Static and Dynamic Cross-Network Functional Connectivity Shows Elevated Entropy in Schizophrenia Patients.

Schizophrenia (SZ) patients exhibit abnormal static and dynamic functional connectivity across various brain domains. We present a novel approach based on static and dynamic inter-network connectivity entropy (ICE), which represents the entropy of a given network's connectivity to all the other brain networks. This novel approach enables the investigation of how connectivity strength is heterogeneously distributed across available targets in both SZ patients and healthy controls. We analyzed fMRI data from 151 schizophrenia patients and demographically matched 160 healthy controls. Our assessment encompassed both static and dynamic ICE, revealing significant differences in the heterogeneity of connectivity levels across available brain networks between SZ patients and healthy controls (HC). These networks are associated with subcortical (SC), auditory (AUD), sensorimotor (SM), visual (VIS), cognitive control (CC), default mode network (DMN) and cerebellar (CB) functional brain domains. Elevated ICE observed in individuals with SZ suggests that patients exhibit significantly higher randomness in the distribution of time-varying connectivity strength across functional regions from each source network, compared to healthy control group. C-means fuzzy clustering analysis of functional ICE correlation matrices revealed that SZ patients exhibit significantly higher occupancy weights in clusters with weak, low-scale functional entropy correlation, while the control group shows greater occupancy weights in clusters with strong, large-scale functional entropy correlation. k-means clustering analysis on time-indexed ICE vectors revealed that cluster with highest ICE have higher occupancy rates in SZ patients whereas clusters characterized by lowest ICE have larger occupancy rates for control group. Furthermore, our dynamic ICE approach revealed that it appears healthy for a brain to primarily circulate through complex, less structured connectivity patterns, with occasional transitions into more focused patterns. However, individuals with SZ seem to struggle with transiently attaining these more focused and structured connectivity patterns. Proposed ICE measure presents a novel framework for gaining deeper insights into understanding mechanisms of healthy and disease brain states and a substantial step forward in the developing advanced methods of diagnostics of mental health conditions.

A Dynamic Entropy Approach Reveals Reduced Functional Network Connectivity Trajectory Complexity in Schizophrenia.

Over the past decade and a half, dynamic functional imaging has revealed low-dimensional brain connectivity measures, identified potential common human spatial connectivity states, tracked the transition patterns of these states, and demonstrated meaningful transition alterations in disorders and over the course of development. Recently, researchers have begun to analyze these data from the perspective of dynamic systems and information theory in the hopes of understanding how these dynamics support less easily quantified processes, such as information processing, cortical hierarchy, and consciousness. Little attention has been paid to the effects of psychiatric disease on these measures, however. We begin to rectify this by examining the complexity of subject trajectories in state space through the lens of information theory. Specifically, we identify a basis for the dynamic functional connectivity state space and track subject trajectories through this space over the course of the scan. The dynamic complexity of these trajectories is assessed along each dimension of the proposed basis space. Using these estimates, we demonstrate that schizophrenia patients display substantially simpler trajectories than demographically matched healthy controls and that this drop in complexity concentrates along specific dimensions. We also demonstrate that entropy generation in at least one of these dimensions is linked to cognitive performance. Overall, the results suggest great value in applying dynamic systems theory to problems of neuroimaging and reveal a substantial drop in the complexity of schizophrenia patients' brain function.

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Association between the oral microbiome and brain resting state connectivity in schizophrenia.

Recent microbiome-brain axis findings have shown evidence of the modulation of microbiome community as an environmental mediator in brain function and psychiatric illness. This work is focused on the role of the microbiome in understanding a rarely investigated environmental involvement in schizophrenia (SZ), especially in relation to brain circuit dysfunction. We leveraged high throughput microbial 16s rRNA sequencing and functional neuroimaging techniques to enable the delineation of microbiome-brain network links in SZ. N = 213 SZ and healthy control subjects were assessed for the oral microbiome. Among them, 139 subjects were scanned by resting-state functional magnetic resonance imaging (rsfMRI) to derive brain functional connectivity. We found a significant microbiome compositional shift in SZ beta diversity (weighted UniFrac distance, p = 6 × 10-3; Bray-Curtis distance p = 0.021). Fourteen microbial species involving pro-inflammatory and neurotransmitter signaling and H2S production, showed significant abundance alterations in SZ. Multivariate analysis revealed one pair of microbial and functional connectivity components showing a significant correlation of 0.46. Thirty five percent of microbial species and 87.8 % of brain functional network connectivity from each component also showed significant differences between SZ and healthy controls with strong performance in classifying SZ from healthy controls, with an area under curve (AUC) = 0.84 and 0.87, respectively. The results suggest a potential link between oral microbiome dysbiosis and brain functional connectivity alteration in relation to SZ, possibly through immunological and neurotransmitter signaling pathways and the hypothalamic-pituitary-adrenal axis, supporting for future work in characterizing the role of oral microbiome in mediating effects on SZ brain functional activity.

