NEUROREPORT
DEVELOPMENTAL NEUROSCIENCE
Thalamic reductions in children with chromosome
22q11.2 deletion syndrome
Joel P. Bish,1,CA Vy Nguyen,1 Lijun Ding,1 Samantha Ferrante1 and Tony J. Simon1,2
1
Children’s Hospital of Philadelphia, 3535 Market St, Philadelphia, PA19104; 2University of Pennsylvania, PA, USA
CA
Corresponding Author: bish@email.chop.edu
Received 9 March 2004; accepted 13 April 2004
DOI: 10.1097/01.wnr.0000129855.50780.85
Children with chromosome 22q11.2 deletion syndrome (22q) su¡er
from physical and behavioral dysfunctions, including neuroanatomical anomalies, visuo-spatial processing de¢cits, and increased risk
for psychopathology. Reduced total brain volume, parietal lobe volume, and cerebellar volumes, enlarged ventricles, and increased
basal ganglia volumes have been reported. Since previous literature
has related the pulvinar nucleus of the thalamus to visuo-spatial
processing, we compared the thalamic volume in children with
22q to typically developing controls. Children with 22q showed a
signi¢cant reduction of the thalamus compared with normally developing children, speci¢cally in the posterior portion of the thalamus, including the pulvinar nucleus.These results provide the ¢rst
evidence for a potential relationship between posterior thalamic
reductions and the characteristic visuo-spatial de¢cits demonc 2004 Lippincott
strated in this group. NeuroReport 15:1413^1415 Williams & Wilkins.
Key words: 22q11.2; Pulvinar; Schizophrenia; Thalamus; Velocardiofacial syndrome; Visuo-spatial
INTRODUCTION
Chromosome 22q11.2 deletion syndrome (22q) encompasses
DiGeorge and velocardiofacial (VCFS) syndromes [1]. It is a
congenital condition resulting from a deletion at chromosome 22q11.2 and has a prevalence of at least 1 in 4000 live
births. The most systematically observed manifestations of
22q include cleft palate, heart defects, T-cell abnormalities,
and neonatal hypocalcemia, as well as facial dysmorphisms
and mild to moderate cognitive deficits [2]. Along with an
overall delay in early cognitive, psychomotor, and language
development and an overall IQ typically in the range 70–85,
a subset of deficits are evident in the areas of visuospatial
and numerical performance [3,4]. Children with 22q also
show an extremely high incidence of psychopathology,
especially schizophrenia, as they reach adulthood. Specifically, it is estimated that around 30% of all children with 22q
will develop a schizophrenia spectrum disorder [5].
Specific patterns of brain abnormalities have also been
demonstrated in 22q and it has been hypothesized [4] that
some of these, particularly in the posterior parietal lobule,
may provide the underlying cause of key aspects of the
cognitive dysfunction displayed in this group. Generally,
total brain volume appears to be reduced by 8–11% in
children with 22q compared to normally developing
children [6,7]. A relatively consistent pattern of focal volume
reductions has also emerged from the literature. Cortical
reductions have been demonstrated in the left parietal lobe
[6,7], right temporal, parietal and occipital lobes [7,8].
Additionally, given the total brain volume reductions in
this group, the suggestion of a relative frontal lobe increase
has been indicated by a number of studies [6–8]. Investiga-
c Lippincott Williams & Wilkins
0959- 4965 tions of subcortical structures have also demonstrated
abnormalities in this group. Specific white matter volume
reductions have been demonstrated in the cerebellum, as
well as abnormal basal ganglia structures, such as increased
size in the caudate head [9]. Our recent data [10], using
voxel-based morphometry, support previous findings that
children with 22q have enlarged lateral ventricles, which
appear to overlap the typical location of the corpus
callosum, anterior and posterior cingulate gyrus, as well
as the superior portion of the thalamus, particularly in the
medial, and posterior region.
With the significant neurological, cognitive, and psychological anomalies demonstrated by individuals with 22q, it
is necessary to determine which areas of the brain may be
directly or indirectly linked to the dysfunctional behaviors.
Much research has supported the view that the thalamus
plays an important role in visuospatial processing [11–15].
