Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities.

A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.

Multimodal active subspace analysis for computing assessment oriented subspaces from neuroimaging data.

BACKGROUND: For successful biomarker discovery, it is essential to develop computational frameworks that summarize high-dimensional neuroimaging data in terms of involved sub-systems of the brain, while also revealing underlying heterogeneous functional and structural changes covarying with specific cognitive and biological traits. However, unsupervised decompositions do not inculcate clinical assessment information, while supervised approaches extract only individual feature importance, thereby impeding qualitative interpretation at the level of subspaces. NEW METHOD: We present a novel framework to extract robust multimodal brain subspaces associated with changes in a given cognitive or biological trait. Our approach involves active subspace learning on the gradients of a trained machine learning model followed by clustering to extract and summarize the most salient and consistent subspaces associated with the target variable. RESULTS: Through a rigorous cross-validation procedure on an Alzheimer's disease (AD) dataset, our framework successfully extracts multimodal subspaces specific to a given clinical assessment (e.g., memory and other cognitive skills), and also retains predictive performance in standard machine learning algorithms. We also show that the salient active subspace directions occur consistently across randomly sub-sampled repetitions of the analysis. COMPARISON WITH EXISTING METHOD(S): Compared to existing unsupervised decompositions based on principle component analysis, the subspace components in our framework retain higher predictive information. CONCLUSIONS: As an important step towards biomarker discovery, our framework not only uncovers AD-related brain regions in the associated brain subspaces, but also enables automated identification of multiple underlying structural and functional sub-systems of the brain that collectively characterize changes in memory and proficiency in cognitive skills related to brain disorders like AD.

Towards a multimodal neuroimaging-based risk score for mild cognitive impairment by combining clinical studies with a large (N>37000) population-based study.

Alzheimer's disease (AD) is the most common form of age-related dementia, leading to a decline in memory, reasoning, and social skills. While numerous studies have investigated the genetic risk factors associated with AD, less attention has been given to identifying a brain imaging-based measure of AD risk. This study introduces a novel approach to assess mild cognitive impairment MCI, as a stage before AD, risk using neuroimaging data, referred to as a brain-wide risk score (BRS), which incorporates multimodal brain imaging. To begin, we first categorized participants from the Open Access Series of Imaging Studies (OASIS)-3 cohort into two groups: controls (CN) and individuals with MCI. Next, we computed structure and functional imaging features from all the OASIS data as well as all the UK Biobank data. For resting functional magnetic resonance imaging (fMRI) data, we computed functional network connectivity (FNC) matrices using fully automated spatially constrained independent component analysis. For structural MRI data we computed gray matter (GM) segmentation maps. We then evaluated the similarity between each participant's neuroimaging features from the UK Biobank and the difference in the average of those features between CN individuals and those with MCI, which we refer to as the brain-wide risk score (BRS). Both GM and FNC features were utilized in determining the BRS. We first evaluated the differences in the distribution of the BRS for CN vs MCI within the OASIS-3 (using OASIS-3 as the reference group). Next, we evaluated the BRS in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (using OASIS-3 as the reference group), showing that the BRS can differentiate MCI from CN in an independent data set. Subsequently, using the sMRI BRS, we identified 10 distinct subgroups and similarly, we identified another set of 10 subgroups using the FNC BRS. For sMRI and FNC we observed results that mutually validate each other, with certain aspects being complementary. For the unimodal analysis, sMRI provides greater differentiation between MCI and CN individuals than the fMRI data, consistent with prior work. Additionally, by utilizing a multimodal BRS approach, which combines both GM and FNC assessments, we identified two groups of subjects using the multimodal BRS scores. One group exhibits high MCI risk with both negative GM and FNC BRS, while the other shows low MCI risk with both positive GM and FNC BRS. Moreover, in the UKBB we have 46 participants diagnosed with AD showed FNC and GM patterns similar to those in high-risk groups, defined in both unimodal and multimodal BRS. Finally, to ensure the reproducibility of our findings, we conducted a validation analysis using the ADNI as an additional reference dataset and repeated the above analysis. The results were consistently replicated across different reference groups, highlighting the potential of FNC and sMRI-based BRS in early Alzheimer's detection.

Learning Active Multimodal Subspaces in the Brain.

Here we introduce a multimodal framework to identify subspaces in the human brain that are defined by collective changes in structural and functional measures and are actively linked to demographic, biological and cognitive indicators in a population. We determine the multimodal subspaces using principles of active subspace learning (ASL) and demonstrate its application on a sample learning task (biological ageing) on a schizophrenia dataset. The proposed multimodal ASL method successfully identifies latent brain representations as subsets of brain regions and connections forming covarying subspaces in association with biological age. We show that schizophrenia is characterized by different subspace patterns compared to those in a cognitively normal brain. The multimodal features generated by projecting structural and functional MRI components onto these active subspaces perform better than several PCA-based transformations and equally well when compared to non-transformed features on the studied learning task. In essence, the proposed method successfully learns active brain subspaces associated with a specific brain condition but inferred from the brain imaging data along with the biological/cognitive traits of interest. Clinical relevance- The work introduces a novel way to create multimodal brain biomarkers based on subspaces computed in association with cognitive or biological traits of interest. These subspaces collectively covary maximally in association with a given trait and successfully retain predictive information.

Building Models of Functional Interactions Among Brain Domains that Encode Varying Information Complexity: A Schizophrenia Case Study.

