Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY)

Abstract

Klinefelter syndrome (47, XXY; henceforth: XXY syndrome) is a high-impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.

Trial registration: ClinicalTrials.gov NCT00001246.

Keywords: X-chromosome; XXY syndrome; aneuploidy; fMRI; sex chromosome.

© Published by Oxford University Press 2021.

Figures

Figure 1

Increased DLPFC global rsFC in XXY syndrome. (A) Unthresholded map of group differences (XXY–XY) in global connectivity while covarying for age and motion effects. (B) Significant 32-voxel cluster of increased global connectivity in the left DLPFC in XXY. Voxels survived 100% of leave-one-out validation permutations at P = 0.002, cluster size threshold = 21 voxels. (C) Average global connectivity in left DLPFC voxels by group.

Figure 2

XXY syndrome increased rsFC between the left DLPFC and a distributed set of cortical and subcortical regions. (A) Regions showing significantly increased connectivity (in red) with the left DLPFC seed (in blue) in XXY syndrome relative to XY controls. (B) Volumetric visualization of regions showing increased DLPFC rsFC in XXY syndrome, grouped and colored according to their overlap with canonical rsFC networks in the Yeo-Krienen 7-network solution [45]: Red = visual/cerebellum, purple = default mode/limbic, turquoise = ventral attention/somatomotor, lime green = dorsal attention/frontoparietal).

Figure 3

Altered regional brain volume in XXY syndrome and its relationship with rsFC changes. (A) Volumetric group differences in (XXY–XY; P < 0.002, cluster size threshold = 306 1 mm isotropic voxels). (B) Scatterplot showing correlation between group difference in DLPFC connectivity (XXY–XY) and magnitude of group difference in VBM (XXY–XY) at each functionally defined ROI.

Figure 4

Relationships between DLPFC rsFC and psychopathology in XXY syndrome. (A) Regions showing significant correlations between DLPFC connectivity and total CBCL score in XXY syndrome (P < 0.002, cluster size threshold = 26 voxels, FWE = 0.025). (B) Scatterplot showing inverse correlation between DLPFC connectivity and total CBCL score among precuneus voxels that also show significant DLPFC increase in XXY. (C). Boxplot showing average DLPFC connectivity in these precuneus voxels by group.