A surface-in gradient of thalamic damage evolves in pediatric multiple sclerosis.

OBJECTIVE: Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface-in" process of injury suggesting progressive biology may begin. METHODS: We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation-based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. RESULTS: Twenty-seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow-up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface-in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021). INTERPRETATION: Our results suggest that a multiple sclerosis disease-specific surface-in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340-351.

Enhanced Recruitment During Executive Control Processing in Cognitively Preserved Patients With Pediatric-Onset MS.

OBJECTIVES: Youth and young adults with pediatric-onset multiple sclerosis (MS) are vulnerable to executive dysfunction; however, some patients do not demonstrate functional deficits despite showing abnormalities on structural magnetic resonance imaging (MRI). Cognitively intact adults with MS have shown enhanced activation patterns relative to healthy controls on working memory tasks. We aim to evaluate whether cognitively preserved pediatric-onset MS patients engage compensatory recruitment strategies to facilitate age-normative performance on a task of working memory. METHODS: Twenty cognitively preserved patients (mean age=18.7±2.7 years; 15 female) and 20 age- and sex-matched controls (mean age=18.5±2.9 years; 15 female) underwent neuropsychological testing and 3.0 Tesla MRI, including structural and functional acquisitions. Patterns of activation during the Alphaspan task, a working memory paradigm with two levels of executive control demand, were examined via whole-brain and region of interest (ROI) analyses. RESULTS: Across all participants, lower accuracy and greater activation of regions implicated in working memory were observed during the high demand condition. MS patients demonstrated 0.21 s longer response time than controls. ROI analyses revealed enhanced activation for pediatric-onset MS patients relative to controls in the right middle frontal, left paracingulate, right supramarginal, and left superior parietal gyri during the low executive demand condition, over and above differences in response time. MS patients also demonstrated heightened activation in the right supramarginal gyrus in the high executive demand condition. CONCLUSIONS: Our findings suggest that pediatric-onset MS patients may engage compensatory recruitment strategies during working memory processing. (JINS, 2019, 25, 432-442).

Impaired growth of the cerebellum in pediatric-onset acquired CNS demyelinating disease.

BACKGROUND: Acquired demyelinating syndromes (ADS) have the potential to negatively impact cerebellar growth, given the proclivity for infratentorial lesions in pediatric-onset multiple sclerosis (MS) and ADS. OBJECTIVE: To investigate cerebellar growth longitudinally in pediatric ADS. METHODS: Cerebellar volumes from 472 magnetic resonance imaging (MRI) scans of 98 patients with monophasic ADS (monoADS), monophasic acute disseminated encephalomyelitis (ADEM), and MS (49 girls; mean age: 11.4 years at first scan, mean follow-up: 3.1 years) imaged serially from onset and 897 MRI scans of 418 healthy children (223 girls, mean age: 11.3 years, mean follow-up: 2.9 years) were segmented automatically, analyzed with mixed-effect models, and compared with cerebral volume. RESULTS: Cerebellar developmental trajectories followed a U-shaped curve, showing larger volumes in boys (p < 0.001). Cerebellar volumes in all three patient groups failed to reach age-expected trajectories, leading to significantly smaller volumes, notably in the posterior lobes. Cerebellar volume reductions were of a similar magnitude to cerebral volume reductions. Cerebellar white matter volume declined in MS and ADEM patients over time, while in monoADS patients it remained similar to controls. Cerebellar volumes did not correlate either with lesion volumes at onset or with physical disability. CONCLUSION: MonoADS, ADEM, and MS in childhood lead to impaired age-expected growth of the cerebellum.

Altered resting-state functional connectivity in cognitively preserved pediatric-onset MS patients and relationship to structural damage and cognitive performance.

