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Calhoun, V.

Publications and source records attributed to Calhoun, V..

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Multi-modal Spatial-modality Attentive Fusion for Studying Neurodegenerative Disorders

Multi-modal learning has emerged as a powerful technique that leverages diverse data sources to enhance learning and decision-making processes. Adapting this approach to analyzing data collected from different biological domains is intuitive, especially for studying neuropsychiatric disorders. A complex neuropsychiatric disorder like schizophrenia (SZ) can affect multiple aspects of the brain and biologies. These biological sources each present distinct yet correlated expressions of subjects underlying physiological processes. Joint learning from these data sources can improve our understanding of the disorder. However, combining these biological sources is challenging for several reasons: (i) observations are domains-specific, leading to data being represented in dissimilar subspaces, and (ii) fused data is often noisy and high-dimensional, making it challenging to identify relevant information. To address these challenges, we propose a multi-modal artificial intelligence (AI) model with a novel fusion module inspired by a bottleneck attention module (BAM). We use deep neural networks (DNN) to learn latent space representations of the input streams. Next, we introduce a two-dimensional (spatio-modality) attention module to regulate the intermediate fusion for SZ classification. We implement spatial attention via a dilated convolutional neural network that creates large receptive fields for extracting significant contextual patterns. The resulting joint learning framework maximizes complementarity allowing us to explore the correspondence among the modalities. We test our model on a multi-modal imaging-genetic dataset and achieve an SZ prediction accuracy of 94.10% (P < 0.0001), outperforming state-of-the-art unimodal and multi-modal models for the task. Moreover, the model provides inherent interpretability that helps identify concepts significant for the neural networks decision and explains the underlying physiopathology of the disorder. Results also show that functional connectivity among subcortical, sensorimotor, and cognitive control domains plays an important role in characterizing SZ. Analysis of the spatio-modality attention scores suggests that structural components like the supplementary motor area, caudate, and insula play a significant role in SZ. Biclustering the attention scores discover a multi-modal cluster that includes genes CSMD1, ATK3, MOB4, and HSPE1, all of which have been identified as relevant to schizophrenia. In summary, feature attribution appears to be especially useful for probing the transient and confined but decisive patterns of complex disorders, and it shows promise for extensive applicability in future studies.

neuroscience↗

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

BackgroundPredicting future brain health is a complex endeavor that often requires integrating diverse data sources. The neural patterns and interactions iden-tified through neuroimaging serve as the fundamental basis and early indica-tors that precede the manifestation of observable behaviors or psychological states. New MethodIn this work, we introduce a multimodal predictive modeling approach that leverages an imaging-informed methodology to gain insights into fu-ture behavioral outcomes. We employed three methodologies for evalua-tion: 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 con-ditional variational autoencoder (PCVAE) to predict brain health constructs in future visits from the behavioral data alone. ResultsOur performance evaluation indicates that the image-assisted method ex-cels 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 in-formation from neuroimaging data, thereby potentially improving accuracy in making future predictions using only assessment data. Comparison with Existing MethodsThe proposed image-assisted method outperforms traditional assessment-only and neuroimaging-only approaches by effectively integrating neuroimag-ing data with assessment factors, ConclusionThis study underscores the potential of neuroimaging-informed predictive modeling to advance our comprehension of the complex relationships between cognitive performance and neural connectivity. HighlightsO_LIMultifaceted perspective for studying longitudinal brain health changes. C_LIO_LIShowcases the versatility of methodologies through assessment-only, neuroimaging-only, and image-assisted predictive approaches. C_LIO_LIProvides predictive insights by revealing the neural patterns corresponding to alterations in behavior. C_LI Graphical Abstract

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A Demographic-Conditioned Variational Autoencoder for fMRI Distribution Sampling and Removal of Confounds

