Abnormal Brain Structure in Children With Isolated Clefts of the Lip or Palate
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ARTICLE
Abnormal Brain Structure in Children
With Isolated Clefts of the Lip or Palate
Peg Nopoulos, MD; Douglas R. Langbehn, MD, PhD; John Canady, MD; Vincent Magnotta, PhD; Lynn Richman, PhD
Objective: To evaluate brain structure in a sample of size, children with ICLP had abnormally small brains with
children with isolated clefts of the lip and/or palate (ICLP). both cerebrum (F = 4.47, P = .04) and cerebellum
(F = 14.56, P ⬍.001) volumes substantially decreased.
Design: Case-control study. Within the cerebrum, the frontal lobe was preferentially
decreased (F=7.22, P=.008) and subcortical nuclei were
Setting: Tertiary care center. also substantially smaller (F=4.18, P=.003). Tissue dis-
tribution of cortical gray matter and white matter within
Participants: A large sample of 74 children aged 7 to the cerebrum were abnormal in boys with ICLP (larger
17 years with ICLP was compared with a healthy con- cortical volume, smaller volume of white matter) but pro-
trol group, matched by age and sex. portional to controls in girls with ICLP.
Main Exposure: Isolated cleft lip and/or palate. Conclusions: Children with ICLP have abnormal brain
structure, potentially due to abnormal brain develop-
Outcome Measures: General measures of height and ment. The fact that the pattern of brain abnormalities in
head circumference were obtained. Brain structure was children with ICLP is dramatically different from the pat-
evaluated using magnetic resonance imaging, generating tern of brain abnormalities seen in adults with ICLP sug-
both general and regional brain measures (volumes). gests that brain growth and development trajectory is also
abnormal in subjects with ICLP.
Results: Height was significantly lower in the ICLP group
(F=4.83, P=.03). After controlling for this smaller body Arch Pediatr Adolesc Med. 2007;161(8):753-758
C
LEFTS OF THE LIP AND/OR is a lower than average general IQ2 with
palate are among the most specific deficits in language function.3 Fur-
common congenital thermore, these language deficits have been
anomalies, occurring in 1 shown to produce reading and memory
of 600 newborns world- deficits similar to those found in chil-
wide. These oral clefts are developmental dren with developmental dyslexia and de-
craniofacial abnormalities that result, at velopmental dysphasia.4,5 These deficits are
least in part, from a failure of neural crest severe enough that reading disabilities have
cells to migrate properly. As a group, 70% been reported to be 6 to 10 times more
of clefting disorders comprise those that prevalent in children with ICLP com-
are isolated to facial clefts only (nonsyn- pared with the general population.6,7
dromic) and 30% are those in which the The etiology of these cognitive deficits
facial cleft is part of a well-defined syn- has most commonly been cited as due to sec-
drome of additional anomalies.1 ondary factors such as hearing and/or speech
deficits (chronic otitis media being very
Author Affiliations: For editorial comment common in this population) or even to the
Departments of Psychiatry see page 811 social effects of facial disfigurement.8,9 How-
(Drs Nopoulos and Langbehn), ever, more recently, the notion that these
Otolaryngology (Dr Canady), Cognitive deficits in syndromic cleft- deficits could be a primary problem re-
Radiology (Dr Magnotta), and ing are frequent and often severe (mental lated to abnormal brain structure and func-
Pediatrics (Dr Richman),
retardation). The cognitive deficits asso- tion has been considered. The develop-
University of Iowa Carver
College of Medicine, and
ciated with isolated clefts of the lip and/or ment of the brain and face are intimately
Department of Biostatistics, palate (ICLP) are less severe, but the func- related in both normal and pathologic con-
University of Iowa School of tional consequences of these deficits ditions10,11 and suggest that abnormal brain
Public Health (Dr Langbehn), should not be underestimated. The pat- development might accompany an abnor-
Iowa City. tern of cognitive deficits reported in ICLP mality in facial development.
