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Possible Sex Differences in the Developing Human Fetal Brain a

a

M C. De Lacoste , D. S. Horvath & D. J. Woodward

a

a

Department of Cell Biology and Neuroscience , University of Texas Southwestern Medical Center at Dallas , Published online: 04 Jan 2008.

To cite this article: M C. De Lacoste , D. S. Horvath & D. J. Woodward (1991) Possible Sex Differences in the Developing Human Fetal Brain, Journal of Clinical and Experimental Neuropsychology, 13:6, 831-846, DOI: 10.1080/01688639108405101 To link to this article: http://dx.doi.org/10.1080/01688639108405101

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Journal of Clinical and Experimental Neuropsychology 1991, Vol. 13, NO. 6, pp. 831-846

0168-8634/91/1306-0831$3.00 0 Swets & Zeitlinger

Possible Sex Differences in the Developing Human Fetal Brain* M-C. de Lacoste, D.S. Horvath, and D.J. Woodward

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Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center at Dallas

ABSTRACT Left-right regional volumetric asymmetries in five telencephalic regions were studied in the developing human fetal brain. Complete series of coronal sections of 21 fetal brains were digitized and regional volumes were integrated. Five regional indices of asymmetry and two overall indices of asymmetry were calculated and compared across the fetal sample. The two most asymmetrical regions in the developing fetal brain were region 1 , roughly equivalent to prefrontal cortex, and region 5, which includes striate and extrastriate cortices. Region 5 also manifested a statistically significant sex difference (p < ,021 in the degree of volumetric asymmetry. It appears that striate-extrastriate cortices are far more asymmetrical in male brains than in their female counterparts (M = 33%; F = 13%). Overall indices of asymmetry indicated that, on the average, volumetric asymmetries in the male brain favor the right hemisphere. In contrast, the human fetal female is likely to have two hemispheres of the same size or a left hemisphere that is slightly larger than its right counterpart. We believe that these results support the hypothesis that testosterone in uteru may lead to a more rapid growth of the right hemisphere or, alternatively, retard the growth of the left hemisphere.

Previous investigators have found that the human fetal cerebrum i s anatomically asymmetrical: Measurements of t h e height and anterior-to-posterior extent of the Sylvian fissure and the area of the planum temporale as well as petalial patterns differ depending on t h e hemisphere (Chi, Dooling, & Gilles, 1977; Deuel & Moran, 1980; Le May, 1976; Le M a y & Culebras, 1972; Wada, Clarke, & Hamm, 1975). A related observation is that the development of t h e right hemisphere

* We are very grateful for the use of the Yakovlev collection and for all of the help we received at the Armed Forces Institute of Pathology. Ms. Chi-Na Kim, M.S., is thanked for her assistance in the computer cytoarchitecture and help in editing this manuscript. This work was supported by HD-21711-01 to MCL and the Biological Humanics Foundation. We are grateful to Miss Rita Guimond for editing and typing the manuscript. Correspondence to: Marie-Christine de Lacoste, Ph.D., Department of Obstetrics and Gynecology, Yale Medical School, 333 Cedar Street. P.O. Box 3333, New Haven, CT 06510, USA. Accepted for publication: February 5, 1991.

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appears to occur at a faster rate than that of the left hemisphere. For example, the Sylvian fissure appears chronologically earlier in the right hemisphere (Chi et al., 1977), and higher order dendritic branching in anterior speech areas first appears in the right hemisphere (Scheibel, 1984). In addition, levels of choline acetyltransferase (ChAT) trail in the left hemisphere relative to the right in 20 to 39 week old fetal brains (Bracco, Tierri, Ginanneschi, Campanella, & Amaduci, 1984). It has been suggested by a number of authors that a possible explanation for these findings is that circulating testosterone levels in utero influence the developing brain and, through yet undeciphered mechanisms, either promote the growth of the right hemisphere or delay the development of the left hemisphere (Bear, Schiff, Saver, Greenberg, &Freeman, 1986; Damasio & Geschwind, 1984; Geschwind & Galaburda, 1984, 1987). If the levels of circulating testosterone do, indeed, influence the developing brain, then there could be a sex difference in the degree of gross anatomical asymmetries. In the adult human brain, sex differences in the degree of frontal and occipital petalial asymmetries, favoring the male, have been documented (Bear, Schiff, Saver, Greenberg, & Freeman, 1986). In the current study, we examined five telencephalic regions in human fetal brains of different ages to determine if these brains exhibit right-left gross asymmetries and, if so, to assess if male and female cerebra manifest the same degree of asymmetry. Right-left asymmetries in five telencephalic regions were calculated by integrating regional volumes across a complete anterior to posterior series of coronal sections. Thereafter, the percentage differences between right and left volumes for each region were computed. Gross anatomical landmarks served as regional delimiters for the five regions. The measures of cortical asymmetry described in this investigation are different than those employed in the studies by the aforementioned authors in that they pertain to volumes and not linear dimensions, These procedures effectively demonstrated differences during the developmental stages.