OBJECTIVE: To evaluate resting-state functional connectivity (FC) and relationship to brain volumes and cognition in a sample of cognitively preserved pediatric-onset multiple sclerosis (MS) patients. METHODS: Sixteen cognitively intact pediatric-onset MS patients and 15 healthy age- and sex-matched controls underwent cognitive testing and 3T anatomical and functional MRI. Resting-state FC patterns were examined using region-of-interest-based timeseries correlations. RESULTS: Compared to controls, pediatric-onset MS patients demonstrated higher FC of the precuneus, particularly with the anterior cingulate cortex (z=4.21, p<.001), frontal medial cortex (z=3.48, p<.001), and cerebellum (z=3.72, p<.001). Greater T2 lesion volume and lower normalized thalamic volume were associated with reduced FC of the thalamus, especially for FC with the right superior occipital region (t=-2.87, p=.0123 and t=2.27, p=.04 respectively). FC of the left frontal medial cortex was negatively correlated with composite cognitive z-score in the pediatric-onset MS group (p<.05). CONCLUSIONS: Greater resting-state FC between posterior and anterior brain regions is present in pediatric-onset MS. With greater disease-related structural pathology, there is a disruption of thalamo-cortical FC. In the absence of actual cognitive impairment, heightened FC of the frontal medial cortex was associated with lower cognitive performance, suggesting that greater functional resources are recruited during resting-state in patients with reduced cognitive efficiency.

Cognitive and Behavioral Functioning in Childhood Acquired Demyelinating Syndromes.

OBJECTIVES: The aim of this study was to describe cognitive, academic, and psychosocial outcomes after an incident demyelinating event (acquired demyelinating syndromes, ADS) in childhood and to investigate the contribution of brain lesions and confirmed MS diagnosis on outcome. METHODS: Thirty-six patients with ADS (mean age=12.2 years, SD=2.7, range: 7-16 years) underwent brain MRI scans at presentation and at 6-months follow-up. T2-weighted lesions on MRI were assessed using a binary classification. At 6-months follow-up, patients underwent neuropsychological evaluation and were compared with 42 healthy controls. RESULTS: Cognitive, academic, and behavioral outcomes did not differ between the patients with ADS and controls. Three of 36 patients (8.3%) were identified with cognitive impairment, as determined by performance falling ≤1.5 SD below normative values on more than four independent tests in the battery. Poor performance on a visuomotor integration task was most common, observed among 6/32 patients, but this did not differ significantly from controls. Twelve of 36 patients received a diagnosis of MS within 3 years post-ADS. Patients with MS did not differ from children with monophasic ADS in terms of cognitive performance at the 6-months follow-up. Fatigue symptoms were reported in 50% of patients, irrespective of MS diagnosis. Presence of brain lesions at onset and 6 months post-incident demyelinating event did not associate with cognitive outcome. CONCLUSIONS: Children with ADS experience a favorable short-term neurocognitive outcome, even those confirmed to have MS. Longitudinal evaluations of children with monophasic ADS and MS are required to determine the possibility of late-emerging sequelae and their time course. (JINS, 2016, 22, 1050-1060).

Motor tract integrity predicts walking recovery: A diffusion MRI study in subacute stroke.

OBJECTIVE: To identify candidate biomarkers of walking recovery with motor tract integrity measurements using fractional anisotropy (FA) from the corticospinal tract (CST) and alternative motor pathways in patients with moderate to severe subacute stroke. METHODS: Walking recovery was first assessed with generalized linear mixed model (GLMM) with repeated measures of walking scores (WS) over 2 years of follow-up in a longitudinal study of 29 patients with subacute ischemic stroke. Baseline FA measures from the ipsilesional and contralesional CST (i-CST and c-CST), cortico-reticulospinal pathway (i-CRP and c-CRP), and cerebellar peduncles were derived from a 60-direction diffusion MRI sequence on a 3T scanner. We performed correlation tests between WS and FA measures. Third, we investigated using GLMM whether motor tract integrity contributes to predict walking recovery. RESULTS: We observed significant improvements of WS over time with a plateau reached at ≈6 months after stroke. WS significantly correlated with FA measures from i-CST, c-CST, i-CRP, and bilateral cerebellar peduncles. Walking recovery was predicted by FA measures from 3 tracts: i-CST, i-CRP, and contralesional superior cerebellar peduncle (c-SCP). Diffusion tensor imaging (DTI) predictors captured 80.5% of the unexplained variance of the model without DTI. CONCLUSIONS: We identified i-CST and alternative motor-related tracts (namely i-CRP and c-SCP) as candidate biomarkers of walking recovery. The role of the SCP in walk recovery may rely on cerebellar nuclei projections to the thalamus, red nucleus, and reticular formation. Our findings suggest that a set of white matter tracts, part of subcortical motor networks, contribute to walking recovery in patients with moderate to severe stroke.

Clustering of atlas-defined cortical regions based on relaxation times and proton density.