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Association. All rights reserved.Parental socioeconomic status of all participants was ob-
Table 1. Demographics of Sample tained using a modified Hollingshead Scale of 1 to 5 with a lower
number corresponding to higher socioeconomic status.16,17 Race
Age, Parental SES, Boys/Girls, of both groups was mostly white (ICLP group: 67 white, 6 Asian
Sample Members Mean (SD), y Mean (SD) a No. American, 1 Hispanic; control group: 65 white, 4 Asian Ameri-
ICLP subjects 12.1 (3.26) 2.69 (0.59) 50/24 can, 5 Hispanic). All participants signed informed consent prior
(n = 74) to enrolling in the protocol, which was approved by the local
Controls (n = 74) 12.3 (3.08) 2.32 (0.53) 50/24 investigational review board. In addition, all participants re-
ceived compensation for their participation in the study.
Abbreviations: ICLP, isolated cleft lip and/or palate; SES, socioeconomic Using a Wilcoxon rank sum test to compare parental so-
status. cioeconomic status between the ICLP subjects and healthy con-
a Parental socioeconomic status was based on a modified Hollingshead
trols, the mean score for the controls was significantly lower
scale of 1-5 with the higher the number, the lower the status. Difference (meaning higher social status) compared with that of the ICLP
between groups has P ⬍ .001 by Wilcoxon rank sum test.
group (mean [SD] for controls, 2.32 [0.53], and for ICLP group,
2.69 [0.59]; P⬍.001). It has been previously shown that lower
socioeconomic status is associated with higher incidence of
In previous studies from our laboratory, men with ICLP ICLP16,18; thus, this difference was expected. Demographic in-
were found to have abnormal brain structure and func- formation for the 2 study groups appears in Table 1.
tion.12-15 The brain of adults with ICLP showed normal
cerebral volumes, but an abnormality in tissue distribu- MEASURES OF COGNITIVE FUNCTION,
tion in which the frontal and parietal lobes were sub- HEIGHT, AND HEAD CIRCUMFERENCE
stantially increased in volume compared with normal, and
the temporal and occipital lobes were significantly de- Each child was assessed using a battery of neuropsychological
creased in volume. The cerebellum was also decreased tests to measure IQ as well as several other cognitive domains.
The results from this assessment appear elsewhere (A. Con-
in volume in the subjects with ICLP.
rad, PhD; L. Richman, PhD; P. Nopoulos, MD; unpublished data,
Our previous study was performed on men with ICLP, November 2006). Similar to other studies, subjects with ICLP
limiting the interpretation as to what potential develop- performed lower on standardized measures of verbal IQ, rapid
mental processes were involved and whether there were verbal labeling, verbal fluency, and verbal memory. Nurses in
any differences between the sexes in regard to brain struc- our General Clinical Research Center assessed all participants
ture abnormalities. The current study was designed there- and obtained measures of height (in centimeters) and head cir-
fore to evaluate brain structure in children (boys and girls) cumference (in centimeters).
with ICLP. Brain structure was evaluated using magnetic
resonance imaging. Our hypotheses were that children IMAGING METHODS
with ICLP would, like the adults we studied, have ab-
normal brain structure, further supporting the notion that Images were obtained on a 1.5-T GE Signa magnetic reso-
the brain structure abnormalities are present early in life nance scanner (General Electric, Milwaukee, Wisconsin). Three
and are likely due to abnormal brain development. different sequences were acquired for each subject: T1, T2, and
proton density. Processing of the images after acquisition was
done using a locally developed family of software programs called
METHODS BRAINS (acronym for Brain Research: Analysis of Images, Net-
works, and Systems). Details of the image analysis are pub-
SUBJECTS lished elsewhere.19-23
Intracranial volume is subdivided into total brain tissue and
All children with ICLP were recruited from our University of cerebrospinal fluid (CSF). Brain tissue is subdivided into the
Iowa Cleft Clinic. Any child with ICLP in whom there was a cerebrum and cerebellum. The cerebrum is then divided fur-
suspicion of genetic syndrome was evaluated by a clinical ge- ther into its 4 lobes (frontal, parietal, temporal, occipital). Sub-
neticist and included in the study only if the child was deemed cortical structure volumes are obtained using an automated neu-
nonsyndromic based on that evaluation. Exclusion criteria for ral net.24 Regions validly obtained by this method include the
the ICLP subjects included presence of braces (which create caudate, putamen, globus pallidus, and thalamus.
