Original Paper Received: March 28, 2014 Accepted after revision: June 19, 2014 Published online: August 23, 2014
Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
Regional Brain Morphometric Characteristics of Nonsyndromic Cleft Lip and Palate Chris L. Adamson a Vicki A. Anderson a, d Peg Nopoulos e Marc L. Seal a, b Annette C. Da Costa c, d
a
Developmental Imaging, Murdoch Childrens Research Institute, and b Department of Paediatrics, The University of Melbourne, Parkville, Vic., c Department of Plastic and Maxillofacial Surgery, The Royal Children’s Hospital, and d Australian Centre for Child Neuropsychology Studies, Murdoch Childrens Research Institute, Melbourne, Vic., Australia ; e Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA
Abstract Nonsyndromic cleft lip and palate (NSCLP) encompasses a group of orofacial abnormalities. Emerging evidence has revealed the presence of structural brain abnormalities in affected individuals. Previous studies have performed structure-based volumetric analysis of the brain assessing gross lobular subdivisions of the cerebral cortex and white matter which may have only vague relationships to the functional subregions implicated in behavioral and cognitive deficits observed in NSCLP patients. High-resolution magnetic resonance imaging structural data were acquired to provide a detailed characterization of the brain with respect to both regional cortical volume and thickness in 26 children with NSCLP and 26 age- and demographically matched typically developing children. Children with NSCLP exhibited abnormally large cerebral cortex grey matter volumes with decreased volumes of subcortical grey matter and cerebral white matter structures. Hemisphere-specific patterns of cortical volume and thickness abnormalities were identified.
© 2014 S. Karger AG, Basel 0378–5866/14/0366–0490$39.50/0 E-Mail [email protected] www.karger.com/dne
This study is the first to examine cortical thickness abnormalities in NSCLP. Overall, these findings suggest that the brains of children with NSCLP are less mature than those of their age-matched peers. Gender-specific comparisons reveal that NSCLP females were more immature compared to their typically developing peers compared to NSCLP males. © 2014 S. Karger AG, Basel
Introduction
Nonsyndromic cleft lip, cleft palate or cleft lip and palate (NSCLP) are a group of congenital craniofacial disorders. These conditions arise from developmental failures of neural crest cells during gestation, resulting in deformities of the oral and/or facial structure. Developmentally, these conditions are characterized by an increased incidence of developmental problems including language and intellectual impairment, learning disabilities, attentional deficits and impaired social function [1–7]; for a review, see Richman et al. [8]. To date, the underlying etiology of these deficits remains unclear. The relatively high incidence of central nervous system anomalies in affected patients, being approximately 13 times higher compared to Chris L. Adamson Murdoch Childrens Research Institute, Royal Children’s Hospital 50 Flemington Road Parkville, VIC 3052 (Australia) E-Mail chris.adamson @ mcri.edu.au
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Key Words Nonsyndromic cleft lip and palate · Magnetic resonance imaging · Volume · Cortex · Thickness
Methods Sample Patients with a confirmed diagnosis of NSCLP were identified from a central hospital Cleft Registry Database at the Royal Children’s Hospital, Melbourne, Vic., Australia. A medical geneticist with specialist expertise in cleft disorders reviewed patient medical histories and available genetics files to confirm diagnosis and eligibility for study participation. Those who displayed clinical features and/or abnormal DNA findings that may be suggestive of a possible syndrome or other complex medical condition were excluded. The final cohort comprised 26 children with NSCLP and a sample of 26 age and demographically matched healthy controls. Study participants ranged between 6 and 14 years of age. The TD control sample was selected from a contiguous research program conducted at the same site [17]. This study received approval from the institution human research and ethics committee. MRI Acquisition MRI data were acquired on a dedicated clinical research scanner (3T Siemens TIM Trio) located at the Royal Children’s Hospital, Melbourne, Vic. Structural T1-weighted images were obtained with a 3-D IR sequence with the following parameters: 0.8 × 0.8 × 0.8 mm voxel size, 320 × 320 matrix size, 208 contiguous sagittal slices, TR: 1,900 ms, TE: 2.63 ms.