ObjectivefMRI and derived measures such as functional connectivity (FC) have been used to predict brain age, general fluid intelligence, psychiatric disease status, and preclinical neurodegenerative disease. However, it is not always clear that all demographic confounds, such as age, sex, and race, have been removed from fMRI data. Additionally, many fMRI datasets are restricted to authorized researchers, making dissemination of these valuable data sources challenging. MethodsWe create a variational autoencoder (VAE)-based model, DemoVAE, to decorrelate fMRI features from demographics and generate high-quality synthetic fMRI data based on user-supplied demographics. We train and validate our model using two large, widely used datasets, the Philadelphia Neurodevel-opmental Cohort (PNC) and Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP). ResultsWe find that DemoVAE recapitulates group differences in fMRI data while capturing the full breadth of individual variations. Significantly, we also find that most clinical and computerized battery fields that are correlated with fMRI data are not correlated with DemoVAE latents. An exception are several fields related to schizophrenia medication and symptom severity. ConclusionOur model generates fMRI data that captures the full distribution of FC better than traditional VAE or GAN models. We also find that most prediction using fMRI data is dependent on correlation with, and prediction of, demographics. SignificanceOur DemoVAE model allows for generation of high quality synthetic data conditioned on subject demographics as well as the removal of the confounding effects of demographics. We identify that FC-based prediction tasks are highly influenced by demographic confounds.

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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.

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Analysis of Longitudinal Change Patterns in Developing Brain Using Functional and Structural Magnetic Resonance Imaging via Multimodal Fusion

Functional and structural magnetic resonance imaging (fMRI and sMRI) are complementary approaches that can be used to study longitudinal brain changes in adolescents. Each individual modality offers distinct insights into the brain. Each individual modality may overlook crucial aspects of brain analysis. By combining them, we can uncover hidden brain connections and gain a more comprehensive understanding. In previous work, we identified multivariate patterns of change in whole-brain function during adolescence. In this work, we focus on linking functional change patterns (FCPs) to brain structure. We introduce two approaches and applied them to data from the Adolescent Brain and Cognitive Development (ABCD) dataset. First, we evaluate voxelwise sMRI-FCP coupling to identify structural patterns linked to our previously identified FCPs. Our approach revealed multiple interesting patterns in functional network connectivity (FNC) and gray matter volume (GMV) data that were linked to subject level variation. FCP components 2 and 4 exhibit extensive associations between their loadings and voxel-wise GMV data. Secondly, we leveraged a symmetric multimodal fusion technique called multiset canonical correlation analysis (mCCA) + joint independent component analysis (jICA). Using this approach, we identify structured FCPs such as one showing increased connectivity between visual and sensorimotor domains and decreased connectivity between sensorimotor and cognitive control domains, linked to structural change patterns (SCPs) including alterations in the bilateral sensorimotor cortex. Interestingly, females exhibit stronger coupling between brain functional and structural changes than males, highlighting sex-related differences. The combined results from both asymmetric and symmetric multimodal fusion methods underscore the intricate sex-specific nuances in neural dynamics. By utilizing two complementary multimodal approaches, our study enhances our understanding of the dynamic nature of brain connectivity and structure during the adolescent period, shedding light on the nuanced processes underlying adolescent brain development.

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Neurodevelopmental Subtypes of Functional Brain Organization in the ABCD Study Using a Rigorous Analytic Framework

The current study demonstrates that an individuals resting-state functional connectivity (RSFC) is a dependable biomarker for identifying differential patterns of cognitive and emotional functioning during late childhood. Using baseline RSFC data from the Adolescent Brain Cognitive Development (ABCD) study, which includes children aged 9-11, we identified four distinct RSFC subtypes We introduce an integrated methodological pipeline for testing the reliability and importance of these subtypes. In the Identification phase, Leiden Community Detection defined RSFC subtypes, with their reproducibility confirmed through a split-sample technique in the Validation stage. The Evaluation phase showed that distinct cognitive and mental health profiles are associated with each subtype, with the Predictive phase indicating that subtypes better predict various cognitive and mental health characteristics than individual RSFC connections. The Replication stage employed bootstrapping and down-sampling methods to substantiate the reproducibility of these subtypes further. This work allows future explorations of developmental trajectories of these RSFC subtypes.

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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

ObjectiveBoth 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. MethodsThis 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. ResultsOur 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. ConclusionOur 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. SignificanceThese findings have interesting implications for understanding the multimodal complexity underlying the development of the neural basis for reading ability in school-aged children.

bioengineering↗

A method for estimating dynamic functional network connectivity gradients (dFNG) from ICA captures smooth inter-network modulation.

