathworks, Sherborne, MA, USA). The symmetric SPECT template was constructed from three of our normal ECD subject images by first smoothing with an 8 8 8 Gaussian kernel, spatially normalizing them to the standard SPM-2 SPECT template, and averaging the normalized images. A copy of this spatially normalized mean image was then flipped laterally using ImageJ (Rasband, 2011), and averaged with the original mean image. Once normalized to this composite, symmetric template all volunteer SPECT images were visually inspected. Images were then smoothed in SPM2 using a three-dimensional 16 mm Gaussian kernel before statistical analysis. A paired t-test was then performed in SPM-2 between the original and flipped copies of the normalized and smoothed SPECT images. Proportional scaling to a global mean value of 50 was used, with a gray matter mask threshold of 0.8 times the mean and a mean voxel value global calculation. Nonsphericity correction was not used. T-contrasts were defined, and results displayed with a significance threshold of P < 0.001 (not corrected for multiple comparisons), and a cluster-level threshold of 125 contiguous voxels (1 cm3) was used (McNally et al, 2005). Prior studies have shown some differences in the uptake patterns of Tc-99m ECD, Tc-99m HMPAO, and other tracers (O’Brien et al, 1999; Inoue et al, 2003). To assess differences in observed asymmetry between different SPECT tracers, we obtained 14 sets of paired resting HMPAO SPECT images of normal volunteers from the Yale University Epilepsy Research Group (http://spect.yale. edu/; McNally et al, 2005). We repeated the mirror image SPM paired t-test analysis using only the initial scan from each subject. Gender, handedness, and age information were not available for the HMPAO scans, and hence these analyses were not repeated on this image set.
Results Statistical Parametric Mapping Results of SPM analysis of the original and mirrored images from the 30 normal subjects injected with Tc-99m ECD are shown in Figure 1. In widespread areas of the cerebral hemispheres the tracer uptake was lower on the right side compared with the left, with the most marked areas of asymmetric SPECT signal in the frontal lobes, Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
Mean
s.d.
Median
Range
Tc-99m ECD Temporal lobe Hemisphere
2.689 1.362
2.223 0.936
2.738 1.235
2.877, 6.939 0.357, 3.259
Tc-99m HMPAO Temporal lobe Hemisphere
1.429 0.512
1.457 0.858
1.197 0.500
1.638, 3.905 0.555, 2.383
ECD, ethyl cysteinate diethylester; HMPAO, hexamethyl propylene amine oxime; ROI, region of interest.
and parietotemporal region near the vertex. Analysis of the 14 normal Tc-99m HMPAO SPECT images shows a similar pattern of asymmetry (Figure 2).
Region of Interest Results Region of interest results for the left–right comparison are shown in Table 1. The mean (±s.d.) asymmetry index overall for the Tc-99m ECD group was 2.689% (2.227) for the temporal lobes (significant with P = 2.992 107, one-sample t-test) and 1.362% (0.9365) for the left and right hemisphere comparison (significant with P = 8.735 109). The mean (±s.d.) asymmetry index for the temporal lobes for males was 2.085% (2.011) compared with 3.294% (2.332) for females, which was not statistically significant (two-sample student’s t-test). The mean (±s.d.) asymmetry index for the left–right hemisphere comparison was 1.373% (0.789) for males compared with 1.351% (1.092) for females (not statistically significant, two-sample t-test). The mean (±s.d.) asymmetry index for right-handed subjects was 1.221% (0.652) and 0.294% (0.359) for left-handed subjects (not statistically significant, two-sample t-test). Asymmetry index values for regions defined in the anatomical automatic labeling template are plotted in Figures 3A and 3B for the 30 Tc-99m ECD normals and the 14 Tc-99m HMPAO normals, respectively. Asymmetry index values from aggregated regions (lobes) in the anatomical automatic labeling template for the ECD and HMPAO groups are shown in Figures 4A and 4B, respectively. Note that in contrast to the results presented in Table 1, these measurements do not include white matter areas, and the hippocampal and parahippocampal regions were grouped with the limbic aggregation. Linear regression analysis of age effects on the asymmetry index for the temporal lobe and interhemispheric comparisons are plotted in Figure 5. Neither the regression for the temporal lobe nor the hemisphere asymmetry achieved statistical significance. Temporal lobe R2 = 0.0279, cerebral hemispheres R2 = 0.0109. Similar findings were obtained for the ROI analysis of the Tc-99m HMPAO SPECT image group, with the overall mean (±s.d.) asymmetry index for the temporal lobes being 1.429% (1.457) (significant with P = 0.00283, one-sample t-test) and for the interhemispheric comparison 0.512% (0.858; significant with P = 0.0438, one-sample t-test).