METHODS Materials Anterior to posterior series of coronal sections (20-120 per series; 6-35 pn) of 21 fetal brains (see Table 1 for listing of cases) from the Yakovlev collection at the Armed Forces Institute of Pathology were photographed with a rnm ruler and case identificationnumber onto 35mm slides (Ektachrome 50). The Yakovlev collection includes an aggregate of specimens (see Table 1) obtained from severaldifferentsources. All brains were processed using the same basic histological protocol, although the plane of section (midsagittal, coronal, horizontal) intentionally varies depending on the case. Right-left orientations were carefully maintained and we found only four reversals in our entire sample of several thousand sections. The fetal cerebra utilized in this study included all of the normative fetal brains of the Yakovlev collection that were sectioned in the coronal plane. The brains used in this study were classified as normative by pathologists, although most of them were obtained from

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Table 1. A listing of the cases (N= 21) obtained from the Yakovlev collection. There are different serial numbers for the cerebra which were obtained from more than one source. However, all brains were processed following the same protocol. In two of the cases (indicated with *), we had to delete a series of sections corresponding to a single region due to histological tearing. In three of the cases (marked with **), deviation of the section from a true orthogonal plane exceeded the width of the section. Regional volumes were not computed for these cases but they were compared for comparisons of IRot) values.

B-397-62 (F) W-215-65 (F) W-149-63 (F) B-303-62 (F)* W- 14-59( F) W- 1 85-64( F) W-5-59(F) W-26-59(F) B-107-61(F) W-240-66(M) B-137-61(M)** W-29-60(M)**

W-206-65(M) LX-143-63(M) LX-144-63(M) W-132-63 (M) BR-21-63(M)** W-91-62(M) B-104-61 (M) W- 156-64(M) W-17 1-64(M)*

** Used only for calculations of I(,otl * Indices of asymmetry not calculated for one of the regions due to damaged tissue. spontaneous abortions or infants who died shortly after birth, albeit from noncerebral causes (Gilles, 1983). Fetal gestational age (GA) ranged from 13 to 37 weeks. Brain weights ranged from 4 to 376 g. Ektachrome slides of the individual sections were projected directly onto a graphics tablet and digitized using the TRACE subprogram of the laboratory software package CARP (Computer Assisted Reconstruction Package, Biographics Inc., Dallas, TX). Hard copies of the digitized sections were compared with the corresponding slides. Sectional volumes were then calculated using the X version of the Statistical Package for the Social Sciences (SPSSx; SPSS, 1983) and the following formula: VOL(,) = area(i) X [0.5 X (di + di+l)]

where area(i)is the planimetric area determined for the ith plane; di is equal to the distance between the ith plane of section and the (i-1)thplane of section. Ifi = I the d i is the distance from the first section to the tip of the frontal pole. When i = is equal to the number of the last plane of section, then d,, I is the distance from the last section to the occipital pole. In effect, the i = 0 and i = n + I planes are just anterior and posterior to bruin tissue, respectively. +

This formula accounts, in part, for the fact that the distance between planes of section may vary. Regional delimiters a n d regional volumes For each case, the series of sections was projected until constellations of diencephalic and telencephalic landmarks, consistent with the age of the fetus, could be identified by two investigators. Dooling et al. (1983) and James and Gilles (1983) provided the critical

