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Foreshortened Dorsal Extension of the Central Sulcus in Williams Syndrome
SPECIAL ISSUE FORESHORTENED DORSAL EXTENSION OF THE CENTRAL SULCUS IN WILLIAMS SYNDROME Andrea P. Jackowski and Robert T. Schultz (Child Study Center, Yale University, New Haven, CT, USA)
ABSTRACT Williams syndrome (WMS) is a genetic condition resulting from a hemideletion on chromosome 7 that causes cognitive impairment, and a variety of growth and physical abnormalities. Little is currently known about brain morphology in WMS, although one recent MRI report suggested that the central sulcus was abnormally short on its dorsal end compared to normal IQ controls. We sought to replicate this finding in a group of 28 persons with WMS in comparison to both an age and sex matched normal IQ control group (n = 22). In addition, we sought to test the specificity of this finding by a further comparison to an IQ matched control group (n = 20). Using high resolution isotropic voxel MRI, the dorsal and ventral extension of the central sulcus was traced and the distance from the interhemispheric and sylvian fissures was measured. The dorsal extension of the central sulcus in both hemispheres was significantly more distant from the interhemispheric fissure in WMS compared to the lower IQ group and to the normal control group (p’s < 0.001). There was no significant difference between groups in the ventral end of the central sulcus. These results suggest that the abnormal dorsal end of the central sulcus may be a specific characteristic of WMS not shared with general mental retardation or low IQ. Key words: Williams syndrome, magnetic resonance imaging, central sulcus, cerebral cortex
INTRODUCTION Williams syndrome (WMS) is a mental retardation syndrome caused by a hemideletion on the long arm of chromosome 7 (7q 11.23), occurring in an estimated one in 25,000 births worldwide (Greenberg, 1989). The neurocognitive profile includes a mean IQ of about 60 (range ~ 40 to 100), hypersensitivity to sound, relative strength in face perception, musical abilities and in some aspects of verbal ability, with weakness in spatial, motor and visual-motor abilities (Bellugi et al., 1990; Schultz et al., 2001). Individuals with WMS show an interesting dissociation of ability within the visual domain, particularly between face perception and visual-spatial tasks (Atkinson et al., 1997). Although visual-spatial ability is profoundly impaired, face recognition skill is significantly greater than expected based on IQ, and group means can be as high as the low average range of normal (Bellugi et al., 1996; Bellugi and St. George, 2001). To understand this dichotomy of functioning, it is necessary to appreciate the segregation of functions within the brain. The primate visual system is subdivided into two anatomically and functionally distinct systems. The ventral stream (occipito-temporal cortex) is principally involved in processing object properties (including the face), whereas the dorsal stream (occipito-parietal lobes) is mainly involved in spatial processes (such as object location) (Ungerleider and Haxby, 1994). Such large disparity between visual-spatial perception and facial recognition in WMS has lead researchers in this area to hypothesize a dissociation between the Cortex, (2005) 41, 282-290
function of the dorsal and the ventral visual pathways in this syndrome (Atkinson et al., 1997, 2001, 2003; Bellugi and St. George, 2001; Jordan et al., 2002; Paul et al., 2002). Given the well documented visual abnormalities in WMS it is somewhat surprising to find only a few anatomical studies of the visual system. The most relevant reports of anomalous anatomy in posterior and dorsal areas are a finding of increased gyrification in the posterior regions of the brain (right parietal and occipital lobes) (Schmitt et al., 2002), decreased neuronal size in the primary visual cortex (Galaburda et al., 2001b) and an anomalous central sulcus (Galaburda et al., 2001a). Given the ease of identifying and measuring the central sulcus, and the importance of replication in the neuroimaging literature, we decided to start a comprehensive investigation of WMS by replicating Galaburda’s et al. (2001a) findings. The central sulcus is the most important and constant landmark on the convexity of the brain, since it divides the sensory and motor areas and contains a representation for each of these functional domains within its walls (Ono et al., 1989). Galaburda et al. have studied the morphology of the central sulcus in WMS. In a postmortem case study, they found an unusual gyral pattern and a shortened central sulcus on its dorsal extension (Galaburda et al., 1994). They later confirmed this finding in an MRI study (Galaburda et al., 2001a). Comparing a sample of 21 WMS subjects with 21 controls with normal IQ they found that the central sulcus was significantly less likely to reach the interhemispheric fissure in WMS (11% vs. 68 % for the controls). This was a qualitative
The central sulcus in Williams syndrome
observation that deserves to be confirmed with more careful quantitative analyses. The dissimilarities between groups in the dorsal extension of the central sulcus were not observed on its ventral end (Galaburda et al., 2001a). Moreover, neither the postmortem study nor the MRI study compared central sulcus morphology in WMS to a control group composed of other persons with mild or borderline mental retardation. Thus, it is not clear if the findings are specific to WMS or whether they represent some nonspecific morphological disturbance characteristic of low intelligence or mental retardation (MR). In this study our goals were to: (1) replicate Galaburda’s et al. (2001a) qualitative findings, (2) determine the specificity of the central sulcus findings in WMS subjects versus an IQ matched control group, (3) quantify the central sulcus measurements and (4) explore the functional significance of foreshortened dorsal extension of the central sulcus through correlational analyses with other anatomical measures and with a set of neuropsychological measurements.
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1991), while subjects over 16 years old were administered the Wechsler Adult Intelligence ScaleThird Edition (WAIS-III) (Wechsler, 1997). The Benton Judgement of Line Orientation (Benton, 1994), the Beery-Buktenica Test of Visual Motor Integration (Beery, 1997), Word Attack and Letter Word Identification subtests of the Woodcock Johnson Test of Achievement (Woodcock and Johnson, 1990), Edinburgh Handedness (Oldfied, 1971), Purdue Pegboard Test (Tiffin, 1948), Finger Tapping Test (Reitan and Davison, 1974) and select subtests of Differential Abilities Scale (Elliot, 1990) were also administered to measure visual, visual-spatial, visual-motor, motor and language competency. We found several significant differences in the neuropsychological profiles of persons with WMS, including the expected dissociation between face perception and visualspatial perception, and these will be the topic of a subsequent report. Standard scores from these measures were used here in correlational analyses with brain variables. Data Acquisition
METHODS MR images of each subject’s brain were acquired with a GE-Signa 1.5T scanner, using a 3D SPGR sagittal acquisition series (TR = 24 msec, TE = 5 msec, flip angle = 45°, NEX = 2, matrix size = 256 × 256 pixels, FOV = 30 mm, slice thickness = 1.2 mm, 124 slices) that yielded 1.2 mm3 isotropic voxels. Initial imaging processing was done using the Analyze AVW 4.0 software platform (Robb and Hansen, 1990) and included stripping off the skull and aligning the images into the AC-PC space.
Subjects Twenty-eight individuals diagnosed with WMS, 22 normal control subjects (IQ range ~ 90-110) matched with the patients for gender and age and 20 lower IQ subjects also matched with the WMS patients for gender and age were studied (Table I). There were no significant differences between the three groups for gender χ2 (2) = 4.97, p > 0.08, and age, F (2, 67) = 0.90, p > 0.40. In addition, there was no significant difference in Wechsler Full Scale IQ between the WMS group and the lower IQ group, t (46) = – 1.89, p > 0.06. All diagnoses of WMS were made by FISH confirmation of elastin gene deletion. All participants gave informed consent for participation in this study, which was approved by the Yale University institutional review board.
