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Williams Syndrome
Neuronal Size and Neuronal-Packing Density in Primary Visual Cortex
Albert M. Galaburda, MD;
Dorothy P. Holinger, PhD;
Ursula Bellugi, EdD;
Gordon F. Sherman, PhD
Arch Neurol. 2002;59:1461-1467.
ABSTRACT
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Background Williams syndrome (WMS) is a rare, genetically based syndrome associated
with a hemideletion in chromosome 7 (7q11.22-23) and characterized by a unique
constellation of somatic, brain, and cognitive features. Individuals with
WMS demonstrate an unusual and uneven neuropsychological profile showing cognitive
and visual spatial deficits juxtaposed with relative language preservation
and excellent facial recognition.
Objectives A neuroanatomical hypothesis for these behavioral findings suggests
predominant involvement of the dorsal portions of the hemispheres relative
to the ventral portions, including preferential involvement of peripheral
visual field cortical representations over central representation. Predominant
involvement of magnocellular visual pathways, as opposed to parvocellular
pathways, is also suggested by this hypothesis.
Subjects We examined primary visual cortical area 17 in the right and left hemispheres
in 6 age- and sex-matched autopsy specimens from 3 WMS-affected brains (1
male and 2 females; mean [SD] age, 44 [14] years) and 3 control brains (1
male and 2 females; mean age, 43 [11] years).
Design Neurons in layers II, III, IVA, IVB,
IVC , IVCß,
V, and VI were measured using an optical dissector method to determine possible differences
between WMS-affected and control brains in cell-packing density, neuronal
size, and neuronal size distribution.
Results We found abnormalities in peripheral visual cortex in WMS-affected brains,
but not in magnocellular subdivisions. There was a hemisphere by layer IV
interaction and a layer IV left hemisphere and diagnosis interaction in cell-packing
density. Williams syndrome–affected brains showed increased cell-packing
density in left sublayer IVCß and an excess of small neurons in left
layers IVA, IVC,
IVCß, V, and VI.
Conclusions Cell measurements differ in peripheral visual cortical fields of WMS,
with significantly smaller, more closely packed cells in some layers on the
left side. These cell-packing density and neuronal size differences may be
related to visuospatial deficits in this population.
INTRODUCTION
WILLIAMS syndrome (WMS), a mental retardation syndrome, consists of
a unique constellation of somatic, brain, and cognitive features, and is associated
with a hemideletion in the short arm of chromosome 7 (7q11.22-23).1-4 At least
15 genes are associated with this hemideletion, which affects the same set
of genes in nearly all clinically identified WMS. However, there are rare
individuals with partial deletions with partial phenotypic manifestations
of WMS.4-5 Approximately 1 in
25 000 births exhibit the deletion and accompanying phenotype. Our histometric
studies are part of a multidisciplinary project involving cognition, brain
morphology (magnetic resonance imaging and functional magnetic resonance imaging),
neurophysiology, and molecular genetics. Specifically, our research has centered
on the description of the neuroanatomical phenotype at the cytoarchitectonic,6-8 histometric, and histochemical
levels for the purpose of linking, on the one hand, brain change to behavior,
and, on the other, brain change to the genomic anomaly.5, 9
The microanatomical brain research in our laboratory is driven by a
general hypothesis derived from the analysis of behaviors exhibited by individuals
who have WMS. The WMS neuropsychological profile is an unusual and uneven
one, consisting of deficits in processing visuospatial tasks, relative strength
in many aspects of language, and a preserved ability to process human faces.9 Figure 1
shows the specific deficits in spatial cognition, deficits that are contrasted
with comparable individuals with Down syndrome. Individuals who have WMS also
demonstrate an unusual personality characterized by a lack of fear of strangers,
highly affective speech, and occasionally, inappropriate friendliness, and
often show a great deal of interest in, and sometimes an ability regarding
things musical.5, 10
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Figure 1. Note that both Williams syndrome–affected
cases and Down syndrome–affected subjects are poor in spatial cognition,
but in contrasting ways. Drawings and block designs of individuals with Williams
syndrome tend to focus on the details at the expense of the whole, whereas
individuals with Down syndrome tend to show global configuration but may be
poor on internal detail. Reprinted with permission from Trends in Neuroscience.5
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The best neuroanatomical fit for many of the behavioral findings seen
in WMS seems to be the primary involvement of the dorsal portions of the hemispheres,
which in the caudal half of the brain is concerned with representation and
processing of visuospatial information11-14
and in the frontal lobes with release and control of behavior.15
By contrast, behaviors associated with the ventral and perisylvian portions
of the hemispheres, concerned with most aspects of language,16-18
object properties of visual and other stimuli,19-21
and programs for the performance of various motor behaviors (eg, speech22-23) seem to be at least relatively spared
in WMS. Therefore, one part of the research in our laboratory has focused
on comparing histometric features between the dorsal and ventral portions
of the cerebral hemispheres. As part of a larger histometric study, we report
herein a histometric analysis of the visual cortex of WMS. Specifically, we
examined primary visual area 17 halfway between the splenium of the corpus
callosum and the occipital pole along the calcarine sulcus (Figure 2); assuming normal topography of visual cortex in WMS, this
sampled region would represent mostly peripheral fields pathways24-27
and relates more to the dorsal visual pathway.11, 28-29
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Figure 2. Blocks of tissue (7 x 5
x 5 cm) were taken from the medial surface of the left and right occipital
lobes, dorsal and ventral to the calcarine sulcus (long arrows). sp indicates
splenium; L, lateral ventricle; fx, fornix; pi, pineal gland; th, thalmus;
ac, anterior commissure; mb, mamillary body; and h, hypothalamus. Reprinted
with permission from Duvernoy HM. The Human Brain, '91 Edition.
