Die Differenzierung männlicher und weiblicher Gehirne bereits im Mutterleib

Eine interessante Studie macht erneut deutlich, dass Geschlechterunterschiede bereits vor der Geburt und damit vor einer Sozialisation entstehen.

It is of considerable scientific, medical, and societal interest to understand the developmental origins of differences between male and female brains. Here we report the use of advances in MR imaging and analysis to accurately measure global, lobe and millimetre scale growth trajectory patterns over 18 gestational weeks in normal pregnancies with repeated measures. Statistical modelling of absolute growth trajectories revealed underlying differences in many measures, potentially reflecting overall body size differences. However, models of relative growth accounting for global measures revealed a complex temporal form, with strikingly similar cortical development in males and females at lobe scales. In contrast, local cortical growth patterns and larger scale white matter volume and surface measures differed significantly between male and female. Many proportional differences were maintained during neurogenesis and over 18 weeks of growth. These indicate sex related sculpting of neuroanatomy begins early in development, before cortical folding, potentially influencing postnatal development.

Quelle: Motion corrected MRI differentiates male and female human brain growth trajectories from mid-gestation

Es wurden also mittels MR-Scans Föten im Mutterleib betrachtet und dort festgestellt, dass bestimmte Formen des Gehirns bei Männern und Frauen schon früh anders ausgebildet werden und das diese Unterschiede über die beobachtete Wachstumsphase festgestellt werden konnten.

Aus der Einleitung:

Differences between adult male and female human brains have been observed in numerous magnetic resonance imaging (MRI) studies and confirmed on increasingly larger populations7. Many sex differences are thought to arise during the critical period of postnatal development when hormones act on brain structural organization8, and may also further influence brain anatomy through puberty and adult life9. Human studies have also examined the separate effects of hormones and sex chromosomes on brain development10.

Prior to the postnatal impact of hormones, earlier differences are believed to originate, at least in part, from differential exposure to androgens during fetal growth11, and also differences in gene expression12. Fetal levels of testosterone are highest in males by 18 weeks gestation13,14 and may remain high through to 24 weeks15. Recent twin studies have also highlighted the possible influence of fetal testosterone on later development16.

Das ist Lesern dieses Blogs nichts neues, gerade Studien bezüglich der pränatalen Hormone sind hier immer wieder Thema gewesen, ebenso wie postnatale Ausprägungen.

Aus den Ergebnissen:

Global, regional, and fine-scale brain growth trajectories have been estimated using repeated measures in a large cohort of healthy human pregnancies with accurate, fine-scale morphometric tools. Unlike earlier smaller-scale studies often based on clinically scanned fetuses and without multiple repeated measures, we have been able to identify statistically significant evidence for the emergence and precise maintenance of differences in brain development in males and females long before birth. These findings confirm the very early prenatal presence of differences previously reported in the adult or pediatric brain. They also identify how sex differences and similarities change or are preserved during dynamic periods of neurogenesis and cortical folding.

Die Luft für Leute, die Geschlechterunterschiede allein Sozial begründen wollen ist erneut dünner gewordne.

The cortical gray matter volume differences of  +5.09% we found in fetuses is approaching that reported at  +8.2% in neonates19, and later in adults at  +7.7% in the recent large UK Biobank study7. Both of these other estimates fall within the 95% confidence intervals of our estimate. In the 4 weeks of in utero development remaining after our study period, and the 4 or more weeks of postnatal growth up to the study period of Dean et al.19, we can hypothesize from the literature and the graphs in Fig. 2 that continued rapid cortical tissue volume increases may be a prominent feature of development, as further surface folding occurs, and that this may account for increasing sex-related differences in global cortical volumes.

Die Daten liefern also Differenzierungen, die deutlich machen, dass im Mutterleib bereits Unterschiede auftreten und sie passen zu den Ergebnissen anderer Studien, die andere Zeiträume behandelt haben.