Dynamic functional network connectivity (dFNC) analysis is a widely used approach for studying brain function and offering insight into how brain networks evolve over time. Typically, dFNC studies utilized fixed spatial maps and evaluate transient changes in coupling among time courses estimated from independent component analysis (ICA). This manuscript presents a complementary approach that relaxes this assumption by spatially reordering the components dynamically at each timepoint to optimize for a smooth gradient in the FNC (i.e., a smooth gradient among ICA connectivity values). Several methods are presented to summarize dynamic FNC gradients (dFNGs) over time, starting with static FNC gradients (sFNGs), then exploring the reordering properties as well as the dynamics of the gradients themselves. We then apply this approach to a dataset of schizophrenia (SZ) patients and healthy controls (HC). Functional dysconnectivity between different brain regions has been reported in schizophrenia, yet the neural mechanisms behind it remain elusive. Using resting state fMRI and ICA on a dataset consisting of 151 schizophrenia patients and 160 age and gender-matched healthy controls, we extracted 53 intrinsic connectivity networks (ICNs) for each subject using a fully automated spatially constrained ICA approach. We develop several summaries of our functional network connectivity gradient analysis, both in a static sense, computed as the Pearson correlation coefficient between full time series, and a dynamic sense, computed using a sliding window approach followed by reordering based on the computed gradient, and evaluate group differences. Static connectivity analysis revealed significantly stronger connectivity between subcortical (SC), auditory (AUD) and visual (VIS) networks in patients, as well as hypoconnectivity in sensorimotor (SM) network relative to controls. sFNG analysis highlighted distinctive clustering patterns in patients and HCs along cognitive control (CC)/ default mode network (DMN), as well as SC/ AUD/ SM/ cerebellar (CB), and VIS gradients. Furthermore, we observed significant differences in the sFNGs between groups in SC and CB domains. dFNG analysis suggested that SZ patients spend significantly more time in a SC/ CB state based on the first gradient, while HCs favor the SM/DMN state. For the second gradient, however, patients exhibited significantly higher activity in CB domains, contrasting with HCs DMN engagement. The gradient synchrony analysis conveyed more shifts between SM/ SC networks and transmodal CC/ DMN networks in patients. In addition, the dFNG coupling revealed distinct connectivity patterns between SC, SM and CB domains in SZ patients compared to HCs. To recap, our results advance our understanding of brain network modulation by examining smooth connectivity trajectories. This provides a more complete spatiotemporal summary of the data, contributing to the growing body of current literature regarding the functional dysconnectivity in schizophrenia patients. By employing dFNG, we highlight a new perspective to capture large scale fluctuations across the brain while maintaining the convenience of brain networks and low dimensional summary measures.

neuroscience↗

A Telescopic Independent Component Analysis on Functional Magnetic Resonance Imaging Data Set

Brain function can be modeled as the dynamic interactions between functional sources at different spatial scales, and each spatial scale can contain its functional sources with unique information, thus using a single scale may provide an incomplete view of brain function. This paper introduces a novel approach, termed "telescopic independent component analysis (TICA)," designed to construct spatial functional hierarchies and estimate functional sources across multiple spatial scales using fMRI data. The method employs a recursive ICA strategy, leveraging information from a larger network to guide the extraction of information about smaller networks. We apply our model to the default mode network (DMN), visual network (VN), and right frontoparietal network (RFPN). We investigate further on DMN by evaluating the difference between healthy people and individuals with schizophrenia. We show that the TICA approach can detect the spatial hierarchy of DMN, VS, and RFPN. In addition, TICA revealed DMN-associated group differences between cohorts that may not be captured if we focus on a single-scale ICA. In sum, our proposed approach represents a promising new tool for studying functional sources. Author summaryOur study introduces "telescopic independent component analysis (TICA)", a novel approach using a recursive ICA strategy for exploring brain function across multiple spatial scales using fMRI data. TICA constructs spatial hierarchies and identifies functional sources such as default mode network (DMN), visual network (VN), and right frontoparietal network (RFPN). By applying TICA, we uncovered hierarchical structures within these networks and revealed differences in the DMN between healthy individuals and those with schizophrenia. This approach offers a promising new tool for studying function dynamics comprehensively.