artifact in magnetic resonance imaging scan) and a known IQ To break down the cerebrum into the component tissue parts
less than 70 (mental retardation). As mentioned previously, men- (gray matter and white matter), a fully automated method based
tal retardation is common in syndromic clefting, and although on discriminant function analysis is used, incorporating data
it has been also documented in ICLP, we chose to exclude chil- from the T1 and the proton density/T2 sequences. The details
dren with known mental retardation to protect against enroll- of this method are published elsewhere.25 Measures obtained
ing subjects with syndromic clefts that had not previously been for analysis included total cerebral gray matter volume and ce-
diagnosed. The sample consisted of 50 boys and 24 girls with rebral white matter volume. Total cerebral gray matter is fur-
ICLP. Cleft type was categorized into clefts of the lip only (CLO) ther divided into volume of the cortex and the gray matter vol-
(n = 18), clefts of the lip and palate (CLP) (n = 33), and cleft ume comprising the 4 subcortical nuclei obtained via the neural
palate only (CPO) (n=23). net described here. Technologists performing image analysis
Healthy normal controls were recruited from the commu- were blind to any demographic characteristics of the brain they
nity via local newspaper advertisements. Exclusion criteria for were working on.
this group included presence of braces; major medical, neuro-
logic, or psychiatric illness; or history of learning disability (in- STATISTICAL ANALYSIS
formation obtained from parents during screening process).
Healthy controls were matched to the ICLP group by age (within All analyses were performed using the SAS language with SAS
1 year) and sex. STAT procedures (SAS Institute Inc, Cary, North Carolina). All
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Association. All rights reserved.Table 2. Results of Analysis on General and Regional Brain Measures
ICLP Subjects Controls
ICLP Effect
Adjusted Adjusted
Measure Mean (SD) Mean a Mean (SD) Mean a Fb P Value
Height, cm c 148.5 (18.6) 148.3 152.6 (17.3) 151.6 4.83 .03
Model 1, general head/brain measures d 3.39 .004
Head circumference, cm d 54.5 (2.68) 54.6 55.6 (2.07) 55.3 4.30 .04
Intracranial volume, cm3 1378 (125) 1377 1449 (109) 1422 5.79 .02
Total brain tissue, cm3 1312 (133) 1310 1394 (114) 1364 7.50 .007
Total CSF 67.0 (44.5) 66.7 55.0 (30.6) 58.1 1.55 .22
Total gray matter 892 (6.5) 890 934 (74.2) 915 3.97 .048
Total white matter 420 (61.3) 419 459.2 (54.6) 449 10.11 .002
Cerebral volume, cm3 1198 (112) 1195 1253 (96) 1231 4.47 .04
Cerebellar volume, cm3 128 (13.0) 127 138 (13.1) 135 14.56 ⬍.001
Model 2, cerebral regions, % cerebral volume e 2.50 .05
Frontal lobe 38.6 (1.3) 38.5 39.1 (1.1) 39.1 7.22 .008
Parietal lobe 22.8 (1.4) 22.8 22.4 (1.0) 22.5 1.58 .21
Temporal lobe 19.7 (1.0) 19.8 19.7 (0.9) 19.7 0.68 .41
Occipital lobe 10.9 (0.7) 11.0 10.7 (0.8) 10.7 3.91 .05
Model 3, subcortical structures, cm3 e 4.18 .003
Caudate 5.65 (0.82) 5.77 6.12 (0.73) 6.06 4.94 .03
Putamen f 8.97 (0.96) 9.08 9.63 (0.89) 9.48 8.26 .005
Globus pallidum g 2.70 (0.45) 2.73 2.98 (0.35) 2.90 8.84 .004
Thalamus 12.9 (1.10) 13.1 13.6 (1.13) 13.3 2.02 .16
Abbreviations: CSF, cerebrospinal fluid; ICLP, isolated cleft lip and/or palate.
a Mean adjusted by covariates.
b All univariate F tests had df = 1,134. Wilks test of ICLP in model 1 had df = 6,128. Models 2 and 3 both had df = 4,131.
c Covariates were age, sex, and parental socioeconomic status.
d Covariates were height, age, sex, and parental socioeconomic status.
e Covariates were cerebral volume, age, sex, and parental socioeconomic status.
f One extreme outlier (volume ⬍5.5 cm3) was removed.
g One extreme outlier (volume ⬎9.0 cm3) was removed.
