Transcriptomic and macroscopic architectures of intersubject functional variability in human brain white-matter.

Intersubject variability is a fundamental characteristic of brain organizations, and not just "noise". Although intrinsic functional connectivity (FC) is unique to each individual and varies across brain gray-matter, the underlying mechanisms of intersubject functional variability in white-matter (WM) remain unknown. This study identified WMFC variabilities and determined the genetic basis and macroscale imaging in 45 healthy subjects. The functional localization pattern of intersubject variability across WM is heterogeneous, with most variability observed in the heteromodal cortex. The variabilities of heteromodal regions in expression profiles of genes are related to neuronal cells, involved in synapse-related and glutamic pathways, and associated with psychiatric disorders. In contrast, genes overexpressed in unimodal regions are mostly expressed in glial cells and were related to neurological diseases. Macroscopic variability recapitulates the functional and structural specializations and behavioral phenotypes. Together, our results provide clues to intersubject variabilities of the WMFC with convergent transcriptomic and cellular signatures, which relate to macroscale brain specialization.

Cortical structural differences in major depressive disorder correlate with cell type-specific transcriptional signatures.

Major depressive disorder (MDD) has been shown to be associated with structural abnormalities in a variety of spatially diverse brain regions. However, the correlation between brain structural changes in MDD and gene expression is unclear. Here, we examine the link between brain-wide gene expression and morphometric changes in individuals with MDD, using neuroimaging data from two independent cohorts and a publicly available transcriptomic dataset. Morphometric similarity network (MSN) analysis shows replicable cortical structural differences in individuals with MDD compared to control subjects. Using human brain gene expression data, we observe that the expression of MDD-associated genes spatially correlates with MSN differences. Analysis of cell type-specific signature genes suggests that microglia and neuronal specific transcriptional changes account for most of the observed correlation with MDD-specific MSN differences. Collectively, our findings link molecular and structural changes relevant for MDD.

White-matter functional topology: a neuromarker for classification and prediction in unmedicated depression.

Aberrant topological organization of brain connectomes underlies pathological mechanisms in major depressive disorder (MDD). However, accumulating evidence has only focused on functional organization in brain gray-matter, ignoring functional information in white-matter (WM) that has been confirmed to have reliable and stable topological organizations. The present study aimed to characterize the functional pattern disruptions of MDD from a new perspective-WM functional connectome topological organization. A case-control, cross-sectional resting-state functional magnetic resonance imaging study was conducted on both discovery [91 unmedicated MDD patients, and 225 healthy controls (HCs)], and replication samples (34 unmedicated MDD patients, and 25 HCs). The WM functional networks were constructed in 128 anatomical regions, and their global topological properties (e.g., small-worldness) were analyzed using graph theory-based approaches. At the system-level, ubiquitous small-worldness architecture and local information-processing capacity were detectable in unmedicated MDD patients but were less salient than in HCs, implying a shift toward randomization in MDD WM functional connectomes. Consistent results were replicated in an independent sample. For clinical applications, small-world topology of WM functional connectome showed a predictive effect on disease severity (Hamilton Depression Rating Scale) in discovery sample (r = 0.34, p = 0.001). Furthermore, the topologically-based classification model could be generalized to discriminate MDD patients from HCs in replication sample (accuracy, 76%; sensitivity, 74%; specificity, 80%). Our results highlight a reproducible topologically shifted WM functional connectome structure and provide possible clinical applications involving an optimal small-world topology as a potential neuromarker for the classification and prediction of MDD patients.