neuroscience↗

Time-varying Spatial Propagation of Brain Networks in fMRI data

Spontaneous neural activity coherently relays information across the brain. Several efforts have been made to understand how spontaneous neural activity evolves at the macro-scale level as measured by resting-state functional magnetic resonance imaging (rsfMRI). Previous studies observe the global patterns and flow of information in rsfMRI using methods such as sliding window or temporal lags. However, to our knowledge, no studies have examined spatial propagation patterns evolving with time across multiple overlapping 4D networks. Here, we propose a novel approach to study how dynamic states of the brain networks spatially propagate and evaluate whether these propagating states contain information relevant to mental illness. We implement a lagged windowed correlation approach to capture voxel-wise network-specific spatial propagation patterns in dynamic states. Results show systematic spatial state changes over time, which we confirmed are replicable across multiple scan sessions using human connectome project data. We observe networks varying in propagation speed; for example, the default mode network (DMN) propagates slowly and remains positively correlated to blood oxygenation level-dependent (BOLD) signal for 6-8 seconds, whereas the visual network propagates much quicker. We also show that summaries of network specific propagative patterns are linked to schizophrenia. More specifically, we find significant group differences in multiple dynamic parameters between schizophrenia patients and controls within four large-scale networks: default mode, temporal lobe, subcortical, and visual network. Individuals with schizophrenia spend more time in certain propagating states. In summary, this study introduces a promising general approach to exploring the spatial propagation in dynamic states of brain networks and their associated complexity and reveals novel insights into the neurobiology of schizophrenia.

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LOCAL SPATIAL FLOWS AND PROPAGATIVE ATTRACTORS: A NOVEL 'FLOWNECTOME' FRAMEWORK FOR ANALYZING BOLD FMRI DYNAMICS

Although the analysis of temporal signal fluctuations and co-fluctuations has long been a fixture of blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) research, the role of local directional flows in both signal propagation and healthy functional integration remains almost entirely neglected. We are introducing an extensible framework, based on localized directional signal flows, to capture and analyze spatial signal propagation and propagative attractor patterns in BOLD fMRI. Novel features derived from this approach are validated in a large resting-state fMRI schizophrenia study where they reveal significant relationships between spatially directional flows, propagative attractor patterns and subject diagnostic status. Plausibly, we find that spatial signal inflow to functional regions tends to positively correlate with net gain/loss in the region's temporal contribution BOLD signal reconstruction. We also find that group ICA (pdGICA) performed on time-varying propagative density maps, which are whole-brain maps of spatial signal inflow to each voxel on successive 30 second windows (ie. propagative attractor maps), produce components that tend to concentrate predominantly in at most six or seven functional regions, in some cases focusing on as few as two. The relationship between the propagative attractor group ICA component maps and functional regions is not sharp, but is focused enough to render the pdGICA component maps functionally tractable. Temporal correlations between pdGICA component timeseries and net gain/loss functional region timeseries on corresponding windows echoes those traditionally observed between functional region timeseries when aligning each pdGICA component with the functional region with which it has greatest spatial overlap. Schizophrenia strongly disrupts the average correlative relationship between pdGICA components and certain functional regions, some of which tend to be implicated in schizophrenia e.g. the thalamus and the anterior cingulate cortex. Schizophrenia also strongly and pervasively linked to the importance of specific pdGICA components in reconstructing subjects' observed time-varying propagative density maps. Over half of the 35 pdGICA component make significantly different average contributions to patient propagative density maps than to those of controls, with the functional footprints of impacted pdGICA components spreading over diverse functional domains. Finally, the magnitudes of local directional flows that carry propagation have spatially structured averages and structured, pervasive schizophrenia effects. The framework introduced here follows a new and fundamentally different data-driven approach to the BOLD fMRI signal. We believe that the empirical measurement of local directional flows and wider spatial signal propagation opens a plethora of new avenues through which to investigate healthy and disordered brain function using BOLD fMRI.

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Neuromark PET: A multivariate method for Estimating and comparing whole brain functional networks and connectomes from fMRI and PET data