measures of body size (height, head circumference) and brain over, social class has been shown to be related to measures such
structure and function were analyzed using covariate-adjusted as brain size.30 Other factors known to influence general and
multivariate analysis of variance (MANOVA).26 Closely related growth measures include age and sex. Therefore, parental so-
outcome variables were grouped into 4 separate covariate- cioeconomic status, age, and sex were used as covariates in the
adjusted MANOVA models. Model 1 simultaneously examined analysis of all measures, including general measures of height,
ICLP influence on head circumference; intracranial volume; ce- head circumference, and all brain measures. Finally, potential
rebral volume; cerebellar volume; and total brain CSF, gray, and sex⫻diagnostic interactions were explored for all analyses. If
white matter. Model 2 examined ICLP influence on the frontal, they were found (model 4), we did not attempt interpretation
parietal, temporal, and occipital lobes, measured as a percent- of diagnostic effect in the absence of sex considerations.
age of cerebral volume. Model 3 examined ICLP influence on Our grouping of brain measures was systematic, starting with
caudate, putamen, globus pallidus, and thalamus volumes. Model the analysis of more general measures in our first model and mov-
4 examined proportional cortical gray and cerebral white matter ing through increasingly smaller portions or regions of the brain.
without reference to regional lobe distinctions. We created these The covariates used in the analyses of the brain measures (in ad-
separate models based on both logical groupings of outcomes dition to age, sex, and parental socioeconomic status) varied with
and the need for different covariate control for various types of the size of the structure. That is, for the general measures in model
brain regions. Within each MANOVA, we used a Wilks test of 1, height was used as an additional covariate. To investigate cor-
overall ICLP effect to control for multiple outcome compari- tical lobes within the cerebrum (model 2), subcortical struc-
sons. Only if Wilks test indicated a significant multivariate as- tures (model 3), and proportional cerebral gray vs white matter
sociation between ICLP and all outcome variables in the model, (model 4), cerebral volume was used as an additional covariate.
we then examined the individual outcomes and reported uncor- Cerebral volume was used as covariate even for the propor-
rected P values. This method has been shown to effectively achieve tional measures to control for the possibility that the propor-
model-level control of type I errors in hypothesis testing.27 tion of cerebral volume occupied by each of the structures may
We checked all models for appropriate parametric assump- depend on the total cerebral volume.
tions by examining distributions of studentized residuals, DFFIT
(difference in fits, standardized) statistics, and predicted vs ob-
served response patterns.28 In 2 cases involving subcortical nu- RESULTS
clei, an extreme outlier (likely due to measurement failures)
was identified and removed.
Although the difference in mean values of parental socio- Table 2 displays the results from the general body size
economic status between the 2 groups was less than 1 point, (height and head circumference) and all brain measures
preliminary analysis showed this difference to be statistically compared across study groups. Adjusted means within the
significant by the Wilcoxon rank sum test (Table 1).29 More- table list estimated means for the ICLP and controls given
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Association. All rights reserved.Table 3. Comparison of Cerebral Gray Matter (Cortex) and White Matter Volumes Between Groups and By Sex (Model 4)
Adjusted Mean a
Sex ⴛ ICLP
Boys Girls Interaction b
Measure ICLP Controls t 133 P Value ICLP Controls t 133 P Value t 133 P Value
Cerebral volume, %
Cortical gray matter 65.0 64.2 2.11 .04 63.8 64.4 0.87 .39 1.99 .05
Cerebral white matter 32.4 33.1 1.86 .06 33.5 32.9 1.11 .34 1.92 .06
Abbreviation: ICLP, isolated cleft lip and/or palate.
a Adjusted for cerebral volume, age, sex, and parental social status.
b Cortical gray and cerebral white matter were nearly collinear (Pearson r = −.998). Multivariate analysis of variance Wilks tests of joint significance for the 2
outcomes were as follows: sex ⫻ ICLP interaction: F2,132 = 2.40, P = .09; joint effect of ICLP diagnosis and sex ⫻ ICLP interaction: F4,264 = 4.59, P = .001.
