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BehavioralSystemsCognitive Gender-Specific Left–Right Asymmetries in Human Visual Cortex

Behavioral/Systems/Cognitive

Gender-Specific Left–Right Asymmetries in Human

Visual Cortex

Katrin Amunts,1,2Este Armstrong,1Aleksandar Malikovic,1Lars Ho¨mke,1Hartmut Mohlberg,1Axel Schleicher,3and Karl Zilles1,3

1Institute of Medicine,Research Center Ju¨lich,D-52525Ju¨lich,Germany,2Department of Psychiatry and Psychotherapy,Rheinisch-Westfa¨lische Technische Hochschule,RWTH Aachen University,D-52074Aachen,Germany,and3C.and O.Vogt Institute of Brain Research,Heine University

Du¨sseldorf,D-40225Du¨sseldorf,Germany

The structural correlates of gender differences in visuospatial processing are essentially unknown.Our quantitative analysis of the cytoarchitecture of the human primary visual cortex[V1/Brodmann area17(BA17)],neighboring area V2(BA18),and the cytoarchitec-tonic correlate of the motion-sensitive complex(V5/MT?/hOc5)shows that the visual areas are sexually dimorphic and that the type of dimorphism differs among the areas.Gender differences exist in the interhemispheric asymmetry of hOc5volumes and in the right-hemispheric volumetric ratio of hOc5to BA17,an area that projects to V5/MT?/hOc5.Asymmetry was also observed in the surface area of hOc5but not in its cortical thickness.The differences give males potentially more space in which to process additional information,a finding consistent with superior male processing in particular visuospatial tasks,such as mental rotation.Gender differences in hOc5 exist with similar volume fractions of cell bodies,implying that,overall,the visual neural circuitry is similar in males and females. Key words:human brain anatomy;visual system;cytoarchitecture;gender differences;asymmetry;cortical surface

Introduction

Aspects of processing visuospatial information differ between males and females.Different strategies in visuospatial navigation separate women,who typically use a landmark strategy for navi-gation,from men,who generally use an orientation strategy (Rahman et al.,2005).Functional magnetic resonance imaging (fMRI)also demonstrates different cortical networks in visuo-spatial processing:women had increased neural activity in the prefrontal and right posterior parietal cortex,whereas men showed an increased activation in the left hippocampus,right parahippocampal region,and left posterior cingulate cortex (Gro¨n et al.,2000).

The motion-sensitive complex V5/MT?(Zeki et al.,1991; Tootell and Taylor,1995)also has gender differences.Potentials evoked by binocular pattern reversal,a strong stimulus to V5/ MT?,had larger amplitudes in the right than left hemisphere in girls than in boys(Cohn et al.,1985).In an fMRI study using flickering stimuli,women had more activation than men in Brod-mann area37(BA37),a region encompassing V5/MT?(Kauf-mann et al.,2001).A pattern reversal study showed that the P1 component of the visual-evoked potential was considerably shorter in female than male infants(Malcolm et al.,2002).Cen-tral field stimulation produced a larger right than left-hemispheric response in females,whereas males had only non-significantly larger left hemisphere event-related potentials, suggesting a greater right-hemispheric responsiveness to moving stimuli in females(Andreassi and Juszczak,1982).

A few studies have analyzed anatomical correlates of gender differences in visuospatial processing,including visual–motion processing.Voxel-based morphometry showed women to have a higher concentration of fibers in the right optic radiation than men(Good et al.,2001).Genders may also differ with respect to the relative size of the splenium of the corpus callosum(de Lacoste-Utamsing and Holloway,1982;Davatzikos and Resnick, 1998),which contains interhemispheric visual fibers(Aboitiz et al.,1992),particularly V5/MT?fibers(Newsome and Allman, 1980;van Essen et al.,1981).These gender differences may indi-cate differences in axon number,size,or myelination,all of which could alter interhemispheric communication(Davatzikos and Resnick,1998).Other studies have not found gender differences in absolute size(Bishop and Wahlsten,1997;Luders et al.,2005). However,most corpus callosum studies used structural MRIs, which do not detect differences in the proportion of fibers com-ing from different cortical areas.

Given the observed gender differences in visual–motion per-ception,one would expect to find correlates in the underlying cortical microstructure.A new cytoarchitectonic area in the re-gion of V5/MT?,hOc5(see Fig.1),has been identified recently (Malikovic et al.,2007)as a plausible anatomical candidate for human V5/MT?(Wilms et al.,2005;Barnikol et al.,2006).In this study,we analyzed the volumes and the volume fraction of cell bodies in hOC5(V5/MT?)and compared them with those

Received Feb.22,2006;revised Dec.22,2006;accepted Dec.22,2006.