Dynamic functional connectivity correlates of trait mindfulness in early adolescence.

Background: Trait mindfulness, the tendency to attend to present-moment experiences without judgement, is negatively correlated with adolescent anxiety and depression. Understanding the neural mechanisms underlying trait mindfulness may inform the neural basis of psychiatric disorders. However, few studies have identified brain connectivity states that correlate with trait mindfulness in adolescence, nor have they assessed the reliability of such states. Methods: To address this gap in knowledge, we rigorously assessed the reliability of brain states across 2 functional magnetic resonance imaging (fMRI) scan from 106 adolescents aged 12 to 15 (50% female). We performed both static and dynamic functional connectivity analyses and evaluated the test-retest reliability of how much time adolescents spent in each state. For the reliable states, we assessed associations with self-reported trait mindfulness. Results: Higher trait mindfulness correlated with lower anxiety and depression symptoms. Static functional connectivity (ICCs from 0.31-0.53) was unrelated to trait mindfulness. Among the dynamic brains states we identified, most were unreliable within individuals across scans. However, one state, an hyperconnected state of elevated positive connectivity between networks, showed good reliability (ICC=0.65). We found that the amount of time that adolescents spent in this hyperconnected state positively correlated with trait mindfulness. Conclusions: By applying dynamic functional connectivity analysis on over 100 resting-state fMRI scans, we identified a highly reliable brain state that correlated with trait mindfulness. The brain state may reflect a state of mindfulness, or awareness and arousal more generally, which may be more pronounced in those who are higher in trait mindfulness.

Neuroimage Analysis Methods and Artificial Intelligence Techniques for Reliable Biomarkers and Accurate Diagnosis of Schizophrenia: Achievements Made by Chinese Scholars Around the Past Decade.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) is characterized by significant cognitive and behavioral disruptions. Neuroimaging techniques, particularly magnetic resonance imaging (MRI), have been widely utilized to investigate biomarkers of SZ, distinguish SZ from healthy conditions or other mental disorders, and explore biotypes within SZ or across SZ and other mental disorders, which aim to promote the accurate diagnosis of SZ. In China, research on SZ using MRI has grown considerably in recent years. STUDY DESIGN: The article reviews advanced neuroimaging and artificial intelligence (AI) methods using single-modal or multimodal MRI to reveal the mechanism of SZ and promote accurate diagnosis of SZ, with a particular emphasis on the achievements made by Chinese scholars around the past decade. STUDY RESULTS: Our article focuses on the methods for capturing subtle brain functional and structural properties from the high-dimensional MRI data, the multimodal fusion and feature selection methods for obtaining important and sparse neuroimaging features, the supervised statistical analysis and classification for distinguishing disorders, and the unsupervised clustering and semi-supervised learning methods for identifying neuroimage-based biotypes. Crucially, our article highlights the characteristics of each method and underscores the interconnections among various approaches regarding biomarker extraction and neuroimage-based diagnosis, which is beneficial not only for comprehending SZ but also for exploring other mental disorders. CONCLUSIONS: We offer a valuable review of advanced neuroimage analysis and AI methods primarily focused on SZ research by Chinese scholars, aiming to promote the diagnosis, treatment, and prevention of SZ, as well as other mental disorders, both within China and internationally.

Providing context: Extracting non-linear and dynamic temporal motifs from brain activity.