Measurements The images were measured using a custom software package (Rambo et al., 1998) written in VTK from the Yale Image Processing and Analysis Group. The procedure involved viewing the 3D rendered cortical surface, which could be freely rotated in space, and interactively marking that surface using a mouse-controlled cursor. The central sulcus was identified and traced from the sylvian fissure to its dorsal extension, terminating near the interhemispheric fissure. The 3D brain
Neuropsychological Assessment Participants 8-16 years of age were administered the Wechsler Intelligence Scale for Children-Third Edition (WISC–III) (Wechsler, TABLE I
Age (years) and Full Scale IQ Mean ± SD and range in WMS, lower IQ controls and normal range IQ controls. (NC) NC (n = 22)
WMS (n = 28)
Lower IQ (n = 20)
M
F
M
F
M
F
9
13
8
20
11
9
Age (years) range
20.3 ± 12.7 11-43
23.6 ± 8.8 12-45
25.5 ± 12 11-39
29.2 ± 12.7 12-48
24.2 ± 11 8-44
25.6 ±13.5 8-34
IQ range
98.3 ± 10.3 91-111
106.3 ± 7.2 96-116
62.5 ±7.6 50-76
64.8±12.2 40-82
68.6 ±11.6 49-87
74.1 ± 9.1 59-88
n
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Fig. 1 – 2D slices and 3D rendered volume showing the central sulcus tracing.
volume was gradually rotated during the tracing to avoid oblique views, allowing easy and accurate marking of the full extent of the central sulcus. In addition, the tracing was automatically projected in real time to 3 orthogonal 2D brain views. These were updated in real time during the trace, and allowed a further check of the tracing accuracy (see Figure 1). Because the underlying MRI data have a resolution of 1.2 mm3, the distance from the dorsal end of the central sulcus to the leading edge of the plane that defines the interhemispheric fissure could easily be computed by counting along a straight line the number of intervening voxels and multiplying that sum by 1.2 mm. The same procedure was applied to calculate the distance between the ventral end of the central sulcus and the sylvian fissure. The rater was blind to all identities and diagnoses of the subjects. Repeat measurements were performed in a random order on all participants, and intra-rater reliability was outstanding (ICC > .99) for all measurements. For comparison to the results of Galaburda et al. (2001a), we also coded as a binary variable (yes or no) whether or not the central sulcus reached the interhemispheric fissure and the sylvian fissure. We also coded the shape of the dorsal extension of the central sulcus as “Y”-shaped, straight or “T”shaped following the classification provided by
Ono et al. (1989). When the dorsal extension was “Y” or “T”-shaped, we connected both terminal ends with a plane that was parallel to the interhemispheric fissure, and we measured the distance to the interhemispheric fissure from the midpoint of that plane. The volumes of the total brain and the individual lobes were calculated as part of a separate research project, and are reported here only for correlational analyses with the main variables of interest. All of the figures displayed in the manuscript follow radiological convention with right and left reversed. The tracings on Figures 2, 3 and 4 were painted over in Adobe Photoshop 7.0.® with a thicker line better suited for viewing in this style presentation. Data Analysis ANOVA was used to test for group differences in MRI distance variables. Chi-square analyses were used to test the qualitative differences between groups regarding the shape of the central sulcus terminal and whether or not the extension of the central sulcus reached the midline. Correlation analyses were conducted within the WMS sample to test for significant linear relationships between the central sulcus, tissue volumes and neuropsychological measurements.
The central sulcus in Williams syndrome
Fig. 2 – Patterns of the shape of the dorsal end of the central sulcus in the WMS group.
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Fig. 3 – Patterns of the shape of the dorsal end of the central sulcus in the normal control group.
RESULTS a. Qualitative analyses The central sulcus in the WMS group reached the interhemispheric fissure (see Figure 2) less often
than in the normal controls (see Figure 3) in the left, χ2 (1) = 4.48, p < 0.05, and in the right hemisphere, χ2 (1) = 9.17, p < 0.05. The central sulcus in the WMS group also reached the interhemispheric fissure less often than the lower IQ group (see Figure 4) in the right hemisphere, χ2 (1) = 4.14, p <
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Fig. 4 – Patterns of the shape of the dorsal end of the central sulcus in the Lower IQ control.
0.05, but not in the left hemisphere, χ2 (1) = 3.01, p > 0.05. Those values are summarized in Table II. Shape There was no significant difference regarding the frequency of the shape (straight or “Y”- shape) TABLE II
Percentage of the Dorsal Central Sulcus that reach the Interhemispheric Fissure Group NC WMS Lower IQ
Left hemisphere
Right hemisphere
50% (11/22) 21% (6/28) 45% (9/20)
55% (12/22) 14% (4/28)* 40% (8/20)l
Significantly lower percentage of WMS cases compared to both control groups (p < 0.05)
of the dorsal extension of the central sulcus between the groups (see Table III) in the left, χ2 (2) = 0.59, p = 0.74, and in the right hemisphere, χ2 (2) = 1.29, p = 0.52. We did not find any “T”-shape dorsal central sulci in our sample. The shape of the dorsal extension of the central sulcus in our normal control sample was compared to the results reported by Ono et al. (1989) and there were no significant differences in the left, χ2 (1) = 1.39, p = 0.25, or in the right hemisphere, χ2 (2) = 2.64, p = 0.23. b. Measurements The distance between the dorsal extension of the central sulcus and the interhemispheric fissure was significantly increased in WMS when compared
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Andrea P. Jackowski and Robert T. Schultz TABLE III
Shape of the Dorsal Extension of the Central Sulcus Group NC WMS Lower IQ Ono et al. (1989)
Straight
“Y” shape
“T” shape
Total (brains)*
21 (96 %, L) 18 (82 %, R) 25 (89 %, L) 23 (82 %, R) 17 (85 %, L) 18 (90 % R) 24 (96 %, L) 20 (84 %, R)
1 (4 %, L) 4 (14 %, R) 3 (11 %, L) 5 (18 %, R) 3 (15 %, L) 2 (10 %, R) 1 (4 %, L) 4 (12 %, R)
______________
82 % (straight) 18 % (“Y”) 82 % (straight) 18 % (“Y”) 80 % (straight) 20 % (“Y”)
______________ ______________ ______________ 1 (4 % R)
N/A
The values are presented in number of subjects (percentage, and hemisphere). L = left hemisphere, R= right hemisphere, N/A = not available. * In the last column “Total” refers to the number of brains with either a right or a left “Y” shaped terminus.
TABLE IV
Measurements (mm) of the Central Sulcus Ventral and Dorsal Distances in WMS and Controls NC (1) Mean (SD) (mm)
WMS(2) Mean (SD) (mm)
Lower IQ (3) Mean (SD) (mm)
P value From 2 Way ANOVA
3.4 (2.39) 0-8.4
6.03 (2.23) 2.4-10.8
3.62 (2.43) 0-9.0
<.001
right range
3.26 (2.41) 0-9.6
7.69 (2.15) 2.6-12
4.99 (3.19) 1.2-15.5
<.001
Ventral distance left right
9.92 (3.97) 9.64 (2.95)
9.98 (4.0) 8.52 (3.29)
9.28 (3.81) 8.85 (4.03)
>.05 >.05
Dorsal distance left range
Posthoc Scheffe F statistic for each pair 8.04 (1 × 2)†* 6.16 (2 × 3)** 0.07 (1 × 3) 18.36 (1 × 2)†* 6.49 (2 × 3)** 2.36 (1 × 3) -------------------------------
†* (1, 48), p < 0.05 ** (1, 46), p < 0.05
to the normal controls and the lower IQ control groups, in both the left and right hemisphere (all p’s < 0.001; see Table IV). There was no significant difference between normal controls and lower IQ control group related to the distance between the end of the dorsal extension of the central sulcus and the interhemispheric fissure, F (1, 41) = 2.36, p > 0.05, or any another morphological measure. There were no significant hemispheric differences for the central sulcus dorsal or ventral measurements. The distance from the ventral end of the central sulcus to the sylvian fissure did not differ between groups (p’s > 0.5). There were no sex differences for any central sulcus measurement and no group by sex interactions. Correlations There were no significant correlations between the central sulcus dorsal and/or ventral distance and any neuropsychological or demographic measure.