New York, NY: Springer-Verlag Wien, 1991:279.
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SUBJECTS AND METHODS
SUBJECTS
We examined the visual cortex in age- and sex-matched autopsy specimens
from 3 WMS-affected cases (1 male and 2 females; mean [SD] age, 44.0 [14]
years) and from 3 neurologically and psychiatrically healthy control subjects
(1 male and 2 females; mean age, 43.3 [11] years; the Harvard Brain Tissue
Resource Center, McLean Hospital, Belmont, Mass). There was no information
on handedness. The WMS cases had the 7q11.22-23 deletion determined by fluorescent
in situ hybridization. The WMS-affected brains (1033 [104] g) were significantly
smaller (P<.05) than the control brains (1426
[177.8] g).
HISTOLOGICAL STUDY
One WMS-affected brain (subject 1) was processed using the Yakovlev
whole-brain method of serial histological sections.30
The postmortem brain tissue from the remaining WMS-affected and control brains
(subjects 2-6) was processed from left and right hemisphere blocks (7 x
5 x 5 cm), including dorsal and ventral calcarine banks, and sectioned
at 30 µm. Every 10th section was stained with cresylechtviolett for
Nissl substance.
AREA 17 CELL MEASURES
The primary visual cortex, area 17,31
was easily identified in WMS-affected and control brains on the calcarine
region. Three fields from the pial surface to the gray-white matter junction
were selected where the plane of section was perpendicular or near perpendicular
to the pial surface and there was no distortion by rippling, tears or other
artifacts. All sections were coded so that the examiner was blind to diagnosis
and hemisphere. The architectonic appearance of area 17 in WMS-affected brains
is indistinguishable from that in controls, so this form of blinding was deemed
to be adequate.
Layers II, III, IVA, IVB,
IVC,
IVCß, V, and VI of area 17
were measured in each hemisphere. Neurons were identified by the presence
of a clearly visible, single nucleolus, a feature that distinguishes them
from glial cells.32 Cross-sectional neuronal
areas and cell packing densities were measured using the modified dissector
method and software of Williams and Rakic.33
Using a universal microscope (Carl Zeiss Inc, Thornwood, NY) under x500
oil magnification, images captured by a camera (Vidicon; Division of Hamamatsu
USA, Bridgewater, NJ) were displayed on a monitor (model GVM 1310; Sony, Toronto,
Ontario) that was connected to a personal computer workstation (Macintosh
Centris 650; Apple Computers, Cupertino, Calif). The counting chamber (95
x 85 x 20 µm, at x500) was placed within these images.
A photoelectric micrometer (Heidenhain MP-25, Heidenhain, Schaumburg, Ill)
interfaced to a National Instruments NB-GPIB card (NB-series cards, NB-GPIB
IEEE-488.2, National Instruments Corp, Austin, Tex) in the Macintosh recorded
movement in the z-axis. The base of the sections
was set to a z-axis reading of 0. A red opaque overlay
precluded cell counting below the dimensions of the counting box. With the
movement of the stage to 5 µm (7.5 µm for subject 1) above the
original position of the base of the section, the screen became transparent
and the cells visible. The soma of the neurons were traced on a digitizing
tablet, whereby neurons touching the top and left side of the screen were
omitted. At a stage level of more than 25 µm (27.5 µm for subject
1) above the original position of the base of the section, the screen turned
opaquely green, which prevented the measurement of any cells above the optical
counting box.