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are both widely used neuroimaging techniques to study brain functional and molecular connec-tivity. Although whole brain resting functional MRI (fMRI) connectomes (a matrix describing the inter-regional connectivity patterns) are widely used, the integration or association of whole brain molecular connectomes with PET data are rarely done. This likely stems from the fact that PET data is typically analyzed by using a region of inter-est approach, while whole brain spatial networks and their connectivity (covariation) receive much less attention. As a result, to date, there have been little focus on di-rectly comparing whole brain PET and fMRI connectomes. In this study, we present a method that uses spatially constrained independent component analysis (scICA) (uti-lizing fMRI components as spatial priors) to estimate corresponding (Amyloid) PET and fMRI connectomes and examine the relationship between them using datasets that include individuals with mild cognitive impairment (MCI). Our results demonstrate highly modularized PET connectome patterns that complement those identified from resting fMRI. In particular, fMRI showed strong intra-domain connectivity with inter-domain anticorrelation in sensorimotor and visual domains as well as default mode network. PET amyloid data showed similar strong intra-domain effects, but showed much higher correlations within cognitive control and default mode domains, as well as anticorrelation between cerebellum and other domains. The estimated fMRI informed PET networks have similar, but not identical, network spatial patterns to the resting fMRI networks, with the fMRI informed PET networks being slightly smoother and, in some cases, showing variations in subnodes. To further compare the two modalities, we also analyzed the differences between individuals with MCI receiving medication versus a placebo. Results show both common and modality specific treatment effects on fMRI and PET connectomes. From our fMRI analysis, we observed higher connec-tivity differences in various regions, such as the connection between the thalamus and middle occipital gyrus, as well as the insula and right middle occipital gyrus. Mean-while, the PET analysis revealed increased activation between the anterior cingulate cortex and the left inferior parietal lobe, along with other regions, in individuals who received medication versus placebo. In sum, our novel approach identifies correspond-ing whole-brain fMRI informed PET and fMRI networks and connectomes. While we observed common patterns of network connectivity, our analysis of the MCI treatment and placebo groups revealed that each modality captures modality and group specific information about brain networks, highlighting differences between the two groups in both network expression and network connectivity.

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Gray Matters: An Efficient Vision Transformer GAN Framework for Predicting Functional Network Connectivity Biomarkers from Brain Structure

The field of brain connectivity research has under-gone revolutionary changes thanks to state-of-the-art advancements in neuroimaging, particularly regarding structural and functional magnetic resonance imaging (MRI). To navigate the intricate neural dynamics, one must possess a keen comprehension of the interdependent links between structure and function. Such relationships are understudied as they are complex and likely nonlinear. To address this, we created a new generative deep learning architecture using a conditional efficient vision transformer generative adversarial network (cEViTGAN) to capture the distinct information in structural and functional MRI of the human brain. Our model generates functional network connectivity (FNC) matrices directly from three-dimensional sMRI data. Two pioneering innovations are central to our approach. First, we use a novel linear embedding method for structural MRI (sMRI) data that retains the 3D spatial detail. This embedding is best for representative learning, and when used on a consistent dataset, and shows that it is good at upstream classification assignments. To estimate neural biomarkers, we need to process much smaller patches using ViT-based architectures, which usually makes the computations more difficult because of the self-attention operations. We present a new, lightweight self-attention mechanism to address this challenge. Our mechanism not only overcomes computational shortcomings of traditional softmax self-attention but also surpasses pure linear self-attention models in accuracy and performance. This optimization enables us to analyze even the tiniest neuroanatomical details with exceptional precision. Our model allows for the identification of functional network connectivity (FNC) with 74.2% accuracy and also predicts subject differences in FNC for schizophrenia patients versus controls. The results are intriguing and suggest the links between gray matter volume and brain function may be stronger than previously considered.

neuroscience↗

Markov Spatial Flows in BOLD fMRI: a Novel Lens on the BOLD Signal Reveals Attracting Patterns of Signal Intensity

While the analysis of temporal signal fluctuations and cofluctuations has long been a fixture of blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) research, the role and implications of spatial propagation within the 4D neurovascular BOLD signal has been almost entirely neglected. As part of a larger research program aimed at capturing and analyzing spatially propagative dynamics in BOLD fMRI, we report here a method that exposes large-scale functional attractors of spatial flows formulated as Markov processes defined at the voxel level. The brainwide stationary distributions of these voxel-level Markov processes represent patterns of signal accumulation toward which we find evidence that the brain exerts a probabilistic propagative undertow. These probabilistic propagative attractors are spatially structured and organized interpretably over functional regions. They also differ significantly between schizophrenia patients and controls.