DISCUSSION We found significant foreshortening of the dorsal extension of the central sulcus in WMS compared to two comparison groups. Our dichotomous data (central sulcus reaches or does not reach the interhemispheric fissure) replicate the qualitative findings of Galaburda et al. (2001a) in
WMS. There were no differences between the WMS, normal controls and the lower IQ groups in the ventral extension of the central sulcus. Our dichotomous data in our normal controls are also in close agreement with those of Ono et al. (1989). In their study of 25 autopsied normal control brains they found that the central sulcus reaches the midline 56 % of the time on the right and 72 % of the cases in the left hemisphere. There are no data available in the literature, for any subject group, regarding the actual distance of the central sulcus to either the interhemispheric or sylvian fissures. Thus, this is the first quantitative study determining central sulcus terminal distances, and the first also to show quantitative differences. An important design issue of this study was the inclusion of a lower intelligence group matched to the WMS group on Wechsler FSIQ. This allowed us to show that the central sulcus abnormalities appear specific to WMS and are probably not a feature of mild or borderline mental retardation more generally. Thus, the central sulcus abnormality would seem to be a direct consequence of this genetic syndrome, but follow up studies with additional MR control samples (including nonspecific MR samples as well as other genetic forms of MR) are warranted before this claim can be made with certainty. Foreshortening of the central sulcus can now be added to a list of reported morphological abnormalities in WMS. Prior studies have shown distinct brain morphology in WMS when compared
The central sulcus in Williams syndrome
to both normal developing subjects and sometimes also to persons with other genetic disorders. This list includes significant reduction in the total brain volume and unusual shape of the adult brain (Jernigan and Bellugi 1990; Reiss et al., 2000; Schmitt et al., 2001a), reduction of the size of the corpus callosum at midline (Schmitt et al., 2001b; Tomaiuolo et al., 2002), enlargement of the cerebellum (Wang et al., 1992; Jernigan et al., 1993; Jones et al., 2002), reduction in size of the brain stem and basal ganglia (Jernigan et al. 1993; Reiss et al. 2000), an unusual gyral pattern (Galaburda et al., 1994), and also a decrease in neuronal cell size in the primary visual cortex (Galaburda et al., 2001b). It will be important to replicate each of these findings, and to assess how specific each is for WMS, apart from other forms of MR. For example, there is a known relationship between intelligence and brain volume (Willerman et al., 1991; Reiss et al., 1996) that suggests that the brain volume reduction in WMS is not a unique feature of the disorder. Sorting specific and nonspecific features will be of great importance, and to do so accurately will require the consistent use of multiple controls, some of which are matched to the WMS sample on IQ measures. It will also be important to inter-relate these findings to each other in order to more fully characterize the nature of WMS pathobiology, as a related system of brain abnormalities, and also to relate the full collection of brain abnormalities to neuropsychological and other behavioral features that accompany this syndrome, in order to build comprehensive brain-behavior models of WMS. In normal development, the primordium of the central sulcus first appears as a distinctive groove at approximately 20 weeks of gestation (Chi et al., 1977). This sulcus begins parasagittally over the convexity and extends downward and laterally to make a distinct linear fissure by 22 to 23 weeks of gestation. During the sixth month of gestation, the dorsal end approaches the superior margin of the hemisphere (England, 1983). Thus, one possibility is that the central sulcus abnormality reported here is a marker for developmental abnormalities occurring around or before the 6th month of gestation. Sulcal shape also has clear anatomical determinants. One influential model posits that tension along the axons in the white matter can explain species-specific patterns of cortical folding (Van Essen, 1997). Interestingly, Reiss et al. (2000) have shown relative preservation of gray matter and disproportional reduction in white matter in subjects with WMS compared to normal controls, especially in the posterior half of the brain. Consistent with this observation, Schmitt et al. (2001b) and Tomaiuolo et al. (2002) have shown that the posterior regions of the corpus callosum (isthmus and splenium) are reduced in volume in WMS subjects when compared to normal controls.
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Those regions of the corpus contain the vast majority of the white matter tracts connecting homologous visual areas within each hemisphere (de Lacoste et al., 1985). Thus, the foreshortening of the central sulcus may be a reflection of some common underlying process that causes a general alteration in white matter connectivity. To corroborate this hypothesis, further studies on regional white matter volume and tract morphology must be performed. The connection between the abnormal dorsal extension and other neuroanatomical and neuropsychological abnormalities (e.g., visualspatial processing deficits) documented in WMS is currently not known. The functional deficits in WMS are well documented, and brain-behavior models of functioning would implicate this dorsal pathway in the pathobiology of WMS. Correlational analyses failed to find significant relationships between neuropsychological and central sulcus measurements in this study. Although it seems a rather far reach at this point to try to relate the behavioral evidence of dorsal visual pathway dysfunction with the dorsal foreshortening of the central sulcus there still might be a direct relationship between central sulcus structure and function, but in such a way that it affects all persons with WMS more or less uniformly. But this remains speculative. It will be important for future studies, especially fMRI studies of visual-spatial functioning in WMS to try to identify links to this abnormality of the central sulcus. Clearly, more research is needed to characterize the functional significance of the increase in the dorsal distance of the central sulcus in WMS.
