An Allometric Analysis of Sex and Sex Chromosome Dosage Effects on Subcortical Anatomy in Humans
Structural neuroimaging of humans with typical and atypical sex chromosome complements has established the marked influence of both Yand X /Y chromosome dosage on total brain volume (TBV) and identified potential cortical substrates for the psychiatric phenotypes associated with sex chromosome aneuploidy (SCA) Here, in a cohort of 354 humans with varying karyotypes (XX, XY, XXX, XXY, XYY, XXYY, XXXXY) we investigate sex and SCA effects on subcortical size and shape; focusing on the striatum, pallidum and thalamus. We find large effect size differences in the volume and shape of all three structures as a function of sex and SCA. We correct for TBV effects with a novel allometric method harnessing normative scaling rules for subcortical size and shape in humans, which we derive here for the first time. We show that all three subcortical volumes scale sublinearly with TBV among healthy humans, mirroring known relationships between subcortical volume and TBV among species. Traditional TBV correction methods assume linear scaling and can therefore invert or exaggerate sex and SCA effects on subcortical anatomy. Allometric analysis restricts sex differences to: (1) greater pallidal volume (PV) in males, and (2) relative caudate head expansion and ventral striatum contraction in females. Allometric analysis of SCA reveals that supernumerary X and Y chromosomes both cause disproportionate reductions in PV, and coordinated deformations of striatopallidal shape. Our study provides a novel understanding of sex and sex chromosome dosage effects on subcortical organization, using an allometric approach that can be generalized to other basic and clinical structural neuroimaging settings. SIGNIFICANCE STATEMENT Sex and sex chromosome dosage (SCD) are known to modulate human brain size and cortical anatomy, but very little is known regarding their impact on subcortical structures that work with the cortex to subserve a range of behaviors in health and disease. Moreover, regional brain allometry (nonlinear scaling) poses largely unaddressed methodological and theoretical challenges for such research. We build the first set of allometric norms for global and regional subcortical anatomy, and use these to dissect out the complex, distributed and topologically organized patterns of areal contraction and expansion, which characterize sex and SCD effects on subcortical anatomy. Our data inform basic research into the patterning of neuroanatomical variation, and the clinical neuroscience of sex chromosome aneuploidy.
The Journal of Neuroscience