Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health concern given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10; N=11,875), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17; N=4,326) and IMAGEN (EUROPE, age of 14; N=1888). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school support index had the most significant and consistent impact across all three cohorts. In both meta, and mega-analysis, SNP rs79878474 in chr11p15 emerged as a particularly promising candidate associated with anxiety and depression, despite not reaching genomic significance. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine, and a trend of enrichment in the cerebellum. Our findings provide evidences of consistent environmental impact from early life stress and school support index on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels, which support the stress-depression connection via hypothalamic-pituitary-adrenal axis, along with the potential modulating role of potassium channels.

Efficient Federated Learning for distributed NeuroImaging Data.

Recent advancements in neuroimaging have led to greater data sharing among the scientific community. However, institutions frequently maintain control over their data, citing concerns related to research culture, privacy, and accountability. This creates a demand for innovative tools capable of analyzing amalgamated datasets without the need to transfer actual data between entities. To address this challenge, we propose a decentralized sparse federated learning (FL) strategy. This approach emphasizes local training of sparse models to facilitate efficient communication within such frameworks. By capitalizing on model sparsity and selectively sharing parameters between client sites during the training phase, our method significantly lowers communication overheads. This advantage becomes increasingly pronounced when dealing with larger models and accommodating the diverse resource capabilities of various sites. We demonstrate the effectiveness of our approach through the application to the Adolescent Brain Cognitive Development (ABCD) dataset.

Dynamic fusion of genomics and functional network connectivity in UK biobank reveals static and time-varying SNP manifolds.

Many psychiatric and neurological disorders show significant heritability, indicating strong genetic influence. In parallel, dynamic functional network connectivity (dFNC) measures functional temporal coupling between brain networks in a time-varying manner and has proven to identify disease-related changes in the brain. However, it remains largely unclear how genetic risk contributes to brain dysconnectivity that further manifests into clinical symptoms. The current work aimed to address this gap by proposing a novel joint ICA (jICA)-based "dynamic fusion" framework to identify dynamically tuned SNP manifolds by linking static SNPs to dynamic functional information of the brain. The sliding window approach was utilized to estimate four dFNC states and compute subject-level state-specific dFNC features. Each state of dFNC features were then combined with 12946 SZ risk SNPs for jICA decomposition, resulting in four parallel fusions in 32861 European ancestry individuals within the UK Biobank cohort. The identified joint SNP-dFNC components were further validated for SZ relevance in an aggregated SZ cohort, and compared for across-state similarity to indicate level of dynamism. The results supported that dynamic fusion yielded "static" and "dynamic" components (i.e., high and low across-state similarity, respectively) for SNP and dFNC modalities. As expected, the SNP components presented a mixture of static and dynamic manifolds, with the latter largely driven by fusion with dFNC. We also showed that some of the dynamic SNP manifolds uniquely elicited by fusion with state-specific dFNC features complemented each other in terms of biological interpretation. This dynamic fusion framework thus allows expanding the SNP modality to manifolds in the time dimension, which provides a unique lens to elicit unique SNP correlates of dFNC otherwise unseen, promising additional insights on how genetic risk links to disease-related dysconnectivity.

Brain Networks and Intelligence: A Graph Neural Network Based Approach to Resting State fMRI Data.

Resting-state functional magnetic resonance imaging (rsfMRI) is a powerful tool for investigating the relationship between brain function and cognitive processes as it allows for the functional organization of the brain to be captured without relying on a specific task or stimuli. In this paper, we present a novel modeling architecture called BrainRGIN for predicting intelligence (fluid, crystallized and total intelligence) using graph neural networks on rsfMRI derived static functional network connectivity matrices. Extending from the existing graph convolution networks, our approach incorporates a clustering-based embedding and graph isomorphism network in the graph convolutional layer to reflect the nature of the brain sub-network organization and efficient network expression, in combination with TopK pooling and attention-based readout functions. We evaluated our proposed architecture on a large dataset, specifically the Adolescent Brain Cognitive Development Dataset, and demonstrated its effectiveness in predicting individual differences in intelligence. Our model achieved lower mean squared errors, and higher correlation scores than existing relevant graph architectures and other traditional machine learning models for all of the intelligence prediction tasks. The middle frontal gyrus exhibited a significant contribution to both fluid and crystallized intelligence, suggesting their pivotal role in these cognitive processes. Total composite scores identified a diverse set of brain regions to be relevant which underscores the complex nature of total intelligence.

"Urban-Satellite" estimates in the ABCD Study: Linking Neuroimaging and Mental Health to Satellite Imagery Measurements of Macro Environmental Factors.