This Human Brain Project/Neuroinformatics research is funded by the National Institute of Biomedical Imaging andBioengineering,theNationalInstituteofNeurologicalDisordersandStroke,andtheNationalInstituteofMental Health.This work was also supported by the Bundesministerium fu¨r Bildung und Forschung(BMBF)(Grant 01GO0104),Brain Imaging Center West(BMBF Grant01GO0204),and the Helmholtz Association(Grant VH-NG-012).We thank Ursula Blohm for excellent histological assistance.

Correspondence should be addressed to Dr.Katrin Amunts,Research Center Ju¨lich,Institute of Medicine,52425 Ju¨lich,Germany.E-mail:k.amunts@fz-juelich.de.

DOI:10.1523/JNEUROSCI.4753-06.2007

1356?The Journal of Neuroscience,February7,2007?27(6):1356–1364

from BA17and BA18.Because of the retinotopic organization of the visual cortex,we also calculated the surfaces areas of BA17,BA18,and hOc5and analyzed those with respect to volume,in-terhemispheric,and gender differences.

Materials and Methods

Although Brodmann’s cytoarchitectonic map is oversimplified (Brod-mann,1909),and new ones have been published (Clarke,1993;Amunts

et al.,2000;Annese et al.,2005;Malikovic et al.,2007;Rottschy et al.,

2007),his nomenclature serves as a general reference.Our study analyzes

BA17and BA18,as well as the recently found microstructural correlate of

the motion-sensitive complex V5/MT ?,area hOc5,part of BA19.Areas

hOc5,BA17,and BA18were studied in cell-body-stained,serial sections

(thickness,0.02mm)from 10human postmortem brains,five males and

five females (Amunts et al.,2000)(Fig.1).The mean age of the subjects

was 66.3years and ranged from 37to 85years;the postmortem delay was

?36h (Table 1).Brains were obtained from the body donor program of

the Institute of Anatomy at the University of Du ¨sseldorf (Du ¨sseldorf,

Germany),in accordance with the guidelines of the Ethics Committee of

the University of Du ¨sseldorf.They were histologically processed and

three-dimensionally (3D)reconstructed as described previously

(Amunts et al.,2000;Zilles et al.,2002).

The cortical regions were delineated by determining significant differ-ences in the gray level index (GLI)(Schleicher and Zilles,1990)(Figs.2,

3).The GLI,the proportion of cell bodies per unit brain tissue,was

collected from profiles made perpendicular to the pial surface using an

image analysis system (KS 400;Zeiss,Oberkochen,Germany).Profiles,

therefore,capture the cytoarchitecture of a cortical area.Ten features

defined the shape of each profile and form the basis for observer-independent definition of area borders (Schleicher et al.,1999;Amunts et

al.,2000).Cytoarchitectonic borders were lo-cated where a multivariate distance measure (Mahalanobis distance)and a subsequent Ho-tellings T 2test showed a significant difference between profiles in shape,thus making the bor-ders of hOc5,BA17,and BA18objective (Schleicher et al.,1999).All analyses used cor-tical parcellations of the same sample of post-mortem brains and have been described in de-tail previously (Amunts et al.,2000;Malikovic et al.,2007).

Cortical volumetrics.The cortical areas were labeled in high-resolution images (resolution of the digitized images,7000?6000pixels)of histological sections using in-house software (Fig.4).The histological sections are 1.2mm apart (each 60th section).The volumes of the structures (Table 1)were calculated from area measurements in the 3D-reconstructed histo-logical sections using the following formula:V ?s ?T ?x ?y ??A i ?F ,where V is the volume of the cortical region (result in cubic millimeters),s is the distance between two mea-sured sections (number of sections),T is the thickness of a histological section (0.020mm),x is the width of a pixel (0.02116mm),y is height of a pixel (0.02116mm),?A i is the sum of areas of the structure over all sections (in pixels),and F is the shrinkage factor of each individual brain.

