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Parieto-occipital grey matter abnormalities in children with Williams syndrome
www.elsevier.com/locate/ynimg NeuroImage 30 (2006) 721 – 725
Parieto-occipital grey matter abnormalities in children with Williams syndrome N. Boddaert,a,b,* F. Mochel,c I. Meresse,a D. Seidenwurm,d A. Cachia,a F. Brunelle,a,b S. Lyonnet,c and M. Zilboviciusa a
ERM 0205 INSERM-CEA, Service Hospitalier Fre´de´ric Joliot, 4, place du General Leclerc, 91406 Orsay, France Service de Radiologie Pe´diatrique, Necker Enfants-Malades, Paris V, 149 rue de Se`vres, 75015 Paris, France c Service de Ge´ne´tique, Necker Enfants-Malades, 149 rue de Se`vres, 75015 Paris, France d Radiological Associates of Sacramento, Sutter Medical Center, Sacramento, CA 95819-3295, USA b
Received 3 June 2005; revised 10 October 2005; accepted 20 October 2005 Available online 27 December 2005
Williams syndrome (WS) is a neurodevelopmental disorder resulting from a hemizygous deletion of chromosome 7q11.23. The phenotype of WS consists of typical dysmorphic features, supravalvular aortic stenosis, infantile hypercalcemia and growth retardation. While language and facial recognition seem to be relatively spared, visuospatial constructive disabilities are a hallmark of the neurobehavioral profile of WS. In order to search for actual structural abnormalities underlying this precisely defined neurodevelopmental disorder, we performed anatomical magnetic resonance imaging (MRI) in 9 WS children (11.6 T 3.1 years; age range: 5.5 – 15 years) and 11 normal agematched control children (11.8 T 2.2 years; age range: 8 – 15 years) using voxel-based morphometry (VBM). VBM is a fully automated whole-brain technique that delivers a voxel-wise assessment of regional grey and white matter concentration. A significant decrease in grey matter concentration was detected in the left parieto-occipital region of WS children (P < 0.05 corrected height threshold). The location of this abnormality in WS children coincides with the location of the structural abnormality previously described using the same method in 13 WS adults. These parieto-occipital abnormalities are consistent with the cognitive profile of WS which includes severe visuospatial construction and numerical cognition deficits. The demonstration of identical structural abnormalities in both adults and children argues for their early origin. Additionally, our study provides support for the use of advanced structural imaging techniques in children, in order to improve our understanding of neurobehavioral phenotypes associated with well-defined genetic disorders. D 2005 Elsevier Inc. All rights reserved.
* Corresponding author. Pediatric Radiology Department, Necker Enfants-Malades Hospital, 149 rue de Se`vres, 75015 Paris, France. Fax: +33 1 44 49 51 70. E-mail address: [email protected] (N. Boddaert). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2005.10.051
Introduction Williams syndrome (WS) is associated with a 1.6 Mb deletion of chromosome 7q11.23 that usually results in the association of a recognizable syndrome including cardiac defects, infantile hypercalcemia, growth retardation, dysmorphic features and neurobehavioral disabilities (Bellugi et al., 1999; Bellugi et al., 2000; Donnai and Karmiloff-Smith, 2000; Tassabehji, 2003). Because multiple genes are thought to be contained in this region, genotype – phenotype correlation of the neurocognitive profile of WS patients is still elusive (Danoff et al., 2004; Frangiskakis et al., 1996; Hoogenraad et al., 2002; Karmiloff-Smith et al., 2003; Morris et al., 2003; Osborne et al., 1997b; Osborne et al., 1997a). Mental retardation is a frequent feature of WS (Bellugi et al., 1999; Bellugi et al., 2000), but more intriguing is the cognitive hallmark observed in WS. As outlined by Mervis et al., the Williams Syndrome Cognitive Profile (WSCP) is characterized by a dissociation between language and auditory rote memory, considered to be relatively unimpaired, and visuospatial construction which is severely impaired (Mervis et al., 2000). While language abilities of WS patients are still controversial (Karmiloff-Smith et al., 1997; Phillips et al., 2004), there is consensus regarding deficits in number and visuospatial processing that are characteristic features associated with WSCP. The intriguing concatenation of abilities and disabilities in this rare microdeletional syndrome has attracted great interest among neuroscientists. Neuroimaging studies might be useful to elucidate the mechanisms underlying such a well-defined cognitive profile. Recently, a significant grey matter volume reduction in the parietooccipital sulcus of mentally retarded WS adults was observed leading to the hypothesis that these abnormalities are responsible for their visuospatial disabilities (Eckert et al., 2005; Reiss et al., 2004). Interestingly, Meyer-Lindenberg et al. observed the same structural abnormalities in WS adults with normal intelligence but
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impaired visuospatial construction (Meyer-Lindenberg et al., 2004). This abnormal grey matter volume also correlated with less activation in the superior parietal lobule during a visual processing task (Meyer-Lindenberg et al., 2004). Moreover, deficits in visuospatial domains observed in WS are already present in childhood (Mervis et al., 2000), as opposed to other cognitive features that seem to vary with age (Paterson et al., 1999). Therefore, we performed an anatomical magnetic resonance imaging (MRI) study using voxel-based morphometry (VBM) in 9 children with typical WS, in order to search for early structural abnormalities that may be associated with the visuospatial impairment of WS children. Here, we show that posterior parietal abnormalities are present in children with WS.