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 195
Figure 3 There is significant heterogenity in the laterality of the single-photon emission computed tomography (SPECT) signal at the spatial scale generated by the automated anatomical labeling (AAL) template. (A) Asymmetry indices (AI) for the 30 Tc-99m ethyl cysteinate diethylester (ECD) SPECTs measured with the AAL MNI brain template. (B) Asymmetry indices for the 14 Tc-99m hexamethyl propylene amine oxime (HMPAO) SPECTs measured with the AAL MNI brain template. Error bars represent 1 standard deviation about the mean. Negative AI values correspond to greater signal on the left, whereas positive values indicate rightward asymmetry.
Discussion The results of this study show that there are significant regional asymmetries between the cerebral hemispheres in SPECT images of neurologically normal volunteers at rest. The similarities in the pattern of asymmetry between the Tc-99m ECD and Tc-99m HMPAO groups suggest that the observed laterality in SPECT tracer uptake reflects differences in anatomy or physiology between the brain
hemispheres rather than particular factors related to retention of the individual tracers. To provide an objective measure of the similarities between the laterality of the two tracers, cluster locations were measured at peak intensity in the SPM-2 brain atlas, coordinates were transformed from MNI space to the Talairach coordinate system using a standard nonlinear transformation (Brent, 2002), and Brodmann areas were identified using the Talairach Applet (Lancaster et al, 2000). Numerous clusters for the Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 196
Figure 4 (A) Asymmetry indices (AI) for the 30 Tc-99m ethyl cysteinate diethylester (ECD) single-photon emission computed tomography (SPECT) measured for aggregated lobes and regions in the anatomical automatic labeling (AAL) MNI brain template. (B) Asymmetry indices for the 14 Tc-99m hexamethyl propylene amine oxime (HMPAO) SPECTs measured for aggregated lobes and regions in the AAL MNI brain template. Error bars represent 1 standard deviation about the mean. Negative AI values correspond to greater signal on the left, whereas positive values indicate rightward asymmetry.
two tracers mapped to identical or adjacent Brodmann areas, including the frontoparietal border (Brodmann area 6), the prefrontal cortex (Brodmann area 10), the inferoposterior temporal lobe (Brodmann 20 for ECD, 37 for HMPAO), and parietal cortex (Brodmann 42 for ECD, and 40 for HMPAO). Prior studies that have analyzed laterality in Tc-99m HMPAO and ECD SPECT brain images have found significant lateral variation in tracer uptake. Many prior studies have shown greater SPECT signal on the right side than on the left, though with a large degree of regional variation between studies. Catafau et al (1996) showed a mixed left–right pattern of asymmetry in a cohort of control subjects of similar age to our ECD group, and a stronger rightward pattern in a much older cohort, suggesting that SPECT laterality becomes progressively rightward with increasing subject age. Other prior reports of rightward laterality with HMPAO or ECD SPECT Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
tracers used subjects significantly older than (Baird et al, 1999; Lobaugh et al, 2000), or spanning a larger age range (Van Laere et al, 2001; Markus et al, 1993; Grova et al, 2003) than our cohort. Krausz et al (1998) showed a mixed pattern of laterality in a group of subjects spanning a wide range of ages. A number of these prior studies relied upon manual ROI placement, which is prone to operator variability, and offers too limited a sampling to reconstruct a comprehensive picture of tracer asymmetry. Although one study (Van Laere et al, 2001) used SPM to analyze changes in uptake pattern with age, no prior study to our knowledge has used SPM to directly examine lateral SPECT asymmetry. In addition, this is the first study to our knowledge to examine lateral asymmetry in SPECT scans reconstructed without rampfiltered back projection (the Tc-99m ECD group was reconstructed with ordered subset expectation maximization). The present study did not find a
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 197
References
Figure 5 Regression analysis of age effects on temporal and hemispheric perfusion asymmetry for the Tc-99m ethyl cysteinate diethylester normals.