STATISTICAL ANALYSIS
Repeated-measures analysis of variance (ANOVA) was used to determine
cell-packing density and neuronal size differences between the WMS and control
cases. The independent measures included diagnosis (WMS and control), hemisphere
(right and left), and layer (II, III, IVA, IVB,
IVC,
IVCß, V,
and VI). The dependent measures were cell size (areas of the nucleus and cytoplasm
together) and cell-packing density. The effect of sex could not be analyzed
with any confidence because of the few cases studied. Differences in neuronal
size distributions were analyzed using  2 tests.
RESULTS
CELL-PACKING DENSITY
Repeated-measures ANOVA revealed significant differences in cell-packing
density between the WMS-affected cases and controls and between hemispheres.
As expected, based on the known difference in neuronal types among the layers,
there was a significant effect of layer overall (F7,28 = 23.28, P<.001) and also for the left hemisphere (F7,28 = 27.42, P<.001) and the right hemisphere
(F7,28 = 9.67, P<.001) separately.
A hemisphere by layer interaction was significant only when layer IV (all
sublaminae combined) was analyzed (F3,12 = 3.58, P<.05). Individual analyses of layers III and
IV showed a significant
increase in cell-packing density in the left hemisphere in the WMS-affected
brains in sublayer IVCß (F1,4 = 8.35, P<.05) compared with the controls (309 598 vs 210 526 neurons/mm3) (Figure 3) but not in layer
III. There was also a significant interaction between layer and diagnosis
in the left hemisphere for layer IV (F3,12 = 3.58, P<.05), but not in the right hemisphere.
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Figure 3. Cell-packing density in layer
IVCß of the left hemisphere was significantly increased in the Williams
syndrome–affected brains compared with the control brains. Whereas in
layer IVCß of the right hemisphere, there was no significant difference
between the 2 groups. Asterisk indicates P<.001.
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MEAN NEURONAL SIZE
Repeated-measures ANOVA analyses of cross-sectional mean neuronal areas
did not result in any significant differences between WMS-affected and control
brains. As expected, by the known differences in cell size between layers,
there was a significant main effect of layer over both hemispheres (F7,28 = 20.63, P<.001) and for each hemisphere
analyzed separately: left (F7,28 = 23.38, P<.001)
and right (F7,28 = 11.11, P<.001).
NEURONAL SIZE DISTRIBUTIONS
Where there is marked variability in neuronal size, as is the case in
the cerebral cortex, significant neuronal differences may be difficult to
demonstrate, as in the case where both large and small neurons increase in
numbers. Therefore, to assess additional differences in neuronal size in each
layer and sublayer, we analyzed the frequency distribution of cell size in
consecutive bins (Figure 4). The
bins were arranged in ascending order of cell size. The number of bins ranged
from 7 to 12, increasing by 10 µm2, and contained neurons
whose size ranged from 30 to 90 µm2. We calculated 2 Values for the distribution of neurons in these bins between WMS-affected
and control brains. We also examined distribution of cell size differences
between hemispheres for WMS-affected and control brains separately. We set
= .001 for rejection of the null hypothesis to compensate for the high sensitivity
of this test.
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Figure 4. Layer IVCß of the left and
right hemispheres. A, There was a signficant difference between the Williams
syndrome–affected brains and the control brains (28 = 33.67, P<.001) with more small cells and fewer large
cells in the Williams syndrome–affected brains compared with the control
brains. Asterisks indicate P<.001. B, There were no significant
differences between the 2 groups.
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We examined each layer collapsed over both hemispheres between control
and WMS-affected brains. There were significant differences for sublayers
IVA (210 = 47.92, P<.001),
IVC (211 = 40.87, P<.001),
IVCß (28 = 54.04, P<.001),
and for layers V (211 = 36.51, P<.001) and VI (210 = 31.34, P<.001). In each case, the most consistent finding was that WMS-affected
brains had more small neurons than the control brains, whereas control brains
had more large neurons. With an additional analysis of hemisphere, it was
apparent that this effect was the result of differences in the left but not
in the right hemisphere. When the hemispheres were analyzed separately, significant
differences in the left hemisphere, but not the right, were found in sublayers
IVA (27 = 32.48, P<.001),
IVC (28 = 31.08, P<.001),
IVCß (28 = 33.67, P<.001),
and layers V (26 = 37.16, P<.001),
and VI (210 = 33.09, P<.001).
Again, this analysis showed the same pattern of more small neurons in the
WMS-affected brains and more large neurons in the control brains (Figure 3 and Figure 4A). When hemispheres were compared for cell size distribution,
no significant asymmetries were seen in either WMS-affected or control brains.