Regional Brain Morphometric Characteristics of NSCLP
Image Analysis T1-weighted images were processed using the default pipeline of FreeSurfer 5.1.0 (http://surfer.nmr.mgh.harvard.edu/). Quality assurance and manual editing of defects was performed after processing by an experienced operator, and reprocessing was performed if required; the operator was aware of diagnostic status. Morphological measurements from regional cortical and cerebellar white and grey tissue structures and subcortical grey nuclei were obtained using FreeSurfer’s automated segmentation procedure and grouped into 5 collections of variables. Collection 1 contains volumetric measures of cerebral and cerebellar white and grey matter tissue and subcortical grey nuclei based on the anatomical atlas of Fischl et al. [18]. Collections 2 through 5 contain volumetric and thickness measures for each hemisphere based on the Desikan-Killiany atlas [15]. Thus, collections 2 and 3 are cortical volume measures for the left and right hemispheres, respectively, and collections 4 and 5 are cortical mean thickness measurements for the left and right hemispheres, respectively. The relative impact of individual differences in whole brain size on volumetric but not thickness measures was accounted for by dividing by total intracranial volume. Statistical comparisons of measures between the NSCLP and control groups within each collection were conducted using mass univariate one-way analysis of variance (ANOVA). For each collection, a Wilks’ λ-test, based on a one-way multivariate ANOVA, was performed to establish main effects of group. Mass univariate ANOVA testing was only conducted for collections that exhibited a significant main effect of group (p < 0.05) according to their Wilks’ λ-tests, which indicates that ANOVA p values can be reported without multiple comparison correction but still be controlled for false discovery rate (FDR) [19]. Age was identified as a nongroup factor that had an influence, which was assumed to be linear given the age range, on volume and thickness measures. This influence was removed by transforming the volume and thickness measures to their residuals after linear fitting with age prior to ANOVA testing. Standard linear least squares estimators were used for linear model parameters. Main effects of group for each collection were computed using mass univariate ANOVA testing on all data collections with mean thickness and volume due to gender regressed out as a covariate of no interest. The resultant p values were corrected for multiple comparisons using FDR with q = 0.05, which was done to highlight the strongest results despite existing FDR correction provided by the MANOVA testing. Gender and group interaction effects were assessed using mass univariate ANOVA testing on all data collections. Resultant p values reported for interaction effects were uncorrected for multiple comparisons. For all ANOVA tests, effect sizes were determined using ω2 values, where ω2 = 0.01, ω2 = 0.06 and ω2 = 0.14 were used as thresholds to denote ‘small’, ‘medium’, and ‘large’ effect sizes [20].
Results
Demographic Results Sample demographic characteristics are presented in table 1. The study sample ranged in age from 6 to 14 years Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
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the general population [9], provides support for the hypothesis that cognitive and language deficits are the result of underlying neurodevelopmental abnormalities. Magnetic resonance imaging (MRI) studies have revealed widespread structural brain anomalies in adult [10–13] and pediatric [14] NSCLP cohorts. Specific abnormalities found in adults included increased frontal lobe volumes, decreased temporal and occipital lobe volumes [10, 11], and higher incidences of cavum septum pellucidum compared with healthy age-matched controls [12]. The single published pediatric NSCLP study found similar volumetric abnormalities with increased global cortical grey matter volumes and decreased cerebellar white matter volumes compared to age-matched controls [14]. This study used an age- and gender-matched cohort of 74 pairs (50 male) ranging from 7 to 17 years. In the current study, we examine brain volumetric characteristics at the more detailed, mesoscopic level in children with NSCLP, and compare this with typically developing (TD), age-matched controls. We utilize an automated tool that subdivides the cortex into 34 regions per cerebral hemisphere [15] and provides volumes of subcortical grey matter nuclei [16]. Both regional volumes and cortical thicknesses are examined, providing a more refined characterization of both gross lobular composition and more specialized cortical subregions.
Table 1. Groupwise demographic
summary details and statistics Age Mean ± SD Range Gender Male Female
t/χ2
p
10.40 ± 2.57 10.46 ± 2.17 7.51 – 13.19 6.53 – 14.68
t = 0.59
0.56
11 15
χ2 = 2
0.16
TD (n = 26)
NSCLP (n = 26)
10.52 ± 1.72 6.53 – 14.68 16 10
Whole cohort
27 25
Table 2. Results of mass univariate ANOVA on whole-brain cerebral and cerebellar white and grey matter tissue volumes and volumes
of selected subcortical grey matter nuclei Structure
Right cortical grey matter Left cortical grey matter Right pallidum Left accumbens Left pallidum Left amygdala Left caudate Left cerebellar cortex Left cerebellar white matter Left hippocampus Left putamen Left thalamus Right accumbens Right amygdala Right caudate Right cerebellar cortex Right cerebellar white matter Right hippocampus Right putamen Right thalamus Left cortical white matter Right cortical white matter
Group mean volumes/ ICV, mm3 (corrected after regression)
Main group effect
NSCLP
p
7.17E-03 7.42E-03 –3.77E-05 –2.72E-05 –4.71E-05 1.80E-05 6.17E-05 8.77E-05 –1.89E-04 –6.29E-05 2.70E-05 –3.21E-05 –6.50E-06 3.09E-05 3.05E-05 1.09E-04 –1.22E-04 –4.83E-05 2.46E-05 4.41E-05 –9.11E-04 –1.20E-03
TD –7.17E-03 –7.42E-03 3.77E-05 2.72E-05 4.71E-05 –1.80E-05 –6.17E-05 –8.77E-05 1.89E-04 6.29E-05 –2.70E-05 3.21E-05 6.50E-06 –3.09E-05 –3.05E-05 –1.09E-04 1.22E-04 4.83E-05 –2.46E-05 –4.41E-05 9.11E-04 1.20E-03
NSCLP TD > NSCLP TD < NSCLP TD > NSCLP TD > NSCLP TD < NSCLP TD < NSCLP TD < NSCLP TD > NSCLP TD > NSCLP TD < NSCLP TD < NSCLP TD > NSCLP TD > NSCLP
p (unc.) 0.27 0.83 0.8 0.14 0.65 0.46 0.54 0.25 0.4 0.55 0.63 0.27 male TD – male NSCLP. The right accumbens showed the opposite relationships: female TD < male TD, female NSCLP > female NSCLP, female TD – female NSCLP < male TD – male NSCLP.