mean values for all other covariates used in each analysis. tion of cerebral volume occupied by the various lobes in
With the exception of total CSF, the children with ICLP ICLP subjects and controls. The standard deviations for
were substantially smaller than normal controls on all gen- the measures of the cerebral regions expressed as a per-
eral measures, including height (F=4.83, P=.03), head cir- centage of cerebral volume were quite small; thus, these
cumference (F=4.30, P=.04), intracranial volume (F=5.79, measures with little variance are sensitive to what appear
P=.02), total brain tissue (F=7.50, P=.007), both total gray to be modest differences in proportional measures. The
matter (F=3.97, P=.048) and total white matter (F=10.11, frontal lobe was substantially decreased in volume com-
P=.002), cerebral volume (F=4.47, P=.04), and cerebel- pared with controls (F=7.22, P=.008). There was equivo-
lar volume (F=14.56, P⬍.001). It is important to note that cal evidence that the occipital lobe occupies a larger por-
the measures of head size and brain volumes were abnor- tion of total brain volume (F=3.91, P=.05). The parietal
mally small, even after controlling for the significantly lower and temporal lobes showed no differences between the
body size (height). groups. There were no sex⫻diagnostic interactions for this
To evaluate tissue distribution of the cerebrum, pro- analysis. Therefore within a smaller than normal cere-
portions of cortical gray matter and cerebral white matter brum in children with ICLP, the frontal lobe is preferen-
were measured after controlling for total cerebral volume. tially decreased in volume.
There were marginally significant sex⫻diagnostic inter- Comparison of volumes of the subcortical nuclei is also
actions for both measures (F=1.99, P=.05, for gray mat- listed in Table 2. Again, after controlling for cerebral vol-
ter interaction and F=1.92, P=.06, for white matter inter- ume, the volumes of the caudate (F=4.94, P=.03), pu-
action). The percentages of cortex and cerebral white matter tamen (F =8.26, P =.005), and globus pallidus (F=8.84,
across groups and broken down by sex are listed in Table 3. P=.004) are all significantly smaller in comparison with
In regard to cerebral cortex, the relative volume in boys healthy controls. The volume of the thalamus, although
with ICLP is significantly increased compared with con- smaller in the ICLP group, was not significantly differ-
trols while there is no significant difference in this mea- ent than controls (F = 2.02, P = .16). There were no
sure between the girls with ICLP and healthy controls. In sex⫻diagnostic interactions for this analysis.
addition, the proportional volume of cerebral white mat- In our previous study of men with ICLP, there was a
ter is significantly decreased compared with controls in the spectrum of severity of in brain structure and function
boys with ICLP while, again, this measure shows no sig- across craniofacial phenotype in which severity of struc-
nificant difference between the girls with ICLP and their ture and function abnormality was found to be stratified
control group. These findings suggest that both boys with by type of cleft: bilateral cleft lip/palate was associated
ICLP and girls with ICLP have lower than normal vol- with the most severe abnormalities and was followed by
umes of the cerebrum (there was no sex⫻diagnostic in- unilateral cleft of the lip/palate, cleft palate only, and no
teraction for the measure of cerebral volume itself). Yet cleft (controls).14,15 In light of these findings, a post hoc
boys with ICLP manifest a further abnormality in that analysis was run, evaluating 1 measure, total brain tis-
there is a tissue distribution shift with proportionately sue (to limit the number of comparisons), across the 3
larger cortical volumes and proportionately smaller white subgroups of ICLP (CLO, CPO, CLP) compared with
matter volumes compared with controls. In girls with controls, using the same MANOVA structure as done
ICLP, the cerebrum is smaller than normal, but vol- previously (covariates were height, parental socioeco-
umes of cortex and white matter are proportional to those nomic status, age, and sex) with type of cleft (CLO, CPO,
seen in healthy controls. CLP, none [controls]) as the between-subjects variable.