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reference on the development of the fetal prosencephalon. A subset of landmarks believed to be symmetrical was used to determine if the sections were cut perpendicular to the long axis. These landmarks included the genu and splenium of the corpus callosum. midline thalamic nuclei and basal ganglia structures. Another group of landmarks served as regional delimiters for five regions (Region(,)to Regiong)).Regionaldelimiters varied with the GA of the fetus since, at 13 weeks, the cerebrum is nearly lissencephalic (Figs. 1 and 2). while at 32-36 weeks GA it exhibits all primary and secondary as well as some tertiary sulci (Fig. 3). Without exception, however, Region(,) was demarcated anteriorly by the frontal pole and posteriorly by the genu of the corpus callosum. Region(, in cerebra less than 18 weeks GA was defined anteriorly by the most anterior extent of the calcarine sulcus and posteriorly by the occipital pole. In cases older than 18 weeks GA, it was delimited anteriorly by the intersection of the calcarine and parieto-occipital sulci and posteriorly by the occipital pole. At all ages, Region(,), Region 3). andRegion(, were defined by midline structures including thalamic nuclei (anterior, puivinar) and the hasal ganglia. It was not possible to defiie regions from gross observation that precisely correspond to cytoarchitectural or functional zones. Rather, this means of definition served as a heuristic tool for a comparative study of regional volumetric asymmetries. Regional volumes were integrated using the following formula:

c II

VOLo =

VOL,,)

(i=l)

where j = the number of the region, n = the total number of sections contained between the landmarks delineating the borders and Vol,, = sectional volume.

Indices of Asymmetry Three indices of asymmetry were computed. These included 1) (wherej = I to 5 ) or the regional index of assymetry for each of the five regions, 2) ,or the average index of or the percentage difference between total asymmetry across all five regions and 3) right and left hemispheric volumes without reference to regions. I(,ti)) (where j = I to 5 ) or the regional index of asymmetry for each of the five regions was computed as follows: ABS (LVOLo, - RVOLQ)

- Itw)oi 0.5 X (LVOLo + RVOLo,)

x 100

where j = the number of the region and LVOL and RVOL refer respectively to the lefi and right regional volumes for a given region. Ilrenti)) is equal to 100 times the absolute value of the difference between the right and left mcremental hemispheric volumes for the given region divided by the average right/ left volume for that same region. It is simply a measure of the percentage lefthight difference in regional volumes. For example, a difference of 2% in volume for a given region would yield an index of 2.0. Index I(reg(jjjwas used to determine which regions in our sample were the most symmetrical or asymmetrical. I, or the average index of asymmetry across all five regions, was calculated using the following formula:

POSSIBLE SEX DIFFERENCES IN THE DEVELOPING HUMAN FETAL BRAIN anterior

RIGHT LEFT

RIGHT

835

LEFT

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15480

20540

25380

Lfj

@Q occ

posterior

Fig. 1. Female brain at 13 weeks GA. The cerebrum is nearly lissencephalic. Note that the left hemisphere is visibly larger than its right counterpart.

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The average index of asymmetry, I. is simply equal to one-fifth the sum of the five regional indices of asymmetry. Note that both and I were based on the absolute value of the difference between the left and right regional volumes. The rationale for ushg absolute values was to facilitate intercase comparisons on the degree of asymmetry for individual regions within a brain as well as for the total cerebrum. As the direction of asymmetry varies with region and case, signed indices would cancel out and give the appearance of a symmetrical brain. For example, if, in a given brain, prefrontal cortex exhibited a 20% asymmetry favoring the left hemisphere (signed regional index = +20.0) while occipital cortex manifested a 21% asymmetry favoring the right hemiphere (signed regional index = -21.O) and the remaining regions were symmetrical,the signed I value would approach zero (-.20) and would not reflect the pronounced (albeit in opposite directions) prefrontal and occipital asymmetries. In contrast, using our formula index I would equal 8.2. However, as we were also interested in whether regional asymmetries favored the right or the left hemispheres the direction of the regional asymmetry was retained in the was data base (see Table 3). Moreover, as described below a third index of asymmetry, Iffof, directional. a measure of the percentage difference between the total right and left hemispheric volumes, was calculated using the following formula:

where n = the total number of sections LVOLQ = 1efLse.ctional volume and R OL(,)- right sectional volume

I(bt)is different from index I in that it is 1) not an average of I reg values since it is based on the total set of sectional volumes for each hemisphere and girectional, with negative and positive values respectively reflecting larger right and left hemispheric volumes. Index Irtot, served to quantitatively assess differential rates of development for the right and left hemispheres.