COMMENT
In this study, we sought an anatomical explanation for the unique behavioral
profile of individuals with WMS. For example, some behaviors are deeply abnormal
while others are relatively preserved. Among the relatively preserved behaviors,
we find language that is rich in vocabulary and affective prosody as well
as excellent face recognition abilities and verbal memory.5, 9, 34-35
More severely affected behaviors include visuospatial-visuomotor abilities
and mathematics. As shown in Figure 1,
individuals with WMS show specific deficits in spatial cognition tasks such
as object assembly, block design, and drawing, suggesting difficulty with
overall configurations.5, 9, 13
Involvement of visuospatial functions implicates either the right hemisphere
or the dorsal visual pathway,14, 36
whereas visual object recognition involves the left hemisphere or the ventral
visual pathway.14 In WMS-affected subjects,
therefore, preservation of facial recognition abilities and affective speech
prosody, which are linked to right hemisphere function, makes us suspect that
the visuospatial and visuomotor deficits are not explained by a right hemisphere
problem, but rather by a problem with the dorsal visual pathway and its connections
to the motor system.37-40
The present study was designed to test this hypothesis.
Based on anatomical, physiological, and clinical data, our hypothesis
was that the abnormalities in WMS would be found in visual cortex that projects
to the dorsal system (the part representing peripheral fields in the anterior
calcarine region), would affect neurons that form part of the magnocellular
system, and would be more striking in the right hemisphere. The anterior calcarine
cortex was sampled and, in fact, the findings were nearly the opposite. Specifically,
although the peripheral visual cortex was found to be abnormal in WMS-affected
brains, parvocellular sublayers in the left hemisphere only were involved.
In the primate visual system, there are structural and functional distinctions
between 2 relatively segregated and independent processing pathways—the
parvocellular and the magnocellular systems. These pathways have been characterized
on the basis of anatomical,41 psychophysical,42-43 and physiological properties.28, 44 Neurons in these 2 systems differ
in terms of receptive field size, sensitivity to color and light contrast,
and timing properties. The parvo system is ideally suited for form, texture,
and color analysis, while magno processes larger sections of space and appears
better designed to calculate spatial location and motion. Anatomically, the
magnoneurons are restricted to the lower 2 layers of the lateral geniculate
nucleus, whereas parvo cells occupy the upper 4 layers. In the cortex, although
a separation still exists (see below), it is less absolute.12, 45
For example, evidence from primate work suggests that segregation of magnocellular
and parvocellular signals continue into extrastriate visual areas into higher-order
visual processing. On the other hand, some primate studies suggest that magnocellular
and parvocellular streams contribute differentially to dorsal and ventral
pathways46 and that V1 neurons integrate some
information carried by both lateral geniculate nucleus magnocellular and parvocellular
pathways.47 Similarly, the visual system is
subdivided into a dorsal and ventral pathway based on anatomical location
and behavioral studies in monkeys and humans.11, 14, 46, 48
The relationship between the parvo-magno and dorsal-ventral subdivisions remains
tentative49 and also controversial,12 but one may argue that the magnocellular system is
the one more likely to contribute particularly to the dorsal visual system,
with the parvo system contributing more specifically to the ventral system.43, 50-51 Also, based on clinical
findings and activation studies, one would then be able to suggest that the
magno system is not only dorsal but also lateralized to the right hemisphere,
with the parvo system being lateralized to the left.14, 36, 48
This suggestion is based on clinical observations that right hemisphere lesions
tend to affect visuospatial abilities while left hemisphere lesions evince
more clearly as visual object anomias and agnosias.52
The findings of this study show that neuronal differences between WMS-affected
cases and controls in primary visual cortex appear to affect the left hemisphere
more than the right, particularly layer IV. Furthermore, the most consistent
finding emerged in cell size distribution: WMS-affected visual cortex had
more small and fewer large neurons than the control brains in layers IVA,
IVC,
IVCß, V, and VI of the left hemisphere.
Williams syndrome–affected brains also showed increased cell-packing density in left layer IVCß.
This layer receives inputs from the lateral geniculate nucleus. The lateral
geniculate nucleus inputs to layer IV are sublaminar specific: layers IVA
and IVCß receive projections from parvocellular layers of the lateral
geniculate nucleus, whereas layers IVB and
IVC28, 46, 50, 53
receive projections from magnocellular layers. However, the differences documented
in this study in the visual cortex do not seem to respect magnocellular-parvocellular
boundaries, as both IVC and
IVCß are affected. On the other hand,
although both IVC and
IVCß show diminution in neuronal sizes,
only IVCß has accompanying increased cell-packing density.