CONCLUSIONS The shortening of the dorsal end of the central sulcus in WMS is now a replicated finding. We showed here that it was not related to impairments in general intelligence per se that are part of WMS, but that the central sulcus finding seems to be a specific attribute of the WMS pathobiology. Additional studies are required to provide more information about the functional significance of this finding, and its relationship to other neuroanatomical abnormalities that characterized WMS. Acknowledgments. We wish to thank Xenophon Papademetris for the technical support with the image analyses, Lawrence Win for the initial processing of the image data, Marc Thioux for the statistical support, Jamie Kleinman and Cheryl Klaiman for neuropsychological and other assessments of the participants, Barbara Teague for coordinating patient visits to the Children’s Clinical Research Center, and Barbara Pober for the clinical referral of the WMS sample. We also thank each of the participants and their families for giving their time and volunteering for this research. This study was supported by grants from the National Institute of Child Health and Human Development (PO1
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HD 03008 and PO1 HD/DC35482), and by the Children’s Clinical Research Center (MO1 RR06022), and Yale Developmental Neuroimaging Program. REFERENCES ATKINSON J, ANKER S, BRADDICK O, NOKES L, MASON A and BRADDICK F. Visual and visuospatial development in young children with Williams syndrome. Developmental Medicine and Child Neurology, 43: 330-337, 2001. ATKINSON J, BRADDICK O, ANKER S, CURRAN W, ANDREW R, WATTAM-BELL J and BRADDICK F. Neurobiological models of visuospatial cognition in children with Williams syndrome: Measures of dorsal stream and frontal function. Developmental Neuropsychology, 23: 139-172, 2003. ATKINSON J, KING J, BRADDICK O and NOKES L. A specific deficit of dorsal stream function in Williams syndrome. Neuroreport, 8: 1919-1922, 1997. BEERY K. Beery-Buktenica Test of Visual-Motor Integration. 4th Edition. Parsippany: Modern Curriculum Press, 1997. BELLUGI U, BIHRLE A, JERNIGANT, TRAUNER D and DOHERTY S. Neuropsychological, neurological and neuroanatomical profile of Williams syndrome. American Journal of Medical Genetics, Supplement, 6: 115-125, 1990. BELLUGI U, KLIMA ES and VAID J. Cognitive and neural development: clues from genetically based syndromes. In D Magnusson (Ed), The Life-span Development of Individual: Behavioral, Neurobiological, and Psychosocial Perspective. The Nobel Symposium. New York: Cambridge University Press, 1996, pp. 223-243. BELLUGI U and ST. GEORGE M. Journey of Cognition to Brain to Gene: Perspectives from Williams Syndrome. Cambridge: MIT Press; 2001. BENTON A. Face Recognition. Los Angeles: Westerns Psychological Services, 1994. CHI JG, DOOLING EC and GILLES FH. Gyral development of human brain. Annals of Neurology, 1: 86-93, 1977. DE LACOSTE MC, KIRKPATRICK JB and ROSS ED. Topography of the human corpus callosum. Journal of Neuropathology and Experimental Neurology, 44: 578-591, 1985 ELLIOT CD. Differential Ability Scale Administration and Scoring Manual. Toronto: The Psychological Corporation Harcourt Brace Jovanovick, 1990. ENGLAND MA. Color Atlas of Life Before Birth. Normal Fetal Development. Chicago: Year Book Medical Publishers, 1983. GALABURDA AM, HOLINGER DP, BELLUGI U and SHERMAN GF. Williams Syndrome. Neuronal size and neuronal-packing density in primary visual cortex. Archives of Neurology, 59: 1461-1467, 2001b. GALABURDA AM, SCHMITT JE, ATLAS SW, ELIEZ S, BELLUGI U and REISS AL. Dorsal forebrain anomaly in Williams Syndrome. Archives of Neurology, 58: 1865-1869, 2001a. GALABURDA AM, WANG PP, BELLUGI U and ROSSEN M. Cytoarchitectonic anomalies in a genetically based disorder: Williams syndrome. Neuroreport, 5: 753-757, 1994. GREENBERG F. Williams syndrome. Pediatrics, 84: 922-923, 1989. JERNIGAN TL and BELLUGI U. Anomalous brain morphology on magnetic resonance images in Williams syndrome and Down syndrome. Archives of Neurology, 50: 186-191, 1990. JERNIGAN TL, BELLUGI U, SOWELL E, DOHERTY S and HESSELINK JR. Cerebral morphologic distinctions between Williams and Down syndromes. Archives of Neurology, 50: 186-191, 1993. JONES W, HESSELINK J, COURCHESNE E, DUNCAN T and BELLUGI U. Cerebellar abnormalities in infants and toddlers with Williams syndrome. Developmental Medicine and Child Neurology, 44: 688-694, 2002. JORDAN H, REISS JE, HOFFMAN JE and LANDAU B. Intact perception of biological motion in the face with profound
spatial deficits: Williams Syndrome. Psychological Science, 13: 162-167, 2002. OLDFIELD R. The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia, 9: 97-113, 1971. ONO M, STEFAN K and CHAD DA. Atlas of the Cerebral Sulci. New York: Thieme Medical Publishers, 1989. PAUL BM, STILES J, PASSAROTTI A, BAVAR N and BELLUGI U. Face and place processing in Williams Syndrome: Evidence for a dorsal-ventral dissociation. Neuroreport, 13: 1115-1119, 2003. RAMBO J, XENG X, SCHULTZ RT, WIN L, SATIB LH and DUNCAN JS. Platform for visualization and measurement of gray matter volume and surface area within discrete cortical regions from MRI images. Abstracts of the fourth international conference on functional mapping of the human brain mapping. Montreal: June 8-12, 1998. REISS AL, ABRAMS MT, SINGER HS, ROSS JL and DENCKLA MB. Brain development, gender and IQ in children. A volumetric imaging study. Brain, 119: 1763-1764, 1996. REISS AL, ELIEZ S, SCHMITT E, STRAUS E, LAI Z, JONES W and BELLUGI U. IV. Neuroanatomy of Williams Syndrome: A highresolution MRI study. Journal of Cognitive Neuroscience, 12: 65-73, 2000. REITAN RM and DAVISON LA. Clinical Neuropsychology: Current status and applications. Washington: Winston, 1974. ROBB RA and HANSEN DP. ANALYZE. Proceedings from the first conference on visualization in biomedical computing. Los Alamitos: IEEE Press, 1990. SCHMITT JE, ELIEZ S, BELLUGI U and REISS AL. Analysis of cerebral shape in Williams syndrome. Archives of Neurology, 58: 283-287, 2001a. SCHMITT JE, ELIEZ S, WARSOFSKY IS, BELLUGI U and REISS AL. Corpus callosum morphology of Williams syndrome: Relation to genetics and behavior. Developmental Medicine and Child Neurology, 43: 155-159, 2001b. SCHMITT JE, WATTS K, ELIEZ S, BELLUGI U, GALABURDA AM and REISS AL. Increased gyrification in Williams syndrome: Evidence using 3D MRI methods. Developmental Medicine and Child Neurology, 44: 292-295, 2002. SCHULTZ RT, GRELOTTI DJ and POBER B. Genetics of childhood disorders: XXVI. Williams syndrome and brain-behavior relationship. Journal of the American Academy of Child and Adolescent Psychiatry, 40: 606-609, 2001. TIFFIN J. The Purdue Pegboard Test. Lafayette, IN: Lafayette Instruments, 1948. TOMAIUOLO F, DI PAOLA M, CARAVALE B, VICARI S, PETRIDES M and CALTAGIRONE C. Morphology and morphometry of the corpus callosum in Williams syndrome: A T1-weighted MRI study. Neuroreport, 13: 2281-2284, 2002. UNGERLEIDER LG and HAXBY JV. ‘What and where’ in the human brain. Current Opinion in Neurobiology, 4: 157-165, 1994. VAN E SSEN DC. A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature, 385: 313-318, 1997. WANG P, HESSELINK J, JERNIGAN T, DOHERTY S and BELLUGI U. Specific neurobehavioral profile of Williams’s syndrome is associated with neocerebellar hemispheric preservation. Neurology, 42: 1999-2002, 1992. WECSHLER D. Wecshler Intelligence Scale for Children. Third Edition. San Antonio: The Psychological Corporation, 1991. WECSHLER D. Wecshler Adult Intelligence Scale. Third Edition. San Antonio: The Psychological Corporation, 1997. WILLERMAN L, SCHULTZ R, RUTLEDGE N and BIGLER E. In vivo brain size and intelligence. Intelligence, 15: 223-228, 1991. WOODCOCK RW and JOHNSON MB. Woodcock-Johnson Test of Achievement. In WJR-Psycho-educational battery revised. Allen: TX: DLM Teaching Resources, 1990.
