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 Frédéric Joliot, 4, place du General Leclerc, 91406 Orsay, France
b
Service de Radiologie Pédiatrique, Necker Enfants-Malades, Paris V, 149 rue de Sèvres, 75015 Paris, France
c
Service de Génétique, Necker Enfants-Malades, 149 rue de Sèvres, 75015 Paris, France
d
Radiological Associates of Sacramento, Sutter Medical Center, Sacramento, CA 95819-3295, USA

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 Introduction

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, visuospa-
tial 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 age-
matched 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 Sèvres, 75015 Paris, France. Fax:
+33 1 44 49 51 70.
E-mail address: nathalie.boddaert@nck.ap-hop-paris.fr (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
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 con-
struction which is severely impaired (Mervis et al., 2000). While
language abilities of WS patients are still controversial (Karmil-
off-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 microdele-
tional 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 parieto-
occipital 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
722 N. Boddaert et al. / NeuroImage 30 (2006) 721 – 725

impaired visuospatial construction (Meyer-Lindenberg et al., Table 1

2004). This abnormal grey matter volume also correlated with Clinical features of Williams patients
less activation in the superior parietal lobule during a visual Subjects 1 2 3 4 5 6 7 8 9
processing task (Meyer-Lindenberg et al., 2004). Moreover, Age 5.6 9.7 10 10.8 13 13.4 13.9 15.1 15.7
deficits in visuospatial domains observed in WS are already Global IQ 75 60 50 65 79 50 63 65 70
present in childhood (Mervis et al., 2000), as opposed to other Performance IQ 65 55 45 52 65 43 46 55 53
cognitive features that seem to vary with age (Paterson et al., Verbal IQ 80 70 65 75 91 62 85 72 85
1999). Therefore, we performed an anatomical magnetic resonance Height (SD) 0 2.5 2 2.5 0 1.5 0 2 0
imaging (MRI) study using voxel-based morphometry (VBM) in 9 HC (SD) 2 2.5 2.5 0 1 1 2 2 0
children with typical WS, in order to search for early structural IQ: intelligence quotient; HC: head circumference.
abnormalities that may be associated with the visuospatial SD: standard deviation; height and head circumference were expressed as
impairment of WS children. SD using Nellhaus, G. Pediatrics, 1968, standard French reference.
Here, we show that posterior parietal abnormalities are present
in children with WS.
MRI images were analyzed using both clinical review of scans
by two independent neuroradiologists from two different neuro-
pediatric referral centers and VBM analysis to search for localized
Subjects and methods
grey and/or white matter anomalies. VBM is a novel method for
characterizing regional differences in cerebral tissue concentration.
Subjects
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
Nine WS patients (7 boys, mean age: 11.6 T 3.1 years; age
automated whole-brain technique that delivers a voxel-wise
range: 5.5 – 15 years) were studied. Inclusion criteria were (i)
assessment of regional grey and white matter concentration.
typical cardiac, dysmorphic and neurobehavioral phenotype of WS
VBM analysis includes 5 steps. The first three determined optimal
confirmed by a cardiologist, a geneticist and a psychologist and (ii)
spatial normalization parameters.
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. (1) Customized templates, i.e., creation of separate grey and
Diagnosis of neuropsychological functioning was assessed by a white matter MRI templates of normal children. We created
neuropsychologist using the Wechsler Intelligence Scale for custom-made templates for grey and for white matter using
Children (Weschler, 1991). The mean IQ of our WS population MRI of our group of normal children in order to reduce any
was 63 T 10, which corresponds to a mild mental retardation, and potential bias for spatial normalization. These custom-made
their cognitive profile was characterized by a dissociation templates were then used in all following process steps.
between a very low intellectual performance score (mean values (2) Segmentation: images are segmented in native space result-
of Performance IQ = 53 T 8), compared to a relatively preserved ing in grey and white matter extracted segmented images.
intellectual verbal score (mean values of Verbal IQ = 76 T 10). This This procedure removes scalp tissue, skull and dural venous
dissociation, largely reported in Williams syndrome (Mervis et al., sinus voxels.
2000), reflected the visuospatial construction deficit of our WS (3) Normalization of grey and white matter images using custom
population. In addition, severe dyscalculia and significant difficul- child template: the extracted segmented grey/white matter
ties in drawing were consistent features of all of the WS children. images are then normalized to the custom-made grey/white
Most of WS children presented with reduced head circumfer- matter templates. Normalization was achieved with a
ence. Neurological examinations were performed by neuropedia- combined linear (12 parameters) and nonlinear transforma-
tricians, who observed no significant abnormalities. However, tion, using 7  8  7 discrete cosine transform basis
slight neurological peculiarities were observed in some WS functions, aiming at minimizing both the sum of squared
patients, such as clumsiness and brisk reflexes in early infancy. differences between image and template and the energy cost
All of them were right handed. function of this transformation. The parameters of this
The control group was composed of 11 healthy children with normalization procedure are applied to the original whole
similar mean age (6 boys, mean age: 11.8 T 2.2 years, age range: brain images.
8 – 15 years). All individuals performed normally in the visuospa- (4) Segmentation of normalized whole brain images: the
tial and language domains. None of them had a history of normalized whole brain images are then segmented into grey
neurological disorder, and all attended normal school. No subject and white matter respectively.
manifested behavioral problem nor social relationship difficulty. (5) Smoothing: as in the standard VBM method, each of the
The protocol was approved by the Ethical Committee of French optimally normalized and segmented images is smoothed
Public Hospitals (CHU Tours CCPPRB), and written informed with a 12-mm full width half maximum kernel (Good et al.,
consent of the parents was obtained in each case. 2001). The intensity in each voxel of the smoothed data is a
locally weighted average of grey matter density from a region
Brain imaging of surrounding voxels, the size of the region being defined by
the size of the smoothing kernel (Ashburner and Friston,
MRI was performed on a 1.5 T Signa General Electric scanner 2000). This procedure conditions the data to conform more
using a 3D T1-weighted FSPGR sequence (TR/TE/TI/NEX: 10.5/ closely to the Gaussian field model underlying the statistical
2.2/600/1, 10-, matrix 256  192, 124 axial slices and a thickness procedures used for making inferences about regionally
of 1.2 mm, 124 contiguous slices; MRI duration:6 min). specific effects.
 N. Boddaert et al. / NeuroImage 30 (2006) 721 – 725 723

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, region-
ally 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 (Meyer-
Lindenberg et al., 2004), we used a SVC (small volume correction)
analysis based upon the localization provided by Meyer-Linden-
berg. Therefore, we defined a 5-mm diameter sphere centered at
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) (one-
tailed 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.
724 N. Boddaert et al. / NeuroImage 30 (2006) 721 – 725
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 corre-
sponded 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 block-
design 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 neuropsy-
chological 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 impair-
ment 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 contri-
bution of the present study is to suggest an early origin of the
parietal structural abnormalities underlying the impaired visuospa-
tial 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.
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