k)

Correction Factors In a number of cases, sections were cut slightly diagonal of a true perpendicular to the long axis. When the deviation from a true orthogonal plane was less than d (thickness of

Line drawings of a series of coronal sections from three of the cases used in the study. Numbers to the left of each section refer to the distance in pn from the frontal pole. Abbreviations: AQ: aqueduct; Ca: caudate; Cal: calcarine sulcus; CB: cerebellum; CC or corpus callosum; cin: cingulate gyrus; cins: cingulate sulcus; Cir: circular sulcus; Col: collateral sulcus; cs: callosal sulcus; ExMx: extraganglionic matrix; Fr: frontal lobe; Frp: frontal pole; Hi: hippocampus; IC or Ic: internal capsule; if or lof: interhemispheric fissure; ifg: inferior frontal gyms; Ins: insula; iP1: inferior parietal lobule; iT: inferior temporal; mfg: middle frontal gyms; m T middle temporal; MxGe: ganglionic matrix; Occ or OCC: occipital lobe; 01s: olfactory sulcus; orb: orbital cortex; para: parahippocampus; Pch: choroid plexus; pCu: cuneus; PT: putamen; Ptg: parietal cortex; rct: gyrus rectus; sFg: superior frontal gyrus; sFs: superior frontal sulcus; sPg: superior parietal lobule; sT: superior temporal; Syl: sylvian fissure; Tern: temporal; Th: thalamus; VT or vt: lateral ventricle. CC:

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anterior

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RIGHT

LEFT

RIGHT

LEFT

k-5

posterior

Fig. 2. Male brain at 15 weeks GA. The right hemisphere is visibly larger than the left counterpart. Since development of the twin cerebrum lags that of the singleton by 2-3 weeks, this case is “age-matched” with the one in Figure 1 .

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RIGHT

LEFT

anterior

RIGHT

LEFT

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7735

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posterior Fig. 3. Female brain at 37 weeks GA. All primary and secondary as well as some tertiary sulci are present by the final weeks of gestation.

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the section), we applied correction factors using previously described formulas (de Lacoste et al., 198Sa). Correction factors were selected to maximize the degree of symmetry or minimize the absolute values of J and In three cases (see Table l), however, the deviation from a true orthogonal plane exceeded d. Regional volumes were not computed for these cases but they were retained for comparisons of f(uo values, since total hemispheric volumes would presumably not be affected by these deviations. Statistical Analysis Student’s t tests and analysis of variance techniques (ANOVA) from the Statistical Package for the Social Sciences (SPSSx) were used to determine if sex differences in values of I, and were statistically significant. Two different ANOVA subroutines were utilized:’ One anayzes only factors, and the other analyzes factors, then covariates, and finally interactions, adjusting for covariates and factors. In this study, sex was considered a factor and age as a covariate.

RESULTS We observed a number of asymmetries that have been previously described, including hemispheric asymmetries in the height of the Sylvian Fissure, but most notably that sulci and gyri appear at different gestational ages in the right and left hemispheres, sometimes up to 2-3 weeks apart (Dooling, Chi, & Gilles, 1983). A more convoluted region in a given hemisphere was almost invariably larger volumetrically than its counterpart in the opposite hemisphere. These data suggest that, in the fetal brain, growth of a region as measured by volume reflects in part, at least, the development of that region. Table 2 presents the average values by sex for all regions across our sample as well as pertinent significance levels from Student’s t tests. ti)) is equivalent to 100 times the absolute value of the difference between the left and right regional volumes for a given region, divided by the average left-right regional values ranged from 2.97 to volume for that same region. Overall, average I(regbj) 33.47. In both sexes, Region(,, was the most symmetrical region (I(re(,)): M = 5.12; F = 2.97). Regional volumetric asymmetries were the most pronouncecf for Region,,,, which is roughly equivalent to prefrontal cortex, and for Region(5) which includes striate and extrastriate cortices (f(reg(l): M = 16.76; F = 11.63; f(reg(5)j: M = 33.47; F = 12.66). However, in addition to being one of the most asymmetncal regions, Region(5)manifested a statistically significant (p < .02) sex difference in the degree of volumetric asymmetry. It appears that, in the developing fetal brain, striate-extrastriate volumetric asymmetries are at least twofold greater in males than in females. In other words, in the developing human brain, occipital areas appear to be more symmetrical in female than in male brains. In either sex, the direction of the asymmetry is not always consistent, although it favors the right hemisphere in about 65% of the cases. Although one may question the significance of a right hemispheric bias of only 65%, this percentage is consistent with findings from other asymmetry studies including that of Geschwind and Levitsky (1968) who reported a 65% bias favoring the left