significant dependence of asymmetry with hand preference, which has been observed in prior anatomical studies (Steinmetz et al, 1991). However, the limited availability of left-handed subjects in our cohort limited the statistical power for this analysis, and future studies with additional left-handed subjects might show such an effect. Factors such as the presence of ambient noise, ambient light, verbal instructions by the technician, the choice of tracer injection site and side, and whether the subject’s eyes were open or closed could potentially affect the baseline pattern of tracer uptake, and these factors should be tightly controlled in the experimental setup, as well as in clinical practice. This study has shown a pattern of asymmetric cerebral uptake of Tc-99m HMPAO and Tc-99m ECD SPECT in two groups of neurologically normal adults, with greater SPECT signal on the left than on the right. This asymmetry was identified via semiautomated and automated region-based analyses, as well as voxel-based SPM analysis, and was observed in SPECT scans of normal subjects from two different imaging centers with two different tracers. Lateral SPECT differences have an important role in diagnosis of epilepsy, stroke, and neurodegenerative disorders, and the results of this study indicate that these clinical SPECT image interpretations should be made using an appropriate baseline taking into account the normal pattern of hemispheric asymmetry.
Acknowledgements We are grateful for the technical assistance of Royce Ruter, Cindy Nelson, and Karla Crockett.
Disclosure/conflict of interest The authors declare no conflict of interest.
Aubert-Broche B, Jannin P, Biraben A, Bernard AM, Haegelen C, Le Jeune FP, Gibaud B (2005) Evaluation of methods to detect interhemispheric asymmetry on cerebral perfusion SPECT: application to epilepsy. J Nuc Med 46:707 Baird AE, Donnan GA, Austin MC, Hennessy OF, Royle J, McKay WJ (1999) Asymmetries of cerebral perfusion in a stroke-age population. J Clin Neurosci 6:113–20 Brain WR (1941) A form of visual disorientation resulting from lesions of the right cerebral hemisphere: (section of neurology). Proc R Soc Med 34:771–6 Brent M (2002) CBU Imaging Wiki. /http://imaging.mrccbu.cam.ac.uk/imaging/MniTalairachS Catafau AM, Lomen˜a FJ, Pavia J, Parellada E, Bernardo M, Setoain J, Tolosa E (1996) Regional cerebral blood flow pattern in normal young and aged volunteers: a 99mTcHMPAO SPET study. Eur J Nucl Med 23:1329–37 Chang L (1978) A method for attenuation correction in radionuclide computed tomography. IEEE Trans Nucl Sci 25:638–43 Chassagnon S, Namer I, Armspach J, Nehlig A, Kahane P, Kehrli P, Valenti M, Hirsch E (2009) SPM analysis of ictal–interictal SPECT in mesial temporal lobe epilepsy: relationships between ictal semiology and perfusion changes. Epilepsy Res 85:252–60 Devous MD, Thisted RA, Morgan GF, Leroy RF, Rowe CC (1998) SPECT brain imaging in epilepsy: a metaanalysis. J Nucl Med 39:285–93 Duncan J (2009) The current status of neuroimaging for epilepsy. Curr Opin Neurol 22:179–84 Felicio AC, Shih MC, Godeiro-Junior C, Andrade LAF, Bressan RA, Ferraz HB (2009) Molecular imaging studies in Parkinson disease: reducing diagnostic uncertainty. Neurologist 15:6–16 Foundas AL, Leonard CM, Heilman KM (1995) Morphologic cerebral asymmetries and handedness. The pars triangularis and planum temporale. Arch Neurol 52:501–8 Frackowiak RSJ, Friston KJ, Frith CD, Dolan RJ, Mazziotta JC (eds). (1997) Human Brain Function. New York: Academic Press Geschwind N, Levitsky W (1968) Human brain: left-right asymmetries in temporal speech region. Science 161: 186–7 Galaburda AM, LeMay M, Kemper TL, Geschwind N (1978) Right-left asymmetrics in the brain. Science 199:852–6 Good CD, Johnsrude I, Ashburner J, Henson RN, Friston KJ, Frackowiak RS (2001) Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains. Neuroimage 14:685–700 Grova C, Jannin P, Biraben A, Buvat I, Benali H, Bernard AM, Scarabin JM, Gibaud B (2003) A methodology for generating normal and pathological brain perfusion SPECT images for evaluation of MRI/SPECT fusion methods: application in epilepsy. Phys Med Biol 48:4023–43 Inoue K, Nakagawa M, Goto R, Kinomura S, Sato T, Sato K, Fukuda H (2003) Regional differences between 99m Tc-ECD and 99m Tc-HMPAO SPET in perfusion changes with age and gender in healthy adults. Eur J Nucl Med Mol Imaging 30:1489–97 Ito H, Inoue K, Goto R, Kinomura S, Taki Y, Okada K, Sato K, Sato T, Kanno I, Fukuda H (2006) Database of normal human cerebral blood flow measured by SPECT: Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
SPM of asymmetric SPECT in normal brain BH Brinkmann et al 198
I. Comparison between I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD as referred with O-15 labeled water PET and voxel-based morphometry. Ann Nucl Med 20:131–8 Jack CR, Jr, Twomey CK, Zinsmeister AR, Sharbrough FW, Petersen RC, Cascino GD (1989) Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults. Radiology 172:549–54 Josephs KA, Duffy JR, Strand EA, Whitwell JL, Layton KF, Parisi JE, Hauser MF, Witte RJ, Boeve BF, Knopman DS, Dickson DW, Jack CR, Petersen RC (2006) Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech. Brain 129:1385–98 Kazemi NJ, Worrell GA, Stead SM, Brinkmann BH, Mullan BP, O’Brien TJ, So EL (2009) Ictal SPECT statistical parametric mapping in temporal lobe epilepsy surgery. Neurology 74:70–6 Koulibaly PM, Nobili F, Migneco O, Vitali P, Robert PH, Girtler N, Darcourt J, Rodriguez G (2003) 99mTcHMPAO and 99mTc-ECD perform differently in typically hypoperfused areas in Alzheimer’s disease. Eur J Nucl Med Mol Imaging 30:1009–13 Krausz Y, Bonne O, Gorfine M, Karger H, Lerer B, Chisin R (1998) Age-related changes in brain perfusion of normal subjects detected by 99m Tc-HMPAO SPECT. Neuroradiology 40:428–34 Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10:120–31 LeMay M (1976) Morphological cerebral asymmetries of modern man, fossil man, and nonhuman primate. Ann N Y Acad Sci 280:349–66 Liebeskind DS (2009) Imaging the future of stroke: I. Ischemia. Ann Neurol 66:574–90 Lobaugh NJ, Caldwell CB, Black SE, Leibovitch FS, Swartz RH (2000) Three brain SPECT region-of-interest templates in elderly people: normative values, hemispheric asymmetries, and a comparison of single- and multihead cameras. J Nucl Med 41:45–56 Markus HS, Ring H, Kouris K, Costa DC (1993) Alterations in regional cerebral blood flow, with increased temporal interhemispheric asymmetries, in the normal elderly: an HMPAO SPECT study. Nucl Med Commun 