Robert T. Schultz, PO Box 207900, Yale University Child Study Center, New Haven, CT 06520. e-mail: [email protected]
ABSTRACT Williams syndrome (WMS) is a genetic condition resulting from a hemideletion on chromosome 7 that causes cognitive impairment, and a variety of growth and physical abnormalities. Little is currently known about brain morphology in WMS, although one recent MRI report suggested that the central sulcus was abnormally short on its dorsal end compared to normal IQ controls. We sought to replicate this finding in a group of 28 persons with WMS in comparison to both an age and sex matched normal IQ control group (n = 22). In addition, we sought to test the specificity of this finding by a further comparison to an IQ matched control group (n = 20). Using high resolution isotropic voxel MRI, the dorsal and ventral extension of the central sulcus was traced and the distance from the interhemispheric and sylvian fissures was measured. The dorsal extension of the central sulcus in both hemispheres was significantly more distant from the interhemispheric fissure in WMS compared to the lower IQ group and to the normal control group (p’s < 0.001). There was no significant difference between groups in the ventral end of the central sulcus. These results suggest that the abnormal dorsal end of the central sulcus may be a specific characteristic of WMS not shared with general mental retardation or low IQ. Key words: Williams syndrome, magnetic resonance imaging, central sulcus, cerebral cortex
INTRODUCTION Williams syndrome (WMS) is a mental retardation syndrome caused by a hemideletion on the long arm of chromosome 7 (7q 11.23), occurring in an estimated one in 25,000 births worldwide (Greenberg, 1989). The neurocognitive profile includes a mean IQ of about 60 (range ~ 40 to 100), hypersensitivity to sound, relative strength in face perception, musical abilities and in some aspects of verbal ability, with weakness in spatial, motor and visual-motor abilities (Bellugi et al., 1990; Schultz et al., 2001). Individuals with WMS show an interesting dissociation of ability within the visual domain, particularly between face perception and visual-spatial tasks (Atkinson et al., 1997). Although visual-spatial ability is profoundly impaired, face recognition skill is significantly greater than expected based on IQ, and group means can be as high as the low average range of normal (Bellugi et al., 1996; Bellugi and St. George, 2001). To understand this dichotomy of functioning, it is necessary to appreciate the segregation of functions within the brain. The primate visual system is subdivided into two anatomically and functionally distinct systems. The ventral stream (occipito-temporal cortex) is principally involved in processing object properties (including the face), whereas the dorsal stream (occipito-parietal lobes) is mainly involved in spatial processes (such as object location) (Ungerleider and Haxby, 1994). Such large disparity between visual-spatial perception and facial recognition in WMS has lead researchers in this area to hypothesize a dissociation between the Cortex, (2005) 41, 282-290
function of the dorsal and the ventral visual pathways in this syndrome (Atkinson et al., 1997, 2001, 2003; Bellugi and St. George, 2001; Jordan et al., 2002; Paul et al., 2002). Given the well documented visual abnormalities in WMS it is somewhat surprising to find only a few anatomical studies of the visual system. The most relevant reports of anomalous anatomy in posterior and dorsal areas are a finding of increased gyrification in the posterior regions of the brain (right parietal and occipital lobes) (Schmitt et al., 2002), decreased neuronal size in the primary visual cortex (Galaburda et al., 2001b) and an anomalous central sulcus (Galaburda et al., 2001a). Given the ease of identifying and measuring the central sulcus, and the importance of replication in the neuroimaging literature, we decided to start a comprehensive investigation of WMS by replicating Galaburda’s et al. (2001a) findings. The central sulcus is the most important and constant landmark on the convexity of the brain, since it divides the sensory and motor areas and contains a representation for each of these functional domains within its walls (Ono et al., 1989). Galaburda et al. have studied the morphology of the central sulcus in WMS. In a postmortem case study, they found an unusual gyral pattern and a shortened central sulcus on its dorsal extension (Galaburda et al., 1994). They later confirmed this finding in an MRI study (Galaburda et al., 2001a). Comparing a sample of 21 WMS subjects with 21 controls with normal IQ they found that the central sulcus was significantly less likely to reach the interhemispheric fissure in WMS (11% vs. 68 % for the controls). This was a qualitative
The central sulcus in Williams syndrome
observation that deserves to be confirmed with more careful quantitative analyses. The dissimilarities between groups in the dorsal extension of the central sulcus were not observed on its ventral end (Galaburda et al., 2001a). Moreover, neither the postmortem study nor the MRI study compared central sulcus morphology in WMS to a control group composed of other persons with mild or borderline mental retardation. Thus, it is not clear if the findings are specific to WMS or whether they represent some nonspecific morphological disturbance characteristic of low intelligence or mental retardation (MR). In this study our goals were to: (1) replicate Galaburda’s et al. (2001a) qualitative findings, (2) determine the specificity of the central sulcus findings in WMS subjects versus an IQ matched control group, (3) quantify the central sulcus measurements and (4) explore the functional significance of foreshortened dorsal extension of the central sulcus through correlational analyses with other anatomical measures and with a set of neuropsychological measurements.
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1991), while subjects over 16 years old were administered the Wechsler Adult Intelligence ScaleThird Edition (WAIS-III) (Wechsler, 1997). The Benton Judgement of Line Orientation (Benton, 1994), the Beery-Buktenica Test of Visual Motor Integration (Beery, 1997), Word Attack and Letter Word Identification subtests of the Woodcock Johnson Test of Achievement (Woodcock and Johnson, 1990), Edinburgh Handedness (Oldfied, 1971), Purdue Pegboard Test (Tiffin, 1948), Finger Tapping Test (Reitan and Davison, 1974) and select subtests of Differential Abilities Scale (Elliot, 1990) were also administered to measure visual, visual-spatial, visual-motor, motor and language competency. We found several significant differences in the neuropsychological profiles of persons with WMS, including the expected dissociation between face perception and visualspatial perception, and these will be the topic of a subsequent report. Standard scores from these measures were used here in correlational analyses with brain variables. Data Acquisition
METHODS MR images of each subject’s brain were acquired with a GE-Signa 1.5T scanner, using a 3D SPGR sagittal acquisition series (TR = 24 msec, TE = 5 msec, flip angle = 45°, NEX = 2, matrix size = 256 × 256 pixels, FOV = 30 mm, slice thickness = 1.2 mm, 124 slices) that yielded 1.2 mm3 isotropic voxels. Initial imaging processing was done using the Analyze AVW 4.0 software platform (Robb and Hansen, 1990) and included stripping off the skull and aligning the images into the AC-PC space.
Subjects Twenty-eight individuals diagnosed with WMS, 22 normal control subjects (IQ range ~ 90-110) matched with the patients for gender and age and 20 lower IQ subjects also matched with the WMS patients for gender and age were studied (Table I). There were no significant differences between the three groups for gender χ2 (2) = 4.97, p > 0.08, and age, F (2, 67) = 0.90, p > 0.40. In addition, there was no significant difference in Wechsler Full Scale IQ between the WMS group and the lower IQ group, t (46) = – 1.89, p > 0.06. All diagnoses of WMS were made by FISH confirmation of elastin gene deletion. All participants gave informed consent for participation in this study, which was approved by the Yale University institutional review board.
