Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance

Abstract

Sex chromosome dosage (SCD) variation increases risk for neuropsychiatric impairment, which may reflect direct SCD effects on brain organization. Here, we 1) map cumulative X- and Y-chromosome dosage effects on regional cortical thickness (CT) and investigate potential functional implications of these effects using Neurosynth, 2) test if this map is organized by patterns of CT covariance that are evident in health, and 3) characterize SCD effects on CT covariance itself. We modeled SCD effects on CT and CT covariance for 308 equally sized regions of the cortical sheet using structural neuroimaging data from 301 individuals with varying numbers of sex chromosomes (169 euploid, 132 aneuploid). Mounting SCD increased CT in the rostral frontal cortex and decreased CT in the lateral temporal cortex, bilaterally. Regions targeted by SCD were associated with social functioning, language processing, and comprehension. Cortical regions with a similar degree of SCD-sensitivity showed heightened CT covariance in health. Finally, greater SCD also increased covariance among regions similarly affected by SCD. Our study both 1) develops novel methods for comparing typical and disease-related structural covariance networks in the brain and 2) uses these techniques to resolve and identify organizing principles for SCD effects on regional cortical anatomy and anatomical covariance.

Trial registration: ClinicalTrials.gov NCT00001246.

Keywords: Klinefelter’s; anatomical coupling; aneuploidy; development; structural magnetic resonance imaging.

Published by Oxford University Press 2019.

Figures

Figure 1

A schematic representation of the analytic pipeline.

Figure 2

Relating SCD effects on local cortical anatomy to patterns of structural covariance in health. (A) Colored regions are where SCD influences on CT survive FDR correction for multiple comparisons. (B) CT covariance in health: brain-wide CT correlation matrix and visualization of each region’s average CT correlation value. (C) Regional differences in r-mapB values. r-mapB correlation coefficients are projected onto the cortical sheet for visualization. Scatterplots demonstrate that region 51 in the medial orbitofrontal cortex demonstrates stronger CT coupling in health with regions that become thicker with mounting SCD, whereas region 212 in the lateral temporal cortex demonstrates stronger CT coupling in health with regions that become thinner with mounting SCD. (D) Scatterplot demonstrates that regional differences in the alignment between normative CT coupling and CT change in SCD are themselves strongly correlated with regional differences in CT change in SCD. (E) Permutation testing distribution containing 1000 null rB values.

Figure 3

SCD effects on structural covariance. (A) SCD effects on CT coupling between each pair of cortical regions: brain-wide coupling change matrix and visualization of top 5% of positive (red) and negative (blue) edges. (B) Regional differences in r-mapC values. r-mapC correlation coefficients are projected onto the cortical sheet for visualization. Scatterplots demonstrate that region 106 in the rostral frontal cortex demonstrates increased coupling to regions that become thicker with mounting SCD, whereas region 173 in the lateral occipitotemporal junction demonstrates increased coupling to regions that become thinner with mounting SCD. (C) Scatterplot demonstrates that regional differences in the alignment between altered CT coupling and CT change in SCD are themselves strongly correlated with regional differences in CT change in SCD. (D) Permutation testing distribution containing 1000 null rC values.

Figure 4

Relating SCD effects on cortical morphology to enriched terms in Neurosynth functional neuroimaging meta-analysis. All Neurosynth Topics (and top three topic terms) with Neurosynth Association Test maps showing an |r| spatial correlation for SCD effects on CT (i.e., SCD-mapCT) > 0.1 in magnitude. The Association Test map for each topic was derived from meta-analysis of functional neuroimaging studies (N-study = number of studies per topic meta-analysis) featuring topic terms. Regions where CT increases with mounting SCD include cortical regions involved in emotion, pain, and inhibitory processing. Conversely, regions where CT decreases with mounting SCD are involved in visual, motor, arithmetic, and attentional processing.