While numerous studies over the last decade have highlighted the important influence of environmental factors on mental health, globally applicable data on physical surroundings are still limited. Access to such data and the possibility to link them to epidemiological studies is critical to unlocking the relationship of environment, brain and behaviour and promoting positive future mental health outcomes. The Adolescent Brain Cognitive Development (ABCD) Study is the largest ongoing longitudinal and observational study exploring brain development and child health among children from 21 sites across the United States. Here we describe the linking of the ABCD study data with satellite-based "Urban-Satellite" (UrbanSat) variables consisting of 11 satellite-data derived environmental indicators associated with each subject's residential address at their baseline visit, including land cover and land use, nighttime lights, and population characteristics. We present these UrbanSat variables and provide a review of the current literature that links environmental indicators with mental health, as well as key aspects that must be considered when using satellite data for mental health research. We also highlight and discuss significant links of the satellite data variables to the default mode network clustering coefficient and cognition. This comprehensive dataset provides the foundation for large-scale environmental epidemiology research.

Decentralized Parallel Independent Component Analysis for Multimodal, Multisite Data.

Large amounts of neuroimaging and omics data have been generated for studies of mental health. Collaborations among research groups that share data have shown increased power for new discoveries of brain abnormalities, genetic mutations, and associations among genetics, neuroimaging and behavior. However, sharing raw data can be challenging for various reasons. A federated data analysis allowing for collaboration without exposing the raw dataset of each site becomes ideal. Following this strategy, a decentralized parallel independent component analysis (dpICA) is proposed in this study which is an extension of the state-of-art Parallel ICA (pICA). pICA is an effective method to analyze two data modalities simultaneously by jointly extracting independent components of each modality and maximizing connections between modalities. We evaluated the dpICA algorithm using neuroimage and genetic data from patients with schizophrenia and health controls, and compared its performances under various conditions with the centralized pICA. The results showed dpICA is robust to sample distribution across sites as long as numbers of samples in each site are sufficient. It can produce the same imaging and genetic components and the same connections between those components as the centralized pICA. Thus our study supports dpICA is an accurate and effective decentralized algorithm to extract connections from two data modalities.

Replication and Refinement of Brain Age Model for adolescent development.

The discrepancy between chronological age and estimated brain age, known as the brain age gap, may serve as a biomarker to reveal brain development and neuropsychiatric problems. This has motivated many studies focusing on the accurate estimation of brain age using different features and models, of which the generalizability is yet to be tested. Our recent study has demonstrated that conventional machine learning models can achieve high accuracy on brain age prediction during development using only a small set of selected features from multimodal brain imaging data. In the current study, we tested the replicability of various brain age models on the Adolescent Brain Cognitive Development (ABCD) cohort. We proposed a new refined model to improve the robustness of brain age prediction. The direct replication test for existing brain age models derived from the age range of 8-22 years onto the ABCD participants at baseline (9 to 10 years old) and year-two follow-up (11 to 12 years old) indicate that pre-trained models could capture the overall mean age failed precisely estimating brain age variation within a narrow range. The refined model, which combined broad prediction of the pre-trained model and granular information with the narrow age range, achieved the best performance with a mean absolute error of 0.49 and 0.48 years on the baseline and year-two data, respectively. The brain age gap yielded by the refined model showed significant associations with the participants' information processing speed and verbal comprehension ability on baseline data.

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health issue given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study investigated the impact of environmental factors and genomics on anxiety and depression in children and adolescents across three cohorts: the Adolescent Brain and Cognitive Development Study (US), the Consortium on Vulnerability to Externalizing Disorders and Addictions (India), and IMAGEN (Europe). Linear mixed-effect models, recursive feature elimination regression, and LASSO regression models were used to identify the environmental impact on anxiety/depression. Genome-wide association analyses were then performed for all three cohorts with consideration of significant environmental effects. The most significant and consistent environmental factors were early life stress and school risk. A novel SNP, rs79878474 in chr11p15, was identified as the most promising SNP associated with anxiety and depression. Gene set analysis found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, particularly Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes, respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine and a trend of enrichment in the cerebellum. The study highlights the consistent impact of early life stress and school risk on anxiety and depression during development and suggests the potential role of mutations in potassium channels and the cerebellum region. Further investigation is needed to better understand these findings.

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression.

Anxiety and depression in children and adolescents warrant special attention as a public health issue given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17) and IMAGEN (EUROPE, age of 14). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta-analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school risk had the most significant and consistent impact across all three cohorts. Both meta and mega-analysis identified a novel SNP rs79878474 in chr11p15 to be the most promising SNP associated with anxiety and depression. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine and a trend of enrichment in the cerebellum. Our findings provide evidence of consistent environmental impact from early life stress and school risks on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels along with the potential role of the cerebellum region, which are worthy of further investigation.