Subjects and methods Subjects Nine WS patients (7 boys, mean age: 11.6 T 3.1 years; age range: 5.5 – 15 years) were studied. Inclusion criteria were (i) typical cardiac, dysmorphic and neurobehavioral phenotype of WS confirmed by a cardiologist, a geneticist and a psychologist and (ii) evidence of chromosome 7q11.23 deletion detected by FISH analysis using the Elastin gene LSI ELN probe (Vysis). Clinical features are described in Table 1. Diagnosis of neuropsychological functioning was assessed by a neuropsychologist using the Wechsler Intelligence Scale for Children (Weschler, 1991). The mean IQ of our WS population was 63 T 10, which corresponds to a mild mental retardation, and their cognitive profile was characterized by a dissociation between a very low intellectual performance score (mean values of Performance IQ = 53 T 8), compared to a relatively preserved intellectual verbal score (mean values of Verbal IQ = 76 T 10). This dissociation, largely reported in Williams syndrome (Mervis et al., 2000), reflected the visuospatial construction deficit of our WS population. In addition, severe dyscalculia and significant difficulties in drawing were consistent features of all of the WS children. Most of WS children presented with reduced head circumference. Neurological examinations were performed by neuropediatricians, who observed no significant abnormalities. However, slight neurological peculiarities were observed in some WS patients, such as clumsiness and brisk reflexes in early infancy. All of them were right handed. The control group was composed of 11 healthy children with similar mean age (6 boys, mean age: 11.8 T 2.2 years, age range: 8 – 15 years). All individuals performed normally in the visuospatial and language domains. None of them had a history of neurological disorder, and all attended normal school. No subject manifested behavioral problem nor social relationship difficulty. The protocol was approved by the Ethical Committee of French Public Hospitals (CHU Tours CCPPRB), and written informed consent of the parents was obtained in each case. Brain imaging MRI was performed on a 1.5 T Signa General Electric scanner using a 3D T1-weighted FSPGR sequence (TR/TE/TI/NEX: 10.5/ 2.2/600/1, 10-, matrix 256 192, 124 axial slices and a thickness of 1.2 mm, 124 contiguous slices; MRI duration:6 min).
Table 1 Clinical features of Williams patients Subjects
1
2
Age 5.6 9.7 Global IQ 75 60 Performance IQ 65 55 Verbal IQ 80 70 Height (SD) 0 2.5 HC (SD) 2 2.5
3
4
5
6
7
8
9
10 50 45 65 2 2.5
10.8 65 52 75 2.5 0
13 79 65 91 0 1
13.4 50 43 62 1.5 1
13.9 63 46 85 0 2
15.1 65 55 72 2 2
15.7 70 53 85 0 0
IQ: intelligence quotient; HC: head circumference. SD: standard deviation; height and head circumference were expressed as SD using Nellhaus, G. Pediatrics, 1968, standard French reference.
MRI images were analyzed using both clinical review of scans by two independent neuroradiologists from two different neuropediatric referral centers and VBM analysis to search for localized grey and/or white matter anomalies. VBM is a novel method for characterizing regional differences in cerebral tissue concentration. The 3D T1 scans were analyzed using the optimized approach of VBM developed by Good et al (Good et al., 2001), which is a fully automated whole-brain technique that delivers a voxel-wise assessment of regional grey and white matter concentration. VBM analysis includes 5 steps. The first three determined optimal spatial normalization parameters. (1) Customized templates, i.e., creation of separate grey and white matter MRI templates of normal children. We created custom-made templates for grey and for white matter using MRI of our group of normal children in order to reduce any potential bias for spatial normalization. These custom-made templates were then used in all following process steps. (2) Segmentation: images are segmented in native space resulting in grey and white matter extracted segmented images. This procedure removes scalp tissue, skull and dural venous sinus voxels. (3) Normalization of grey and white matter images using custom child template: the extracted segmented grey/white matter images are then normalized to the custom-made grey/white matter templates. Normalization was achieved with a combined linear (12 parameters) and nonlinear transformation, using 7 8 7 discrete cosine transform basis functions, aiming at minimizing both the sum of squared differences between image and template and the energy cost function of this transformation. The parameters of this normalization procedure are applied to the original whole brain images. (4) Segmentation of normalized whole brain images: the normalized whole brain images are then segmented into grey and white matter respectively. (5) Smoothing: as in the standard VBM method, each of the optimally normalized and segmented images is smoothed with a 12-mm full width half maximum kernel (Good et al., 2001). The intensity in each voxel of the smoothed data is a locally weighted average of grey matter density from a region of surrounding voxels, the size of the region being defined by the size of the smoothing kernel (Ashburner and Friston, 2000). This procedure conditions the data to conform more closely to the Gaussian field model underlying the statistical procedures used for making inferences about regionally specific effects.