14:628 McNally KA, Paige AL, Varghese G, Zhang H, Novotny EJ, Spencer SS, Zubal IG, Blumenfeld H (2005) Localizing value of ictal-interictal SPECT analyzed by SPM (ISAS). Epilepsia 46:1450–64 Mountz JM, Liu H, Deutsch G (2003) Neuroimaging in cerebrovascular disorders: measurement of cerebral physiology after stroke and assessment of stroke recovery. Semin Nucl Med 33:56–76 Newton MR, Berkovic SF, Austin MC, Rowe CC, McKay WJ, Bladin PF (1994) Ictal postictal and interictal singlephoton emission tomography in the lateralization of temporal lobe epilepsy. Eur J Nucl Med 21:1067–71 O’Brien TJ, Brinkmann BH, Mullan BP, So EL, Hauser MF, O’Connor MK, Hung J, Jack CR (1999) Comparative
Journal of Cerebral Blood Flow & Metabolism (2012) 32, 190–198
study of 99mTc-ECD and 99mTc-HMPAO for peri-ictal SPECT: qualitative and quantitative analysis. J Neurol Neurosurg Psychiatry 66:331 O’Brien TJ, So EL, Mullan BP, Cascino GD, Hauser MF, Brinkmann BH, Sharbrough FW, Meyer FB (2000) Subtraction peri-ictal SPECT is predictive of extratemporal epilepsy surgery outcome. Neurology 55:1668–77 Penfield W, Jasper H (1954) Epilepsy and the Functional Anatomy of the Human Brain. Boston, MA: Little, Brown, & Co Pieniadz JM, Naeser MA (1984) Computed tomographic scan cerebral asymmetries and morphologic brain asymmetries. Correlation in the same cases post mortem. Arch Neurol 41:403–9 Rasband WS (2011) ImageJ, US National Institutes of Health, Bethesda, MD, USA, http://imagej.nih.gov/ij/ Rasmussen T, Milner B (1977) The role of early left-brain injury in determining lateralization of cerebral speech functions. Ann N Y Acad Sci 299:355–69 Risberg J, Halsey JH, Wills EL, Wilson EM (1975) Hemispheric specialization in normal man studied by bilateral measurements of the regional cerebral blood flow. A study with the 133-Xe inhalation technique. Brain 98:511–24 Rowe CC, Berkovic SF, Austin MC, Saling M, Kalnins RM, McKay WJ, Bladin PF (1991) Visual and quantitative analysis of interictal SPECT with technetium-99mHMPAO in temporal lobe epilepsy. J Nucl Med 32:1688–94 Shapleske J, Rossell SL, Woodruff PW, David AS (1999) The planum temporale: a systematic, quantitative review of its structural, functional and clinical significance. Brain Res Brain Res Rev 29:26–49 Steinmetz H, Volkmann J, Ja¨ncke L, Freund HJ (1991) Anatomical left-right asymmetry of language-related temporal cortex is different in left- and right-handers. Ann Neurol 29:315–9 Takahashi R, Ishii K, Shimada K, Ohkawa S, Nishimura Y (2010) Hypoperfusion of the motor cortex associated with parkinsonism in dementia with Lewy bodies. J Neurol Sci 288:88–91 Toga AW, Thompson PM (2003) Mapping brain asymmetry. Nat Rev Neurosci 4:37–48 Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15:273–89 Van Laere K, Versijpt J, Audenaert K, Koole M, Goethals I, Achten E, Dierckx R (2001) 99mTc-ECD brain perfusion SPET: variability, asymmetry and effects of age and gender in healthy adults. Eur J Nucl Med 28:873–87 Wada JA, Clarke R, Hamm A (1975) Cerebral hemispheric asymmetry in humans. Cortical speech zones in 100 adults and 100 infant brains. Arch Neurol 32:239–46 Watkins KE (2001) Structural asymmetries in the human brain: a voxel-based statistical analysis of 142 MRI scans. Cerebral Cortex 11:868–77