Magnetic resonance parameters, such as longitudinal (T1) and transverse (T2) relaxation times and proton density (PD) provide intrinsic information about the human brain. In vivo quantification of these parameters may enable detection of subtle regional grey matter (GM) or white matter (WM) differences and permit neurological disease detection and monitoring. The aims of the study were to quantify T1, T2 and PD values in all cortical gray matter regions for a group of healthy volunteers scanned at 1.5 T and to cluster regions showing statistically distinguishable tissue characteristics. Using a combination of spoiled gradient recalled echo (SPGR) and fast spin echo (FSE) sequences, 3D T1, T2 and PD of the brain were measured at 1.5 T for twenty healthy young volunteers. Cortical GM volumes of interest (VOIs) were identified by transforming 56 labels from an atlas onto each subject volumes: 8 frontal, 5 parietal, 6 occipital and 9 temporal on both the left and right sides. T1, T2 and PD measurements within these anatomical regions were quantified and reported here. Correspondence analysis (CA) and hierarchical clustering (HC) were combined and applied to averaged T1, T2 and PD values within each VOI in order to identify groups of anatomical structures that are related statistically. Interestingly, except for one structure, all VOIs were grouped with left-right symmetry and showed an interesting pattern: the four lobes (frontal, occipital, parietal and temporal) were roughly clustered and the precentral and postcentral gyri were merged together. Our study shows that CA and HC analysis of MRI relaxation parameters and proton density can be used for cortical clustering of atlas-defined cortical regions.

Physical activity and dentate gyrus volume in pediatric acquired demyelinating syndromes.

OBJECTIVE: To assess the association between daily moderate-to-vigorous physical activity (MVPA) and dentate gyrus volume (DGv) in pediatric patients with acquired demyelinating syndromes (ADSs) of the CNS. METHODS: Cross-sectional analysis of accelerometry (7 days) and research protocol MRI data from 12 pediatric MS and 18 children with monophasic ADS (monoADS). Total brain and DGv were quantified using standardized methods. The association of daily minutes of MVPA with normalized DGv (nDGv) was assessed using multivariable generalized linear models. RESULTS: Median (interquartile range) MVPA was lower in MS patients [9.5 (14)] and exhibited less variation than in monoADS patients [24.5 (47)]. nDGv did not differ significantly between groups [mean nDGv (SD) [cm3]: MS 0.34 (0.1); monoADS 0.4 (0.1); p = 0.100]. In the monoADS group, every 1-minute increase in MVPA was associated with a 2.4-mm3 increase in nDGv (p = 0.0017), an association that was independent of age at incident demyelination, time from incident demyelination, sex, and brain white matter T2 lesion volume. No significant association was found between MVPA and nDGv (-2.6 mm3/min, p = 0.16) in the MS group. CONCLUSIONS: Higher MVPA associates with greater nDGv in children who have recovered from monophasic demyelination. Larger studies are required to determine whether MVPA can promote regional brain development, or limit tissue damage, in youth with MS.

Monophasic demyelination reduces brain growth in children.

OBJECTIVE: To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time. METHODS: We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness. RESULTS: Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories. CONCLUSIONS: Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process.

Twenty new digital brain phantoms for creation of validation image data bases.

Simulations provide a way of generating data where ground truth is known, enabling quantitative testing of image processing methods. In this paper, we present the construction of 20 realistic digital brain phantoms that can be used to simulate medical imaging data. The phantoms are made from 20 normal adults to take into account intersubject anatomical variabilities. Each digital brain phantom was created by registering and averaging four T1, T2, and proton density (PD)-weighted magnetic resonance imaging (MRI) scans from each subject. A fuzzy minimum distance classification was used to classify voxel intensities from T1, T2, and PD average volumes into grey-matter, white matter, cerebro-spinal fluid, and fat. Automatically generated mask volumes were required to separate brain from nonbrain structures and ten fuzzy tissue volumes were created: grey matter, white matter, cerebro-spinal fluid, skull, marrow within the bone, dura, fat, tissue around the fat, muscles, and skin/muscles. A fuzzy vessel class was also obtained from the segmentation of the magnetic resonance angiography scan of the subject. These eleven fuzzy volumes that describe the spatial distribution of anatomical tissues define the digital phantom, where voxel intensity is proportional to the fraction of tissue within the voxel. These fuzzy volumes can be used to drive simulators for different modalities including MRI, PET, or SPECT. These phantoms were used to construct 20 simulated T1-weighted MR scans. To evaluate the realism of these simulations, we propose two approaches to compare them to real data acquired with the same acquisition parameters. The first approach consists of comparing the intensities within the segmented classes in both real and simulated data. In the second approach, a whole brain voxel-wise comparison between simulations and real T1-weighted data is performed. The first comparison underlines that segmented classes appear to properly represent the anatomy on average, and that inside these classes, the simulated and real intensity values are quite similar. The second comparison enables the study of the regional variations with no a priori class. The experiments demonstrate that these variations are small when real data are corrected for intensity nonuniformity.