F
M
F
level group × gender interaction effect. Error bars show ± standard error of the mean. Values in this plot are residuals from linear fitting of age to the original data.
(λ = 0.19078, p = 0.0137) and right (λ = 0.092364, p < 0.0001) hemispheres. Figures 2 and 3 present the significant main effects of group (NSCLP vs. TD) with respect to regional cortical volume measurements based on mass univariate ANOVA analysis; figure 2 shows FDR-corrected p values; figure 3 shows effect sizes (ω2). All statistically significant main effects of group indicated larger volumes in the NSCLP group. Regions with statistically significant main effects of group, categorized by hemisphere, were as follows. Bilateral: fusiform, inferior parietal, lateral orbitofrontal, precentral, superior frontal, transverse temporal; left: bank of superior temporal sulcus, caudal middle frontal, inferior temporal, paracentral lobule, posterior cingulate, pars opercularis, pars orbitalis, postcentral, rostral middle frontal, superior temporal; right: cuneus, lingual, lateral occipital, medial orbitofrontal, superior parietal. For these regions, all effect sizes were classified as ‘medium’ to ‘large’ (see fig. 2). There were no cortical regions that exhibited statistically significant group × gender effects for regional cortical volumes.
Regional Cortical Volumes Multivariate ANOVA analysis revealed significant main effects of group for regional cortical volumes in left
Regional Mean Cortical Thickness Multivariate ANOVA analysis revealed significant main effects of group (TD vs. NSCLP) for regional mean cortical thickness in left (λ = 0.16372, p = 0.0013) and right (λ = 0.13313, p = 0.0042) hemispheres. Figures 4 and 5 present significant main effects of group with respect to regional mean cortical thickness measurements; figure 4 shows FDR-corrected p values;
Regional Brain Morphometric Characteristics of NSCLP
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Volume/ICV (mm3, residuals after correction)
× 10–3
Color version available online
Fig. 2. FDR-corrected p values of statisti-
cally significant main group effects of regional cortical volumes. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their p values and group direction, i.e. blue to purple denotes TD > NSCLP and yellow to red denotes TD < NSCLP (colors refer to the online version only). BSTS = Bank of superior temporal sulcus; CMF = caudal middle frontal; CUN = cuneus; FUS = fusiform; INFP = inferior parietal; IT = inferior temporal; LIN = lingual; LOCC = lateral occipital; LORB = lateral orbitofrontal; MORB = medial orbitofrontal; PARC = paracentral lobule; PC = posterior cingulate; POPE = pars opercularis; PORB = pars orbitalis; PREC = precentral; PSTS = postcentral; RMF = rostral middle frontal; SF = superior frontal; SP = superior parietal; ST = superior temporal; TT = transverse temporal. MANOVA results: left hemisphere λ = 0.19078, p = 0.0137; right hemisphere λ = 0.092364, p < 0.0001. Fig. 3. Effect size values (ω2) of statistically significant main group effects of regional cortical volumes. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their ω2 values. For abbreviations, see legend to figure 2.
494
Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
Color version available online
3
ness in the NSCLP group. All effect sizes for the main effects of group previously mentioned were either ‘medium’ or ‘large’ (see fig. 5). Figures 6 and 7 show significant gender × group interaction effects for regional mean cortical thickness; figure 6 shows uncorrected p values; figure 7 shows effect sizes (ω2). Regions of significant gender × group interaction effects were the insula bilaterally and the left hemisphere superior temporal cortex. Effect sizes were Adamson /Anderson /Nopoulos /Seal / Da Costa
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figure 5 shows effect sizes (ω2). Regions with statistically significant main effects of group with increased thickness in the NSCLP group, by hemisphere, were as follows. Left: pars opercularis, pars orbitalis, precentral, pars triangularis, rostral middle frontal; right: cuneus, inferior parietal, pericalcarine, precuneus, superior parietal, and transverse temporal. In contrast, the right superior frontal cortex exhibited a significant main effect of group with decreased thick-
2
Color version available online
Fig. 4. FDR-corrected p values of statisti-
Color version available online
cally significant main group effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their p values and group direction, i.e. blue to purple denotes TD > NSCLP and yellow to red denotes TD < NSCLP (colors refer to the online version only). MANOVA results: left hemisphere λ = 0.16372, p = 0.0013; right hemisphere λ = 0.13313, p = 0.0042. PCAL = Pericalcarine; PCUN = precuneus; PTRI = pars triangularis. For all other abbreviations, see legend to figure 2.
Fig. 5. Effect sizes (ω2) of statistically sig-
nificant differences of main group effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their ω2 values. For abbreviations, see legend to figure 2.
‘medium’ (see fig. 6). Figure 8 displays the gender × group means for regions that exhibited significant gender × group interaction effects just mentioned. The difference between group means was greater for males in the insula bilaterally with TD > NSCLP. For all three regions, there were the following gender and group relationships: female NSCLP > male NSCLP, female TD < male TD.
The NSCLP sample examined in this study exhibited widespread brain morphological abnormalities compared with their TD peers. This was represented by hemisphericdependent patterns of regional cortical volumes and thickness abnormalities as well as altered tissue proportions in cortical white and subcortical grey matter structures.