Approximately 20sections were analyzed per area,hemisphere,and brain.To estimate the true volumes,shrinkage from histological pro-cessing was taken into account by calculating individual shrinkage factors for each brain (Ta-ble 1)(Amunts et al.,2005).Shrinkage differs with respect to age,sex,clinical history,brain size,cause of death,autopsy conditions,histo-logical techniques,and other factors (Vierordt,

1893;Blinkov and Glezer,1968;Haug,1980;Skullerud,1985).Volumes of hOc5,BA17,and BA18were analyzed statistically using an ANOVA

with repeated-measures design (within factors,area and hemisphere;between factor,gender).A significance level of ??0.05was set for all tests.Age was used as a covariate.

The volumetric ratios of hOc5to BA17and to BA18were calculated for each hemisphere and separately for males and females.These ratios exclude effects related to differences in the absolute brain size between males and females.The ratios were analyzed using an ANOVA [within factors,pair of area (hOc5and BA17,hOc5and BA18)and hemisphere;between factor,gender]for main effects and interactions.Volume fractions of cell bodies.Analyses on gender,inter-area,and interhemispheric differences in the volume fractions of cell bodies were based on mean GLI values calculated for areas hOc5,BA17,and BA18.The mean values came from GLIs measured in 10–20profiles in each histological section and from at least three sections per area,hemisphere,and brain.This approach ensured that profiles were collected from sim-ilar parts of the cortex (i.e.,from the wall of gyri in which geometrical distortions attributable to the sectioning plane are minimal).An ANOVA with a repeated-measure design (within factors,area and hemi-sphere;between factor,gender)checked for significance (significance level of ??0.05).Surface areas and cortical thickness.The present study extracts surface measurements from three-dimensional reconstructions of delineated cortical areas.Although several powerful tools exist to analyze cortical surfaces of whole hemispheres of the living human brain (Fischl et al.,1999;van Essen et al.,1998,2001),such methods cannot be directly applied to individual cortical areas delineated in histological sections of postmortem brains.In contrast to whole hemispheres,which have closed contours,areas defined in histological sections have two open

contours:Figure 1.A ,Surface rendering of a 3D-reconstructed dataset of a human brain (female,72years of age).Right hemisphere,

posterolateral view.hOc5(red)was projected to the free surface of the brain.The area is mainly hidden in the depths of two sulci;theanterioroccipitalsulcus(aqua)andtheinferiorlateraloccipitalsulcus(yellow).Thedottedlinemarkstheapproximatelocation of the histological section shown in B .B ,The location of hOc5is labeled in red.C ,Cytoarchitecture of area hOc5(red transparency)in the histological section at higher magnification.

Amunts et al.?Gender Differences and Asymmetry in Visual Cortex J.Neurosci.,February 7,2007?27(6):1356–1364?1357

the outer (pial)and inner (white matter)boundaries.Many methods are not suitable for processing datasets containing open contour lines (e.g.,NUAGE software)(Geiger,1993).

Furthermore,generating topologically correct representations of sliced objects when the distances between slices are much greater than the within-plane resolution is not trivial (Boissonnat,1988;Meyers et al.,1991;Meyers,1994).The difficulties are compounded when the number of contour lines in consecutive sections differs,the reconstructed surface patch is not closed,or it ramifies into multiple endings in different sec-tions.These difficulties confront researchers analyzing cortical areas.Ad-ditionally,in most previous approaches,adjacent layers were assumed to be independent,and,thus,the process of reconstruction merged inter-polated models derived from pairs of successive parallel slices (Barequet et al.,2004).This assumption may result in frequent topological defects for highly folded surfaces,like cortical areas.Finally,the data modalities,spatial resolution of the images,and image artifacts are also different in histological sections of postmortem brains compared with in vivo MR data.

Therefore,for the present study,we adapted and extended existing methods to measure surfaces.Before beginning the triangulation pro-cess,we fixed topological problems using a Reeb graph-based represen-tation of the topology (Reeb,1946;Biasotti,2004,2005).For each con-tour lying in the x–y plane of section z i ,we computed a bounding box with a height 0.5(z i ?1?z i ?1).Next,we enlarged the height of each bounding box until it overlapped those of its neighbors and adequately represented the surface.