Is the decrement in the volume of the cerebrum global Overall effect of type of cleft was significant (F = 4.37,
or regionally specific? The measures of the 4 regions of P=.005). In review of the post hoc analyses, we once again
the cerebrum are displayed in Table 2. Consistent with over- observed a spectrum of severity in which brain volume,
all smaller cerebral volumes, the unadjusted volumes of compared with the control group, was stratified by type
each lobe is smaller in the ICLP group compared with con- of cleft: none (controls) larger than CLO, CPO, and then
trols. Thus, like the cerebral tissue segmentation analy- CLP. Adjusted mean volume of total brain tissue in con-
sis, we investigate this question by comparing the propor- trols was 1366 cm3 and that of the CLO subgroup (n=18)
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Association. All rights reserved.was not significantly different (adjusted mean=1360 cm3, seems counterintuitive, the phenomenon of “patho-
t=0.21, P=.84). Adjusted mean volume for the CPO group logic enlargement” of cortex has been previously well
was 1310 cm3, which was marginally significantly lower documented. Specifically, this phenomenon has been seen
than controls (t=1.99, P=.048) while the adjusted mean almost exclusively in neurodevelopmental disorders, in-
volume in the CLP group was substantially smaller than cluding autism.34 Moreover, in our previous study of men
controls (volume = 1261 cm3, t = 3.74, P = .003). with ICLP, there was abnormal enlargement in the fron-
tal and parietal cortex14 as well as the superior temporal
COMMENT plane.35 In addition, these enlargements were truly patho-
logical in that the volume of these cortical regions was
inversely correlated with IQ: the larger the volume, the
It is a commonly believed, even among medical profes- lower the IQ.
sionals, that an isolated cleft of the lip and/or palate is a Sex differences in diseases that affect brain develop-
birth defect limited to a facial deformity, which is sur- ment are common, and in fact almost all neurodevelop-
gically corrected early in life. Even for those profession- mental disorders are more common and more severe in
als who understand that children with ICLP often suffer male subjects, including mental retardation, autism, at-
from additional problems such as cognitive deficit, the tention-deficit disorder, dyslexia, all developmental read-
etiology of these deficits has been considered secondary ing disorders, and schizophrenia.36 Isolated cleft lip and/or
to other factors and the scientific research to investigate palate is no exception with the incidence of CLP nearly
the neurobiology of these deficits has been limited. The 2:1 men to women (although CPO is more common in
current study provides evidence that ICLP is not lim- female subjects).36-39 With the etiology of the brain ab-
ited to a facial defect but is accompanied by abnormali- normalities in ICLP hypothesized to be due to abnor-
ties in both general growth and development with spe- mal brain development, the sex findings of the current
cific structural abnormalities of the brain. study (boys manifesting more severe brain abnormali-
ties than girls) are not unexpected.
GENERAL GROWTH
The current study found that school-aged children with GROWTH TRAJECTORIES OVER TIME
ICLP are substantially smaller in stature compared with
their matched healthy control group. At least 3 previous Although it is suggested that for height, boys with ICLP
studies have examined height in school-aged children with may eventually catch up and attain normal height, this
ICLP, all of them reporting lower than normal measures is not expected for brain morphology. The pattern of ab-
for the ICLP group.31-33 Cunningham and Jerome31 found normal brain morphology in our previous study of men
that the growth trajectories of boys with ICLP are such with ICLP is substantially different from the pattern of
that although in childhood this group is smaller than ex- abnormalities seen in the childhood sample. The chil-
pected, normal height could eventually be reached. This dren with ICLP have smaller brain volume, preferen-
is supported by our previous study of men with ICLP, tially in the frontal lobe and subcortical gray matter. In
which found the height of the ICLP group to be no dif- men with ICLP, volumes of total brain and cerebrum are
ferent than healthy controls (and in fact, nonsignifi- normal. Within the cerebrum, the frontal and parietal
cantly taller).14 lobes are enlarged and there is decrement in size of the
temporal and occipital lobes.14 No studies of brain mor-
BRAIN STRUCTURE phology have been completed in women.
