Neuroscience Letters 399 (2006) 245–248
Specific cerebellar reductions in children with chromosome
22q11.2 deletion syndrome
Joel P. Bish a,b,∗ , Akshay Pendyal c , Lijun Ding a , Heather Ferrante d , Vy Nguyen d ,
Donna McDonald-McGinn a , Elaine Zackai a , Tony J. Simon d
b
a Children’s Hospital of Philadelphia, USA
Department of Neuroscience and Psychology, Ursinus College, 316 Thomas Hall, Collegeville, PA 19426, USA
c University of Pennsylvania, USA
d University of California, Davis, USA
Received 22 November 2005; received in revised form 19 January 2006; accepted 1 February 2006
Abstract
Children with chromosome 22q11.2 deletion syndrome commonly are found to have morphological brain changes, cognitive impairments, and
elevated rates of psychopathology. One of the most commonly and consistently reported brain changes is reduced cerebellar volume. Here, we
demonstrate that, in addition to the global cerebellum reductions previously reported, volumetric reductions of the anterior lobule and the vermal
region of the neo-cerebellum in the mid-sagittal plane best differentiate children with the deletion from typically developing children. These results
suggest that the morphological changes of specific portions of the cerebellum may be an important underlying substrate of cognitive impairments
and increased incidence of psychopathology in this group.
© 2006 Elsevier Ireland Ltd. All rights reserved.
Keywords: Chromosome 22q11.2; VCFS; Cerebellum; Visuospatial; Psychopathology
The chromosome 22q11.2 deletion syndrome (DS22q11.2)
results from a submicroscopic deletion of 1.5–3.0 mb on the long
(q) arm of chromosome 22 [10]. DS22q11.2 encompasses DiGeorge [9], and Velocardiofacial syndromes (VCFS) [23] and has
a prevalence of around in 4000 live births [6]. Common manifestations of the syndrome include heart defects, cleft palate,
T-cell abnormalities, neonatal hypocalcaemia, brain morphological changes, facial dysmorphisms, velopharyngeal insufficiency, elevated rates of psychopathology, and mild to moderate
cognitive impairment [27].
While evidence of specific brain development abnormalities in DS22q11.2 have been reported, a consensus on the
most characteristic changes and their implications for cognitive function has yet to emerge. Two studies reported overall
brain volume reduction in children with DS22q11.2 in the range
of 8–11% [11,20]. Both of these studies revealed that the predominant reductions were in the volume of non-frontal white
matter and some focal gray matter regions. Specific reduc-
∗
Corresponding author. Tel.: +1 610 489 6486.
E-mail address: jbish@ursinus.edu (J.P. Bish).
0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.neulet.2006.02.001
tions were noted in the white matter of the right cerebellum
and the gray matter of the left parietal lobe [11]. In a similar study of adults with DS22q11.2 and IQ-matched controls,
regional gray matter reductions were found in the left cerebellum and right temporal lobes, and white matter reductions were
found in frontal, bilateral temporo-parietal, and occipital regions
[30].
In addition to these global anatomical findings, a number
of studies have reported morphological changes in the cerebellum in individuals with DS22q11.2. There have been reports of
reductions in the posterior fossa and the cerebellar vermis in
addition to the mid-brain and pons [12,21] in children with the
deletion. Van Amelsvoort et al. [29] recently demonstrated that
global reductions in cerebellar volumes continue into adulthood.
Our recent voxel-based morphometry (VBM) findings included
reductions in cerebellar volume in children with DS22q11.2
[25]. Specifically, we reported gray matter (GM) reductions in
children with DS22q11.2 in the anterior lobe, or culmen, of the
cerebellum including both vermal and lingual regions. Additionally, we reported increased cerebro-spinal fluid (CSF) volume
bilaterally in regions including the cerebellar culmen, the vermis, and the tonsil region.
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J.P. Bish et al. / Neuroscience Letters 399 (2006) 245–248
In addition to these anatomical differences, children with
DS22q11.2 also show a characteristic pattern of neurocognitive impairments, which may be related to the anatomical
reductions mentioned above. Several studies used standardized neuropsychological evaluations to define the cognitive
profile of individuals with DS22q11.2 as an overall delay
in cognitive, psychomotor, and language development with
an overall IQ in the range of 70–85 [13,27]. Along with
these generalized impairments, more specific impairments are
apparent in the domains of arithmetic and visuospatial processing [3]. More recent evidence has extended the findings
of specific cognitive processing impairments in the areas of
visuospatial attention and executive control in children with
DS22q11.2 [5,24,26]. Additionally, impairments in visuoperceptual and executive functions have been demonstrated in
adults with DS22q11.2 [18]. However, the relationship between
specific cognitive impairments and volumetric differences in
brain anatomy remains unclear for both children and adults with
DS22q11.2.
Numerous studies have demonstrated the role of the cerebellum in a variety of non-motor functions, including attentional processing shown to be dysfunctional in children with
DS22q11.2 (e.g. [1,15]). However, the particular cognitive function implicated depends upon the particular focal region of the
cerebellum [16]. Therefore, the objective of this paper was to
investigate the location of the specific morphological changes
in cerebellar volumes in children with DS22q11.2. As a starting
point, these results will enable the consideration of the implications of specific cerebellar alterations for the specific cognitive
impairments shown in this group. To accomplish this objective
we measured and compared the areas of specific cerebellar lobules in children with DS22q11.2 and typically developing children using standard magnetic resonance imaging (MRI) region
of interest tracing methods.
A total of 54 children participated in this study. Of these 31
were children with DS22q11.2 whose diagnosis was confirmed
via a Flourescence In Situ Hybridization (FISH) test. The mean
age of the children with DS22q11.2 was 9 years, 11 months
with 19 females and 12 males. The children with DS22q11.2
were recruited through their participation in the “22q and You”
Clinic at the Children’s Hospital of Philadelphia. A comparison, control group of 23 children had a mean age of 10 years,
8 months with 11 females and 12 males. The control children
were recruited for participation via newspaper advertisements
and posted fliers. In compliance with Internal Review Board of
the Children’s Hospital of Philadelphia, the parents of all children gave informed consent prior to participation. Additionally,
all children involved assented to participating.
Magnetic resonance imaging was performed on a Siemens
MAGNETOM Vision 1.5 T scanner (Siemens Medical Solutions, Erlangen, Germany). For each subject, a high-resolution
three-dimensional structural MRI was acquired using a T1weighted MP-RAGE sequence with the following parameters:
repetition time (TR) 9.7 ms, echo time (TE) 4 ms, 12◦ flip angle,
number of excitations = 1, matrix size = 256 × 256, slice thickness of 1.0 mm, yielding 160 sagittal slices with an in-plane
resolution of 1 mm × 1 mm.
Area measurement for the various cerebellar regions of interest were completed by manual tracing of regions using MRICro
(v. 1.392) by a single trained tracer. For reliability purposes, a
second tracer independently computed area measurements for
a subset of 10 randomly selected participants. For a complete
description of the regional tracing method, including pictures,
see Pierson et al. [22]. For each participant, the mid-saggital slice
was obtained by using the slice in which the Sylvian Aqueduct
was most clearly visible. Using this slice, five distinct regions
were traced manually and the area within the traced region was
computed. The anterior lobe (AL) consisted of lobules I–V and
continued downward to primary fissure. The superior posterior
lobule (SPL) consisted of lobules VI–VII. The upper bound of
the SPL was the primary fissure and the lower bound was the
horizontal fissure. The inferior posterior lobule (IPL) consisted
of lobules VIII–X. The upper bound of the IPL is the horizontal
fissure and the lower bound is the inferior border of the cerebellum. The neo-cerebellum (NEO) consisted of lobules VI–VII
and overlapped the SPL and posterior portions of the IPL. The
total area of the cerebellum and the area of the tonsils of the
cerebellum at the mid-sagittal slice were also measured (Fig. 1).
Each measure was submitted to an ANCOVA, comparing
the specific volumetric measures between the two groups, while
controlling for differences in total brain volume, age, and gender.
These analyses were not corrected for multiple comparisons.
For the purposes of reliability of measurements, intra-class
correlations were performed on the data of the 10 subjects in
which 2 independent tracings were performed. Inter-rater reliability was above 90% for all measures, including the selection
of the mid-sagittal slice on which all measures were taken.
The results of the cerebellar comparisons between groups are
reported in Table 1. The overall brain volumes for these samples were obtained as part of a previously published report [25]
and were significantly reduced (p < .05) by 9.8% in children with
DS22q11.2 compared to control children. To determine whether
cerebellar differences were beyond those expected by this global
volume reduction we used total brain volume as a covariate, in
addition to age and gender. The following cerebellar mid-sagittal
areas were significantly reduced in children with DS22q11.2
when controlling for total brain volume, age, and gender: total
cerebellum (p = .013), anterior lobule (p = .014), neo-cerebellum
(p = .015), and the tonsils (p = .010). The inferior posterior lobule trended towards a significant reduction (p = .056) in children
with DS22q11.2 and the superior posterior lobule was not significantly different between groups (p = .119).
To determine which of these regions were most distinctive
between groups, we further submitted the data from each of the
cerebellar measures to a stepwise discriminant function analysis predicting group membership (DS22q11.2 versus Controls).
The discriminant function analysis revealed that the combination of the anterior lobule and the neo-cerebellum significantly
predicted group membership, F(2,51) = 10.201, p < .001, with
85.9% accuracy. The other cerebellar regions were excluded in
the model using a minimum partial F to enter of 3.84, and maximum partial F to remove of 2.71.
In this paper we have demonstrated that, in addition to
the global reductions in cerebellar tissue reported elsewhere
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J.P. Bish et al. / Neuroscience Letters 399 (2006) 245–248
Fig. 1. Representative mid-sagittal slice from which all cerebellar regions of interest were computed. Control: left; DS22q11.2: right.
[12,21,29], children with DS22q11.2 have specific reductions
in various cerebellar lobules. The anterior lobule and the midline regions of the neo-cerebellum are particularly affected in
this group. These regions of the vermis (VI–VII) have previously been related to attentional orienting impairments [28],
which appear to be an important area of cognitive dysfunction for children with D22q11.2. However, because there are
reductions in all measured regions of the cerebellum (some nonsignificant), it would be erroneous to conclude that the specific
regions, shown significantly reduced here, are responsible for
the cognitive impairments in this group.
The abnormal cerebellar vermis morphometry shown in
DS22q11.2 have been reported in a number of other disorders,
such as, schizophrenia [31], autism [7], and attention deficit
hyperactivity disorder [4]. In individuals with schizophrenia,
altered vermal volumes have been related to psychotic symptoms [19] and to cognitive impairments [2]. A recent fMRI study
comparing individuals with autism spectrum disorders found a
lack of consistent activation of posterior vermal regions during
spatial attention tasks [17].
Interestingly, each of these disorders has an increased prevalence among individuals with DS22q11.2. Therefore, it is
quite possible that cerebellar dysmorphology in children with
DS22q11.2 is a significant neural feature that plays an important
role in the cognitive and behavioral phenotype of the disorder.
This suggests that specific, hypothesis driven studies of that putative link would be very valuable to carry out.
Since the causes and progression of the morphometric
changes within the cerebellum of children with DS22q11.2 are
as yet questionable, we cannot presently determine whether
these reductions in childhood and adolescents will continue into
adulthood, as do the behavioral features of interest. Since this
paper focuses on the role that cerebellar changes in children with
DS22q11.2 might play in the neurocognitive phenotype, we must
at least acknowledge the fact that regions of the cerebellum, particularly the neo-cerebellum, are not fully mature until at least
puberty [8]. So, although the significant results are maintained
when covarying for the effects of age, we cannot rule out the
possibility that brain development in children with DS22q11.2
may be on a different maturational timeline and that this contributes to group differences in regional brain volumes that are
not directly related to behavioral impairments. A longitudinal
investigation is necessary to rule out this potential interpretation.
However, Van Amelsvoort et al. [29] did show cerebellar reductions in adults with DS22q11.2 lending support to the idea that
the global cerebellar reductions shown here last into adulthood.
Additionally, a recent study has demonstrated that the COMT
low-activity allele contributes to prefrontal cortical volumes,
cognitive decline, and the development of psychopathological
symptoms during adolescence in children with DS22q11.2 [14].
A similar pattern may be at work within the cerebellum.
In this study, we have replicated the previous reports of
cerebellar reductions in individuals with DS22q11.2, and have
extended those findings to demonstrate that along the midline,
Table 1
Region of interest results (in mm2 )
Group
Total cerebellum
Anterior lobule
Inferior posterior lobule
Superior posterior lobule
Neo-cerebellum
Tonsils
DS22q11.2 (N = 31)
Controls (N = 23)
Percentage of reduction
1114.09 (236.55)
1359.56 (261.89)
18.1*
362.94 (62.36)
430.39 (61.93)
15.7*
583.77 (175.1)
722.96 (204.52)
19.3
143.87 (38.95)
171.48 (45.32)
16.1
295.09 (101.49)
379.26 (129.89)
23.2*
110.52 (20.24)
128.91 (18.16)
14.3*
*
Significant difference between groups when covarying for age, gender, and total brain volume, p < .05.
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J.P. Bish et al. / Neuroscience Letters 399 (2006) 245–248
the anterior lobule and the neo-cerebellar regions of the vermis
are most extensively affected. These specific regions have been
implicated in a number of other disorders in which individuals with DS22q11.2 have an increased incidence. Additionally,
these same regions have been recently related to the proper functioning in specific cognitive domains, in which individuals with
DS22q11.2 have difficulties. While strong structure/function
inferences should not be drawn from this data, the results of
this paper suggest further investigation into the functionality of
cerebellar processing in individuals with DS22q11.2.
Acknowledgments
We would like to thank the children and families of the “22q
and You” clinic of the Children’s Hospital of Philadelphia.
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