After this,two consecutive contour lines,one from each edge,were

Table 1.Postmortem sample,fresh brain weights (in grams),and volumes of areas (V,mm 3)Age (years)Sex Fresh brain weight Shrinkage correction f V V(BA17)left V(BA17)right V(BA18)left V(BA18)right V(hOc5)left V(hOc5)right 37m 1437 2.02942392074134440535764854m 1757 2.45104371105253855900591116056m 1270 2.20751871606698699924439175m 1349 2.15852886676369714047577269m 1360 2.13921990007723841848360185f 1046 1.67530253594520526642226659f 1142 2.06602560356194651722828379f 1350 1.93761668726718626933019572f 1216 1.82542558204847323930226779f

1110

1.477040673540544709323356Mean 1.997653759156645886376494SD

0.28

1752

1817

1255

1518

115

302

Mean fresh brain weight of females (f)was 1137g and that of males (m)was 1390

Figure 2.A ,Definition of cortical borders of hOc5in a cell-body-stained histological section of a postmortem brain using an observer-independent method (Schleicher et al.,1999).GLI image of a coronal section from the region of the anterior occipital sulcus (SOA)and the inferior lateral occipital sulcus (SOL 1).Arrowheads and lines indicate the borders between area hOc5and the neighboring dorsal (D)and ventral (V)areas.The cortex is covered from the layer I/II border to the layer VI/white matter border by a series of traverses.Along these traverses,profiles,which capture laminar changes of the GLI (i.e.,the volume fraction of cell bodies)from the surface to the white matter,i.e.,the cytoarchitecture,were extracted.Profiles are num-bered from 1to 169.B ,Multivariate distance D (Mahalanobis distance)as a measure of similar-ity of neighboring blocks of profiles in dependence on the profile number.Block size b ?14profiles.Significant peaks of D indicate positions of cytoarchitectonic borders.They were found at positions 39(dorsal border)and 126(ventral border).C ,The distance D was calculated for different block sizes ranging from b ?8to 24.The distance for b ?14is

highlighted.

Figure 3.Dorsal border of area hOc5with area D.The sizes of pyramidal cells in sublayer IIIc are larger in area hOc5than in area D.Roman numerals indicate cortical layers.Scale bar,0.5mm.Same border as in Figure 2at position 39.

1358?J.Neurosci.,February 7,2007?27(6):1356–1364Amunts et al.?Gender Differences and Asymmetry in Visual Cortex

automatically triangulated.Triangles were built so that they did not in-tersect any existing triangle,and the lengths of its edges were as similar as possible.The quality of individual triangulations was checked by com-paring actual values with the mean regularity value ?,defined as the ratio between the inner and outer circle radius,where ?best ?0.5for an equi-lateral triangle.Triangles closest to the optimal value were processed further.As a result of the larger interslice distance than in-plane resolu-tion and the local heuristic tiling,the approach produced many relatively small triangles.

To get a smooth surface without significantly altering the distance between the inner and outer surfaces,we implemented a Laplace mesh

smoothing method,which enabled relatively large movements of vertices along the original contour line but prevented movement perpendicular to the surface.Next,a global mesh refinement,which divided each trian-gle into four smaller triangles,was applied.Afterward,we flipped all nonlocally Delaunay edges to be locally (O’Rourke,1998)[vTK software package (https://www.wendangku.net/doc/5d1789494.html,/VTK/get-software.php)].The sur-face was smoothed again with the same Laplace smoothing method de-scribed above except that minor movements perpendicular to the surface were allowed.Finally,we checked and manually corrected the triangula-tion in places in which the topology determined by the algorithm was obviously erroneous.That was the case in some parts of area V1/BA17,in which the structure is highly complex (Fig.5).

The quality of the total triangulation,like that of individual triangles,was checked by calculating the mean of the regularity factor ?:?V1/BA17?0.408?0.009,?V2/BA18?0.392?0.013,and ?hOc5?0.401?0.017.The small SDs indicate a regular triangulation,whereas differences of mean values ?,from ?best ,reflect the relatively large interslice distance,which could not be totally removed.

The contour-labeled areas served as a basis for subsequent brain mor-phometry.Surface areas were analyzed using ANOVA with repeated-measures design as described above.Areas were corrected for shrinkage by using the same shrinkage factor determined for the volume of the brain,f ,raised to the two-thirds power (f 2/3).We assumed an isometric shrinkage in all three spatial directions.

