Amyloid- β (A β ) plaques in conjunction with hyperphosphorylated tau proteins in the form of neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease. It is well-known that the identification of individuals with A β positivity could enable early diagnosis. In this work, we aim at capturing the A β positivity status in an unbalanced cohort enclosing subjects at different disease stages, exploiting the underlying structural and connectivity disease-induced modulations as revealed by structural, functional, and diffusion MRI. Of note, due to the unbalanced cohort, the outcomes may be guided by those factors rather than amyloid accumulation. The partial views provided by each modality are integrated in the model, allowing to take full advantage of their complementarity in encoding the effects of the A β accumulation, leading to an accuracy of 0.762 ± 0.04. The specificity of the information brought by each modality is assessed by post hoc explainability analysis (guided backpropagation), highlighting the underlying structural and functional changes. Noteworthy, well-established biomarker key regions related to A β deposition could be identified by all modalities, including the hippocampus, thalamus, precuneus, and cingulate gyrus, witnessing in favor of the reliability of the method as well as its potential in shedding light on modality-specific possibly unknown A β deposition signatures. Author Summary In this work, we employed a multimodal MRI-based deep learning framework for the classification of unbalanced cohorts relying on the amyloid- β status in the Alzheimer’s disease continuum. To this end, structural, functional, and diffusion MRI data were used to feed a 3D-convolutional neural network and two different graph neural networks, respectively, reaching an accuracy of 0.762 ± 0.04. Post hoc explainability analysis was performed to extract the most relevant regions that led to the outcome, highlighting the involvement of different cortical and subcortical regions. This work provides evidence of the added value brought by exploiting different imaging modalities in decrypting the nature and extent of brain alterations in the amyloid-guided classification outcome.

Brain function can be modeled as 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 independent component analysis (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 the DMN by evaluating the difference between healthy people and individuals with schizophrenia. We show that the TICA approach can detect the spatial hierarchy of the DMN, VN, and RFPN. In addition, the 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.

There are a growing number of neuroimaging studies motivating joint structural and functional brain connectivity. The brain connectivity of different modalities provides an insight into brain functional organization by leveraging complementary information, especially for brain disorders such as schizophrenia. In this paper, we propose a multimodal 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 multiobjective optimization framework. We evaluated our model using synthetic and real datasets (including dMRI and rs-fMRI from 149 schizophrenia patients and 162 controls). Multimodal 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 with 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. Author Summary The brain can be modeled as distinct functional networks, interacting with each other to construct an integrated system. Each network, named intrinsic connectivity network (ICN) is associated with a specific brain function. Neuroimaging studies increasingly explore combined structural and functional brain connectivity networks to identify ICNs, offering valuable insights into brain organization. This paper introduces a multimodal independent component analysis (ICA) model, structural-functional connectivity and spatially constrained ICA (sfCICA), which uses both structural (diffusion-weighted MRI) and functional (resting-state functional MRI) connectivity information guided by spatial maps to estimate ICNs. The proposed model reveals improved functional coupling, modularity, and network distinction, especially in schizophrenia. Statistical analysis shows more significant group differences compared with unimodal models. In summary, the sfCICA model, by jointly considering structural and functional connectivity, demonstrates advantages in simultaneous learning and enhanced connectivity estimates.

Emotion perception is essential to affective and cognitive development which involves distributed brain circuits. Emotion identification skills emerge in infancy and continue to develop throughout childhood and adolescence. Understanding the development of the brain’s emotion circuitry may help us explain the emotional changes during adolescence. In this work, we aim to deepen our understanding of emotion-related functional connectivity (FC) from association to causation. We proposed a Bayesian incorporated linear non-Gaussian acyclic model (BiLiNGAM), which incorporated association model into the estimation pipeline. Simulation results indicated stable and accurate performance over various settings, especially when the sample size was small. We used fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC) to validate the approach. It included 855 individuals aged 8–22 years who were divided into five different adolescent stages. Our network analysis revealed the development of emotion-related intra- and intermodular connectivity and pinpointed several emotion-related hubs. We further categorized the hubs into two types: in-hubs and out-hubs, as the center of receiving and distributing information, respectively. In addition, several unique developmental hub structures and group-specific patterns were discovered. Our findings help provide a directed FC template of brain network organization underlying emotion processing during adolescence. Author Summary Our study introduces a novel method for analyzing directed graphs across multiple groups and demonstrates its effectiveness through a series of simulation studies. This method is applied to investigate the development of directed functional connectivity for emotion processing across diverse adolescent periods. Our findings unveil a notable increase in interfunctional connectivity with age, specifically involved with the executive control and memory retrieval, indicating the maturation of emotion processing function. