Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis

Regional Cortical White Matter Reductions in Velocardiofacial Syndrome: A Volumetric MRI Analysis Wendy R. Kates, Courtney P. Burnette, Ethylin W. Jabs, Julie Rutberg, Anne M. Murphy, Marco Grados, Michael Geraghty, Walter E. Kaufmann, and Godfrey D. Pearlson Background: Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabilities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. Methods: Subjects were ten children with velocardiofacial syndrome and ten age- and gender-matched unaffected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue boundaries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. Results: Analyses indicated that children with velocardiofacial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. Conclusions: The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocognitive and neuropsychiatric phenotype of velocardiofacial syndrome. Biol Psychiatry 2001;49:677– 684 © 2001 Society of Biological Psychiatry

From the Kennedy Krieger Institute (WRK, CPB, MGr, WEK); the Division of Psychiatric Neuroimaging (WRK, GDP), and the Departments of Psychiatry and Behavioral Science (WRK, MGr, WEK, GDP), Pediatrics (EWJ, JR, AMM, MGe, WEK), Medicine (EWJ), Plastic Surgery (EWJ), Pathology (WEK), and Neurology (WEK), Johns Hopkins University School of Medicine; and the Department of Mental Hygiene, Johns Hopkins University School of Public Health (GDP), Baltimore, Maryland. Address reprint requests to Wendy R. Kates, Ph.D., Division of Psychiatric Neuroimaging, Johns Hopkins University School of Medicine, Meyer 3-166, 600 N. Wolfe Street, Baltimore, MD 21287. Received January 28, 2000; revised July 24, 2000; accepted July 31, 2000.

© 2001 Society of Biological Psychiatry

Key Words: Velocardiofacial syndrome, volumetric MRI, chromosome 22q11, cerebral lobes, white matter

Introduction

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elocardiofacial syndrome (VCFS) is a relatively common genetic disorder that affects between 1:2000 and 1:5000 individuals (du Montcel et al 1996). Caused by a microdeletion on chromosome 22q.11 (Driscoll et al 1992; Edelmann et al 1999; Scambler et al 1992), the syndrome is associated with multiple anomalies, including cardiac defects, cleft palate, a characteristic facial appearance, pharyngeal structural abnormalities leading to hypernasal speech, language deficits, attentional deficits, executive domain dysfunction, and learning disabilities (GoldingKushner et al 1985; Moss et al 1999; Shprintzen et al 1978; Swillen et al 1997). The behavioral and psychiatric phenotype associated with VCFS includes disinhibition, impulsivity, schizoid features, and flat affect (Papolos et al 1996). Between 10% and 30% of patients with VCFS develop severe psychiatric illness during late adolescence (Shprintzen et al 1992), including schizophrenia (Bassett and Chow 1999; Pulver et al 1994a, 1994b) and bipolar disorder (Papolos et al 1996). Murphy et al (1999), for example, evaluated a cohort of 50 adults with VCFS, and found that 30% had a psychotic disorder, with 24% of those individuals meeting the criteria for schizophrenia. In addition, 12% of the total cohort had symptoms that fulfilled the criteria for major depression without psychosis. Little is known about how the 22q.11 deletion affects brain development, ultimately producing the neurocognitive and neuropsychiatric phenotype that is characteristic of VCFS patients. Initial qualitative reports of MRI findings in these patients described the presence of smaller than normal cerebellar vermi, brainstem and posterior fossa, enlarged sylvian fissure, cysts adjacent to the anterior ventricular horns, and white matter hyperintensi0006-3223/01/$20.00 PII S0006-3223(01)01002-7

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ties (Altman et al 1995; Bingham et al 1997; Mitnick et al 1994). Only recently have quantitative, volumetric neuroimaging studies been initiated (Amelsvoort et al 1999; Chow et al 1999; Eliez et al 2000), which are critical to our understanding of neuroanatomic development in VCFS. In a preliminary study of ten adults with VCFS and ten matched controls, (Amelsvoort and coworkers 1999) reported that subjects with VCFS had significantly smaller cerebellum and occipital lobes, larger parietal lobes, and loss of ventricular asymmetry. In a recently published study by Eliez et al (2000), the authors compared 15 children and adolescents with VCFS to 15 matched controls, and found that in children with VCFS, white matter was reduced to a greater extent (16.3%) than gray matter (7.5%), frontal lobe tissue was relatively preserved, and parietal lobe gray matter was significantly reduced. Contributing to that growing literature, we report here the results of an anatomic MRI study in which we compared the relative proportions of gray matter and white matter in major lobar regions of the brains of ten children with VCFS and ten age- and gender-matched controls. We first hypothesized that white matter would be specifically compromised in VCFS. This hypothesis was based on the assumption that the T2 hyperintensities that have been found in patients with VCFS represent the presence of white matter anomalies even in brains where white matter lesions have not been clinically recognized. The neurocognitive phenotype that characterizes VCFS formed the basis of our second hypothesis, which was that the frontal lobe (implicated in ADHD and in disorders of executive function) (Mega and Cummings 1994) and the parietal lobe (a component of the “attentional network” as well as a substrate of visuospatial perception, which is often compromised in children with VCFS) (Moss et al 1999; Posner and Peterson 1990) would be particularly affected in this disorder. The neuropsychiatric phenotype associated with VCFS formed the basis of the third hypothesis, which was that in addition to the frontal lobe, the temporal lobe which is altered in schizophrenia (Pearlson and Marsh, 1999) may also be altered in VCFS.

Methods and Materials Sample The sample, ranging in age from 7.9 to 14.5 years, consisted of ten children with VCFS (seven girls and three boys), mean age 10.1 (SD, 1.8); mean IQ, 73 (SD, 15.0); and ten unaffected children, individually matched by age and gender, mean age 10.1(SD, 1.9); mean IQ, 96.6 (SD 10.4). The study was explained to all participants in language appropriate to their level of cognitive functioning. Each participant and parent signed a consent form that met the institutional review board standards of the Johns Hopkins Medical Institutions. Velocardiofacial syn-

drome participants were recruited from the Medical Genetics Clinic at Johns Hopkins Hospital and from local family support groups. All the VCFS patients were clinically examined and had the common characteristics of cardiac disease, craniofacial anomalies, and confirmed deletion on chromosome 22q11.2 by fluorescent in situ hybridization (FISH). All unaffected children were screened for the presence of learning and emotional disorders at the time that they were recruited as controls for ongoing studies of neurodevelopment in our laboratory. Three out of the ten children with VCFS had a history of cardiac surgery; one with an aortic arch repair (3 months of age) and atrial septal defect (ASD) repair (2 years of age), and the other two with Tetralogy of Fallot repair (8 weeks and 2 years of age).

Image Acquisition and Processing Coronal, axial, and sagittal MRI images of each subject’s brain were acquired with a GE-Signa 1.5 Tesla scanner (General Electric, Milwaukee, WI). The sagittal T1-weighted scout was acquired with the following parameters: TR ⫽ 500 – 600, TE ⫽ 20, NEX ⫽ 1, matrix size ⫽ 256 ⫻ 256, field of view ⫽ 24 cm. Axial images were obtained using a double echo proton density T2-weighted sequence with the following parameters: TR ⫽ 3000, TE ⫽ 30/100, NEX ⫽ 1/2, matrix size ⫽ 256 ⫻ 192, field of view ⫽ 24 cm. Coronal images were acquired with a 3-D volumetric radiofrequency spoiled gradient echo (SPGR) series with the following scan parameters: TR ⫽ 35– 45, TE ⫽ 5–7, flip angle ⫽ 45, NEX ⫽ 1, matrix size ⫽ 256 ⫻ 128, field of view ⫽ 20 –24. This SPGR series was partitioned into 124, 1.5-mm contiguous slices. Raw, GE-Signa formatted image data were transferred from the MRI scanner at Johns Hopkins Hospital to Apple Macintosh Power PC workstations via existing network connections. The SPGR image data were imported into the program BrainImage (Reiss 1999) for visualization, processing, and quantitation (Subramaniam et al 1997). The importation process creates a 124-slice image stack composed of spatially registered, 8-bit images that have been processed to minimize signal artifacts related to RF field inhomogeneity. To prepare the stacks for measurement, nonbrain material (e.g., skull, scalp, and vasculature) is removed from these image stacks using a semi-automated edge detection routine that involves region growing as well as stepwise morphologic operations (Subramaniam et al 1997). These “skull stripped” images are resliced so that the interpolated slice thickness (z-dimension) is the same as the x and y pixel dimensions thereby converting the image stacks into cubic voxel data sets. The cubic voxel data sets are opened into the multiplanar visualization module of BrainImage so that three orthogonal representations of the data can be viewed simultaneously. Three out of ten MRI scans in the VCFS group (and none in the control group) were clinically abnormal as assessed by an experienced neuroradiologist. One subject had a variant of cavum septum pellucidum/vergae as well as asymmetry in the size of hippocampi with the left being slightly smaller than the right. T2 hyperintensities were observed on the scans of two children. In one subject, these were limited to the cerebellum. In the second subject, white matter hyperintensities were diffuse

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Table 1. Gray Matter Cerebral and Lobar Volumes in Children with Velocardiofacial Syndrome (VCFS) and Healthy Control Subjects

Brain region Cerebral gray Left Right Frontal gray Left Right Nonfrontal Cerebral gray Left Right Parietal gray Left Right Temporal gray Left Right Occipital gray Left Right

VCFS (N ⫽ 10)

Control (N ⫽ 10)

% difference

p value uncorrected for cerebral volumea

p value corrected for cerebral volumeb

615.35 (69.48) 302.13 (33.74) 313.22 (36.25) 226.84 (25.70) 108.73 (11.38) 118.11 (14.97)

660.33 (70.83) 325.98 (33.33) 334.36 (37.91) 233.41 (27.14) 114.44 (12.18) 118.97 (15.24)

7.1 7.6 6.5 2.9 5.1 1.0

.29 .26 .33 .71 .26 .82

.004 .01 .001

388.51 (44.79) 193.33 (22.91) 195.12 (22.08) 146.27 (19.11) 72.56 (9.73) 73.71 (9.56) 128.29 (15.57) 63.08 (7.48) 65.21 (8.27) 70.71 (8.21) 36.05 (4.66) 34.66 (3.94)

426.92 (45.34) 211.58 (21.89) 215.39 (23.96) 160.15 (20.06) 79.10 (8.87) 81.05 (11.45) 140.82 (13.85) 69.84 (7.18) 70.98 (6.92) 81.18 (10.77) 40.54 (5.22) 40.63 (6.04)

9.4 9.0 9.9 9.1 8.6 9.4 9.3 10.2 8.5 13.8 11.7 15.9

.13 .13 .08 .13 .13 .15 .08 .07 .11 .03 .09 .02

.54 .71 .70 .70 .70 .88 .82 .76 .94 .06 .10 .04

a

Volumetric comparisons between study groups were completed with the Mann–Whitney U test. Volumes for nonfrontal regions were corrected for cerebral volume by creating a ratio of a given lobar region to total cerebral tissue. Volumes for frontal lobe were corrected by creating a ratio of frontal lobe to nonfrontal cerebral tissue. b

throughout the cerebral cortex. Although cardiac repair surgery has been linked to white matter hyperintensities (Ozeren et al 1998), neither of the children with MRI hyperintensities had a history of cardiac defects.

Image Measurement The isolated brain tissue was subdivided into cerebral lobes, subcortical, brainstem, and cerebellar regions according to a revised Talairach (Talairach and Tournoux 1988) stereotaxic grid specific for measurement in pediatric study groups (Andreasen et al 1996; Kaplan et al 1997; Kates et al 1999). With this approach, high levels of sensitivity and specificity are achieved for all revised Talairach-based calculations of lobar brain regions (Kates et al 1999). Each region was then segmented into gray, white, and CSF compartments using an algorithm that assigns voxels to one or more tissue categories based on intensity values and tissue boundaries (Reiss et al 1998). The segmentation method used was determined reliable for all gray matter, white matter, and CSF volumes (Reiss et al 1998). All measurements were carried out by a research assistant who was blind to the diagnosis of each subject.

IQ Determination IQ scores were obtained with the Wechsler Intelligence Scale for Children (third edition; WISC-III) (Wechsler 1991).

Data Analysis The distribution of the volumetric data were found to be mildly skewed, so nonparametric methods of analysis were primarily

used for intergroup comparisons. The Mann–Whitney U test was used to compare cerebral and lobar volumes of gray matter and white matter. Ratios of lobar volume/cerebral tissue volume were used to correct for the effects of cerebral volume. Within-group associations between brain regions and IQ scores were calculated with Spearman Rank Order correlations.

Results The gray, white, and total cerebral tissue volumes of children with VCFS were somewhat, but not significantly, smaller than that of their age-matched peers (total cerebral tissue: 8.5% difference; cerebral gray: 7% difference; cerebral white: 10.7% difference). No significant differences were found between the two groups in the volume of CSF. To determine whether the magnitude of volume reductions in parietal, temporal, or occipital regions exceeded reductions in total cerebral volumes, statistical comparisons were made prior to and following correcting for cerebral tissue volume. Corrections consisted of ratios between the volumes of a given lobar region and total cerebral tissue. Both uncorrected and corrected analyses are reported in Tables 1 and 2; however, the text focuses primarily on the results of analyses using corrected volumes (except in instances where the two sets of findings are not consistent). Because the frontal lobe contributes such a large proportion of tissue relative to total cerebral volume, corrections for the frontal lobe were calculated

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Table 2. White Matter Cerebral and Lobar Volumes in Children with Velocardiofacial Syndrome (VCFS) and Healthy Control Subjects

Brain region Cerebral white Left Right Frontal white Left Right Nonfrontal Cerebral white Left Right Parietal white Left Right Temporal white Left Right Occipital white Left Right

VCFS (N ⫽ 10)

Control (N ⫽ 10)

% difference

p value uncorrected for cerebral volumea

p value corrected for cerebral volumeb

381.31 (62.58) 190.24 (31.74) 191.07 (30.90) 156.12 (27.15) 77.60 (14.11) 78.52 (13.34)

424.52 (47.76) 212.09 (22.81) 212.43 (25.23) 161.56 (19.61) 79.37 (9.22) 82.19 (11.30)

10.7 10.7 10.6 3.4 2.3 4.6

.11 .13 .13 .45 .50 .36

.01 .02 .05

225.19 (36.23) 112.65 (18.39) 112.55 (18.00) 104.29 (17.94) 51.12 (9.24) 53.17 (8.97) 49.59 (8.17) 25.47 (4.41) 24.13 (4.36) 37.78 (8.69) 18.89 (4.80) 18.89 (4.07)

262.96 (29.75) 132.72 (15.61) 130.24 (14.52) 121.42 (15.36) 60.27 (7.59) 61.15 (8.01) 58.01 (8.24) 30.16 (4.54) 27.85 (4.24) 45.09 (6.82) 22.93 (4.57) 22.16 (2.99)

15.5 16.3 14.6 15.2 16.4 13.9 15.7 16.9 14.3 17.6 19.3 15.9

.02 .03 .03 .04 .04 .08 .04 .04 .07 .08 .10 .04

.003 .003 .007 .04 .02 .13 .05 .05 .23 .13 .20 .15

a

Volumetric comparisons between study groups were completed with the Mann–Whitney U test. Nonfrontal lobar volumes were corrected for cerebral volume by creating a ratio of a given lobar region to total cerebral tissue. Frontal lobe volumes were corrected by creating a ratio of a given lobar region to nonfrontal cerebral tissue. b

using the summed volume of tissue in all nonfrontal lobar compartments (i.e., parietal ⫹ temporal ⫹ occipital tissue). Analyses indicated that both frontal gray and frontal white tissue compartments were preserved in children with VCFS relative to nonfrontal cerebral tissue volume. Although frontal lobe gray and white volumes in children with VCFS were only 2.9% and 3.4% smaller than frontal lobe volume in controls, respectively, nonfrontal cerebral tissue volume in children with VCFS was approximately 8.5% smaller than controls. Therefore, when frontal lobe volumes were expressed as a ratio of nonfrontal cerebral tissue volume, the relative proportion of frontal lobe tissue was significantly higher in VCFS children than in healthy controls. In contrast, nonfrontal lobar regions were decreased in children with VCFS (Tables 1 and 2). Left, right, and total nonfrontal white matter (calculated by summing parietal, temporal, and occipital white volumes) were significantly reduced in the VCFS group following correction for total cerebral tissue volume. In the right hemisphere, these white matter reductions seemed to be distributed throughout all nonfrontal lobar regions. In the left hemisphere, these reductions were driven primarily by reductions in volumes of the parietal and temporal lobes. (Although the volume of the white matter in the left occipital lobe was reduced by 19.3% in the VCFS group relative to controls,

this was attributable to an outlying data point. This was accounted for by correcting for cerebral tissue volume: corrected occipital lobe differences were not statistically significant.) When corrected volumes of nonfrontal gray matter were compared, only right occipital gray volumes were significantly reduced in VCFS children relative to controls. To determine the impact of white matter hyperintensities on volume reductions, a jack-knife statistical procedure was applied by individually removing each subject with white matter hyperintensities from the active data set and reanalyzing the data. When the procedure was applied to the subject whose white matter hyperintensities were limited to the cerebellum, no differences in statistical effects were found. When gray and white matter volumes of the groups were compared following removal of the subject whose white matter anomalies were spread diffusely throughout the cerebral cortex, the significance values associated with the statistical comparisons increased. This suggests that differences in white matter volumes between the study groups were not driven primarily by the white matter hyperintensities of either subject. Cardiac bypass surgery has been associated with white matter lesions (Goto et al 1997). Although hyperintensities were not apparent in any of the three subjects with a history of cardiac surgery, we attempted to rule out