To estimate the mean cortical thickness of the areas,the area volume was divided by its mean surface,which was calculated as the average of the outer (pial)and the inner (cortex/white matter border);additional information is shown in the supplemental data (available at

www.jneu-

Figure 4.Definition of the surfaces of area hOc5in a 3D-reconstructed postmortem brain.A ,Label of the area in a histological section.B ,Region of interest of A but at higher magnification.Bold lines mark the outer (dark yellow)and inner (red)contours of the area.C ,Surface recon-struction of the area,view from the sulcus.The approximate positions of the histological sec-tions,in which hOc5was delineated,are indicated by green lines.The topmost line corresponds to the section shown in A

Figure 5.Reconstruction of the inner (cortex–white matter)surface of BA17in serial histo-logical sections of a left hemisphere.View into the calcarine sulcus.A ,The sequence of contours of the delineated area (“tubes”)in histological sections is projected to the surface.The distance between histological sections is 1.2mm (distance between tubes).The calcarine sulcus can be identified as the elongated concave structure,which is surrounded by the “U-shaped”area.B and C show two regions with triangulation (yellow triangles)at higher magnification.Note the regularshapeofthetriangles.Atotalof200,000triangleshavebeengeneratedinthisparticular area to create its surface.The arrow cross shows the orientation within the brain:green arrow,dorsal/ventral;blue arrow,caudal/rostral;red arrow,medial/lateral.

Amunts et al.?Gender Differences and Asymmetry in Visual Cortex J.Neurosci.,February 7,2007?27(6):1356–1364?1359

https://www.wendangku.net/doc/5d1789494.html, as supplemental material).The mean cortical thickness was corrected for shrinkage with f 1/3.

Results

Previous structure/function studies determined that V5/MT ?overlaps and is coterminous with the cytoarchitectonically de-fined area hOc5(Wilms et al.,2005;Barnikol et al.,2006).A distinct microstructure separates area hOc5from neighboring extrastriate areas;it includes a broader layer III,a higher cell density in layers II/III,and a lower one in layer V (Fig.3).Most of hOc5was found deep in the anterior part of the inferior lateral occipital sulcus or in the anterior occipital sulcus (Fig.1).The cytoarchitectonic details of hOc5(Malikovic et al.,2007)as well as of BA17and BA18(Amunts et al.,2000)have been published previously.

The ANOVA of pooled gender data showed a significant volu-metric difference between males and females (p ?0.01)and a significant area by gender interaction (p ?0.05)(Fig.6,Tables 1,2).Subsequent univariate F tests showed significant size differ-ences between males and females in left and right BA17,as well as in the right hOc5(p ?0.01),with the right hOc5being signifi-cantly larger in male than female brains (Fig.6).Moreover,three of five female brains had smaller right than left hOc5volumes,whereas all of the male brains of this study had larger right than

left hOc5volumes (Table 1).Although the mean size of male brains in this study was larger than that of female brains (by a factor of 1.2),the difference between the genders in the right hOc5volume (factor of 2.6)was considerably greater than ex-pected on the basis of brain size.The gender difference in the left hOc5volume resembles that of brain size (factor of 1.3).

Given that BA17and BA18interconnect with V5/MT ?,we next determined whether or not earlier node(s)in the serial pro-cessing of visual information were also asymmetric:is asymmetry observed in beginning stages of visual processing,in BA17,and/or does it appear only later,in higher associative visual areas,i.e.,in BA18or hOc5(V5/MT ?)?The data showed that both BA17and BA18were bilaterally symmetric with respect to vol-ume (p ?0.05)(Table 1).However,the volume of BA17differed between males and females,with males having larger volumes than females on both sides (Fig.6)(p ?0.05).The volume of right BA18was larger than the left in all male brains but only in three female brains;this difference did not reach significance (Fig.6,Table 1).The observed gender-related interhemispheric asymmetry of hOc5in volume is therefore not a feature of the entire visual cortex or even the whole brain but a specific aspect of the anatomy of hOc5.

The volumetric ratio of hOc5-to-BA17was significantly smaller in the female right hemisphere than it was in males (p ?0.05)(Fig.7).The right hOc5-to-BA18ratio only approached significance (p ?0.06).Both ratios were approximately twice as small in female brains as they are in male brains.Thus,females had more primary and secondary visual cortex per volume unit hOc5in the right hemisphere than do males.Age effect was not a significant factor in any of the parameters (p ?0.05).

To examine whether and how the observed quantitative shifts in the volumes of hOc5,BA17,and BA18affected the underlying cytoarchitecture,we analyzed the volume fraction of regions of cell bodies.A decreased volume fraction of cell bodies is equiva-lent to an increased proportion of neuropil,i.e.,more space be-tween cell bodies that is occupied by dendrites,axons,and syn-apses.To begin answering this question,we averaged the GLI,the proportion of cell bodies per unit brain tissue,across all cell layers and compared the mean GLI between the two hemispheres and genders (Fig.8).