N. Boddaert et al. / NeuroImage 30 (2006) 721 – 725
Additionally, we measured the global volume of grey matter, white matter, total brain volume and ratio of grey-to-white matter of the Williams and the controls children. The global volumes of grey and white matter were obtained from the segmentation maps of the raw (nonnormalized) MRI. For each subject, the grey (respectively white) matter volume was estimated as the sum of the voxel values over the grey (respectively white) matter segmentation map multiplied by the voxel volume. Statistical analysis Anatomical data were analyzed using SPM99 (Friston, 1995) (http//www.fil.ion.ucl.ac.uk/spm). For statistical analyses, regionally specific differences in grey and white matter between 2 groups were assessed using a two-tailed contrast, namely testing for an increased or decreased probability of a voxel being grey or white matter. Normalization for global differences in grey matter concentration across scans was performed by including the global mean voxel value as a confounding covariate in an analysis of covariance (ANCOVA). Consequently, the analysis will detect regional difference rather than overall, large-scale variations in grey and white matter concentrations. The resulting Z maps were thresholded at P < 0.05 corrected height threshold. In order to search for the right hemisphere grey matter abnormality previously described in adults with WS (MeyerLindenberg et al., 2004), we used a SVC (small volume correction) analysis based upon the localization provided by Meyer-Lindenberg. Therefore, we defined a 5-mm diameter sphere centered at
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the Talairach coordinates (x = +32, y = 75, z = +29), the site of abnormality identified in adults. The brain tissue volumes were analyzed with parametric tests (t test) and nonparametric rank-based tests (Wilcoxon test) (onetailed alpha level of 0.05).
Results Clinical review by two pediatric neuroradiologists of the anatomical MRI scans demonstrated normal MRI in the 9 WS children and in the 11 control subjects without any motion artifact. VBM analysis revealed that grey matter concentration was significantly decreased in the left parieto-occipital region in WS children compared to normal children (P < 0.05 corrected for multiple comparisons). These abnormalities are localized in front of the left parieto-occipital sulcus between the superior parietal lobule and the superior occipital gyrus. Additionally, we have performed an SPM analysis including age as a covariate (ANCOVA), and we have found exactly the same grey matter parietal decrease in WS subjects. Fig. 1 shows the topography of grey matter decrease in WS subjects compared to the age-matched control group. Using an SVC analysis based upon the localization provided by Meyer-Lindenberg et al. (2004), we also found decreased grey matter concentration located in the right parieto-occipital region in the WS children compared to the control children (P < 0.05 corrected for multiple comparisons). No significant decrease in white matter concentration was found in the WS children compared to normal children.
Fig. 1. Parieto-occipital grey matter abnormality in children with Williams syndrome. VBM analysis revealed that grey matter concentration was significantly decreased in the left parieto-occipital region in 11 Williams children compared to 9 normal children (P < 0.05 corrected for multiple comparisons), the Z score is 4.82 and the coordinates in the Talairach space are X, Y, Z = 28, 68, 32; Brodmann’s area 19.
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No significant difference in grey and white matter global volumes between patients and control children was found. Additionally, the ratio between the grey and white matter did not differ significantly between the two groups.