The global white matter differences we found in fetuses of  +7.37% closely match those reported in neonates of  +8.4%19, but are still appreciably lower than the  +13% reported in the large study of adults7. This later adult estimate also falls beyond the upper 95% confidence interval of our estimate. Later development, perhaps influenced by known further increases in hormones, such as testosterone during childhood31, may further drive changes in white matter proportions in a similar manner to white matter microstructure32, from the comparable fetal and neonatal levels, up to those seen in the adult brain.

Zu der „Weißen Substanz“ und ihrer Bedeutung im Gehirn vgl auch:

(…)

In other regions, for example, deep gray matter, direct comparison to adults and even neonates is more difficult because of the challenge of extracting equivalent regions in fetuses across a range of gestational ages. This is due to lower or changing tissue contrast of some boundaries for many weeks of fetal development, and also partly because of the transient presence of neighboring developmental zones, such as the germinal matrix. We detected a difference in a combined region of deep gray matter of +3.50% in absolute volume, which did not survive statistical correction for multiple comparisons. In neonates individual measures that form part of our combined region have been reported, where Dean et al.19 found differences of ~+6.9% to +7.0% in the thalamus, +6.8% to +7.7% in the pallidum, +7.6% to +8.5% in the putamen, and conversely −8.2% to −8.0% in the caudate. All of these fall beyond the upper 95% confidence bound of our collective DGM estimate. The question of whether these are inconsistent with our fetal measures, however, may require a fetal study specifically limited to late gestation neuroanatomy that focuses on extracting adult corresponding subregions of the deep gray matter, rather than studying the longer growth trajectories of age-consistent anatomical MRI boundaries we have measured here.

Also konnte in den untersuchten frühen Perioden noch nicht alle Unterschiede, die man später vorfindet nachgewiesen werden, was keine Unstimmigkeit ist, sondern eben schlicht darauf beruhen kann, dass diese später entstehen.

Overall, these global comparisons indicate that a significant fraction of the tissue volume sex differences seen in the cerebrum in adults are established, but do not yet attain their adult magnitude, throughout the later half of pregnancy, while sex differences in other regions, such as the cerebellum, may emerge more strongly during postnatal growth.

Das passt auch ganz gut zu der Idee, dass früh bereits eine gewisse „Grundanlage“ erfolgt, die dann später ausgebaut und etwa in der Pubertät mit den gewaltigen hormonellen Veränderungen weiter aktiviert wir.

Beyond differences in raw tissue volumes, there is clear evidence in our data for the controlled sculpting of tissues to create different regional anatomical proportions during the 18 weeks of growth that we studied. After accounting for ICV, there was no difference in global or lobe cortical volume or brain surface area. However, WM contributes to a significantly greater fraction of cranial volume in male fetuses. This appears to arise from greater relative volume in the frontal, temporal, and occipital lobes with, in striking contrast to these lobes, no statistical difference in the relative parietal WM volume. Conversely, the relative proportion of the brain surface area occupied by the parietal lobe is greater in female fetuses than males, which is not the case for the other lobes.

In neonates, a similar greater relative parietal lobe volume in females has been reported in a recent study21, after correction for total gray matter volume. In adults, it has been reported that there is no sex difference in the parietal lobe in either cortical gray matter or white matter volumes37, after correcting for global volumes. For surface curvature measures, the more recent larger neonatal studies have either not found or examined regional surface curvature differences, whereas in fetuses we found strong statistical evidence for greater occipital lobe curvature in females and (less significantly) greater temporal lobe curvature.