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Complexity Measures Of Psychotic Brain Activity In The fMRI Signal

When viewing the brain as a sophisticated, nonlinear dynamic system, employing complexity measures offers a valuable way to measure the intricate and dynamic aspects of spontaneous psychotic brain activity. These measures can help us identify irregularities and patterns in complex systems. In our study, we utilized fuzzy recurrence plots and sample entropy to evaluate the dynamic characteristics of psychiatric disorders. This assessment focused on understanding the temporal and spatial neural activity patterns, and more specifically, we applied complexity measures to investigate the functional connectivity within the psychotic brain. This involves understanding how different brain regions synchronize their activity, and complexity measures can reveal the patterns of these connections. It provides a means to understand how different brain regions interact and communicate under resting-state abnormal conditions. This study offers evidence demonstrating that fuzzy recurrence plots can serve as descriptors for functional connectivity and discusses their relevance to sample entropy in the context of the psychotic brain. In summary, complexity measures offer valuable insights that enrich our comprehension of atypical brain activity and the complexities present in the psychotic brain1.

neuroscience↗

Estimating multimodal brain variability in schizophreniaspectrum disorders: A worldwide ENIGMA study

ObjectiveSchizophrenia is a multifaceted disorder associated with structural brain heterogeneity. Despite its relevance for identifying illness subtypes and informative biomarkers, structural brain heterogeneity in schizophrenia remains incompletely understood. Therefore, the objective of this study was to provide a comprehensive insight into the structural brain heterogeneity associated with schizophrenia. MethodsThis meta- and mega-analysis investigated the variability of multimodal structural brain measures of white and gray matter in individuals with schizophrenia versus healthy controls. Using the ENIGMA dataset of MRI-based brain measures from 22 international sites with up to 6139 individuals for a given brain measure, we examined variability in cortical thickness, surface area, folding index, subcortical volume and fractional anisotropy. ResultsWe found that individuals with schizophrenia are distinguished by higher heterogeneity in the frontotemporal network with regard to multimodal structural measures. Moreover, individuals with schizophrenia showed higher homogeneity of the folding index, especially in the left parahippocampal region. ConclusionsHigher multimodal heterogeneity in frontotemporal regions potentially implies different subtypes of schizophrenia that converge on impaired frontotemporal interaction as a core feature of the disorder. Conversely, more homogeneous folding patterns in the left parahippocampal region might signify a consistent characteristic of schizophrenia shared across subtypes. These findings underscore the importance of structural brain variability in advancing our neurobiological understanding of schizophrenia, and aid in identifying illness subtypes as well as informative biomarkers.

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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 net-works 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. 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 voxelwise changes within and between brain networks.

neuroscience↗

Multimodal subspace independent vector analysis captures latent subspace structures in large multimodal neuroimaging studies

A key challenge in neuroscience is to infer the relationships between brain structure and function from high-dimensional, multimodal neuroimaging data. While conventional multivariate approaches often simplify statistical assumptions and estimate one-dimensional independent sources shared across modalities, the true relationships between latent sources are likely more complex--statistical dependence may exist both within and between modalities, and possibly span more than one dimension per modality. Here we present Multimodal Subspace Independent Vector Analysis (MSIVA), a methodology to capture both joint and unique vector sources from multiple data modalities by defining both cross-modal and unimodal subspaces with variable dimensions. In particular, MSIVA enables flexible estimation of varying-size independent subspaces within modalities and their one-to-one linkage to corresponding subspaces across modalities. A key advantage is its ability to capture subjectlevel variability at the voxel level within independent subspaces, in contrast to traditional methods that share the same independent components across subjects. We evaluated three initialization workflows with five candidate subspace structures in multiple synthetic datasets and two large multimodal neuroimaging datasets, both including structural MRI (sMRI) and functional MRI (fMRI). After confirming that MSIVA successfully recovered the ground-truth subspace structures in the synthetic data, we then applied MSIVA to identify the latent subspace structure in the neuroimaging data. Subsequent subspace-specific canonical correlation analysis, brain-phenotype prediction, and voxelwise brain-age delta analysis suggest that the estimated sources from MSIVA with the optimal subspace structure are strongly associated with multiple phenotype variables, including age, sex, schizophrenia, lifestyle factors, and cognitive functions. Further, we identified modality- and group-specific brain regions related to multiple phenotype measures such as age (for example, cerebellum, precentral gyrus, and cingulate gyrus in sMRI; occipital lobe and superior frontal gyrus in fMRI), sex (for example, cerebellum in sMRI, frontal lobe in fMRI, and precuneus in both sMRI and fMRI), schizophrenia (for example, cerebellar, frontal, and insular cortices in sMRI; occipital pole, lingual gyrus, and precuneus in fMRI), shedding light on phenotypic and neuropsychiatric biomarkers of linked brain structure and function.

neuroscience↗