Discussion In the present study, we demonstrated a significant decrease in grey matter concentration localized to the parieto-occipital region in children with WS using MRI and voxel-based morphometry (VBM). Interestingly, using similar MRI analysis, two recent studies reported identical structural abnormalities in adults with WS (Meyer-Lindenberg et al., 2004; Reiss et al., 2004). It is of importance to note that reduced grey matter density in the human regions of the visual spatial system were found both in WS adults with mental retardation (Reiss et al., 2004) and with normal intelligence (Meyer-Lindenberg et al., 2004). In addition, previous anatomical studies, using different MRI strategies in Williams syndrome, reported a significant grey matter volume reduction in the parieto-occipital region of WS adults (Eckert et al., 2005) and an abnormal gyrification pattern in the parietal and occipital regions (Schmitt et al., 2002) corresponding to occipital postmortem cytoarchitectonic anomalies (Galaburda et al., 2002). More recently, Kippenhan et al. found bilateral reductions in the intraparietal/occipito-parietal sulcal depth of participants with WS. These sulcal depth abnormalities corresponded closely to our present results showing grey matter concentration decrease in the fundus of the parieto-occipital sulcus (Kippenhan et al., 2005). Finally, functional activation studies showed less activation during a visual task in these cortical regions in WS patients compared to controls (Meyer-Lindenberg et al., 2004). The parieto-occipital sulcus is implicated in visuospatial construction, and abnormalities in this parieto-occipital region may be a structural deficit that leads to visuospatial processing deficit of WS patients. In Williams syndrome, disturbed visuospatial construction is a hallmark of the disorder, and individuals with WS have marked difficulty in tasks requiring the use of a pattern or object assembly (e.g., following a pattern to build a model or assembling a simple piece of furniture) (Bellugi et al., 1999, 2000; Mervis et al., 2000; Mervis and Robinson, 2000). Bellugi et al. (1988) and Wang et al. (1995) have made important contributions to our understanding of the difficulties evidenced by individuals with Williams syndrome on blockdesign tasks and other measures of visuospatial construction and discussed the significance of these deficits. The visuospatial deficit in WS children has also been demonstrated by neuropsychological testing (Atkinson et al., 1997). Although Williams syndrome is a well-characterized syndrome on a genetic level, the specific gene implicated in the visuospatial constructive impairment is not yet identified (Karmiloff-Smith et al., 2003; Tassabehji, 2003). Considering the observation of localized parieto-occipital abnormalities, it would be of great interest to perform additional specific tests in our WS population in order to search for correlations between the VBM findings and indices of visuospatial disabilities. We have found alterations of the parieto-occipital region in WS mentally retarded children that are identical to those shown previously in WS adults with mental retardation (Reiss et al., 2004) or without mental retardation (Meyer-Lindenberg et al.,
2004), leading to the hypothesis that these abnormalities are responsible for their visuospatial disabilities and are not a nonspecific manifestation of mental retardation. The main contribution of the present study is to suggest an early origin of the parietal structural abnormalities underlying the impaired visuospatial processing of WS patients. It is interesting to note that the parietal grey matter appears to develop earlier than that of others regions in the normal brain (Giedd et al., 1999). Most of our WS children presented with reduced head circumference, likely related to their reduced cerebral volume. Nonetheless, low head circumference is often associated with nonspecific mental retardation or neurological features. VBM findings appear as more interesting as we demonstrate regional brain area abnormalities, possibly related to the peculiar phenotype of WS. Despite the difficulty in performing MRI examination on children, it might be of interest to extend VBM studies to larger populations of younger WS patients. However, unlike the adult MRI studies, no other significant anatomical abnormalities were found in our pediatric population. Therefore, the additional structural alterations found in WS adults, such as in the cerebellar, orbitofrontal, or thalamic regions (Jones et al., 2002; Meyer-Lindenberg et al., 2004; Reiss et al., 2004) might be related to the different age of the two WS populations, or related to other neurobehavioral features in adult population of WS. It is also possible that the small size of the population we tested lacked sufficient statistical power to demonstrate weaker effects in different anatomical regions. Numerical cognition has also been reported to be a feature of the clinical profile of patients with Williams syndrome (Ansari et al., 2003). The region of abnormality that we have identified with VBM corresponds to anatomical localization within the posterior parietal lobe, which has previously been identified as abnormal in two other patient groups exhibiting severe dyscalculia with differing pathophysiological mechanisms. In Turner’s syndrome, a genetic abnormality (Molko et al., 2003), as well as in prematurity (Isaacs et al., 2001), presumably via a vascular mechanism, dyscalculia has been associated with anatomical abnormalities in this region. It is tempting to speculate that the abnormality of posterior parietal lobe identified in this study may be responsible for numerical cognition deficits in William’s syndrome. In conclusion, we present anatomical evidence for abnormality of the parieto-occipital region in WS children, likely related to their visuospatial construction and numerical cognition deficits. The demonstration of identical structural abnormalities in both children and adults argues for their early origin. Our study provides additional support for the use of advanced structural imaging techniques in children, in order to improve our understanding of neurobehavioral phenotypes associated with well-defined genetic disorders. References Ansari, D., Donlan, C., Thomas, M.S., Ewing, S.A., Peen, T., KarmiloffSmith, A., 2003. What makes counting count? Verbal and visuo-spatial contributions to typical and atypical number development. J. Exp. Child Psychol. 85, 50 – 62. Ashburner, J., Friston, K.J., 2000. Voxel-based morphometry—The methods. NeuroImage 11, 805 – 821 (Review). Atkinson, J., King, J., Braddick, O., Nokes, L., Anker, S., Braddick, F., 1997. A specific deficit of dorsal stream function in Williams’ syndrome. NeuroReport 8, 1919 – 1922.