Early fetal brain asymmetry in cortical folding has been studied in normative clinical cohorts using manual measures in 2D slices38 and later using early motion corrected methods for fetal MRI39, and have identified statistically significant local differences in cortical folding in the left and right hemispheres before birth. Asymmetries were also detected in fetuses in local volume estimates in a tensor-based morphometry study over a smaller cohort and age range30. However, none of these studies reported statistically significant differences in asymmetry between males and females. Building on this work, our newer imaging measurements detected strong statistical evidence for sex-related differences in frontal white matter volume asymmetry, with greater asymmetry occurring in males, which remained proportionately unchanged with gestational age. This finding appears to agree, at least in general, with the reported presence of greater adult asymmetry occurring in males40. We also found some less statistically significant differences in asymmetry. Of these, the closest to surviving correction for multiple comparisons was the difference in the occipital lobe curvature. In addition, temporal lobe curvature asymmetry appeared significantly different, but only just below an uncorrected P < 0.05 level. Measures of asymmetry of global white matter volume, whole brain surface area, and average whole brain curvature were also significant, but again not approaching a level of surviving correction for multiple comparisons. Finally, there were age interactions in the sex-related asymmetry differences in occipital cortical volume. Overall, these observed effects were perhaps complimentary to the occipital curvature differences, reflecting greater male rightward cortical volume asymmetry and conversely lesser male rightward surface curvature asymmetry.

Tensor-based morphometry was able to detect fine-scale differences in growth trajectories that could not be detected using larger-scale region-based hypothesis testing. In particular, we observed consistently larger proportions of tissue volume in regions of the INS bilaterally in females, but with a larger anterior extent on the right. This appears to reflect findings in a recent study of adults who reported larger relative gray matter bilaterally in the posterior INS in a large (2838 sample) voxel-based morphometry study of adults41. The right INS was also reported to be larger in adult females after accounting for brain volume in the large 5216 subjects in UK Biobank study7 and in a voxel-based morphometry study34. In a recent study of fetal testosterone exposure, smaller gray matter in the anterior insula was associated with higher levels of fetal testosterone42. Interestingly, however, our finding disagrees with the results of a study of neonates19, which reported greater gray matter volume in males in the INS, hippocampal, and amygdalae after accounting for global volume.

Second, the volume growth trajectory maps also revealed evidence for a relatively larger size of the SPL in females in relation to male fetuses over the 18 weeks of growth studied. Many studies have explored differences in the corpus callosum anatomy in the male and female adult brain, and generally there is support for a greater relative overall size of the corpus callosum in adult women43. One of a limited number of developmental studies examining the corpus callosum reported regionally greater corpus callosum size in females, which remained after accounting for brain size, in neonates19. For the gestational period we studied, it is interesting to note that the larger relative splenium white matter in females may be linked to the more similar relative size of the neighboring parietal lobe white matter in males and females. In contrast, other lobes, associated with more anterior corpus callosum connections, show greater relative volume increases from females to males.

Third, we also detected evidence for greater relative cortical tissue volume in females in a region of the cortex in the CING extending into the superior frontal gyrus. This appears to agree with neonatal findings19 of larger tissue volumes in female neonates in the middle and anterior cingulate gyrus. However, in our fetal age range, we did not find evidence for the sex difference that was reported for neonates in the posterior cingulate gyrus19.

There are a number of anatomical measures that follow identical growth in male and female fetuses. The raw measures of CEREB are statistically indistinguishable, even without accounting for ICV differences. The development of cortical anatomy at a global and lobe scale after accounting for global measures also appears remarkably similar (as seen in Fig. 3). However, given the similarity of these measures, the large-scale differences in white matter proportions between male and female are, in contrast, also remarkable, as these represent a significant fraction of the differences reported in adults. Second, it is interesting that many of the differences in tissue proportions appear to be carefully maintained on a lobe scale as large changes in brain volume and shape occur, and the developmental machinery and processes of axonal outgrowth, glial proliferation, dendritic and synaptic development, and neuronal connectivity and circuit formation44 transform the brain into mature white matter and cortex. This may indicate that overall proportions may have been predetermined in earlier phases of hormone release and neurogenesis. Third, beyond head size effects, the parietal lobe white matter volume appears to follow a much more similar path of development in males and females than the other lobes (Table 2 and Fig. 3), which, in general, appear to grow relatively larger in male fetuses than in females. Conversely, parietal lobe area appears to occupy a proportionately larger area of the cortex in females than in males, although global area measures may be smaller. Finally, another interesting observation is the evidence for the emergence of some early differences in asymmetry between male and female fetal brains in the form of frontal white matter growth and some less significant differences in occipital lobe growth.