Regional Brain Morphometric Characteristics of NSCLP
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Discussion
Color version available online Color version available online
Fig. 6. Uncorrected p values of statistically significant gender × group interaction effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their p values and group direction, i.e. blue to purple denotes TD > NSCLP and yellow to red denotes TD < NSCLP (colors refer to the online version only). INS = Insula. For all other abbreviations, see legend to figure 2.
Fig. 7. Effect sizes (ω2) of statistically sig-
Regional abnormalities of cortical thickness and volume were concentrated in the frontal, superior and inferior temporal and parietal lobes of the left hemisphere and, in contrast, the occipital, parietal and medial frontal regions of the right hemisphere. The majority of findings indicated increased volumes and thicknesses in the NSCLP sample. Overall cortical grey volumes were increased in the NSCLP, whilst cortical white and subcorti496
Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
cal grey matter volumes were decreased in the NSCLP sample compared to the TD peers. These findings are consistent with that of the single pediatric NSCLP [14] in that both studies found elevated cortical grey matter volumes. From a neurodevelopmental perspective, studies in TD cohorts reveal that cortical thickness generally increases from early childhood, peaking approximately at the onset Adamson /Anderson /Nopoulos /Seal / Da Costa
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nificant gender × group interaction effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their ω2 values. For abbreviations, see legend to figure 2.
Thickness (mm, residuals after correction)
Left insula
0.15
Right insula
0.15
0.10
0.10
0.05
0.05
0
0
–0.05
–0.05
0.08
Left superior temporal cortex
0.06 0.04
–0.02
–0.10
–0.15
–0.06
–0.15
M
Regression line
0
–0.04
TD NSCLP
–0.10
0.02
F
–0.08
M
F
M
F
of puberty and then progressively thinning occurs, as a consequence of synaptic pruning, until reaching a steady state in adulthood [21, 22]. Typically, the cortical thinning process occurs earlier in girls. In contrast, white matter volume increases until reaching a steady state in early adulthood [23]. The results of this study may well suggest that the NSCLP brains are less mature or follow a modified trajectory compared to their otherwise healthy peers. Gender-specific group differences of volume and regional cortical thickness were observed. Relevant volumetric measures were cortical white matter bilaterally and the right accumbens, and relevant regional mean cortical thickness measures were observed for the insula and left superior temporal cortices. Both cortical white matter regions showed clear group differences for males (TD < NSCLP) and females (NSCLP > TD) and the group differences for females were evidently greater than those for males. For the right accumbens, the directions of group differences for each gender were (TD > NSCLP) for males and (TD < NSCLP) for females. The only clear group difference for regional mean cortical thickness measures were observed in the left and right insula for males (TD > NSCLP). Thus, for the insula, the NSCLP males exhibited decreased thickness compared to TD controls, while NSCLP females did not. Given the maturation trajectory of increasing white matter and subcortical grey volumes and decreasing cortical thicknesses with age, the NSCLP females are immature compared to their age-matched female peers, whereas NSCLP males are of similar maturity.
This conclusion disagrees with previous research [14] that showed NSCLP males to have significantly increased cortical grey matter and significantly decreased cortical white matter volumes compared to controls. There is a well-established body of literature showing widespread cognitive impairments in adult and pediatric cohorts with NSCLP that revealed coexisting structural brain abnormalities [13–15, 23]. An important line of further inquiry will be to establish the functional significance of the current study findings through combined neuroimaging and neuropsychological investigations. The cognitive domain of attention is of particular interest since NSCLP patients exhibit elevated levels of attentional dysfunction [24]. The NSCLP cohort in this study had previously been shown to have cognitive deficits in attention. The human brain features dorsal and ventral attention networks [25], which have been linked to mediating orienting towards a stimulus based on behavioral significance [26] and detection of salient targets, particularly in unattended locations [27]. The dorsal attention network is comprised of the intraparietal sulcus and the frontal eye field, while the ventral attention network is located in the right temporal-parietal junction and the ventral-frontal cortex [26]. Attention as well as many other cognitive and behavioral domains have sublobular-associated structural landmarks. In order to perform accurate structure function correlation analysis, a fine parcellation of the cortex across both cerebral hemispheres is necessary.
Regional Brain Morphometric Characteristics of NSCLP
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Fig. 8. Group × gender regional cortical thickness means for regions that exhibited significant group × gender interaction effects (see fig. 7); these regions were the left and right insula and the left superior temporal cortex. Error bars show ± standard error of the mean. Values in this plot are residuals from linear fitting of age to the original data.
This study was novel since it employed a more detailed segmentation technique (FreeSurfer) than the methods used in previous studies, which enabled a comparatively more fine-grained morphological analysis. Previous studies have focused on the specific regions of interest of the orbitofrontal cortex and straight gyrus employing both manual [13] and automated segmentation techniques [7].
Acknowledgments This research was conducted within the Developmental Imaging research group, Murdoch Childrens Research Institute at the Children’s MRI Centre, Royal Children’s Hospital, Melbourne, Vic. It was supported by the Murdoch Childrens Research Institute, Royal Children’s Hospital, The University of Melbourne Department of Paediatrics and the Victorian Government’s Operational Infrastructure Support Program. This research was funded by a National Health and Medical Research Council Health Professional Research Fellowship (No. 436999) for Dr. Annette C. Da Costa. We thank the participants and their families for their involvement in this study.
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Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
Regional Brain Morphometric Characteristics of Nonsyndromic Cleft Lip and Palate Chris L. Adamson a Vicki A. Anderson a, d Peg Nopoulos e Marc L. Seal a, b Annette C. Da Costa c, d
a
Developmental Imaging, Murdoch Childrens Research Institute, and b Department of Paediatrics, The University of Melbourne, Parkville, Vic., c Department of Plastic and Maxillofacial Surgery, The Royal Children’s Hospital, and d Australian Centre for Child Neuropsychology Studies, Murdoch Childrens Research Institute, Melbourne, Vic., Australia ; e Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA
Abstract Nonsyndromic cleft lip and palate (NSCLP) encompasses a group of orofacial abnormalities. Emerging evidence has revealed the presence of structural brain abnormalities in affected individuals. Previous studies have performed structure-based volumetric analysis of the brain assessing gross lobular subdivisions of the cerebral cortex and white matter which may have only vague relationships to the functional subregions implicated in behavioral and cognitive deficits observed in NSCLP patients. High-resolution magnetic resonance imaging structural data were acquired to provide a detailed characterization of the brain with respect to both regional cortical volume and thickness in 26 children with NSCLP and 26 age- and demographically matched typically developing children. Children with NSCLP exhibited abnormally large cerebral cortex grey matter volumes with decreased volumes of subcortical grey matter and cerebral white matter structures. Hemisphere-specific patterns of cortical volume and thickness abnormalities were identified.
© 2014 S. Karger AG, Basel 0378–5866/14/0366–0490$39.50/0 E-Mail [email protected] www.karger.com/dne
This study is the first to examine cortical thickness abnormalities in NSCLP. Overall, these findings suggest that the brains of children with NSCLP are less mature than those of their age-matched peers. Gender-specific comparisons reveal that NSCLP females were more immature compared to their typically developing peers compared to NSCLP males. © 2014 S. Karger AG, Basel
Introduction
Nonsyndromic cleft lip, cleft palate or cleft lip and palate (NSCLP) are a group of congenital craniofacial disorders. These conditions arise from developmental failures of neural crest cells during gestation, resulting in deformities of the oral and/or facial structure. Developmentally, these conditions are characterized by an increased incidence of developmental problems including language and intellectual impairment, learning disabilities, attentional deficits and impaired social function [1–7]; for a review, see Richman et al. [8]. To date, the underlying etiology of these deficits remains unclear. The relatively high incidence of central nervous system anomalies in affected patients, being approximately 13 times higher compared to Chris L. Adamson Murdoch Childrens Research Institute, Royal Children’s Hospital 50 Flemington Road Parkville, VIC 3052 (Australia) E-Mail chris.adamson @ mcri.edu.au
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Key Words Nonsyndromic cleft lip and palate · Magnetic resonance imaging · Volume · Cortex · Thickness
Methods Sample Patients with a confirmed diagnosis of NSCLP were identified from a central hospital Cleft Registry Database at the Royal Children’s Hospital, Melbourne, Vic., Australia. A medical geneticist with specialist expertise in cleft disorders reviewed patient medical histories and available genetics files to confirm diagnosis and eligibility for study participation. Those who displayed clinical features and/or abnormal DNA findings that may be suggestive of a possible syndrome or other complex medical condition were excluded. The final cohort comprised 26 children with NSCLP and a sample of 26 age and demographically matched healthy controls. Study participants ranged between 6 and 14 years of age. The TD control sample was selected from a contiguous research program conducted at the same site [17]. This study received approval from the institution human research and ethics committee. MRI Acquisition MRI data were acquired on a dedicated clinical research scanner (3T Siemens TIM Trio) located at the Royal Children’s Hospital, Melbourne, Vic. Structural T1-weighted images were obtained with a 3-D IR sequence with the following parameters: 0.8 × 0.8 × 0.8 mm voxel size, 320 × 320 matrix size, 208 contiguous sagittal slices, TR: 1,900 ms, TE: 2.63 ms.
Regional Brain Morphometric Characteristics of NSCLP
Image Analysis T1-weighted images were processed using the default pipeline of FreeSurfer 5.1.0 (http://surfer.nmr.mgh.harvard.edu/). Quality assurance and manual editing of defects was performed after processing by an experienced operator, and reprocessing was performed if required; the operator was aware of diagnostic status. Morphological measurements from regional cortical and cerebellar white and grey tissue structures and subcortical grey nuclei were obtained using FreeSurfer’s automated segmentation procedure and grouped into 5 collections of variables. Collection 1 contains volumetric measures of cerebral and cerebellar white and grey matter tissue and subcortical grey nuclei based on the anatomical atlas of Fischl et al. [18]. Collections 2 through 5 contain volumetric and thickness measures for each hemisphere based on the Desikan-Killiany atlas [15]. Thus, collections 2 and 3 are cortical volume measures for the left and right hemispheres, respectively, and collections 4 and 5 are cortical mean thickness measurements for the left and right hemispheres, respectively. The relative impact of individual differences in whole brain size on volumetric but not thickness measures was accounted for by dividing by total intracranial volume. Statistical comparisons of measures between the NSCLP and control groups within each collection were conducted using mass univariate one-way analysis of variance (ANOVA). For each collection, a Wilks’ λ-test, based on a one-way multivariate ANOVA, was performed to establish main effects of group. Mass univariate ANOVA testing was only conducted for collections that exhibited a significant main effect of group (p < 0.05) according to their Wilks’ λ-tests, which indicates that ANOVA p values can be reported without multiple comparison correction but still be controlled for false discovery rate (FDR) [19]. Age was identified as a nongroup factor that had an influence, which was assumed to be linear given the age range, on volume and thickness measures. This influence was removed by transforming the volume and thickness measures to their residuals after linear fitting with age prior to ANOVA testing. Standard linear least squares estimators were used for linear model parameters. Main effects of group for each collection were computed using mass univariate ANOVA testing on all data collections with mean thickness and volume due to gender regressed out as a covariate of no interest. The resultant p values were corrected for multiple comparisons using FDR with q = 0.05, which was done to highlight the strongest results despite existing FDR correction provided by the MANOVA testing. Gender and group interaction effects were assessed using mass univariate ANOVA testing on all data collections. Resultant p values reported for interaction effects were uncorrected for multiple comparisons. For all ANOVA tests, effect sizes were determined using ω2 values, where ω2 = 0.01, ω2 = 0.06 and ω2 = 0.14 were used as thresholds to denote ‘small’, ‘medium’, and ‘large’ effect sizes [20].
Results
Demographic Results Sample demographic characteristics are presented in table 1. The study sample ranged in age from 6 to 14 years Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
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the general population [9], provides support for the hypothesis that cognitive and language deficits are the result of underlying neurodevelopmental abnormalities. Magnetic resonance imaging (MRI) studies have revealed widespread structural brain anomalies in adult [10–13] and pediatric [14] NSCLP cohorts. Specific abnormalities found in adults included increased frontal lobe volumes, decreased temporal and occipital lobe volumes [10, 11], and higher incidences of cavum septum pellucidum compared with healthy age-matched controls [12]. The single published pediatric NSCLP study found similar volumetric abnormalities with increased global cortical grey matter volumes and decreased cerebellar white matter volumes compared to age-matched controls [14]. This study used an age- and gender-matched cohort of 74 pairs (50 male) ranging from 7 to 17 years. In the current study, we examine brain volumetric characteristics at the more detailed, mesoscopic level in children with NSCLP, and compare this with typically developing (TD), age-matched controls. We utilize an automated tool that subdivides the cortex into 34 regions per cerebral hemisphere [15] and provides volumes of subcortical grey matter nuclei [16]. Both regional volumes and cortical thicknesses are examined, providing a more refined characterization of both gross lobular composition and more specialized cortical subregions.
Table 1. Groupwise demographic
summary details and statistics Age Mean ± SD Range Gender Male Female
t/χ2
p
10.40 ± 2.57 10.46 ± 2.17 7.51 – 13.19 6.53 – 14.68
t = 0.59
0.56
11 15
χ2 = 2
0.16
TD (n = 26)
NSCLP (n = 26)
10.52 ± 1.72 6.53 – 14.68 16 10
Whole cohort
27 25
Table 2. Results of mass univariate ANOVA on whole-brain cerebral and cerebellar white and grey matter tissue volumes and volumes
of selected subcortical grey matter nuclei Structure
Right cortical grey matter Left cortical grey matter Right pallidum Left accumbens Left pallidum Left amygdala Left caudate Left cerebellar cortex Left cerebellar white matter Left hippocampus Left putamen Left thalamus Right accumbens Right amygdala Right caudate Right cerebellar cortex Right cerebellar white matter Right hippocampus Right putamen Right thalamus Left cortical white matter Right cortical white matter
Group mean volumes/ ICV, mm3 (corrected after regression)
Main group effect
NSCLP
p
7.17E-03 7.42E-03 –3.77E-05 –2.72E-05 –4.71E-05 1.80E-05 6.17E-05 8.77E-05 –1.89E-04 –6.29E-05 2.70E-05 –3.21E-05 –6.50E-06 3.09E-05 3.05E-05 1.09E-04 –1.22E-04 –4.83E-05 2.46E-05 4.41E-05 –9.11E-04 –1.20E-03
TD –7.17E-03 –7.42E-03 3.77E-05 2.72E-05 4.71E-05 –1.80E-05 –6.17E-05 –8.77E-05 1.89E-04 6.29E-05 –2.70E-05 3.21E-05 6.50E-06 –3.09E-05 –3.05E-05 –1.09E-04 1.22E-04 4.83E-05 –2.46E-05 –4.41E-05 9.11E-04 1.20E-03
NSCLP TD > NSCLP TD < NSCLP TD > NSCLP TD > NSCLP TD < NSCLP TD < NSCLP TD < NSCLP TD > NSCLP TD > NSCLP TD < NSCLP TD < NSCLP TD > NSCLP TD > NSCLP
p (unc.) 0.27 0.83 0.8 0.14 0.65 0.46 0.54 0.25 0.4 0.55 0.63 0.27 male TD – male NSCLP. The right accumbens showed the opposite relationships: female TD < male TD, female NSCLP > female NSCLP, female TD – female NSCLP < male TD – male NSCLP.
F
M
F
level group × gender interaction effect. Error bars show ± standard error of the mean. Values in this plot are residuals from linear fitting of age to the original data.
(λ = 0.19078, p = 0.0137) and right (λ = 0.092364, p < 0.0001) hemispheres. Figures 2 and 3 present the significant main effects of group (NSCLP vs. TD) with respect to regional cortical volume measurements based on mass univariate ANOVA analysis; figure 2 shows FDR-corrected p values; figure 3 shows effect sizes (ω2). All statistically significant main effects of group indicated larger volumes in the NSCLP group. Regions with statistically significant main effects of group, categorized by hemisphere, were as follows. Bilateral: fusiform, inferior parietal, lateral orbitofrontal, precentral, superior frontal, transverse temporal; left: bank of superior temporal sulcus, caudal middle frontal, inferior temporal, paracentral lobule, posterior cingulate, pars opercularis, pars orbitalis, postcentral, rostral middle frontal, superior temporal; right: cuneus, lingual, lateral occipital, medial orbitofrontal, superior parietal. For these regions, all effect sizes were classified as ‘medium’ to ‘large’ (see fig. 2). There were no cortical regions that exhibited statistically significant group × gender effects for regional cortical volumes.
Regional Cortical Volumes Multivariate ANOVA analysis revealed significant main effects of group for regional cortical volumes in left
Regional Mean Cortical Thickness Multivariate ANOVA analysis revealed significant main effects of group (TD vs. NSCLP) for regional mean cortical thickness in left (λ = 0.16372, p = 0.0013) and right (λ = 0.13313, p = 0.0042) hemispheres. Figures 4 and 5 present significant main effects of group with respect to regional mean cortical thickness measurements; figure 4 shows FDR-corrected p values;
Regional Brain Morphometric Characteristics of NSCLP
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Volume/ICV (mm3, residuals after correction)
× 10–3
Color version available online
Fig. 2. FDR-corrected p values of statisti-
cally significant main group effects of regional cortical volumes. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their p values and group direction, i.e. blue to purple denotes TD > NSCLP and yellow to red denotes TD < NSCLP (colors refer to the online version only). BSTS = Bank of superior temporal sulcus; CMF = caudal middle frontal; CUN = cuneus; FUS = fusiform; INFP = inferior parietal; IT = inferior temporal; LIN = lingual; LOCC = lateral occipital; LORB = lateral orbitofrontal; MORB = medial orbitofrontal; PARC = paracentral lobule; PC = posterior cingulate; POPE = pars opercularis; PORB = pars orbitalis; PREC = precentral; PSTS = postcentral; RMF = rostral middle frontal; SF = superior frontal; SP = superior parietal; ST = superior temporal; TT = transverse temporal. MANOVA results: left hemisphere λ = 0.19078, p = 0.0137; right hemisphere λ = 0.092364, p < 0.0001. Fig. 3. Effect size values (ω2) of statistically significant main group effects of regional cortical volumes. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their ω2 values. For abbreviations, see legend to figure 2.
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Color version available online
3
ness in the NSCLP group. All effect sizes for the main effects of group previously mentioned were either ‘medium’ or ‘large’ (see fig. 5). Figures 6 and 7 show significant gender × group interaction effects for regional mean cortical thickness; figure 6 shows uncorrected p values; figure 7 shows effect sizes (ω2). Regions of significant gender × group interaction effects were the insula bilaterally and the left hemisphere superior temporal cortex. Effect sizes were Adamson /Anderson /Nopoulos /Seal / Da Costa
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figure 5 shows effect sizes (ω2). Regions with statistically significant main effects of group with increased thickness in the NSCLP group, by hemisphere, were as follows. Left: pars opercularis, pars orbitalis, precentral, pars triangularis, rostral middle frontal; right: cuneus, inferior parietal, pericalcarine, precuneus, superior parietal, and transverse temporal. In contrast, the right superior frontal cortex exhibited a significant main effect of group with decreased thick-
2
Color version available online
Fig. 4. FDR-corrected p values of statisti-
Color version available online
cally significant main group effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their p values and group direction, i.e. blue to purple denotes TD > NSCLP and yellow to red denotes TD < NSCLP (colors refer to the online version only). MANOVA results: left hemisphere λ = 0.16372, p = 0.0013; right hemisphere λ = 0.13313, p = 0.0042. PCAL = Pericalcarine; PCUN = precuneus; PTRI = pars triangularis. For all other abbreviations, see legend to figure 2.
Fig. 5. Effect sizes (ω2) of statistically sig-
nificant differences of main group effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their ω2 values. For abbreviations, see legend to figure 2.
‘medium’ (see fig. 6). Figure 8 displays the gender × group means for regions that exhibited significant gender × group interaction effects just mentioned. The difference between group means was greater for males in the insula bilaterally with TD > NSCLP. For all three regions, there were the following gender and group relationships: female NSCLP > male NSCLP, female TD < male TD.
The NSCLP sample examined in this study exhibited widespread brain morphological abnormalities compared with their TD peers. This was represented by hemisphericdependent patterns of regional cortical volumes and thickness abnormalities as well as altered tissue proportions in cortical white and subcortical grey matter structures.
Regional Brain Morphometric Characteristics of NSCLP
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Discussion
Color version available online Color version available online
Fig. 6. Uncorrected p values of statistically significant gender × group interaction effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their p values and group direction, i.e. blue to purple denotes TD > NSCLP and yellow to red denotes TD < NSCLP (colors refer to the online version only). INS = Insula. For all other abbreviations, see legend to figure 2.
Fig. 7. Effect sizes (ω2) of statistically sig-
Regional abnormalities of cortical thickness and volume were concentrated in the frontal, superior and inferior temporal and parietal lobes of the left hemisphere and, in contrast, the occipital, parietal and medial frontal regions of the right hemisphere. The majority of findings indicated increased volumes and thicknesses in the NSCLP sample. Overall cortical grey volumes were increased in the NSCLP, whilst cortical white and subcorti496
Dev Neurosci 2014;36:490–498 DOI: 10.1159/000365389
cal grey matter volumes were decreased in the NSCLP sample compared to the TD peers. These findings are consistent with that of the single pediatric NSCLP [14] in that both studies found elevated cortical grey matter volumes. From a neurodevelopmental perspective, studies in TD cohorts reveal that cortical thickness generally increases from early childhood, peaking approximately at the onset Adamson /Anderson /Nopoulos /Seal / Da Costa
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nificant gender × group interaction effects of regional mean cortical thickness. The surfaces are the ‘inflated’ versions of the average FreeSurfer brain fsaverage. The cortical regions that yielded statistically significant group differences are labeled and colored according to their ω2 values. For abbreviations, see legend to figure 2.
Thickness (mm, residuals after correction)
Left insula
0.15
Right insula
0.15
0.10
0.10
0.05
0.05
0
0
–0.05
–0.05
0.08
Left superior temporal cortex
0.06 0.04
–0.02
–0.10
–0.15
–0.06
–0.15
M
Regression line
0
–0.04
TD NSCLP
–0.10
0.02
F
–0.08
M
F
M
F
of puberty and then progressively thinning occurs, as a consequence of synaptic pruning, until reaching a steady state in adulthood [21, 22]. Typically, the cortical thinning process occurs earlier in girls. In contrast, white matter volume increases until reaching a steady state in early adulthood [23]. The results of this study may well suggest that the NSCLP brains are less mature or follow a modified trajectory compared to their otherwise healthy peers. Gender-specific group differences of volume and regional cortical thickness were observed. Relevant volumetric measures were cortical white matter bilaterally and the right accumbens, and relevant regional mean cortical thickness measures were observed for the insula and left superior temporal cortices. Both cortical white matter regions showed clear group differences for males (TD < NSCLP) and females (NSCLP > TD) and the group differences for females were evidently greater than those for males. For the right accumbens, the directions of group differences for each gender were (TD > NSCLP) for males and (TD < NSCLP) for females. The only clear group difference for regional mean cortical thickness measures were observed in the left and right insula for males (TD > NSCLP). Thus, for the insula, the NSCLP males exhibited decreased thickness compared to TD controls, while NSCLP females did not. Given the maturation trajectory of increasing white matter and subcortical grey volumes and decreasing cortical thicknesses with age, the NSCLP females are immature compared to their age-matched female peers, whereas NSCLP males are of similar maturity.
This conclusion disagrees with previous research [14] that showed NSCLP males to have significantly increased cortical grey matter and significantly decreased cortical white matter volumes compared to controls. There is a well-established body of literature showing widespread cognitive impairments in adult and pediatric cohorts with NSCLP that revealed coexisting structural brain abnormalities [13–15, 23]. An important line of further inquiry will be to establish the functional significance of the current study findings through combined neuroimaging and neuropsychological investigations. The cognitive domain of attention is of particular interest since NSCLP patients exhibit elevated levels of attentional dysfunction [24]. The NSCLP cohort in this study had previously been shown to have cognitive deficits in attention. The human brain features dorsal and ventral attention networks [25], which have been linked to mediating orienting towards a stimulus based on behavioral significance [26] and detection of salient targets, particularly in unattended locations [27]. The dorsal attention network is comprised of the intraparietal sulcus and the frontal eye field, while the ventral attention network is located in the right temporal-parietal junction and the ventral-frontal cortex [26]. Attention as well as many other cognitive and behavioral domains have sublobular-associated structural landmarks. In order to perform accurate structure function correlation analysis, a fine parcellation of the cortex across both cerebral hemispheres is necessary.
Regional Brain Morphometric Characteristics of NSCLP
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Fig. 8. Group × gender regional cortical thickness means for regions that exhibited significant group × gender interaction effects (see fig. 7); these regions were the left and right insula and the left superior temporal cortex. Error bars show ± standard error of the mean. Values in this plot are residuals from linear fitting of age to the original data.
This study was novel since it employed a more detailed segmentation technique (FreeSurfer) than the methods used in previous studies, which enabled a comparatively more fine-grained morphological analysis. Previous studies have focused on the specific regions of interest of the orbitofrontal cortex and straight gyrus employing both manual [13] and automated segmentation techniques [7].
Acknowledgments This research was conducted within the Developmental Imaging research group, Murdoch Childrens Research Institute at the Children’s MRI Centre, Royal Children’s Hospital, Melbourne, Vic. It was supported by the Murdoch Childrens Research Institute, Royal Children’s Hospital, The University of Melbourne Department of Paediatrics and the Victorian Government’s Operational Infrastructure Support Program. This research was funded by a National Health and Medical Research Council Health Professional Research Fellowship (No. 436999) for Dr. Annette C. Da Costa. We thank the participants and their families for their involvement in this study.
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