Measurements The images were measured using a custom software package (Rambo et al., 1998) written in VTK from the Yale Image Processing and Analysis Group. The procedure involved viewing the 3D rendered cortical surface, which could be freely rotated in space, and interactively marking that surface using a mouse-controlled cursor. The central sulcus was identified and traced from the sylvian fissure to its dorsal extension, terminating near the interhemispheric fissure. The 3D brain
Neuropsychological Assessment Participants 8-16 years of age were administered the Wechsler Intelligence Scale for Children-Third Edition (WISC–III) (Wechsler, TABLE I
Age (years) and Full Scale IQ Mean ± SD and range in WMS, lower IQ controls and normal range IQ controls. (NC) NC (n = 22)
WMS (n = 28)
Lower IQ (n = 20)
M
F
M
F
M
F
9
13
8
20
11
9
Age (years) range
20.3 ± 12.7 11-43
23.6 ± 8.8 12-45
25.5 ± 12 11-39
29.2 ± 12.7 12-48
24.2 ± 11 8-44
25.6 ±13.5 8-34
IQ range
98.3 ± 10.3 91-111
106.3 ± 7.2 96-116
62.5 ±7.6 50-76
64.8±12.2 40-82
68.6 ±11.6 49-87
74.1 ± 9.1 59-88
n
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Fig. 1 – 2D slices and 3D rendered volume showing the central sulcus tracing.
volume was gradually rotated during the tracing to avoid oblique views, allowing easy and accurate marking of the full extent of the central sulcus. In addition, the tracing was automatically projected in real time to 3 orthogonal 2D brain views. These were updated in real time during the trace, and allowed a further check of the tracing accuracy (see Figure 1). Because the underlying MRI data have a resolution of 1.2 mm3, the distance from the dorsal end of the central sulcus to the leading edge of the plane that defines the interhemispheric fissure could easily be computed by counting along a straight line the number of intervening voxels and multiplying that sum by 1.2 mm. The same procedure was applied to calculate the distance between the ventral end of the central sulcus and the sylvian fissure. The rater was blind to all identities and diagnoses of the subjects. Repeat measurements were performed in a random order on all participants, and intra-rater reliability was outstanding (ICC > .99) for all measurements. For comparison to the results of Galaburda et al. (2001a), we also coded as a binary variable (yes or no) whether or not the central sulcus reached the interhemispheric fissure and the sylvian fissure. We also coded the shape of the dorsal extension of the central sulcus as “Y”-shaped, straight or “T”shaped following the classification provided by
Ono et al. (1989). When the dorsal extension was “Y” or “T”-shaped, we connected both terminal ends with a plane that was parallel to the interhemispheric fissure, and we measured the distance to the interhemispheric fissure from the midpoint of that plane. The volumes of the total brain and the individual lobes were calculated as part of a separate research project, and are reported here only for correlational analyses with the main variables of interest. All of the figures displayed in the manuscript follow radiological convention with right and left reversed. The tracings on Figures 2, 3 and 4 were painted over in Adobe Photoshop 7.0.® with a thicker line better suited for viewing in this style presentation. Data Analysis ANOVA was used to test for group differences in MRI distance variables. Chi-square analyses were used to test the qualitative differences between groups regarding the shape of the central sulcus terminal and whether or not the extension of the central sulcus reached the midline. Correlation analyses were conducted within the WMS sample to test for significant linear relationships between the central sulcus, tissue volumes and neuropsychological measurements.
The central sulcus in Williams syndrome
Fig. 2 – Patterns of the shape of the dorsal end of the central sulcus in the WMS group.
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Fig. 3 – Patterns of the shape of the dorsal end of the central sulcus in the normal control group.
RESULTS a. Qualitative analyses The central sulcus in the WMS group reached the interhemispheric fissure (see Figure 2) less often
than in the normal controls (see Figure 3) in the left, χ2 (1) = 4.48, p < 0.05, and in the right hemisphere, χ2 (1) = 9.17, p < 0.05. The central sulcus in the WMS group also reached the interhemispheric fissure less often than the lower IQ group (see Figure 4) in the right hemisphere, χ2 (1) = 4.14, p <
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Fig. 4 – Patterns of the shape of the dorsal end of the central sulcus in the Lower IQ control.
0.05, but not in the left hemisphere, χ2 (1) = 3.01, p > 0.05. Those values are summarized in Table II. Shape There was no significant difference regarding the frequency of the shape (straight or “Y”- shape) TABLE II
Percentage of the Dorsal Central Sulcus that reach the Interhemispheric Fissure Group NC WMS Lower IQ
Left hemisphere
Right hemisphere
50% (11/22) 21% (6/28) 45% (9/20)
55% (12/22) 14% (4/28)* 40% (8/20)l
Significantly lower percentage of WMS cases compared to both control groups (p < 0.05)
of the dorsal extension of the central sulcus between the groups (see Table III) in the left, χ2 (2) = 0.59, p = 0.74, and in the right hemisphere, χ2 (2) = 1.29, p = 0.52. We did not find any “T”-shape dorsal central sulci in our sample. The shape of the dorsal extension of the central sulcus in our normal control sample was compared to the results reported by Ono et al. (1989) and there were no significant differences in the left, χ2 (1) = 1.39, p = 0.25, or in the right hemisphere, χ2 (2) = 2.64, p = 0.23. b. Measurements The distance between the dorsal extension of the central sulcus and the interhemispheric fissure was significantly increased in WMS when compared
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Andrea P. Jackowski and Robert T. Schultz TABLE III
Shape of the Dorsal Extension of the Central Sulcus Group NC WMS Lower IQ Ono et al. (1989)
Straight
“Y” shape
“T” shape
Total (brains)*
21 (96 %, L) 18 (82 %, R) 25 (89 %, L) 23 (82 %, R) 17 (85 %, L) 18 (90 % R) 24 (96 %, L) 20 (84 %, R)
1 (4 %, L) 4 (14 %, R) 3 (11 %, L) 5 (18 %, R) 3 (15 %, L) 2 (10 %, R) 1 (4 %, L) 4 (12 %, R)
______________
82 % (straight) 18 % (“Y”) 82 % (straight) 18 % (“Y”) 80 % (straight) 20 % (“Y”)
______________ ______________ ______________ 1 (4 % R)
N/A
The values are presented in number of subjects (percentage, and hemisphere). L = left hemisphere, R= right hemisphere, N/A = not available. * In the last column “Total” refers to the number of brains with either a right or a left “Y” shaped terminus.
TABLE IV
Measurements (mm) of the Central Sulcus Ventral and Dorsal Distances in WMS and Controls NC (1) Mean (SD) (mm)
WMS(2) Mean (SD) (mm)
Lower IQ (3) Mean (SD) (mm)
P value From 2 Way ANOVA
3.4 (2.39) 0-8.4
6.03 (2.23) 2.4-10.8
3.62 (2.43) 0-9.0
<.001
right range
3.26 (2.41) 0-9.6
7.69 (2.15) 2.6-12
4.99 (3.19) 1.2-15.5
<.001
Ventral distance left right
9.92 (3.97) 9.64 (2.95)
9.98 (4.0) 8.52 (3.29)
9.28 (3.81) 8.85 (4.03)
>.05 >.05
Dorsal distance left range
Posthoc Scheffe F statistic for each pair 8.04 (1 × 2)†* 6.16 (2 × 3)** 0.07 (1 × 3) 18.36 (1 × 2)†* 6.49 (2 × 3)** 2.36 (1 × 3) -------------------------------
†* (1, 48), p < 0.05 ** (1, 46), p < 0.05
to the normal controls and the lower IQ control groups, in both the left and right hemisphere (all p’s < 0.001; see Table IV). There was no significant difference between normal controls and lower IQ control group related to the distance between the end of the dorsal extension of the central sulcus and the interhemispheric fissure, F (1, 41) = 2.36, p > 0.05, or any another morphological measure. There were no significant hemispheric differences for the central sulcus dorsal or ventral measurements. The distance from the ventral end of the central sulcus to the sylvian fissure did not differ between groups (p’s > 0.5). There were no sex differences for any central sulcus measurement and no group by sex interactions. Correlations There were no significant correlations between the central sulcus dorsal and/or ventral distance and any neuropsychological or demographic measure.