At this level,GLIs were not sexually dimorphic.Instead,the GLIs of hOc5,BA17,and BA18were similar in having a small but significant right-larger-than-left asymmetry (p ?0.05).The lower GLI values of the left hemispheres indicate that all three visual areas have more neuropil than the structures do in the right hemispheres.

Differences in the volume of hOc5between males and females can be caused on a macroscopic level by two factors:differences in the surface of the areas and/or differences in cortical thickness.Surface measures of cortical areas are highly relevant parameters considering the retinotopic organization of visual areas (Huk et al.,2002).

Areas,like volumes,have similar patterns of male–female dif-ferences (Fig.6,Table 2).Male and female surface areas differed significantly between each other (p ?0.001),and there was a significant gender by area interaction (p ?0.05).Right area hOc5was significantly smaller in female than in male brains,whereas left hOc5did not differ between genders (Fig.6).Signif-icant differences between males and females were found in the left and right BA17as well as in left BA18,with males having larger surface areas than females;the latter differences,however,did not interact with hemisphere.The ratios of all

left-

Figure 6.Mean ?SE volumes and surface areas of areas hOc5(top row),BA17(middle row),and BA18(bottom row)of right and left hemispheres,in males and females.The amount anddirectionofthebilateralasymmetryofhOc5differsbetweengenders(p ?0.05).Whereas males showed a significant right-larger-than-left asymmetry in volume and surface of hOc5,females were more symmetrical.

1360?J.Neurosci.,February 7,2007?27(6):1356–1364Amunts et al.?Gender Differences and Asymmetry in Visual Cortex

hemispheric combinations of areas did not differ significantly between males and females (Fig.7)(all p ?0.05).

In contrast to volume and surface area,cortical thickness is not an independent parameter with patterns that differ from those of volumes or surface areas (Fig.9).Cortical thickness seems to differ between males and females in hOc5,with males having thicker cortices than females in both hemispheres.The opposite was found in BA18,with females having thicker cortices than males.Thickness was generally greater in hOc5than in both BA17and BA18(supplemental data,available at https://www.wendangku.net/doc/5d1789494.html, as supplemental material).

Discussion

Methodical considerations

The present morphometric study is based on (1)an objective definition of borders between cytoarchitectonically defined cor-

tical areas,(2)the calculation of volumes using a stereological formula,and (3)the calculation of areal surfaces based on three-dimensional reconstructions of the areas.Whereas the first two steps have been proven in many studies,the third step represents a new methodological development (for comparison of area estimates of the literature and that of the present study,see sup-plemental data,available at https://www.wendangku.net/doc/5d1789494.html, as supplemental

Table 2.Postmortem sample,surfaces of areas (A,mm 2)Age (years)Sex Fresh brain weight (g)Shrinkage correction f A ?f V 2/3A(BA17)left A(BA17)right A(BA18)left A(BA18)right A(hOc5)left A(hOc5)right 37m 1437 1.60800174163395220614627854m 1757 1.82624050324329528520942456m 1270 1.69437349346457532810116775m 1349 1.67635661095801652422729269m 1360 1.65625563496061656619221585f 1046 1.41382538752468213618810159f 1142 1.6244145449421949649813179f 1350 1.55642556753573343315413572f 1216 1.49375927982734180913412179f

1110

1.293602313622973067162183Mean 1.585325507741344132161205SD

0.15

1511

1456

1524

1820

100

m,Male;f,female.

Figure 7.Ratios (in percentage,?SE)between volumes of hOc5-to-BA17and hOc5-to-BA18(top row)show a significant gender difference for right hOc5-to-BA17(p ?0.05)and a similar but nonsignificant tendency for right hOc5-to-BA18(p ?0.06).In the right hemi-sphere,the female ratios were approximately twice as small as they are in male brains (for both hOc5-to-BA17and hOc5-to-BA18).Ratios did not differ between each other in the left hemi-sphere.Ratios between surfaces of the areas (bottom row)show similar directions of asymme-try (p ?0.05).

Figure 8.Volume fraction of cell bodies (GLI ?SE)has significantly higher values on the right than left side,in all three areas,regardless of gender.The larger GLI values on the right mean that there are more cell bodies and less room for neuropil;dendrites,axons,synapses.