We also found that the size of the WMS-affected brains was significantly
smaller than the healthy control brains (P<.05),
an observation also made in several structural magnetic resonance imaging
studies.54 Structural magnetic resonance imaging
studies suggest that an important contributor to this reduction in size is
diminished subcortical white matter.54-56
There is also increased cortical folding54
suggesting that, since the brain is reduced in size, it requires increased
folding of the cortex to accommodate itself to the reduced core. On the other
hand, an important source of the white matter is in fact the cortex, so reduction
both of connectivity in the cortex and accompanying neuropil is also likely
in a smaller brain. In this case, one would also expect that the reduced cortex
in the WMS-affected brain should show some histometric changes. For instance,
there may be fewer neurons. Conversely, the number of neurons could be relatively
preserved, but the individual cell size is decreased and the cell-packing
density is increased in accord with the reduction in the connectivity. Thus,
we could interpret the present findings with reference not only to the healthy
control brain, but also to what is expected given the reduction in overall
brain size in those affected by WMS. Therefore, given our rationale that decreased
cell size should be accompanied by increased cell-packing density in a smaller
brain, the finding shown in IVC, which shows only decreased cell size
but not increased cell-packing density, is also anomalous. It is possible,
therefore, that this finding points to an added anomaly affecting the magnocellular
visual system. One could not make this statement, however, without also saying
that, even though packing densities appear normal in the suspected layers,
the neurons must not function normally by virtue of abnormal, albeit not decreased,
connectivity. Such a decrease in connectivity and neuropil may be a contributory
mechanism for dysfunction in this system. One final point is that the decrease
in white matter is compatible with the loss of long corticocortical connections,
the main source of which is layer V pyramids and the main receptors of which
is layer II. Excess of small neurons in layer V may indicate impoverished
circuits affecting these long corticocortical connections, which are important
for visuospatial functions.
CONCLUSIONS
These conclusions are based on the assumption that the sampled area
represents the peripheral visual fields in the WMS-affected brains and, thus,
the dorsal visual pathways. We can be certain of this in the control brains,
but less so in the WMS-affected cases. Thus, even though recent maps of central
vision show an expanded area subserving foveal vision26-27
than earlier estimates,24-25 we
are certain to have sampled peripheral visual cortex in controls. However,
if it were the case that central vision is even more expanded in WMS (which
makes sense on theoretical grounds), it could be that, while we thought we
were sampling peripheral visual cortex on topographic grounds, we were actually
sampling cortex representing central vision in the WMS-affected cases. In
that case the comparisons to the control samples would not be meaningful.
While we cannot solve this conundrum—to ascertain the functional topography
of the visual cortex—until functional activation studies are performed
in WMS-affected subjects, our postmortem findings—more compaction and
smaller cells in WMS-affected brains—may be related to the visuospatial
deficits in this intriguing syndrome.
AUTHOR INFORMATION
Accepted for publication March 7, 2002.
Author contributions: Study
concept and design (Drs Galaburda and Holinger); acquisition of data (Drs Holinger and Bellugi); analysis and interpretation of data (Drs Galaburda, Holinger, Bellugi,
and Sherman); drafting of the manuscript (Drs Holinger,
Bellugi, and Sherman); critical revision of the manuscript
for important intellectual content (Drs Galaburda, Holinger, and Sherman); statistical expertise (Drs Holinger and Sherman); obtained funding (Drs Galaburda and Bellugi); administrative, technical, and material support (Dr Galaburda); study supervision (Dr Galaburda); graphics (Dr Holinger).
The study was supported by grant HD33113 to the Salk Institute for Biological
Studies from the National Institutes of Health, Bethesda, Md (Dr Bellugi).The
brain tissue for controls was provided by the Harvard Brain Tissue Resource
Center supported in part by grant MN/NS 31862 from the Public Health Service,
Washington, DC.
We are grateful to the families who have donated the WMS-affected brains
and to the local, regional, and national Williams Syndrome Associations. We
appreciate technical assistance from Antis Zalkalns, BS.
Corresponding author and reprints: Albert M. Galaburda, MD, Beth
Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215
(e-mail: agalabur{at}caregroup.harvard.edu).
From the Division of Behavioral Neurology, Departments of Neurology
(Drs Galaburda and Holinger) and Psychiatry (Dr Holinger), Beth Israel Deaconess
Medical Center and Harvard Medical School, Boston, Mass; Laboratory for Cognitive
Neuroscience, The Salk Institute for Biological Studies, La Jolla, Calif (Dr
Bellugi); and The Newgrange School Educational Outreach Center, Princeton,
NJ (Dr Sherman).
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