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Table 2. Average I(= 5)y I, and I tot) values for the entire sample. Reg,,, is the most symmetricatregion in both sexes. Reg(,, and RegQ are the two most asymmetrical regions. The latter region is also significantly more asymmetrical in males than in females. Index of asymmetry I(mf)indicates that the right hemisphere (negative value of index) is on the average larger than the left one in the developing male brain. In females, either the two hemispherestend to be nearly equal or the left hemisphere is larger (positive value of index). Male

Female

Significance

16.76 (N=9)

11.63 (N=8)

n.s.

7.27 (N= 10)

7.60 (N=8)

ns.

5.12

2.97 (N=8)

n.s.

(N=lO)

6.33 (N=10)

8.99 (N=8)

n.s.

33.47 (N=9)

12.66 (N=8)

p < .02

13.35 (N=lO)

8.06

n.s.

-3.13 (N= 12)

+0.63 (N=9)

(N=@

p c .003

hemisphere in the size of the planum temporale (see also Geschwind & Galaburda, 1984). However, our results on the direction of occipital asymmetry in our sample appear to be discordant with published findings (Bear et al., 1986; for a review see de Lacoste, Horvath, & Woodward, 1988a) that the left occipital pole is longer and extends beyond its right counterpart. The findings need not be contradictory, as they relate to different dimensions of asymmetry. In fact, in the course of our experience sectioning occipital lobes, we have frequently noticed that the left occipital pole tends to be longer but narrower than the right one. Moreover, data from our laboratory on asymmetries using cytoarchitecturally defined visual areas suggest that the issue is further complicated by the fact that striate versus extrastriate asymmetries can favor opposite hemispheres (de Lacoste, Kim, Smith, & Woodward, 1988b). A thorough understanding of asymmetries in occipital cortex will require an extensive study of cytoarchitecturally defined areas.

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Table 2 also displays average I and I(tot)values and pertinent significance levels from Student's t tests. Index of asymmetry I is equivalent to the average absolute value of the percentage left-right volume difference across all five regions. Index f(bt)is a measure of the percentage difference in the total hemispheric volumes without reference to regions. It is also a directional index and negative values reflect a larger right hemisphere while positive ones indicate a larger left hemisphere (see methods). I values, which can be translated into the average percentage difference between the volumes of the five regions, were about 13% for males and 8% for females. This sex difference in index f was not statistically significant. In contrast, values which do account for the direction of asymM = -3.13; F = metry evidenced a statistically significant sex difference (I(tot): +0.63;p < .003). These results suggest that, on the average, the male fetal cerebrum is more likely than its female counterpart to have a larger right hemisphere. Conversely, females in utero are more likely than males to have two hemispheres of equal size or a left hemisphere that is slightly larger than the right one. This sex difference is clear-cut in cases that are less than 18 weeks GA and, in fact, can be seen with gross inspection of coronal series (see Figs. 1 and 2), although in fetal cerebra older than 24-29 weeks GA, this sex difference is not as apparent upon gross observation. A concern, therefore, was that this sex difference is spurious and is a function of the unequal distribution of the sexes within two of

Table 3. Indices of asymmetry I(regli)) for regions 1-5, I, and I for four cases (M = 2; F = 2). The two male cases are 14 and 18 weeks GA; &?two female cases are 13 and 29 weeks GA. In both male cases, regional volumes and values consistently favor the right hemisphere. In the female cases, both and a majority of I(rc favored the left hemisphere. LH and RH refer to the larger hemisphere. Rg'right hemisphere; LH: left hemisphere. Only four regional volumes were calculated for case 206 because the brain was too small to further subdivide. 206(M)

13 2(M)

397(F)

1936(F)

'(reg(1))

42.19-RH

3.33-RH

4.36-LH

2.37-RH

l(reg(2))

1 1.32-RH

1.71-RH

7.80-LH

1.75-RH

'(reg(%)

.48-RH

3.51 -RH

.99-LH

5.43-LH

I(reg(4))

9.86-RH

4.10-RH

2.00-LH

7.5 8 -LH

'(reg(5))

n.a.