The significant differential effect of sex on white matter development we observe before birth could potentially be linked to reported differences in white matter connectivity patterns reported in adults45, where findings suggest that male brains may be more optimized for intrahemispheric communications, while female brains tend to be more optimized for interhemispheric communication. White matter tissue properties in adults have been shown to be related to exposure to sex hormones32, and in young adults, hormones have been shown possibly to be a factor in sex differences seen in regional white matter structure46.

Before birth it is believed that as part of normal sexual differentiation47, brain development may begin to differ at the scale of cellular organization in the male and female, due at least in part to androgen production11. GWs 8–24 have been postulated to be a critical period for the influence of testosterone48,49 on fetal development. Fetal testosterone levels have been hypothesized to peak between 14 and 18 weeks13,14. Studies of amniotic fluid measures of testosterone have indicated that the levels may then remain consistent over the remaining weeks of pregnancy50. This stable level may relate to our findings of consistent differential proportionate growth in males and females in many brain regions after 18 GWs.

In adults, the proportion of parietal lobe tissues has been found to be greater in females than males51, which our prenatal findings appear to agree with. Such differences found in adults have been linked to differing performance on the mental rotation test37. Postnatal human studies have found that in male–female twin pairs, female twins exhibited statistically better performance on this task52,53, which raises the possibility of twin–twin testosterone exposure modulating brain anatomy and later function. Our findings on prenatal parietal lobe development in males and females may fit in with the anatomical aspect of this hypothesis of testosterone exposure.

Our results examining differences in brain asymmetry indicate evidence that there are weaker statistical differences in asymmetry in total white matter, surface area, and curvature. There is stronger statistical support for regional differences in frontal white matter volume asymmetry and also occipital lobe surface curvature. There is also lesser statistical support for differences in temporal lobe curvature. Over the period of development, that we studied, there is also some statistical evidence of changes in the asymmetry differences in the OC tissue volume and surface curvature. It is interesting to note that our findings of frontal lobe and occipital lobe asymmetry differences may relate to the development of the known frontal–occipital torque in adult brain asymmetry54.

In conclusion, using the latest developments in neuroimaging and image analysis, these findings provide, to the best of our knowledge, the first clear statistical evidence in healthy human pregnancies of the dynamic emergence of early anatomical differences in male and female brain development and how they change over long periods of prenatal growth. Collectively, these findings indicate that it is not simply postnatal or childhood growth, or adolescent pruning of cells, that contribute to larger scale, and some finer scale, differences reported in adult and pediatric neuroanatomy. Sex-specific characteristics in the fetal brain go beyond simple global scaling effects to include the differential sculpting of brain regions at the scale of lobes and tissue types. These differences are already present half way through pregnancy and many are preserved during rapid cortical growth over the final half of gestation.

A practical message from this work is the importance of accounting for potential normal male − female differences in new anatomical studies of early human brain growth, either in utero or after premature birth. Further, from our complex growth trajectory estimates, it may also be advisable to maintain a sex–age balance in studies covering more than a narrow age range to account for the rapid changes occurring before normal term age. Finally, studies covering many weeks of growth, and that aim to examine the relative development in different regions of the brain, might consider the complex form of relative growth trajectories and the use of models that can account for changes in the variance in different developmental measures over time. Such study guidance is also applicable to imaging of early functional activity, which may rely on unbiased anatomical localization of functional signals, and thus may be susceptible to possible confounds arising when anatomical differences potentially impact functional data analysis.

It is important to note that, similar to studies of adults, our findings show differences in statistical distributions of neuroanatomical characteristics, and not binary definitions of neuroanatomy and, as with features in adult male and female brains, there is an overlap in the range of characteristics associated with potential male or female assignments. The studies that are now possible with modern imaging and image analysis techniques open up many new directions for research into this very early normal variation in brain anatomy, as well as factors such as maternal, environmental, hormonal, or genetic variables potentially affecting it. How these prenatal features may be related to postnatal growth and how they may be modified over the course of pregnancy are also promising directions for new studies using increasingly sensitive fetal neuroimaging techniques.