Revealing associations among various structural and functional patterns of the brain can yield highly informative results about the healthy and disordered brain. Studies using neuroimaging data have more recently begun to utilize the information within as well as across various functional and anatomical domains (i.e., groups of brain networks). However, most whole-brain approaches assume similar complexity of interactions throughout the brain. Here we investigate the hypothesis that interactions between brain networks capture varying amounts of complexity, and that we can better capture this information by varying the complexity of the model subspace structure based on available training data. To do this, we employ a Bayesian optimization-based framework known as the Tree Parzen Estimator (TPE) to identify, exploit and analyze patterns of variation in the information encoded by temporal information extracted from functional magnetic resonance imaging (fMRI) subdomains of the brain. Using a repeated cross-validation procedure on a schizophrenia classification task, we demonstrate evidence that interactions between specific functional subdomains are better characterized by more sophisticated model architectures compared to less complicated ones required by the others for optimally contributing towards classification and understanding the brain's functional interactions. We show that functional subdomains known to be involved in schizophrenia require more complex architectures to optimally unravel discriminatory information about the disorder. Our study points to the need for adaptive, hierarchical learning frameworks that cater differently to the features from different subdomains, not only for a better prediction but also for enabling the identification of features predicting the outcome of interest.

Uncovering Active Structural Subspaces Associated with Changes in Indicators for Alzheimer's Disease.

We present a framework for identifying subspaces in the brain that are associated with changes in biological and cognitive indicators for a given disorder. By employing a method called active subspace learning (ASL) on structural MRI features from an Alzheimer's disease dataset, we identify subsets of regions that form co-varying subspaces in association with biological age and mini-mental state exam (MMSE) scores. Features generated by projecting structural MRI components onto these subspaces performed equally well on regression tasks when compared to non-transformed features as well as PCA-based transformations. Thus, without compromising on predictive performance, we present a way to extract sparse subspaces in the brain which are associated with a particular disorder but inferred only from the neuroimaging data along with relevant biological and cognitive test measures.Clinical relevance-This work provides a way to identify active structural subspaces in the brain, i.e. subsets of brain regions which collectively change the most, in association with changes in the indicators of a given disorder.

A weighted network analysis framework for the hourglass effect-And its application in the C. elegans connectome.

Understanding hierarchy and modularity in natural as well as technological networks is of utmost importance. A major aspect of such analysis involves identifying the nodes that are crucial to the overall processing structure of the network. More recently, the approach of hourglass analysis has been developed for the purpose of quantitatively analyzing whether only a few intermediate nodes mediate the information processing between a large number of inputs and outputs of a network. We develop a new framework for hourglass analysis that takes network weights into account while identifying the core nodes and the extent of hourglass effect in a given weighted network. We use this framework to study the structural connectome of the C. elegans and identify intermediate neurons that form the core of sensori-motor pathways in the organism. Our results show that the neurons forming the core of the connectome show significant differences across the male and hermaphrodite sexes, with most core nodes in the male concentrated in sex-organs while they are located in the head for the hermaphrodite. Our work demonstrates that taking weights into account for network analysis framework leads to emergence of different network patterns in terms of identification of core nodes and hourglass structure in the network, which otherwise would be missed by unweighted approaches.

Neuroimaging PheWAS (Phenome-Wide Association Study): A Free Cloud-Computing Platform for Big-Data, Brain-Wide Imaging Association Studies.

Large-scale, case-control genome-wide association studies (GWASs) have revealed genetic variations associated with diverse neurological and psychiatric disorders. Recent advances in neuroimaging and genomic databases of large healthy and diseased cohorts have empowered studies to characterize effects of the discovered genetic factors on brain structure and function, implicating neural pathways and genetic mechanisms in the underlying biology. However, the unprecedented scale and complexity of the imaging and genomic data requires new advanced biomedical data science tools to manage, process and analyze the data. In this work, we introduce Neuroimaging PheWAS (phenome-wide association study): a web-based system for searching over a wide variety of brain-wide imaging phenotypes to discover true system-level gene-brain relationships using a unified genotype-to-phenotype strategy. This design features a user-friendly graphical user interface (GUI) for anonymous data uploading, study definition and management, and interactive result visualizations as well as a cloud-based computational infrastructure and multiple state-of-art methods for statistical association analysis and multiple comparison correction. We demonstrated the potential of Neuroimaging PheWAS with a case study analyzing the influences of the apolipoprotein E (APOE) gene on various brain morphological properties across the brain in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Benchmark tests were performed to evaluate the system's performance using data from UK Biobank. The Neuroimaging PheWAS system is freely available. It simplifies the execution of PheWAS on neuroimaging data and provides an opportunity for imaging genetics studies to elucidate routes at play for specific genetic variants on diseases in the context of detailed imaging phenotypic data.

Parity is associated with cognitive function and brain age in both females and males.

Previous studies of the association between parity and long-term cognitive changes have primarily focused on women and have shown conflicting results. We investigated this association by analyzing data collected on 303,196 subjects from the UK Biobank. We found that in both females and males, having offspring was associated with a faster response time and fewer mistakes made in the visual memory task. Subjects with two or three children had the largest differences relative to those who were childless, with greater effects observed in men. We further analyzed the association between parity and relative brain age (n = 13,584), a brain image-based biomarker indicating how old one's brain structure appears relative to peers. We found that in both sexes, subjects with two or three offspring had significantly reduced brain age compared to those without offspring, corroborating our cognitive function results. Our findings suggest that lifestyle factors accompanying having offspring, rather than the physical process of pregnancy experienced only by females, contribute to these associations and underscore the importance of studying such factors, particularly in the context of sex.