13.58-RH

3.25-RH

2.99-LH

I

15.96

5.25

3.68

4.02

9.56-RH

4.15-RH

3.02-LH

3.09-LH

'(lot)

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the age brackets. However, an analysis of variance (ANOVA, SPSSx)using age as a covariate and sex as a factor indicated that the variable sex accounts for most, if not all, of the sample variation in values (covariate age: p = .468; factor sex: p = .004) Table 3 presents I(reg(l-5)), I and I(mt) values for four individual cases. Note that here we have included the direction of the regional index of asymmetry. For the two male cerebra (GA 14 and 18 weeks), all and I(,t) values favored the right hemisphere. In contrast, in the two female cases (GA 13 and 29 weeks), indices favored either the right or the left hemisphere, although more frequently the latter. In the same two cases, index indicated larger left hemisphere volumes. It should be noted that these differences were not absolute across our entire fetal sample. Two of the twelve males demonstrated positive I(tot)values, or a larger left hemisphere, while in several female cases the total right hemisphere volume was larger than the left counterpart. Thus, the sex differences documented in this study represent general trends and not absolutes and there is some overlap between the sexes.

DISCUSSION Our study of regional volumetric asymmetries in the developing fetal brain yielded three major findings: (1) The two most asymmetrical regions involved prefrontal and striate-extrastriate cortical areas. (2) Striate-extrastriate asymmetries were more pronounced in male than in female fetuses. (3) Accelerated development of the right hemisphere and/or delayed development of the left hemisphere appears to be more prevalent in male than in female cerebra. We will discuss each of these findings individually.

Striate/extrastriate Asymmetries Our previous studies of regional volumetric asymmetries in a large group of primates have indicated that prefrontal and striate-extrastriate telencephalic areas are the most susceptible to asymmetry. New world monkeys, in particular, exhibit striking prefrontal asymmetry (de Lacoste, Adesanya, & Woodward, 1987). Striateextrastriate or, what we have termed “retrocalcarine”, asymmetries are pronounced in lemurs (de Lacoste et al., 1988a), lorises, old world monkeys (Brown et al., 1986), pongids, and in juvenile and adult human brains (de Lacoste, Horvath. & Woodward, 1986; de Lacoste et al., 1988b). Work in other laboratories has revealed sex differences in left/right asymmetries of cortical thickness in visual cortex in several mammalian species, including rats and mice (Diamond, Dowling, & Johnson, 1981; Stewart & Kolb, 1988). More recent data from our laboratory indicate that regional volumetric asymmetries in the human visual cortex using architecturally defined regions are two- to six-fold more pronounced in terms of percent differences in volumes than are those that we have documented at the

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gross level (de Lacoste et al., 1988b). Results from another laboratory suggest that, in the rhesus monkey, the lateral geniculate nucleus, the thalamic relay nucleus for the visual system, is also asymmetrical, with a cumulative rightward bias of 4.5% (Williams & Rakic, 1988). While the functional significance of retrocalcarine asymmetries remains to be determined, we find it provocative that both the visual system and its associated lateral geniculate nucleus are asymmetrical, and that both have undergone substantial elaboration in the course of primate evolution. A possible hypothesis is that asymmetry provides some adaptive advantage in visuo-spatial perception. Our findings of a larger degree of striate-extrastriate asymmetries in male than in female cerebra need to be further investigated using cytoarchitecturally defined regions. Preliminary work in our laboratory on regional volumetric asymmetries in cytoarchitecturally defined visual areas in pediatric cerebra does suggest that peristriate association cortex is more sexually dimorphic than are primary visual cortex or parastriate visual cortex (unpublished observation). These data lead to the speculation that sex differences in the degree of striate-extrastriate asymmetries may, in part, provide a specific anatomical basis for the welldocumented sex differences in visuo-spatial functions (e.g., Harris, 1978; Maccoby & Jacklin, 1974; Newcombe, 1982).