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Parieto-occipital grey matter abnormalities in children with Williams syndrome N. Boddaert,a,b,* F. Mochel,c I. Meresse,a D. Seidenwurm,d A. Cachia,a F. Brunelle,a,b S. Lyonnet,c and M. Zilboviciusa a
ERM 0205 INSERM-CEA, Service Hospitalier Fre´de´ric Joliot, 4, place du General Leclerc, 91406 Orsay, France Service de Radiologie Pe´diatrique, Necker Enfants-Malades, Paris V, 149 rue de Se`vres, 75015 Paris, France c Service de Ge´ne´tique, Necker Enfants-Malades, 149 rue de Se`vres, 75015 Paris, France d Radiological Associates of Sacramento, Sutter Medical Center, Sacramento, CA 95819-3295, USA b
Received 3 June 2005; revised 10 October 2005; accepted 20 October 2005 Available online 27 December 2005
Williams syndrome (WS) is a neurodevelopmental disorder resulting from a hemizygous deletion of chromosome 7q11.23. The phenotype of WS consists of typical dysmorphic features, supravalvular aortic stenosis, infantile hypercalcemia and growth retardation. While language and facial recognition seem to be relatively spared, visuospatial constructive disabilities are a hallmark of the neurobehavioral profile of WS. In order to search for actual structural abnormalities underlying this precisely defined neurodevelopmental disorder, we performed anatomical magnetic resonance imaging (MRI) in 9 WS children (11.6 T 3.1 years; age range: 5.5 – 15 years) and 11 normal agematched control children (11.8 T 2.2 years; age range: 8 – 15 years) using voxel-based morphometry (VBM). VBM is a fully automated whole-brain technique that delivers a voxel-wise assessment of regional grey and white matter concentration. A significant decrease in grey matter concentration was detected in the left parieto-occipital region of WS children (P < 0.05 corrected height threshold). The location of this abnormality in WS children coincides with the location of the structural abnormality previously described using the same method in 13 WS adults. These parieto-occipital abnormalities are consistent with the cognitive profile of WS which includes severe visuospatial construction and numerical cognition deficits. The demonstration of identical structural abnormalities in both adults and children argues for their early origin. Additionally, our study provides support for the use of advanced structural imaging techniques in children, in order to improve our understanding of neurobehavioral phenotypes associated with well-defined genetic disorders. D 2005 Elsevier Inc. All rights reserved.
* Corresponding author. Pediatric Radiology Department, Necker Enfants-Malades Hospital, 149 rue de Se`vres, 75015 Paris, France. Fax: +33 1 44 49 51 70. E-mail address: [email protected] (N. Boddaert). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2005.10.051
Introduction Williams syndrome (WS) is associated with a 1.6 Mb deletion of chromosome 7q11.23 that usually results in the association of a recognizable syndrome including cardiac defects, infantile hypercalcemia, growth retardation, dysmorphic features and neurobehavioral disabilities (Bellugi et al., 1999; Bellugi et al., 2000; Donnai and Karmiloff-Smith, 2000; Tassabehji, 2003). Because multiple genes are thought to be contained in this region, genotype – phenotype correlation of the neurocognitive profile of WS patients is still elusive (Danoff et al., 2004; Frangiskakis et al., 1996; Hoogenraad et al., 2002; Karmiloff-Smith et al., 2003; Morris et al., 2003; Osborne et al., 1997b; Osborne et al., 1997a). Mental retardation is a frequent feature of WS (Bellugi et al., 1999; Bellugi et al., 2000), but more intriguing is the cognitive hallmark observed in WS. As outlined by Mervis et al., the Williams Syndrome Cognitive Profile (WSCP) is characterized by a dissociation between language and auditory rote memory, considered to be relatively unimpaired, and visuospatial construction which is severely impaired (Mervis et al., 2000). While language abilities of WS patients are still controversial (Karmiloff-Smith et al., 1997; Phillips et al., 2004), there is consensus regarding deficits in number and visuospatial processing that are characteristic features associated with WSCP. The intriguing concatenation of abilities and disabilities in this rare microdeletional syndrome has attracted great interest among neuroscientists. Neuroimaging studies might be useful to elucidate the mechanisms underlying such a well-defined cognitive profile. Recently, a significant grey matter volume reduction in the parietooccipital sulcus of mentally retarded WS adults was observed leading to the hypothesis that these abnormalities are responsible for their visuospatial disabilities (Eckert et al., 2005; Reiss et al., 2004). Interestingly, Meyer-Lindenberg et al. observed the same structural abnormalities in WS adults with normal intelligence but
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impaired visuospatial construction (Meyer-Lindenberg et al., 2004). This abnormal grey matter volume also correlated with less activation in the superior parietal lobule during a visual processing task (Meyer-Lindenberg et al., 2004). Moreover, deficits in visuospatial domains observed in WS are already present in childhood (Mervis et al., 2000), as opposed to other cognitive features that seem to vary with age (Paterson et al., 1999). Therefore, we performed an anatomical magnetic resonance imaging (MRI) study using voxel-based morphometry (VBM) in 9 children with typical WS, in order to search for early structural abnormalities that may be associated with the visuospatial impairment of WS children. Here, we show that posterior parietal abnormalities are present in children with WS.