DISCUSSION We found significant foreshortening of the dorsal extension of the central sulcus in WMS compared to two comparison groups. Our dichotomous data (central sulcus reaches or does not reach the interhemispheric fissure) replicate the qualitative findings of Galaburda et al. (2001a) in
WMS. There were no differences between the WMS, normal controls and the lower IQ groups in the ventral extension of the central sulcus. Our dichotomous data in our normal controls are also in close agreement with those of Ono et al. (1989). In their study of 25 autopsied normal control brains they found that the central sulcus reaches the midline 56 % of the time on the right and 72 % of the cases in the left hemisphere. There are no data available in the literature, for any subject group, regarding the actual distance of the central sulcus to either the interhemispheric or sylvian fissures. Thus, this is the first quantitative study determining central sulcus terminal distances, and the first also to show quantitative differences. An important design issue of this study was the inclusion of a lower intelligence group matched to the WMS group on Wechsler FSIQ. This allowed us to show that the central sulcus abnormalities appear specific to WMS and are probably not a feature of mild or borderline mental retardation more generally. Thus, the central sulcus abnormality would seem to be a direct consequence of this genetic syndrome, but follow up studies with additional MR control samples (including nonspecific MR samples as well as other genetic forms of MR) are warranted before this claim can be made with certainty. Foreshortening of the central sulcus can now be added to a list of reported morphological abnormalities in WMS. Prior studies have shown distinct brain morphology in WMS when compared
The central sulcus in Williams syndrome
to both normal developing subjects and sometimes also to persons with other genetic disorders. This list includes significant reduction in the total brain volume and unusual shape of the adult brain (Jernigan and Bellugi 1990; Reiss et al., 2000; Schmitt et al., 2001a), reduction of the size of the corpus callosum at midline (Schmitt et al., 2001b; Tomaiuolo et al., 2002), enlargement of the cerebellum (Wang et al., 1992; Jernigan et al., 1993; Jones et al., 2002), reduction in size of the brain stem and basal ganglia (Jernigan et al. 1993; Reiss et al. 2000), an unusual gyral pattern (Galaburda et al., 1994), and also a decrease in neuronal cell size in the primary visual cortex (Galaburda et al., 2001b). It will be important to replicate each of these findings, and to assess how specific each is for WMS, apart from other forms of MR. For example, there is a known relationship between intelligence and brain volume (Willerman et al., 1991; Reiss et al., 1996) that suggests that the brain volume reduction in WMS is not a unique feature of the disorder. Sorting specific and nonspecific features will be of great importance, and to do so accurately will require the consistent use of multiple controls, some of which are matched to the WMS sample on IQ measures. It will also be important to inter-relate these findings to each other in order to more fully characterize the nature of WMS pathobiology, as a related system of brain abnormalities, and also to relate the full collection of brain abnormalities to neuropsychological and other behavioral features that accompany this syndrome, in order to build comprehensive brain-behavior models of WMS. In normal development, the primordium of the central sulcus first appears as a distinctive groove at approximately 20 weeks of gestation (Chi et al., 1977). This sulcus begins parasagittally over the convexity and extends downward and laterally to make a distinct linear fissure by 22 to 23 weeks of gestation. During the sixth month of gestation, the dorsal end approaches the superior margin of the hemisphere (England, 1983). Thus, one possibility is that the central sulcus abnormality reported here is a marker for developmental abnormalities occurring around or before the 6th month of gestation. Sulcal shape also has clear anatomical determinants. One influential model posits that tension along the axons in the white matter can explain species-specific patterns of cortical folding (Van Essen, 1997). Interestingly, Reiss et al. (2000) have shown relative preservation of gray matter and disproportional reduction in white matter in subjects with WMS compared to normal controls, especially in the posterior half of the brain. Consistent with this observation, Schmitt et al. (2001b) and Tomaiuolo et al. (2002) have shown that the posterior regions of the corpus callosum (isthmus and splenium) are reduced in volume in WMS subjects when compared to normal controls.
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Those regions of the corpus contain the vast majority of the white matter tracts connecting homologous visual areas within each hemisphere (de Lacoste et al., 1985). Thus, the foreshortening of the central sulcus may be a reflection of some common underlying process that causes a general alteration in white matter connectivity. To corroborate this hypothesis, further studies on regional white matter volume and tract morphology must be performed. The connection between the abnormal dorsal extension and other neuroanatomical and neuropsychological abnormalities (e.g., visualspatial processing deficits) documented in WMS is currently not known. The functional deficits in WMS are well documented, and brain-behavior models of functioning would implicate this dorsal pathway in the pathobiology of WMS. Correlational analyses failed to find significant relationships between neuropsychological and central sulcus measurements in this study. Although it seems a rather far reach at this point to try to relate the behavioral evidence of dorsal visual pathway dysfunction with the dorsal foreshortening of the central sulcus there still might be a direct relationship between central sulcus structure and function, but in such a way that it affects all persons with WMS more or less uniformly. But this remains speculative. It will be important for future studies, especially fMRI studies of visual-spatial functioning in WMS to try to identify links to this abnormality of the central sulcus. Clearly, more research is needed to characterize the functional significance of the increase in the dorsal distance of the central sulcus in WMS.