Approaches studying the dynamics of resting-state functional magnetic resonance imaging (rs-fMRI) activity often focus on time-resolved functional connectivity (tr-FC). While many approaches have been proposed, these typically focus on linear approaches like computing the linear correlation at a timestep or within a window. In this work, we propose to use a generative non-linear deep learning model, a disentangled variational autoencoder (DSVAE), that factorizes out window-specific (context) information from timestep-specific (local) information. This has the advantage of allowing our model to capture differences at multiple temporal scales. For the timestep-specific scale, which has higher temporal precision, we find significant differences between schizophrenia patients and control subjects in their temporal step distance through our model's latent space. We also find that window-specific embeddings, or as we refer to them, context embeddings, more accurately separate windows from schizophrenia patients and control subjects than the standard tr-FC approach. Moreover, we find that for individuals with schizophrenia, our model's context embedding space is significantly correlated with both age and symptom severity. Interestingly, patients appear to spend more time in three clusters, one closer to controls which shows increased visual-sensorimotor, cerebellar-subcortical, and reduced cerebellar-sensorimotor functional network connectivity (FNC), an intermediate station showing increased subcortical-sensorimotor FNC, and one that shows decreased visual-sensorimotor, decreased subcortical-sensorimotor, and increased visual-subcortical domains. We verify that our model captures features that are complementary to - but not the same as - standard tr-FC features. Our model can thus help broaden the neuroimaging toolset in analyzing fMRI dynamics and shows potential as an approach for finding psychiatric links that are more sensitive to individual and group characteristics.

A Deep Dynamic Causal Learning Model to Study Changes in Dynamic Effective Connectivity during Brain Development.

OBJECTIVE: Brain dynamic effective connectivity (dEC), characterizes the information transmission patterns between brain regions that change over time, which provides insight into the biological mechanism underlying brain development. However, most existing methods predominantly capture fixed or temporally invariant EC, leaving dEC largely unexplored. METHODS: Herein we propose a deep dynamic causal learning model specifically designed to capture dEC. It includes a dynamic causal learner to detect time-varying causal relationships from spatio-temporal data, and a dynamic causal discriminator to validate these findings by comparing original and reconstructed data. RESULTS: Our model outperforms established baselines in the accuracy of identifying dynamic causalities when tested on the simulated data. When applied to the Philadelphia Neurodevelopmental Cohort, the model uncovers distinct patterns in dEC networks across different age groups. Specifically, the evolution process of brain dEC networks in young adults is more stable than in children, and significant differences in information transfer patterns exist between them. CONCLUSION: This study highlights the brain's developmental trajectory, where networks transition from undifferentiated to specialized structures with age, in accordance with the improvement of an individual's cognitive and information processing capability. SIGNIFICANCE: The proposed model consists of the identification and verification of dynamic causality, utilizing the spatio-temporal fusing information from fMRI. As a result, it can accurately detect dEC and characterize its evolution over age.

Inter-modality source coupling: a fully-automated whole-brain data-driven structure-function fingerprint shows replicable links to reading in a large-scale (N∼8K) analysis.

OBJECTIVE: Both structural and functional brain changes have been individually associated with developing cognitive processes such as reading. However, there is limited research about the combined influence of resting-state functional and structural magnetic resonance imaging (rs-fMRI and sMRI) features in reading development, which could provide insights into the interplay between brain structure and function in shaping cognitive growth. We propose a method called inter-modality source coupling (IMSC) to study the coupling between the rs-fMRI and sMRI and its relationship to reading ability in school-age children. METHODS: This approach is applied to baseline data from four thousand participants (9-11 years) and replicated in a second group. Our analysis focused on the relationship of IMSC to overall reading score. RESULTS: Our findings indicate that higher reading ability was linked with increased function-structure coupling among higher-level cortical regions, particularly those links between the inferior parietal lobule and inferior frontal areas, and conversely, lower reading ability was associated with enhanced function-structure coupling among the fusiform and lingual gyrus. Our study found evidence of spatial correspondence between the data indicating an interplay between brain structure and function in our participants. CONCLUSION: Our approach revealed a linked pattern of whole brain structure to the corresponding functional connectivity pattern that correlated with reading ability. This novel IMSC analysis method provides a new approach to study the multimodal relationship between brain function and structure. SIGNIFICANCE: These findings have interesting implications for understanding the multimodal complexity underlying the development of the neural basis for reading ability in school-aged children.

An interpretable generative multimodal neuroimaging-genomics framework for decoding Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia, affecting millions worldwide with a progressive decline in cognitive abilities. The AD continuum encompasses a prodormal stage known as Mild Cognitive Impairment (MCI), where patients may either progress to AD (MCIc) or remain stable (MCInc). Understanding the underlying mechanisms of AD requires complementary analysis derived from different data sources, leading to the development of multimodal deep learning models. In this study, we leveraged structural and functional Magnetic Resonance Imaging (sMRI/fMRI) to investigate the disease-induced grey matter and functional network connectivity changes. Moreover, considering AD's strong genetic component, we introduce Single Nucleotide Polymorphisms (SNPs) as a third channel. Given such diverse inputs, missing one or more modalities is a typical concern of multimodal methods. We hence propose a novel deep learning based classification framework where generative module employing Cycle Generative Adversarial Networks (cGAN) was adopted to impute missing data within the latent space. Additionally, we adopted an Explainable Artificial Intelligence (XAI) method, Integrated Gradients (IG), to extract input features relevance, enhancing our understanding of the learned representations. Two critical tasks were addressed: AD detection and MCI conversion prediction. Experimental results showed that our framework was able to reach the state-of-the-art in the classification of CN vs AD reaching an average test accuracy of 0.926 ± 0.02. For the MCInc vs MCIc task, we achieved an average prediction accuracy of 0.711 ± 0.01 using the pre-trained model for CN and AD. The interpretability analysis revealed that the classification performance was led by significant grey matter modulations in cortical and subcortical brain areas well known for their association with AD. Moreover, impairments in sensory-motor and visual resting state network connectivity along the disease continuum, as well as mutations in SNPs defining biological processes linked to amyloid-beta and cholesterol formation clearance and regulation, were identified as contributors to the achieved performance. Overall, our integrative deep learning approach shows promise for AD detection and MCI prediction, while shading light on important biological insights.

Multi-modal deep learning from imaging genomic data for schizophrenia classification.

Background: Schizophrenia (SZ) is a psychiatric condition that adversely affects an individual's cognitive, emotional, and behavioral aspects. The etiology of SZ, although extensively studied, remains unclear, as multiple factors come together to contribute toward its development. There is a consistent body of evidence documenting the presence of structural and functional deviations in the brains of individuals with SZ. Moreover, the hereditary aspect of SZ is supported by the significant involvement of genomics markers. Therefore, the need to investigate SZ from a multi-modal perspective and develop approaches for improved detection arises. Methods: Our proposed method employed a deep learning framework combining features from structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and genetic markers such as single nucleotide polymorphism (SNP). For sMRI, we used a pre-trained DenseNet to extract the morphological features. To identify the most relevant functional connections in fMRI and SNPs linked to SZ, we applied a 1-dimensional convolutional neural network (CNN) followed by layerwise relevance propagation (LRP). Finally, we concatenated these obtained features across modalities and fed them to the extreme gradient boosting (XGBoost) tree-based classifier to classify SZ from healthy control (HC). Results: Experimental evaluation on clinical dataset demonstrated that, compared to the outcomes obtained from each modality individually, our proposed multi-modal approach performed classification of SZ individuals from HC with an improved accuracy of 79.01%. Conclusion: We proposed a deep learning based framework that selects multi-modal (sMRI, fMRI and genetic) features efficiently and fuse them to obtain improved classification scores. Additionally, by using Explainable AI (XAI), we were able to pinpoint and validate significant functional network connections and SNPs that contributed the most toward SZ classification, providing necessary interpretation behind our findings.

A new transfer entropy method for measuring directed connectivity from complex-valued fMRI data.

Background: Inferring directional connectivity of brain regions from functional magnetic resonance imaging (fMRI) data has been shown to provide additional insights into predicting mental disorders such as schizophrenia. However, existing research has focused on the magnitude data from complex-valued fMRI data without considering the informative phase data, thus ignoring potentially important information. Methods: We propose a new complex-valued transfer entropy (CTE) method to measure causal links among brain regions in complex-valued fMRI data. We use the transfer entropy to model a general non-linear magnitude-magnitude and phase-phase directed connectivity and utilize partial transfer entropy to measure the complementary phase and magnitude effects on magnitude-phase and phase-magnitude causality. We also define the significance of the causality based on a statistical test and the shuffling strategy of the two complex-valued signals. Results: Simulated results verified higher accuracy of CTE than four causal analysis methods, including a simplified complex-valued approach and three real-valued approaches. Using experimental fMRI data from schizophrenia and controls, CTE yields results consistent with previous findings but with more significant group differences. The proposed method detects new directed connectivity related to the right frontal parietal regions and achieves 10.2-20.9% higher SVM classification accuracy when inferring directed connectivity using anatomical automatic labeling (AAL) regions as features. Conclusion: The proposed CTE provides a new general method for fully detecting highly predictive directed connectivity from complex-valued fMRI data, with magnitude-only fMRI data as a specific case.

4D dynamic spatial brain networks at rest linked to cognition show atypical variability and coupling in schizophrenia.