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subclinical effects of the surgical procedure by removing these subjects from the active data set and reanalyzing the data. No differences in statistical effects were found. The association between Full Scale IQ (FSIQ) and cerebral tissue was examined with the Spearman Rank correlation coefficient. Separate analyses were run on each study group. For the control group, FSIQ was significantly correlated with cerebral tissue (␳ ⫽ .71, p ⫽ .03). For the group of children with VCFS, initial analyses yielded no significant correlations; however, following removal of an outlying data point representing both the lowest IQ (49) and the largest cerebral tissue volume in the total sample, FSIQ was also significantly correlated with cerebral tissue (␳ ⫽ .88, p ⫽ .01). Because of the disparity in Full Scale IQ (FSIQ) scores between the children with VCFS and the controls, and the high degree of association between FSIQ and cerebral gray and white matter, additional nonparametric analyses on a subset of the sample were carried out to attempt to control for the contribution of IQ to the volumetric differences in cortical regions between the two groups. The subsample consisted of six children with VCFS whose FSIQ scores were 70 or above. The mean IQ for this subsample was 82.7 (SD, 10.5). A series of Mann– Whitney U tests were then repeated comparing this subsample to the total control sample. Similar to the findings for the entire sample of children with VCFS, corrected frontal gray and white matter were found to be relatively preserved, whereas corrected nonfrontal white matter and right occipital gray matter were significantly reduced. However, white matter in the parietal and temporal lobes were not selectively reduced beyond the overall nonfrontal white matter reductions that were found. Overall, these findings suggest that although IQ may be accounting for the between-group differences in brain volumes to some extent, diagnosis is most likely accounting for the differences as well.

Discussion This investigation suggests that children with VCFS have significantly reduced tissue volumes in nonfrontal lobar regions of the brain. These volume reductions seem to affect nonfrontal white matter to a greater extent than nonfrontal gray matter. In the right hemisphere, reductions in white matter seem to be distributed relatively evenly throughout all of the posterior lobar regions. In the left hemisphere, white matter in the left parietal and temporal lobes seem disproportionately reduced relative to total cerebral tissue. The frontal lobe seems to be relatively preserved in VCFS. With the exception of regional differences in individual lobar volumes, results were similar following attempts to control for IQ. Because volumetric

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differences between groups may still be confounded to some extent by FSIQ, future studies will need to control more systematically for IQ to clarify these findings. These findings are in moderate agreement with the published study by Eliez et al (2000). Both studies found comparable levels of reductions in total cerebral gray and white matter, relatively preserved frontal tissue in children with VCFS following correcting for total cerebral volume, and significant reductions in the left parietal lobe. However, Eliez and coworkers found reductions in parietal gray matter, whereas the current study found reductions in parietal white matter. Also in contrast to the findings reported by Eliez and colleagues, the current study found reductions in temporal white matter tissue. Reductions in parietal and temporal lobe regions are consistent with the neurocognitive phenotype of VCFS. Children with VCFS have been reported to exhibit deficits in visual-perceptual skills, subserved in part by the left inferior parietal lobe (Alivisatos and Petrides 1997; Vandenberghe et al 1996), and semantic and phonological processing, subserved in part by the temporal lobe and temporo-parietal cortex (Rumsey et al 1997; Shaywitz et al 1998). Evidence that cortical alterations affect white matter to a greater extent than gray matter is also consistent with the neurocognitive phenotype found in children with VCFS. Neuropsychological data collected on the same sample (Kates et al 2000) whose imaging data are reported here suggested that the most prominent deficits in VCFS were on tasks (judgment of spatial orientation, phonological processing) that require parietal or temporal lobe processing of information that is then transmitted to the frontal lobe. These deficits support the notion that white matter reductions might reflect disturbances in cortico-cortical networks that relay information between the posterior and anterior regions of the brain. This notion is further supported by a recent study, using diffusion tensor imaging (DTI), of the microstructural integrity of white matter in adults. Klingberg et al (2000) found that subjects with reading difficulties (which are generally linked to difficulties in phonological processing) exhibited decreased diffusion anisotropy in the temporo-parietal regions of the brain. Reductions in white matter are also consistent with the neuropsychiatric phenotype in VCFS. Individuals with schizophrenia, for which children with VCFS are at significant risk, have been found to display alterations in both parietal (Frederikse et al 2000) and temporal lobe regions. Although the majority of brain-imaging studies of schizophrenia have reported gray matter anomalies, several recent imaging and postmortem studies have also described disturbances in white matter. Postmortem data on schizophrenia provide evidence for axonal disorganization (Harrison 1999) and reductions in the number of