CONCLUSIONS The shortening of the dorsal end of the central sulcus in WMS is now a replicated finding. We showed here that it was not related to impairments in general intelligence per se that are part of WMS, but that the central sulcus finding seems to be a specific attribute of the WMS pathobiology. Additional studies are required to provide more information about the functional significance of this finding, and its relationship to other neuroanatomical abnormalities that characterized WMS. Acknowledgments. We wish to thank Xenophon Papademetris for the technical support with the image analyses, Lawrence Win for the initial processing of the image data, Marc Thioux for the statistical support, Jamie Kleinman and Cheryl Klaiman for neuropsychological and other assessments of the participants, Barbara Teague for coordinating patient visits to the Children’s Clinical Research Center, and Barbara Pober for the clinical referral of the WMS sample. We also thank each of the participants and their families for giving their time and volunteering for this research. This study was supported by grants from the National Institute of Child Health and Human Development (PO1
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HD 03008 and PO1 HD/DC35482), and by the Children’s Clinical Research Center (MO1 RR06022), and Yale Developmental Neuroimaging Program. REFERENCES ATKINSON J, ANKER S, BRADDICK O, NOKES L, MASON A and BRADDICK F. Visual and visuospatial development in young children with Williams syndrome. Developmental Medicine and Child Neurology, 43: 330-337, 2001. ATKINSON J, BRADDICK O, ANKER S, CURRAN W, ANDREW R, WATTAM-BELL J and BRADDICK F. Neurobiological models of visuospatial cognition in children with Williams syndrome: Measures of dorsal stream and frontal function. Developmental Neuropsychology, 23: 139-172, 2003. ATKINSON J, KING J, BRADDICK O and NOKES L. A specific deficit of dorsal stream function in Williams syndrome. Neuroreport, 8: 1919-1922, 1997. BEERY K. Beery-Buktenica Test of Visual-Motor Integration. 4th Edition. Parsippany: Modern Curriculum Press, 1997. BELLUGI U, BIHRLE A, JERNIGANT, TRAUNER D and DOHERTY S. Neuropsychological, neurological and neuroanatomical profile of Williams syndrome. American Journal of Medical Genetics, Supplement, 6: 115-125, 1990. BELLUGI U, KLIMA ES and VAID J. Cognitive and neural development: clues from genetically based syndromes. In D Magnusson (Ed), The Life-span Development of Individual: Behavioral, Neurobiological, and Psychosocial Perspective. The Nobel Symposium. New York: Cambridge University Press, 1996, pp. 223-243. BELLUGI U and ST. GEORGE M. Journey of Cognition to Brain to Gene: Perspectives from Williams Syndrome. Cambridge: MIT Press; 2001. BENTON A. Face Recognition. Los Angeles: Westerns Psychological Services, 1994. CHI JG, DOOLING EC and GILLES FH. Gyral development of human brain. Annals of Neurology, 1: 86-93, 1977. DE LACOSTE MC, KIRKPATRICK JB and ROSS ED. Topography of the human corpus callosum. Journal of Neuropathology and Experimental Neurology, 44: 578-591, 1985 ELLIOT CD. Differential Ability Scale Administration and Scoring Manual. Toronto: The Psychological Corporation Harcourt Brace Jovanovick, 1990. ENGLAND MA. Color Atlas of Life Before Birth. Normal Fetal Development. Chicago: Year Book Medical Publishers, 1983. GALABURDA AM, HOLINGER DP, BELLUGI U and SHERMAN GF. Williams Syndrome. Neuronal size and neuronal-packing density in primary visual cortex. Archives of Neurology, 59: 1461-1467, 2001b. GALABURDA AM, SCHMITT JE, ATLAS SW, ELIEZ S, BELLUGI U and REISS AL. Dorsal forebrain anomaly in Williams Syndrome. Archives of Neurology, 58: 1865-1869, 2001a. GALABURDA AM, WANG PP, BELLUGI U and ROSSEN M. Cytoarchitectonic anomalies in a genetically based disorder: Williams syndrome. Neuroreport, 5: 753-757, 1994. GREENBERG F. Williams syndrome. Pediatrics, 84: 922-923, 1989. JERNIGAN TL and BELLUGI U. Anomalous brain morphology on magnetic resonance images in Williams syndrome and Down syndrome. Archives of Neurology, 50: 186-191, 1990. JERNIGAN TL, BELLUGI U, SOWELL E, DOHERTY S and HESSELINK JR. Cerebral morphologic distinctions between Williams and Down syndromes. Archives of Neurology, 50: 186-191, 1993. JONES W, HESSELINK J, COURCHESNE E, DUNCAN T and BELLUGI U. Cerebellar abnormalities in infants and toddlers with Williams syndrome. Developmental Medicine and Child Neurology, 44: 688-694, 2002. JORDAN H, REISS JE, HOFFMAN JE and LANDAU B. Intact perception of biological motion in the face with profound
spatial deficits: Williams Syndrome. Psychological Science, 13: 162-167, 2002. OLDFIELD R. The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia, 9: 97-113, 1971. ONO M, STEFAN K and CHAD DA. Atlas of the Cerebral Sulci. New York: Thieme Medical Publishers, 1989. PAUL BM, STILES J, PASSAROTTI A, BAVAR N and BELLUGI U. Face and place processing in Williams Syndrome: Evidence for a dorsal-ventral dissociation. Neuroreport, 13: 1115-1119, 2003. RAMBO J, XENG X, SCHULTZ RT, WIN L, SATIB LH and DUNCAN JS. Platform for visualization and measurement of gray matter volume and surface area within discrete cortical regions from MRI images. Abstracts of the fourth international conference on functional mapping of the human brain mapping. Montreal: June 8-12, 1998. REISS AL, ABRAMS MT, SINGER HS, ROSS JL and DENCKLA MB. Brain development, gender and IQ in children. A volumetric imaging study. Brain, 119: 1763-1764, 1996. REISS AL, ELIEZ S, SCHMITT E, STRAUS E, LAI Z, JONES W and BELLUGI U. IV. Neuroanatomy of Williams Syndrome: A highresolution MRI study. Journal of Cognitive Neuroscience, 12: 65-73, 2000. REITAN RM and DAVISON LA. Clinical Neuropsychology: Current status and applications. Washington: Winston, 1974. ROBB RA and HANSEN DP. ANALYZE. Proceedings from the first conference on visualization in biomedical computing. Los Alamitos: IEEE Press, 1990. SCHMITT JE, ELIEZ S, BELLUGI U and REISS AL. Analysis of cerebral shape in Williams syndrome. Archives of Neurology, 58: 283-287, 2001a. SCHMITT JE, ELIEZ S, WARSOFSKY IS, BELLUGI U and REISS AL. Corpus callosum morphology of Williams syndrome: Relation to genetics and behavior. Developmental Medicine and Child Neurology, 43: 155-159, 2001b. SCHMITT JE, WATTS K, ELIEZ S, BELLUGI U, GALABURDA AM and REISS AL. Increased gyrification in Williams syndrome: Evidence using 3D MRI methods. Developmental Medicine and Child Neurology, 44: 292-295, 2002. SCHULTZ RT, GRELOTTI DJ and POBER B. Genetics of childhood disorders: XXVI. Williams syndrome and brain-behavior relationship. Journal of the American Academy of Child and Adolescent Psychiatry, 40: 606-609, 2001. TIFFIN J. The Purdue Pegboard Test. Lafayette, IN: Lafayette Instruments, 1948. TOMAIUOLO F, DI PAOLA M, CARAVALE B, VICARI S, PETRIDES M and CALTAGIRONE C. Morphology and morphometry of the corpus callosum in Williams syndrome: A T1-weighted MRI study. Neuroreport, 13: 2281-2284, 2002. UNGERLEIDER LG and HAXBY JV. ‘What and where’ in the human brain. Current Opinion in Neurobiology, 4: 157-165, 1994. VAN E SSEN DC. A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature, 385: 313-318, 1997. WANG P, HESSELINK J, JERNIGAN T, DOHERTY S and BELLUGI U. Specific neurobehavioral profile of Williams’s syndrome is associated with neocerebellar hemispheric preservation. Neurology, 42: 1999-2002, 1992. WECSHLER D. Wecshler Intelligence Scale for Children. Third Edition. San Antonio: The Psychological Corporation, 1991. WECSHLER D. Wecshler Adult Intelligence Scale. Third Edition. San Antonio: The Psychological Corporation, 1997. WILLERMAN L, SCHULTZ R, RUTLEDGE N and BIGLER E. In vivo brain size and intelligence. Intelligence, 15: 223-228, 1991. WOODCOCK RW and JOHNSON MB. Woodcock-Johnson Test of Achievement. In WJR-Psycho-educational battery revised. Allen: TX: DLM Teaching Resources, 1990.
Robert T. Schultz, PO Box 207900, Yale University Child Study Center, New Haven, CT 06520. e-mail: [email protected]