Figure 9.Mean ?SD cortical thicknesses of areas hOc5,BA17,and BA18for the left and the right hemisphere,separately for males (n ?5)and females (n ?5).Note that the thickness is smaller in BA17plus BA18than in hOc5.Females have a thicker cortex than males in BA18,whereas males have a thicker hOc5cortex than females.

Amunts et al.?Gender Differences and Asymmetry in Visual Cortex J.Neurosci.,February 7,2007?27(6):1356–1364?1361

material).The present study provides,for the first time,three-dimensional surfaces of microstructurally defined areas of the visual cortex.Such measurements represent a methodical advan-tage compared with measurements from serial sections,which systematically underestimate the true surface(Fahle and Palm, 1983).

With surfaces defined in three dimension,it is possible to estimate,in a first approach,the mean cortical thicknesses for each area.Because the thickness value is derived from volumes and surfaces,it is not an independent parameter and was not analyzed statistically.The advantage of this way to estimate the cortical thickness is the robustness of the parameter.Thickness provides a measure to test the plausibility of areal surfaces(sup-plemental data,available at https://www.wendangku.net/doc/5d1789494.html, as supplemental material).

The estimated thicknesses coincide well with the data pro-vided by von Economo and Koskinas,who reported that the calcarine cortex is?2mm thick in the convexities and1.2mm thick in the bank of the sulcus.According to their Figures28and 29(von Economo and Koskinas,1925),cortical thickness in the region approximating hOc5ranges from2.7to2.9mm(supple-mental data,available at https://www.wendangku.net/doc/5d1789494.html, as supplemental material).

The volumes of cortical regions can be estimated with high precision in serial sections using Cavalieri’s principle(Uylings et al.,1986).The sample size of the present study is relatively low compared with MR studies in the living human brain(Mac-donald et al.,2000;Kovalev et al.,2003;Lerch and Evans,2005). Advantages of the present approach,however,include the high spatial resolution and,therefore,precise measurements,as well as associating the latter with cytoarchitectonically defined areas in-stead of with brain macroscopy.Finally,it has to be mentioned that a systematic cytoarchitectonical analysis and mapping study as presented here is extremely time consuming and labor inten-sive.Such constraints limited the size of the sample,which was subjected to detailed brain morphometry.As a consequence,we may assume that certain gender,age,areal,and/or interhemi-spheric differences did not reach significance because of a con-siderable amount of intersubject variability.

Gender-related differences in visual areas

As described above,gender differences in the visual cortices may link to well described brain functions.V5/MT?is part of the dorsal stream(“where”system),i.e.,the occipitoparietal pathway (Ungerleider and Mishkin,1982;Ungerleider and Haxby,1994). It is widely accepted that V5/MT?makes important contribu-tions to a number of aspects of motion perception(Schenk et al., 2005).V5/MT?receives projections from areas V1(BA17)and V2(BA18)(van Essen et al.,1981,1986;Maunsell and van Essen, 1983;Shipp and Zeki,1989;Fellemann and van Essen,1991)and from subcortical regions,e.g.,the lateral geniculate body and the pulvinar(Yoshida and Benevento,1981;Rodman et al.,1990; Shipp,2001;Sincich et al.,2004).It sends feedback projections to the primary visual cortex(Pascual-Leone and Walsh,2001;Sillito and Jones,2002;Muckli et al.,2005;Silvanto et al.,2005).As part of the dorsal stream,V5/MT?projects to VIP and LIP in the cortex of nonhuman primates,areas that are located in the in-traparietal sulcus(Maunsell and van Essen,1983;Fellemann and van Essen,1991;Orban,1997;Lewis and van Essen,2000).

Several lines of evidence support the notion that area hOc5is the cytoarchitectonic correlate of functionally defined V5/MT?:

(1)an observer-independent method has identified and mapped

a distinct microstructure(Malikovic et al.,2006),which(2)co-incides with the stereotaxic location and sulcal landmarks of an area whose functional activities characterize V5/MT?(Wilms et al.,2005;Barnikol et al.,2006)and to(3)the overlapping locales of an in vivo observer-independent high-resolution MR map and fMRI of V5/MT?(Walters et al.,2007).The location of hOc5on the posterior bank of the anterior occipital sulcus(Malikovic et al.,2007)also makes it unlikely to be part of MT or MST(Huk et al.,2002),