Evaluation of methods to detect interhemispheric asymmetry on cerebral perfusion SPECT: application to epilepsy.

UNLABELLED: Detecting perfusion interhemispheric asymmetry in neurologic nuclear medicine imaging is an interesting approach to epilepsy. METHODS: This study compared 4 methods that detect interhemispheric asymmetries of brain perfusion in SPECT. The first (M1) was conventional side-by-side expert-based visual interpretation of SPECT. The second (M2) was visual interpretation assisted by an interhemispheric difference (IHD) volume. The last 2 were automatic methods: unsupervised analysis using volumes of interest (M3) and unsupervised analysis of the IHD volume (M4). Use of these methods to detect possible perfusion asymmetry was compared on 60 simulated SPECT datasets by controlling the presence and location of asymmetries. From the detection results, localization receiver operating characteristic curves were generated and areas under curves were estimated and compared. Finally, the methods were applied to analyze interictal SPECT datasets to localize the epileptogenic focus in temporal lobe epilepsies. RESULTS: This study showed an improvement in asymmetry detection on SPECT images with the methods using IHD volume (M2 and M4), in comparison with the other methods (M1 and M3). However, the most useful method for analyzing clinical SPECT datasets appeared to be visual inspection assisted by the IHD volume, since the automatic method using the IHD volume was less specific. CONCLUSION: The use of quantitative methods can improve performance in detection of perfusion asymmetry over visual inspection alone.

Spatio-Temporal Regularization for Longitudinal Registration to Subject-Specific 3d Template.

Neurodegenerative diseases such as Alzheimer's disease present subtle anatomical brain changes before the appearance of clinical symptoms. Manual structure segmentation is long and tedious and although automatic methods exist, they are often performed in a cross-sectional manner where each time-point is analyzed independently. With such analysis methods, bias, error and longitudinal noise may be introduced. Noise due to MR scanners and other physiological effects may also introduce variability in the measurement. We propose to use 4D non-linear registration with spatio-temporal regularization to correct for potential longitudinal inconsistencies in the context of structure segmentation. The major contribution of this article is the use of individual template creation with spatio-temporal regularization of the deformation fields for each subject. We validate our method with different sets of real MRI data, compare it to available longitudinal methods such as FreeSurfer, SPM12, QUARC, TBM, and KNBSI, and demonstrate that spatially local temporal regularization yields more consistent rates of change of global structures resulting in better statistical power to detect significant changes over time and between populations.

Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis.

OBJECTIVE: To evaluate the association between physical activity (PA) and multiple sclerosis (MS) disease activity, depression, and fatigue in a cohort of children with MS and monophasic acquired demyelinating syndrome (mono-ADS). METHODS: In this cross-sectional study of consecutive patients attending a specialized pediatric MS clinic, we administered the PedsQL Multidimensional Fatigue Scale, Center for Epidemiological Studies Depression Scale, and Godin Leisure-Time Exercise Questionnaire. Quantitative MRI analysis was performed to obtain whole brain and T2 lesion volume in a subset of participants (n = 60). RESULTS: A total of 110 patients (79 mono-ADS; 31 MS; 5-18 years; M:F 1:1.2) were included. Patients with MS reported less strenuous (33.21 ± 31.88 metabolic equivalents [METs] vs 15.97 ± 22.73 METs, p = 0.002) and total (44.48 ± 39.35 METs vs 67.28 ± 59.65 METs; p = 0.0291) PA than those with mono-ADS. Patients with MS who reported greater amounts of moderate PA METs had fewer sleep/rest fatigue symptoms (r = -0.4). Participation in strenuous PA was associated with smaller T2 lesion volumes (r = -0.66) and lower annualized relapse rate (r = -0.66). No associations were found between total brain volume and participation in PA. CONCLUSIONS: Children with MS are less physically active than children with mono-ADS. Reasons for this are unclear, but may be related to ongoing disease activity, perceived limitations, or symptoms such as depression or fatigue. Children with MS reporting higher levels of strenuous PA had lower T2 lesion volumes and lower relapse rates, suggesting a potential protective effect of strenuous PA in this population. Further longitudinal studies are needed to establish the relationship of PA to MS symptoms and disease activity in this population.

Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth.

OBJECTIVE: To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth. METHODS: Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2-11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age- and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects. RESULTS: Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (p < 10(-4)). These findings indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups. CONCLUSIONS: Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS.

Changes in cognitive performance over a 1-year period in children and adolescents with multiple sclerosis.

OBJECTIVE: Cognitive impairment is a core symptom of pediatric-onset multiple sclerosis (MS), although relatively little is known regarding the rate of cognitive decline. This study examined the extent, pattern, and correlates of change in cognitive functioning in youth with MS. METHOD: Changes in cognitive performance in 28 patients with pediatric-onset MS and 26 age-matched controls were ascertained through repeat comprehensive neuropsychological assessment conducted over a 1-year period. Change was evaluated by using a mixed factorial design with repeated measures to determine the interaction between group and time and using the Reliable Change Index (RCI) to determine individual differences on test scores over time. Participants were classified as showing "decline" or "improvement" if change scores exceeded the RCI on three or more tests. RESULTS: The pattern of change over time differed by group. At the group level, healthy controls were more likely to show improvement across multiple domains of function relative to the MS group. Using the RCI, 7 of 28 patients (25%) showed cognitive deterioration compared with only 1 of 26 controls (3.8%; p < .05). Performance on measures of attention and processing speed, visuomotor integration, verbal fluency, visual memory, and calculation and spelling ability were most responsive to deterioration in functioning over time. Longer disease duration was associated with greater deterioration in visuomotor integration. Increased lesion volume was associated with slower psychomotor speed over time. CONCLUSION: Lower rates of improvement in the pediatric MS group may be suggestive of a lack of age-appropriate cognitive development and warrant further evaluation over time.

A new improved version of the realistic digital brain phantom.

Image analysis methods must be tested and evaluated within a controlled environment. Simulations can be an extremely helpful tool for validation because ground truth is known. We created the digital brain phantom that is at the heart of our publicly available database of realistic simulated magnetic resonance image (MRI) volumes known as BrainWeb. Even though the digital phantom had l mm(3) isotropic voxel size and a small number of tissue classes, the BrainWeb database has been used in more than one hundred peer-reviewed publications validating different image processing methods. In this paper, we describe the next step in the natural evolution of BrainWeb: the creation of digital brain phantom II that includes three major improvements over the original phantom. First, the realism of the phantom, and the resulting simulations, was improved by modeling more tissue classes to include blood vessels, bone marrow and dura mater classes. In addition. a more realistic skull class was created. The latter is particularly useful for SPECT, PET and CT simulations for which bone attenuation has an important effect. Second, the phantom was improved by an eight-fold reduction in voxel volume to 0.125 mm(3). Third, the method used to create the new phantom was modified not only to take into account the segmentation of these new structures, but also to take advantage of many more automated procedures now available. The overall process has reduced subjectivity and manual intervention when compared to the original phantom, and the process may be easily applied to create phantoms from other subjects. MRI simulations are shown to illustrate the difference between the previous and the new improved digital brain phantom II. Example PET and SPECT simulations are also presented.

Realistic simulated MRI and SPECT databases. Application to SPECT/MRI registration evaluation.

This paper describes the construction of simulated SPECT and MRI databases that account for realistic anatomical and functional variability. The data is used as a gold-standard to evaluate four SPECT/MRI similarity-based registration methods. Simulation realism was accounted for using accurate physical models of data generation and acquisition. MRI and SPECT simulations were generated from three subjects to take into account inter-subject anatomical variability. Functional SPECT data were computed from six functional models of brain perfusion. Previous models of normal perfusion and ictal perfusion observed in Mesial Temporal Lobe Epilepsy (MTLE) were considered to generate functional variability. We studied the impact noise and intensity non-uniformity in MRI simulations and SPECT scatter correction may have on registration accuracy. We quantified the amount of registration error caused by anatomical and functional variability. Registration involving ictal data was less accurate than registration involving normal data. MR intensity nonuniformity was the main factor decreasing registration accuracy. The proposed simulated database is promising to evaluate many functional neuroimaging methods, involving MRI and SPECT data.