Subjects and methods Subjects Nine WS patients (7 boys, mean age: 11.6 T 3.1 years; age range: 5.5 – 15 years) were studied. Inclusion criteria were (i) typical cardiac, dysmorphic and neurobehavioral phenotype of WS confirmed by a cardiologist, a geneticist and a psychologist and (ii) evidence of chromosome 7q11.23 deletion detected by FISH analysis using the Elastin gene LSI ELN probe (Vysis). Clinical features are described in Table 1. Diagnosis of neuropsychological functioning was assessed by a neuropsychologist using the Wechsler Intelligence Scale for Children (Weschler, 1991). The mean IQ of our WS population was 63 T 10, which corresponds to a mild mental retardation, and their cognitive profile was characterized by a dissociation between a very low intellectual performance score (mean values of Performance IQ = 53 T 8), compared to a relatively preserved intellectual verbal score (mean values of Verbal IQ = 76 T 10). This dissociation, largely reported in Williams syndrome (Mervis et al., 2000), reflected the visuospatial construction deficit of our WS population. In addition, severe dyscalculia and significant difficulties in drawing were consistent features of all of the WS children. Most of WS children presented with reduced head circumference. Neurological examinations were performed by neuropediatricians, who observed no significant abnormalities. However, slight neurological peculiarities were observed in some WS patients, such as clumsiness and brisk reflexes in early infancy. All of them were right handed. The control group was composed of 11 healthy children with similar mean age (6 boys, mean age: 11.8 T 2.2 years, age range: 8 – 15 years). All individuals performed normally in the visuospatial and language domains. None of them had a history of neurological disorder, and all attended normal school. No subject manifested behavioral problem nor social relationship difficulty. The protocol was approved by the Ethical Committee of French Public Hospitals (CHU Tours CCPPRB), and written informed consent of the parents was obtained in each case. Brain imaging MRI was performed on a 1.5 T Signa General Electric scanner using a 3D T1-weighted FSPGR sequence (TR/TE/TI/NEX: 10.5/ 2.2/600/1, 10-, matrix 256 192, 124 axial slices and a thickness of 1.2 mm, 124 contiguous slices; MRI duration:6 min).
Table 1 Clinical features of Williams patients Subjects
1
2
Age 5.6 9.7 Global IQ 75 60 Performance IQ 65 55 Verbal IQ 80 70 Height (SD) 0 2.5 HC (SD) 2 2.5
3
4
5
6
7
8
9
10 50 45 65 2 2.5
10.8 65 52 75 2.5 0
13 79 65 91 0 1
13.4 50 43 62 1.5 1
13.9 63 46 85 0 2
15.1 65 55 72 2 2
15.7 70 53 85 0 0
IQ: intelligence quotient; HC: head circumference. SD: standard deviation; height and head circumference were expressed as SD using Nellhaus, G. Pediatrics, 1968, standard French reference.
MRI images were analyzed using both clinical review of scans by two independent neuroradiologists from two different neuropediatric referral centers and VBM analysis to search for localized grey and/or white matter anomalies. VBM is a novel method for characterizing regional differences in cerebral tissue concentration. The 3D T1 scans were analyzed using the optimized approach of VBM developed by Good et al (Good et al., 2001), which is a fully automated whole-brain technique that delivers a voxel-wise assessment of regional grey and white matter concentration. VBM analysis includes 5 steps. The first three determined optimal spatial normalization parameters. (1) Customized templates, i.e., creation of separate grey and white matter MRI templates of normal children. We created custom-made templates for grey and for white matter using MRI of our group of normal children in order to reduce any potential bias for spatial normalization. These custom-made templates were then used in all following process steps. (2) Segmentation: images are segmented in native space resulting in grey and white matter extracted segmented images. This procedure removes scalp tissue, skull and dural venous sinus voxels. (3) Normalization of grey and white matter images using custom child template: the extracted segmented grey/white matter images are then normalized to the custom-made grey/white matter templates. Normalization was achieved with a combined linear (12 parameters) and nonlinear transformation, using 7 8 7 discrete cosine transform basis functions, aiming at minimizing both the sum of squared differences between image and template and the energy cost function of this transformation. The parameters of this normalization procedure are applied to the original whole brain images. (4) Segmentation of normalized whole brain images: the normalized whole brain images are then segmented into grey and white matter respectively. (5) Smoothing: as in the standard VBM method, each of the optimally normalized and segmented images is smoothed with a 12-mm full width half maximum kernel (Good et al., 2001). The intensity in each voxel of the smoothed data is a locally weighted average of grey matter density from a region of surrounding voxels, the size of the region being defined by the size of the smoothing kernel (Ashburner and Friston, 2000). This procedure conditions the data to conform more closely to the Gaussian field model underlying the statistical procedures used for making inferences about regionally specific effects.