Despite increasing interest in the dynamics of functional brain networks, most studies focus on the changing relationships over time between spatially static networks or regions. Here we propose an approach to study dynamic spatial brain networks in human resting state functional magnetic resonance imaging (rsfMRI) data and evaluate the temporal changes in the volumes of these 4D networks. Our results show significant volumetric coupling (i.e., synchronized shrinkage and growth) between networks during the scan, that we refer to as dynamic spatial network connectivity (dSNC). We find that several features of such dynamic spatial brain networks are associated with cognition, with higher dynamic variability in these networks and higher volumetric coupling between network pairs positively associated with cognitive performance. We show that these networks are modulated differently in individuals with schizophrenia versus typical controls, resulting in network growth or shrinkage, as well as altered focus of activity within a network. Schizophrenia also shows lower spatial dynamical variability in several networks, and lower volumetric coupling between pairs of networks, thus upholding the role of dynamic spatial brain networks in cognitive impairment seen in schizophrenia. Our data show evidence for the importance of studying the typically overlooked voxel-wise changes within and between brain networks.

Constrained Independent Vector Analysis with Reference for Multi-Subject fMRI Analysis.

Independent component analysis (ICA) is now a widely used solution for the analysis of multi-subject functional magnetic resonance imaging (fMRI) data. Independent vector analysis (IVA) generalizes ICA to multiple datasets (multi-subject data). Along with higher-order statistical information in ICA, it leverages the statistical dependence across the datasets as an additional type of statistical diversity. As such, IVA preserves variability in the estimation of single-subject maps but its performance might suffer when the number of datasets increases. Constrained IVA is an effective way to bypass computational issues and improve the quality of separation by incorporating available prior information. Existing constrained IVA approaches often rely on user-defined threshold values to define the constraints. However, an improperly selected threshold can have a negative impact on the final results. This paper proposes two novel methods for constrained IVA: one using an adaptive-reverse scheme to select variable thresholds for the constraints and a second one based on a threshold-free formulation by leveraging the unique structure of IVA. Notably, the proposed algorithms do not require all components to be constrained, utilizing free components to model interferences and components that might not be in the reference set. We demonstrate that our solutions provide an attractive solution to multi-subject fMRI analysis both by simulations and through analysis of resting state fMRI data collected from 98 subjects - the highest number of subjects ever used by IVA algorithms. Our results show that both proposed approaches obtain significantly better separation quality and model match while providing computationally efficient and highly reproducible solutions.

Effects of endogenous testosterone on oscillatory activity during verbal working memory in youth.

Testosterone levels sharply rise during the transition from childhood to adolescence and these changes are known to be associated with changes in human brain structure. During this same developmental window, there are also robust changes in the neural oscillatory dynamics serving verbal working memory processing. Surprisingly, whereas many studies have investigated the effects of chronological age on the neural oscillations supporting verbal working memory, none have probed the impact of endogenous testosterone levels during this developmental period. Using a sample of 89 youth aged 6-14 years-old, we collected salivary testosterone samples and recorded magnetoencephalography during a modified Sternberg verbal working memory task. Significant oscillatory responses were identified and imaged using a beamforming approach and the resulting maps were subjected to whole-brain ANCOVAs examining the effects of testosterone and sex, controlling for age, during verbal working memory encoding and maintenance. Our primary results indicated robust testosterone-related effects in theta (4-7 Hz) and alpha (8-14 Hz) oscillatory activity, controlling for age. During encoding, females exhibited weaker theta oscillations than males in right cerebellar cortices and stronger alpha oscillations in left temporal cortices. During maintenance, youth with greater testosterone exhibited weaker alpha oscillations in right parahippocampal and cerebellar cortices, as well as regions across the left-lateralized language network. These results extend the existing literature on the development of verbal working memory processing by showing region and sex-specific effects of testosterone, and are the first results to link endogenous testosterone levels to the neural oscillatory activity serving verbal working memory, above and beyond the effects of chronological age.

A spatially constrained independent component analysis jointly informed by structural and functional network connectivity.

There are a growing number of neuroimaging studies motivating joint structural and functional brain connectivity. Brain connectivity of different modalities provides insight into brain functional organization by leveraging complementary information, especially for brain disorders such as schizophrenia. In this paper, we propose a multi-modal independent component analysis (ICA) model that utilizes information from both structural and functional brain connectivity guided by spatial maps to estimate intrinsic connectivity networks (ICNs). Structural connectivity is estimated through whole-brain tractography on diffusion-weighted MRI (dMRI), while functional connectivity is derived from resting-state functional MRI (rs-fMRI). The proposed structural-functional connectivity and spatially constrained ICA (sfCICA) model estimates ICNs at the subject level using a multi-objective optimization framework. We evaluated our model using synthetic and real datasets (including dMRI and rs-fMRI from 149 schizophrenia patients and 162 controls). Multi-modal ICNs revealed enhanced functional coupling between ICNs with higher structural connectivity, improved modularity, and network distinction, particularly in schizophrenia. Statistical analysis of group differences showed more significant differences in the proposed model compared to the unimodal model. In summary, the sfCICA model showed benefits from being jointly informed by structural and functional connectivity. These findings suggest advantages in simultaneously learning effectively and enhancing connectivity estimates using structural connectivity.