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fibers in the corpus callosum (Highley et al 1999). In a DTI study of patients with schizophrenia, Lim et al (1999) found widespread evidence for compromised white matter tract integrity, even in the absence of white matter volume reductions. Moreover, in a small anatomic imaging study of children comorbid for VCFS and schizophrenia (Usiskin et al 1999), reductions in the midbody of the corpus callosum were found. Disturbances in white matter may be due to alterations in myelin, or to the organization or size of axon bundles (Klingberg et al 2000). Shprintzen et al (1997) have proposed that patients with VCFS may have anomalous myelination due to ischemia, which they attribute to cerebrovascular insults (Isaka et al 1997). Shprintzen’s hypothesis is based upon frequently reported clinical findings of cerebrovascular malformations in patients with VCFS (Goldberg et al 1993). Although only one child in our sample had a confirmed cerebrovascular anomaly (a medial displacement of the carotid artery), subclinical effects of ischemia cannot be ruled out; however, the studies cited above suggest that disturbances in axonal organization may underlie white matter reductions as well as disturbances in myelination. As will be discussed, future studies using imaging modalities that can elucidate the specific nature of the white matter anomalies in VCFS are critical to our understanding of the pathophysiology of this disorder. We do not yet understand the specific genetic mechanisms by which disturbances in myelination or axonal organization might occur; however, the fact that anomalies (e.g., cardiac and facial) in VCFS have been linked to one or more of the 30 genes contained within the 22q11 deleted region (Yamagishi et al 1999) raises the possibility that myelination or axonal development may be regulated, in part, by one or more of these genes as well. Although the relative preservation of the frontal lobe is consistent with other recent reports of neuroanatomic anomalies in VCFS, the data did not support our hypothesis. It is possible that, as is found in individuals with schizophrenia, subregions of the frontal lobe may differ significantly between study groups, but due to their relatively small size, would not necessarily contribute to differences in total frontal lobe volume (Buchanan et al 1998). A manual subparcellation of the frontal lobe is currently underway in our laboratory to clarify this issue. In addition, the findings by Lim and colleagues, based on a sample of individuals with schizophrenia, suggest that despite the absence of global white matter reductions in the frontal lobe of children with VCFS, disturbances in white matter tract integrity may still be present (and may be evident on DTI). The selective reductions of occipital gray matter found in patients with VCFS are consistent with the findings

reported by Amelsvoort et al (1999), and may contribute to the visual perceptual deficits that have been found in children with VCFS. However, one would also expect reductions in parietal gray regions, which would potentially be included in a neural circuit that underlies visual perceptual processing. This finding may reflect reduced sensitivity in the ability of the Talairach method to delineate the border between the parietal and occipital lobes. In conclusion, the present findings constitute an important first step (particularly in the absence of neuropathological data) in identifying the nature of white matter anomalies in children with VCFS. Potential explanations for white matter anomalies, which require further investigation, include disturbances in myelination and axonal organization. Future studies of children with VCFS require larger sample sizes, to parse out potential effects of IQ, cardiac surgery, vascular anomalies, and white matter hyperintensities on white matter reductions. Because choline levels in the brain provide information about degree of myelination (Cady et al 1996; Scarabino et al 1999), MR spectroscopy studies of choline levels are needed to clarify the relation between white matter anomalies and myelination in this disorder. Diffusion tensor imaging studies are needed to assess the integrity of white matter tracts. Manual subparcellation of cerebral lobes is needed to achieve greater precision and accuracy in identifying affected brain regions. Finally, studies of brain– behavior relations are essential to link significant neuroanatomic findings to variation in the neurocognitive and neuropsychiatric phenotype of VCFS.

This work was supported by a Young Investigator Award from the National Alliance for Research in Schizophrenia and Depression (WRK) and National Institutes of Health Grants Nos. HD 24061, P60 DE13078, and M01 RR00052 (EWJ).

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