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Additionally, we measured the global volume of grey matter, white matter, total brain volume and ratio of grey-to-white matter of the Williams and the controls children. The global volumes of grey and white matter were obtained from the segmentation maps of the raw (nonnormalized) MRI. For each subject, the grey (respectively white) matter volume was estimated as the sum of the voxel values over the grey (respectively white) matter segmentation map multiplied by the voxel volume. Statistical analysis Anatomical data were analyzed using SPM99 (Friston, 1995) (http//www.fil.ion.ucl.ac.uk/spm). For statistical analyses, regionally specific differences in grey and white matter between 2 groups were assessed using a two-tailed contrast, namely testing for an increased or decreased probability of a voxel being grey or white matter. Normalization for global differences in grey matter concentration across scans was performed by including the global mean voxel value as a confounding covariate in an analysis of covariance (ANCOVA). Consequently, the analysis will detect regional difference rather than overall, large-scale variations in grey and white matter concentrations. The resulting Z maps were thresholded at P < 0.05 corrected height threshold. In order to search for the right hemisphere grey matter abnormality previously described in adults with WS (MeyerLindenberg et al., 2004), we used a SVC (small volume correction) analysis based upon the localization provided by Meyer-Lindenberg. Therefore, we defined a 5-mm diameter sphere centered at
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the Talairach coordinates (x = +32, y = 75, z = +29), the site of abnormality identified in adults. The brain tissue volumes were analyzed with parametric tests (t test) and nonparametric rank-based tests (Wilcoxon test) (onetailed alpha level of 0.05).
Results Clinical review by two pediatric neuroradiologists of the anatomical MRI scans demonstrated normal MRI in the 9 WS children and in the 11 control subjects without any motion artifact. VBM analysis revealed that grey matter concentration was significantly decreased in the left parieto-occipital region in WS children compared to normal children (P < 0.05 corrected for multiple comparisons). These abnormalities are localized in front of the left parieto-occipital sulcus between the superior parietal lobule and the superior occipital gyrus. Additionally, we have performed an SPM analysis including age as a covariate (ANCOVA), and we have found exactly the same grey matter parietal decrease in WS subjects. Fig. 1 shows the topography of grey matter decrease in WS subjects compared to the age-matched control group. Using an SVC analysis based upon the localization provided by Meyer-Lindenberg et al. (2004), we also found decreased grey matter concentration located in the right parieto-occipital region in the WS children compared to the control children (P < 0.05 corrected for multiple comparisons). No significant decrease in white matter concentration was found in the WS children compared to normal children.
Fig. 1. Parieto-occipital grey matter abnormality in children with Williams syndrome. VBM analysis revealed that grey matter concentration was significantly decreased in the left parieto-occipital region in 11 Williams children compared to 9 normal children (P < 0.05 corrected for multiple comparisons), the Z score is 4.82 and the coordinates in the Talairach space are X, Y, Z = 28, 68, 32; Brodmann’s area 19.
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No significant difference in grey and white matter global volumes between patients and control children was found. Additionally, the ratio between the grey and white matter did not differ significantly between the two groups.