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.

Gray matters: ViT-GAN framework for identifying schizophrenia biomarkers linking structural MRI and functional network connectivity.

Brain disorders are often associated with changes in brain structure and function, where functional changes may be due to underlying structural variations. Gray matter (GM) volume segmentation from 3D structural MRI offers vital structural information for brain disorders like schizophrenia, as it encompasses essential brain tissues such as neuronal cell bodies, dendrites, and synapses, which are crucial for neural signal processing and transmission; changes in GM volume can thus indicate alterations in these tissues, reflecting underlying pathological conditions. In addition, the use of the ICA algorithm to transform high-dimensional fMRI data into functional network connectivity (FNC) matrices serves as an effective carrier of functional information. In our study, we introduce a new generative deep learning architecture, the conditional efficient vision transformer generative adversarial network (cEViT-GAN), which adeptly generates FNC matrices conditioned on GM to facilitate the exploration of potential connections between brain structure and function. We developed a new, lightweight self-attention mechanism for our ViT-based generator, enhancing the generation of refined attention maps critical for identifying structural biomarkers based on GM. Our approach not only generates high quality FNC matrices with a Pearson correlation of 0.74 compared to real FNC data, but also uses attention map technology to identify potential biomarkers in GM structure that could lead to functional abnormalities in schizophrenia patients. Visualization experiments within our study have highlighted these structural biomarkers, including the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DL-PFC), and cerebellum. In addition, through cross-domain analysis comparing generated and real FNC matrices, we have identified functional connections with the highest correlations to structural information, further validating the structure-function connections. This comprehensive analysis helps to understand the intricate relationship between brain structure and its functional manifestations, providing a more refined insight into the neurobiological research of schizophrenia.

Multimodal Predictive Modeling: Scalable Imaging Informed Approaches to Predict Future Brain Health.

Background: Predicting future brain health is a complex endeavor that often requires integrating diverse data sources. The neural patterns and interactions identified through neuroimaging serve as the fundamental basis and early indicators that precede the manifestation of observable behaviors or psychological states. New Method: In this work, we introduce a multimodal predictive modeling approach that leverages an imaging-informed methodology to gain insights into future behavioral outcomes. We employed three methodologies for evaluation: an assessment-only approach using support vector regression (SVR), a neuroimaging-only approach using random forest (RF), and an image-assisted method integrating the static functional network connectivity (sFNC) matrix from resting-state functional magnetic resonance imaging (rs-fMRI) alongside assessments. The image-assisted approach utilized a partially conditional variational autoencoder (PCVAE) to predict brain health constructs in future visits from the behavioral data alone. Results: Our performance evaluation indicates that the image-assisted method excels in handling conditional information to predict brain health constructs in subsequent visits and their longitudinal changes. These results suggest that during the training stage, the PCVAE model effectively captures relevant information from neuroimaging data, thereby potentially improving accuracy in making future predictions using only assessment data. Comparison with Existing Methods: The proposed image-assisted method outperforms traditional assessment-only and neuroimaging-only approaches by effectively integrating neuroimaging data with assessment factors. Conclusion: This study underscores the potential of neuroimaging-informed predictive modeling to advance our comprehension of the complex relationships between cognitive performance and neural connectivity.

A survey of brain functional network extraction methods using fMRI data.

Functional network (FN) analyses play a pivotal role in uncovering insights into brain function and understanding the pathophysiology of various brain disorders. This paper focuses on classical and advanced methods for deriving brain FNs from functional magnetic resonance imaging (fMRI) data. We systematically review their foundational principles, advantages, shortcomings, and interrelations, encompassing both static and dynamic FN extraction approaches. In the context of static FN extraction, we present hypothesis-driven methods such as region of interest (ROI)-based approaches as well as data-driven methods including matrix decomposition, clustering, and deep learning. For dynamic FN extraction, both window-based and windowless methods are surveyed with respect to the estimation of time-varying FN and the subsequent computation of FN states. We also discuss the scope of application of the various methods and avenues for future improvements.