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ABSTRACT Mediation analysis is widely utilized in neuroscience to investigate the role of brain image phenotypes in the neurological pathways from genetic exposures to clinical outcomes. However, it is still difficult to conduct mediation analyses with whole genome‐wide exposures and brain subcortical shape mediators due to several challenges including (i) large‐scale genetic exposures, that is, millions of single‐nucleotide polymorphisms (SNPs); (ii) nonlinear Hilbert space for shape mediators; and (iii) statistical inference on the direct and indirect effects. To tackle these challenges, this paper proposes a genome‐wide mediation analysis framework with brain subcortical shape mediators. First, to address the issue caused by the high dimensionality in genetic exposures, a fast genome‐wide association analysis is conducted to discover potential genetic variants with significant genetic effects on the clinical outcome. Second, the square‐root velocity function representations are extracted from the brain subcortical shapes, which fall in an unconstrained linear Hilbert subspace. Third, to identify the underlying causal pathways from the detected SNPs to the clinical outcome implicitly through the shape mediators, we utilize a shape mediation analysis framework consisting of a shape‐on‐scalar model and a scalar‐on‐shape model. Furthermore, the bootstrap resampling approach is adopted to investigate both global and spatial significant mediation effects. Finally, our framework is applied to the corpus callosum shape data from the Alzheimer's Disease Neuroimaging Initiative. 

Brain large-scale dynamics is constrained by the heterogeneity of intrinsic anatomical substrate. Little is known how the spatiotemporal dynamics adapt for the heterogeneous structural connectivity (SC). Modern neuroimaging modalities make it possible to study the intrinsic brain activity at the scale of seconds to minutes. Diffusion magnetic resonance imaging (dMRI) and functional MRI reveals the large-scale SC across different brain regions. Electrophysiological methods (i.e. MEG/EEG) provide direct measures of neural activity and exhibits complex neurobiological temporal dynamics which could not be solved by fMRI. However, most of existing multimodal analytical methods collapse the brain measurements either in space or time domain and fail to capture the spatio-temporal circuit dynamics. In this paper, we propose a novel spatio-temporal graph Transformer model to integrate the structural and functional connectivity in both spatial and temporal domain. The proposed method learns the heterogeneous node and graph representation via contrastive learning and multi-head attention based graph Transformer using multimodal brain data (i.e. fMRI, MRI, MEG and behavior performance). The proposed contrastive graph Transformer representation model incorporates the heterogeneity map constrained by T1-to-T2-weighted (T1w/T2w) to improve the model fit to structurefunction interactions. The experimental results with multimodal resting state brain measurements demonstrate the proposed method could highlight the local properties of large-scale brain spatio-temporal dynamics and capture the dependence strength between functional connectivity and behaviors. In summary, the proposed method enables the complex brain dynamics explanation for different modal variants. 

Understanding the intrinsic patterns of human brain is important to make inferences about the mind and brain-behavior association. Electrophysiological methods (i.e. MEG/EEG) provide direct measures of neural activity without the effect of vascular confounds. The blood oxygenated level-dependent (BOLD) signal of functional MRI (fMRI) reveals the spatial and temporal brain activity across different brain regions. However, it is unclear how to associate the high temporal resolution Electrophysiological measures with high spatial resolution fMRI signals. Here, we present a novel interpretable model for coupling the structure and function activity of brain based on heterogeneous contrastive graph representation. The proposed method is able to link manifest variables of the brain (i.e. MEG, MRI, fMRI and behavior performance) and quantify the intrinsic coupling strength of different modal signals. The proposed method learns the heterogeneous node and graph representations by contrasting the structural and temporal views through the mind to multimodal brain data. The first experiment with 1200 subjects from Human connectome Project (HCP) shows that the proposed method outperforms the existing approaches in predicting individual gender and enabling the location of the importance of brain regions with sex difference. The second experiment associates the structure and temporal views between the low-level sensory regions and high-level cognitive ones. The experimental results demonstrate that the dependence of structural and temporal views varied spatially through different modal variants. The proposed method enables the heterogeneous biomarkers explanation for different brain measurements.