Discussion In the present study, we demonstrated a significant decrease in grey matter concentration localized to the parieto-occipital region in children with WS using MRI and voxel-based morphometry (VBM). Interestingly, using similar MRI analysis, two recent studies reported identical structural abnormalities in adults with WS (Meyer-Lindenberg et al., 2004; Reiss et al., 2004). It is of importance to note that reduced grey matter density in the human regions of the visual spatial system were found both in WS adults with mental retardation (Reiss et al., 2004) and with normal intelligence (Meyer-Lindenberg et al., 2004). In addition, previous anatomical studies, using different MRI strategies in Williams syndrome, reported a significant grey matter volume reduction in the parieto-occipital region of WS adults (Eckert et al., 2005) and an abnormal gyrification pattern in the parietal and occipital regions (Schmitt et al., 2002) corresponding to occipital postmortem cytoarchitectonic anomalies (Galaburda et al., 2002). More recently, Kippenhan et al. found bilateral reductions in the intraparietal/occipito-parietal sulcal depth of participants with WS. These sulcal depth abnormalities corresponded closely to our present results showing grey matter concentration decrease in the fundus of the parieto-occipital sulcus (Kippenhan et al., 2005). Finally, functional activation studies showed less activation during a visual task in these cortical regions in WS patients compared to controls (Meyer-Lindenberg et al., 2004). The parieto-occipital sulcus is implicated in visuospatial construction, and abnormalities in this parieto-occipital region may be a structural deficit that leads to visuospatial processing deficit of WS patients. In Williams syndrome, disturbed visuospatial construction is a hallmark of the disorder, and individuals with WS have marked difficulty in tasks requiring the use of a pattern or object assembly (e.g., following a pattern to build a model or assembling a simple piece of furniture) (Bellugi et al., 1999, 2000; Mervis et al., 2000; Mervis and Robinson, 2000). Bellugi et al. (1988) and Wang et al. (1995) have made important contributions to our understanding of the difficulties evidenced by individuals with Williams syndrome on blockdesign tasks and other measures of visuospatial construction and discussed the significance of these deficits. The visuospatial deficit in WS children has also been demonstrated by neuropsychological testing (Atkinson et al., 1997). Although Williams syndrome is a well-characterized syndrome on a genetic level, the specific gene implicated in the visuospatial constructive impairment is not yet identified (Karmiloff-Smith et al., 2003; Tassabehji, 2003). Considering the observation of localized parieto-occipital abnormalities, it would be of great interest to perform additional specific tests in our WS population in order to search for correlations between the VBM findings and indices of visuospatial disabilities. We have found alterations of the parieto-occipital region in WS mentally retarded children that are identical to those shown previously in WS adults with mental retardation (Reiss et al., 2004) or without mental retardation (Meyer-Lindenberg et al.,
2004), leading to the hypothesis that these abnormalities are responsible for their visuospatial disabilities and are not a nonspecific manifestation of mental retardation. The main contribution of the present study is to suggest an early origin of the parietal structural abnormalities underlying the impaired visuospatial processing of WS patients. It is interesting to note that the parietal grey matter appears to develop earlier than that of others regions in the normal brain (Giedd et al., 1999). Most of our WS children presented with reduced head circumference, likely related to their reduced cerebral volume. Nonetheless, low head circumference is often associated with nonspecific mental retardation or neurological features. VBM findings appear as more interesting as we demonstrate regional brain area abnormalities, possibly related to the peculiar phenotype of WS. Despite the difficulty in performing MRI examination on children, it might be of interest to extend VBM studies to larger populations of younger WS patients. However, unlike the adult MRI studies, no other significant anatomical abnormalities were found in our pediatric population. Therefore, the additional structural alterations found in WS adults, such as in the cerebellar, orbitofrontal, or thalamic regions (Jones et al., 2002; Meyer-Lindenberg et al., 2004; Reiss et al., 2004) might be related to the different age of the two WS populations, or related to other neurobehavioral features in adult population of WS. It is also possible that the small size of the population we tested lacked sufficient statistical power to demonstrate weaker effects in different anatomical regions. Numerical cognition has also been reported to be a feature of the clinical profile of patients with Williams syndrome (Ansari et al., 2003). The region of abnormality that we have identified with VBM corresponds to anatomical localization within the posterior parietal lobe, which has previously been identified as abnormal in two other patient groups exhibiting severe dyscalculia with differing pathophysiological mechanisms. In Turner’s syndrome, a genetic abnormality (Molko et al., 2003), as well as in prematurity (Isaacs et al., 2001), presumably via a vascular mechanism, dyscalculia has been associated with anatomical abnormalities in this region. It is tempting to speculate that the abnormality of posterior parietal lobe identified in this study may be responsible for numerical cognition deficits in William’s syndrome. In conclusion, we present anatomical evidence for abnormality of the parieto-occipital region in WS children, likely related to their visuospatial construction and numerical cognition deficits. The demonstration of identical structural abnormalities in both children and adults argues for their early origin. Our study provides additional support for the use of advanced structural imaging techniques in children, in order to improve our understanding of neurobehavioral phenotypes associated with well-defined genetic disorders. References Ansari, D., Donlan, C., Thomas, M.S., Ewing, S.A., Peen, T., KarmiloffSmith, A., 2003. What makes counting count? Verbal and visuo-spatial contributions to typical and atypical number development. J. Exp. Child Psychol. 85, 50 – 62. Ashburner, J., Friston, K.J., 2000. Voxel-based morphometry—The methods. NeuroImage 11, 805 – 821 (Review). Atkinson, J., King, J., Braddick, O., Nokes, L., Anker, S., Braddick, F., 1997. A specific deficit of dorsal stream function in Williams’ syndrome. NeuroReport 8, 1919 – 1922.
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