Morphometric differences in the cytoarchitecture of hOc5, BA17,and BA18may underlie observed gender differences in processing of visuospatial and motion information.Considering that V5/MT?has been characterized as an area,which combines information about space,integrates V1input,and,under some conditions,integrates them to compute pattern motion(Born and Bradley,2005),we may speculate that the sexually dimorphic differences in the ratios of primary and secondary visual cortices to hOc5/V5/MT?suggest a stronger convergence of visual infor-mation from BA17/BA18to the right hOc5in females than in males.The increased amplitudes and activations in right female hemispheres noted above accord with that interpretation(An-dreassi and Juszczak,1982;Cohn et al.,1985;Kaufmann et al., 2001).Alternatively,smaller female hOc5volumes may reflect a sparser sampling of BA17/BA18by the right hOc5of women than of men.This alternative,however,seems less plausible;more activation has been observed in female BA37than in male(Kauf-mann et al.,2001).

Right-hemispheric dominance in a mental rotation task, which was independent of the response hand,was observed in males,but not females,and was interpreted as reflecting a more bilateral organization of visuospatial processing in females than in males(Johnson et al.,2002).At a structural level,an MRI texture analysis of290subjects found males to be more asymmet-ric in the majority of brain regions,including the presumed re-gion of V5/MT?(Kovalev et al.,2003).Volumetric analyses in a sample of postmortem fetal brains in the Yakovlev Collection showed that male striate–extrastriate cortices were far more asymmetrical than they were in female brains(de Lacoste et al., 1991).Another study failed to demonstrate a significant gender difference but did find a significant right-larger-than-left volu-metric asymmetry of the human striate cortex(Murphy et al., 1996).Summarizing,most studies,including ours,find that fe-male visual structures are more bilaterally symmetric.Further-more,male asymmetry in mental rotation tasks accords with our findings:a larger right male V5/MT?has more space in which to process information from regions outside BA17/BA18.

The present data of interhemispheric asymmetry of the visual cortex supplement those of previous studies:areas BA17and BA18extend more medially and caudally in the left hemisphere than in the right(Amunts et al.,2000).Analyses of petalia also demonstrated interhemispheric differences in occipital protru-sions(Zilles et al.,1996).In addition,interhemispheric,but not gender,differences have been observed in area17of the rat cortex (Galaburda et al.,1986).

The small but significant right-larger-than-left GLI values in V5/MT?,BA17,and BA18indicate that the left hemisphere has more neuropil in all three visual areas than does the right hemi-sphere,regardless of gender.Our findings do not rule out the possibility that gender-related differences exist on a finer micro-structural level,in individual layers,or with respect to glial cell number,for example(Galaburda et al.,1986;Reid and Juraska, 1992;Seymoure and Juraska,1992),but they show that volumet-ric differences do not stem from gross differences in volume frac-tions of cell bodies across all cell layers.

1362?J.Neurosci.,February7,2007?27(6):1356–1364Amunts et al.?Gender Differences and Asymmetry in Visual Cortex

Interhemispheric differences in the volume fraction of cell bodies have been found previously in the presumed hand region of the primary motor cortex,BA4,in which a left-greater-than-right asymmetry of neuropil was observed but in which gender-related differences were not present(Amunts et al.,1996).That study also analyzed the depths of the central sulcus in the motor hand region in a sample of in vivo MR datasets of tested right-handed subjects and demonstrated that the central sulcus was deeper on the left than right side.Both findings,postmortem and in vivo,have been interpreted as showing more space for connec-tions in the hemisphere of the dominant hand.The similar direc-tion of interhemispheric asymmetry in the amount of neuropil in BA4of the motor cortex and V5/MT?,BA17,and BA18of the visual cortex is consistent with a relationship between handed-ness and eye dominance(Bourassa et al.,1996;McManus et al., 1999)or may represent a broader hemispheric dissimilarity.

Combining the gender equivalent GLI values with asymmetric volumetric data suggests that a higher proportion of the right female V5/MT?is involved with processing direct visual infor-mation from BA17and BA18than is that of males.At the same time,the larger absolute volume of the male V5/MT?may indi-cate that males may process the same(or more)absolute amount of visual information.Another way to state this is that the male V5/MT?has relatively and absolutely more space to process information from regions outside BA17/BA18,which may sup-port the superior visuospatial processing observed in some cog-nitive tasks.Because males and females resemble each other in other motion tasks(Eals,1986;Wendt and Risberg,1994;Peters et al.,1995;Tran et al.,1998),we may assume the presence of additional neural strategies and their anatomical correlates. References

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