Accelerated Development of the Right Hemisphere? The data obtained in this study are congruent with results from other studies (Bracco et al., 1984; Chi et al., 1977; Scheibel, 1984) indicating that the right and left hemispheres develop at different rates. Differential right/left developmental rates are not surprising, given the fact that the.overal1 development of the brain manifests heterochronous characteristics, with different regions exhibiting different temporal patterns of growth spurts (Koop, Rilling, Herrmann, & Kretschmann, 1986). However, unique to this study was the finding of possible sex differences in the degree to which there are differential right/left developmental rates. In our sample of female brains, the index of asymmetry, I,,, throughout gestation approached zero (+ .63). In other words, the two hemispheres appeared to develop at similar rates. In contrast, growth favored the right hemisphere throughout gestation in the developing male brain (Itot = -3.13). These results appear to support the hypothesis proposed by Geschwind and Galaburda (1984,1987) that, in ufero, certain modifying factors, possibly testosterone, may lead to a more rapid growth of the right hemisphere or, alternatively, retard the growth of the left hemisphere. In either case, according to Geschwind & Galaburda (1984, 1987), the right hemisphere would be more successful in the competition for synapses, and the implication is that, because more neurons would have viable connections, less neurons would undergo selective cell death. It should be kept in mind that, in our study, the average total volumetric differences between the hemispheres were quite small, indicating that overall the processes of neurogenesis and selective cell death are quite well balanced.

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However, caution must be exerted in interpreting our fetal data. In this connection, we have a number of concerns: First, although the Yakovlev collection has been used by a number of authors to study the developing human brain, a large number of the fetuses were obtained from spontaneous abortions. Hence, there is the possibility that our data base is not entirely “normal”. We did, however, carefully examine the clinical data associated with each case that we selected and found no reason for suspecting aberrant cerebral development. A second concern is that, as documented by Kretschmann (1986) and his associates who worked extensively with materials from the Yakovlev collection, there is significant intercase variation in the amount of shrinkage of the tissue due to histological processing. Hopefully, variation in shrinkage rates had little effect in our study, since we had an internal control in that we were comparing right and left hemispheres. However, we cannot preclude differential shrinkage rates for the two hemispheres. A final and, perhaps, the most important concern is that sex differences in right/left regional volumetric hemispheric asymmetries might simply be a function of sex differences in maturational rates. In other words, if male brains develop more slowly than their female counterparts, the “lag” in the development of the left hemisphere would be attenuated in an older sample of brains, i.e., neonatal cerebra. There is evidence that, in rats at least, the male cortex exhibits delayed maturation relative to the female cerebrum (Yanai, 1979). However, we do not think that a slower maturation rate can account for the findings in the present study since ANOVA techniques did not delineate a significant effect of age as a covariate. Nonetheless, a definitive answer could be obtained by conducting further studies and extending the sample to include postnatal cases. Unfortunately, the Yakovlev collection does not include enough neonatal material to conduct such a study at the present time.

Mechanisms for the Development of Asymmetries The same mechanisms that produce anatomical sex differences may govern the development of right-left asymmetries. Geschwind and Galaburda (1987) propose that asymmetries may begin as early as neural induction, and subsequently involve a long term interplay between various processes, including cell proliferation, neuronal migration, neuritic arborization, and selective cell death. There is considerable evidence that steroid action directly or indirectly affects diverse developmental processes,including neurogenesis (Jacobson & Gorski, 1981;Nordeen, Nordeen, & Arnold, 1985; Williams & Rakic, 1988), selective cell death (Gorski, 1984; Jordan, Breedlove, & Arnold. 1982; Kirn & DeVoogd. 1985; Nordeen et al., 1985; Sengelaub, Nordeen, Nordeen, & Arnold. 1985). neuronal migration (Damasio & Geschwind, 1984; De Bassio & Kemper, 1982; Geschwind & Galaburda, 1984, 1987). and neuritic outgrowth (Toran-Allerand, 1980, 1984; Toran-Allerand, Gerlach, & McEwen, 1980). The relative contribution of these mechanisms remains to be resolved.

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Possible sex differences in the developing human fetal brain.

Left-right regional volumetric asymmetries in five telencephalic regions were studied in the developing human fetal brain. Complete series of coronal ...
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