Neuroimaging studies have shown topological disruptions of both functional and structural whole-brain networks in major depressive disorder (MDD). This study examined common and specific alterations between these two types of networks and whether the alterations were differentially involved in the two hemispheres. Multimodal MRI data were collected from 35 MDD patients and 35 healthy controls, whose functional and structural hemispheric networks were constructed, characterized, and compared. We found that functional brain networks were profoundly altered at multiple levels, while structural brain networks were largely intact in patients with MDD. Specifically, the functional alterations included decreases in intra-hemispheric (left and right) and inter-hemispheric (heterotopic) functional connectivity; decreases in local, global and normalized global efficiency for both hemispheric networks; increases in normalized local efficiency for the left hemispheric networks; and decreases in intra-hemispheric integration and inter-hemispheric communication in the dorsolateral superior frontal gyrus, anterior cingulate gyrus and hippocampus. Regarding hemispheric asymmetry, largely similar patterns were observed between the functional and structural networks: the right hemisphere was over-connected and more efficient than the left hemisphere globally; the occipital and partial regions exhibited leftward asymmetry, and the frontal and temporal sites showed rightward lateralization with regard to regional connectivity profiles locally. Finally, the functional–structural coupling of intra-hemispheric connections was significantly decreased and correlated with the disease severity in the patients. Overall, this study demonstrates modality- and hemisphere-dependent and invariant network alterations in MDD, which are helpful for understanding elaborate and characteristic patterns of integrative dysfunction in this disease.

Morphological brain networks, in particular those at the individual level, have become an important approach for studying the human brain connectome; however, relevant methodology is far from being well-established in their formation, description and reproducibility. Here, we extended our previous study by constructing and characterizing single-subject morphological similarity networks from brain volume to surface space and systematically evaluated their reproducibility with respect to effects of different choices of morphological index, brain parcellation atlas and similarity measure, sample size-varying stability and test-retest reliability. Using the Human Connectome Project dataset, we found that surface-based single-subject morphological similarity networks shared common small-world organization, high parallel efficiency, modular architecture and bilaterally distributed hubs regardless of different analytical strategies. Nevertheless, quantitative values of all interregional similarities, global network measures and nodal centralities were significantly affected by choices of morphological index, brain parcellation atlas and similarity measure. Moreover, the morphological similarity networks varied along with the number of participants and approached stability until the sample size exceeded ~70. Using an independent test-retest dataset, we found fair to good, even excellent, reliability for most interregional similarities and network measures, which were also modulated by different analytical strategies, in particular choices of morphological index. Specifically, fractal dimension and sulcal depth outperformed gyrification index and cortical thickness, higher-resolution atlases outperformed lower-resolution atlases, and Jensen-Shannon divergence-based similarity outperformed Kullback-Leibler divergence-based similarity. Altogether, our findings propose surface-based single-subject morphological similarity networks as a reliable method to characterize the human brain connectome and provide methodological recommendations and guidance for future research.

Although single-subject morphological brain networks provide an important way for human connectome studies, their roles and origins are poorly understood. Combining cross-sectional and repeated structural magnetic resonance imaging scans from adults, children and twins with behavioral and cognitive measures and brain-wide transcriptomic, cytoarchitectonic and chemoarchitectonic data, this study examined phenotypic associations and neurobiological substrates of single-subject morphological brain networks. We found that single-subject morphological brain networks explained inter-individual variance and predicted individual outcomes in Motor and Cognition domains, and distinguished individuals from each other. The performance can be further improved by integrating different morphological indices for network construction. Low-moderate heritability was observed for single-subject morphological brain networks with the highest heritability for sulcal depth-derived networks and higher heritability for inter-module connections. Furthermore, differential roles of genetic, cytoarchitectonic and chemoarchitectonic factors were observed for single-subject morphological brain networks. Cortical thickness-derived networks were related to the three factors with contributions from genes enriched in membrane and transport related functions, genes preferentially located in supragranular and granular layers, overall thickness in the molecular layer and thickness of wall in the infragranular layers, and metabotropic glutamate receptor 5 and dopamine transporter; fractal dimension-, gyrification index- and sulcal depth-derived networks were only associated with the chemoarchitectonic factor with contributions from different sets of neurotransmitter receptors. Most results were reproducible across different parcellation schemes and datasets. Altogether, this study demonstrates phenotypic associations and neurobiological substrates of single-subject morphological brain networks, which provide intermediate endophenotypes to link molecular and cellular architecture and behavior and cognition.