Specifically, the pulvinar has been demonstrated to be
necessary for the spatial registration of visual features
[11,12], engaging attention at new locations [15], and may be
partially responsible for spatial neglect syndromes [14].
Given these connections between thalamic processing and
visuospatial attention, and our current data demonstrating
possible expansion of the lateral ventricles into the posterior
thalamic region, we hypothesized that direct measurement
of the thalamus would reveal volumetric reductions in
children with 22q when compared to normally developing
children. Particular interest will be paid to the posterior
region of the thalamus, given the specific aforementioned
connections between the pulvinar nucleus and visuospatial
processing.
Vol 15 No 9 28 June 2004
1413
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
NEUROREPORT
J. P. BISH ETAL.
MATERIALS AND METHODS
MRI was performed on 36 total participants, 18 children
with 22q (mean (7s.d.) age 118.6717 months) and 18
typically developing children (125.0723.8 months). Diagnosis of chromosome 22q11.2 deletion was confirmed using
fluorescent in situ hybridization. All participants and their
parents voluntarily signed a written consent form prior to
participation. The experimental protocol was approved by
the Institutional Review Board of the Children’s Hospital of
Philadelphia.
MRI was performed on a 1.5 T Siemens Magnetom Vision
scanner (Siemens Medical Solutions, Erlangen, Germany).
For each subject, a high-resolution 3D structural MRI was
obtained. The structural MRI was acquired using a T1weighted magnetization prepared rapid gradient echo (MPRAGE) sequence with the following parameters: repetition
time (TR) 9.7 ms, echo time (TE) 4 ms, 121 flip angle, matrix
size 256 256, slice thickness 1.0 mm, yielding 160 sagittal
slices with in-plane resolution of 1 1 mm. Total brain
volume measures were determined as part of a previous
study (Simon et al. submitted).
Two independent tracers determined the volumetric
measures of the whole thalamus (TH) and the posterior
portion of the thalamus, including the pulvinar. For
simplicity we will refer to the latter region as the posterior
thalamus (PT). Tracers were blind to the group status of the
individual while tracing. The first tracer (JB) completed
volumetric measures, using MRIcro software (version 1.36,
build 7) for all 36 participants, while the second tracer
completed volumetric measures on 10 pseudo-randomly
selected participants (5 22q patients, 5 controls) for the
purpose of reliability measures. All results discussed,
beyond reliability measures, are based on the volumetric
measures of the first tracer. Volumetric measures were
computed by using the axial and sagittal views to trace the
outline of the total thalamus. Upon determining that the
total thalamus was included within the trace, a volumetric
analysis was performed on the region of interest (ROI) to
determine the volume within the borders of the trace.
The volume of the PT was determined by using the predetermined total volumetric measure of the thalamus. The
pulvinar volume was determined using a previously
developed method [11,18]. The anterior border of the
pulvinar was approximated by the plane perpendicular to
the anterior tip of the posterior commissure. The posterior
border was determined as the posterior border of the total
thalamus. Thus, to determine the volume of the posterior
thalamus, inclusive of the pulvinar, the volume anterior to
the posterior commissure was subtracted from the total
thalamic volume (see Fig. 1 for representative participants).
RESULTS
Inter-rater reliabilities for total thalamic and posterior
thalamic volumes were determined using intra-class correlation coefficients. The reliability for the total thalamic
volume was 0.91 and for the posterior thalamic volume was
0.89. A multivariate ANCOVA was used to determine
whether group differences occurred for both the total
thalamic volume and the posterior thalamic volume. The
model used group as the independent variable, total
thalamic and posterior thalamic volumes as dependent
variables, and age, gender, and total brain volume as covariates. For the overall model, the total brain volume was a
1414
Fig. 1. Axial view of MRI image of representative participants from each
group. (a) Normal control. (b) 22q. Blackened area indicates total thalamic outline for the given slice.White line demonstrates location of posterior commissure. Posterior thalamus was de¢ned as volume posterior to
the anterior tip of the posterior commissure.
Table 1. Demographic and volumetric data for each group.