How can the different patterns of brain abnormali-
This study finds children with ICLP to have significant ties between children and adults with ICLP be recon-
abnormalities in the structure of the brain. After con- ciled? The growth and development of the human brain
trolling for smaller body size (height), children with ICLP is very prolonged. Although the volume of the cere-
had reduced head circumference with smaller volumes brum reaches 95% of adult volume by age 5 years, the
of brain tissue, both in the cerebrum and cerebellum. changes in volumes of the gray and white matter within
Moreover, within the small cerebrum, the frontal lobes the cerebrum undergo substantial changes, especially dur-
and subcortical nuclei of the caudate, putamen, and glo- ing puberty,40 and continue through the second decade
bus pallidus are preferentially affected. of life.41 Although the volume of the ICLP cerebrum may
eventually reach a normal measure, the tissue distribu-
SEX DIFFERENCES IN TISSUE DISTRIBUTION tion within the cerebrum is abnormal both in childhood
and in adulthood, suggesting that later phases of growth
Although both male and female children with ICLP had and development, from school age to age 30 years, has
reduction in the volume of the cerebrum, boys with ICLP an abnormal trajectory in subjects with ICLP compared
had an additional abnormality in that the tissue distri- with normal. One region of the brain, the cerebellum, is
bution within the cerebrum was abnormal compared with abnormally small in the childhood sample and re-
controls. Specifically, boys with ICLP had proportion- mained abnormally small in the adult sample. Longitu-
ately more cortical volume than controls and less cere- dinal assessment of both girls and boys with ICLP would
bral white matter compared with controls. This tissue dis- be useful in better understanding the pattern of brain
tribution shift was not seen in girls with ICLP. Although growth and development in ICLP and how it differs from
the notion of abnormally increased volumes of cortex healthy controls and by sex.
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Association. All rights reserved.Accepted for Publication: February 8, 2007. 16. Clark JD, Mossey PA, Sharp L, Little J. Socioeconomic status and orofacial clefts
in Scotland, 1989 to 1998. Cleft Palate Craniofac J. 2003;40(5):481-485.
Correspondence: Peg Nopoulos, MD, University of Iowa
17. Hollingshead AB, Redlich FC. Social Class and Mental Illness. New York, NY: John
Hospitals and Clinics, 200 Hawkins Dr, W278 GH, Iowa Wiley & Sons; 1958.
City, IA 52242 (peggy-nopoulos@uiowa.edu). 18. Murray JC, Daack-Hirsch S, Buetow KH, et al. Clinical and epidemiologic studies of
Author Contributions: Study concept and design: Nopou- cleft lip and palate in the Philippines. Cleft Palate Craniofac J. 1997;34(1):7-10.
los and Langbehn. Acquisition of data: Nopoulos, Canady, 19. Magnotta V, Harris G, Andreasen NC, O’Leary DS, Yuh WT, Heckel D. Structural
MR image processing using the BRAINS2 toolbox. Comput Med Imaging Graph.
and Magnotta. Analysis and interpretation of data: Nopou- 2002;26(4):251-264.
los, Langbehn, Magnotta, and Richman. Drafting of the 20. Andreasen NC, Cizadlo T, Harris G, et al. Voxel processing techniques for the
manuscript: Nopoulos, Langbehn, and Magnotta. Critical antemortem study of neuroanatomy and neuropathology using magnetic reso-
revision of the manuscript for important intellectual con- nance imaging. J Neuropsychiatry Clin Neurosci. 1993;5(2):121-130.
tent: Nopoulos, Langbehn, Canady, Magnotta, and Rich- 21. Andreasen NC, Cohen G, Harris G, et al. Image processing for the study of brain
structure and function: problems and programs. J Neuropsychiatry Clin Neurosci.
man. Statistical analysis: Nopoulos and Langbehn. Ob- 1992;4(2):125-133.
tained funding: Nopoulos and Langbehn. Administrative, 22. Andreasen NC, Harris G, Cizadlo T, et al. Techniques for measuring sulcal/
technical, and material support: Nopoulos, Magnotta, and gyral patterns in the brain as visualized through magnetic resonance scan-
Richman. Study supervision: Nopoulos and Magnotta. ning: BRAINPLOT and BRAINMAP. Proc Natl Acad Sci U S A. 1994;91(1):
Financial Disclosure: None reported. 93-97.
23. Cohen G, Andreasen NC, Alliger R, et al. Segmentation techniques for the clas-
Funding/Support: This study was supported by grant 5 sification of brain tissue using magnetic resonance imaging. Psychiatry Res. 1992;
R01 DE014399-05 from the National Institutes of Den- 45(1):33-51.
tal and Craniofacial Research. 24. Magnotta VA, Heckel D, Andreasen NC, et al. Measurement of brain structures
with artificial neural networks: two- and three-dimensional applications. Radiology.
1999;211(3):781-790.
25. Harris G, Andreasen NC, Cizadlo T, et al. Improving tissue segmentation in MRI:
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