Group
n
Age
(months)
Total volume
(mm3)
Thalamus
(mm3)
Pulvinar
(mm3)
22q11.2
Controls
18
18
118.6
125.0
1243100.0
1364500.0
11807.17
12847.89
2828.78
3655.61
significant co-variate for the combination of the total
thalamic and posterior thalamic volumes (F(2,31)¼7.702,
p¼0.002), indicating that group differences for the combination of total thalamic and posterior thalamic volumes can be
explained in terms of overall brain volume reduction.
However, investigation of the separate univariate models
yielded different results. For the total thalamic volume, the
total brain volume was again a significant co-variate
(F(1.32)¼15.775, p¼0.000), and the group difference did
not survive the co-variate (F(1,32)¼0.806, p¼0.376). However, for the posterior thalamic volume, the total brain
volume co-variate only showed a trend towards significance
(F(1,32)¼3.620, p¼0.066), yet the group effect was significant, even after covarying for total brain volume, age, and
gender (F(1,32)¼5.113, p¼0.031). This indicates that posterior thalamic volumes were smaller in children with 22q and
that this result cannot be explained solely by reductions in
overall brain volume. Relative to normally developing
children, the total brain volume in this sample was reduced
by 9.9%, the total thalamic volume was reduced by 9.2%,
and the posterior thalamus was reduced by 22.7% (Table 1).
DISCUSSION
These data demonstrate a specific volume reduction of the
thalamus in children with 22q when compared with the
normally developing children. Specifically, total brain
volume reductions account for the reductions in the
thalamus of children with 22q, but do not account for the
reductions limited to the posterior thalamus. Although
the reduction in posterior thalamus may be related to the
overall reduction in brain volume for 22q children, the
degree of reduction in the posterior portion of the thalamus,
an area known to contain the pulvinar nucleus, is reduced
beyond the level expected by the overall volumetric
reductions. These alterations of the posterior thalamic
volumes in children with 22q are consistent with a number
of underlying assumptions regarding this disorder. The
extensive volumetric decrease in the posterior portion of the
Vol 15 No 9 28 June 2004
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
THALAMIC REDUCTIONS IN 22q11.2
thalamus and relative sparing of the anterior portion of the
thalamus is consistent with the suggestion of an anterior to
posterior gradient in brain abnormalities in 22q [6,7,9]. The
alterations in the posterior portion of the thalamus may also
help to explain the deficits found in visuospatial processing
in this group [12,13]. Specifically, our previous behavioral
data in a spatial cueing paradigm reveal patterns consistent
with those reported in a previous thalamic lesion study
[4,15]. Therefore, studies using individuals with thalamic
lesions and individuals with posterior thalamic volume
reductions have established the role of the pulvinar nucleus
of the thalamus in using spatial cues to re-orient attention to
a particular spatial location.
Given the high incidence of schizophrenia within the 22q
population, the relationship between thalamic reductions in
these groups is also of interest. Thalamic reductions,
specifically in the pulvinar and medial dorsal nuclei, have
been reported in individuals with schizophrenia [16,17]. A
number of similar visuospatial deficits are also common
amongst these groups [19]. The reduction of specific
thalamic nuclei volumes in children with 22q may provide
a biological marker for both the development of schizophrenia and deficits in visuospatial attentional processing
within this group.
In order to investigate the direct behavioral effects of the
reduced volumes in the posterior thalamus of children with
22q, functional studies are currently planned. Additionally,
longitudinal studies are needed to follow the thalamic
reductions into adulthood in this population and conclude
whether the thalamic reductions are related to later
psychopathology.
CONCLUSIONS
Children with chromosome 22q11.2 deletion syndrome
demonstrate a reduction in thalamic volumes consistent
with their overall brain volume reductions. Reductions in
the posterior region of the thalamus, an area known to be
involved in visuospatial processing, is reduced to an even
greater extent than that expected by the total volume
reductions. Previous findings in this population have
demonstrated a number of neurological anomalies but have
not focused on relating those measures to specific cognitive
performance.
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Acknowledgements: We would like to thank the children and families for participation in this study. Project funded by: NIH National
Research Service Award T32-NS007413 to J.P.B., NIH RO1HD42974 - 01, MRDDRC P30HD26979, GCRC M01-RR00240, and
The Philadelphia Fund toT.J.S.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.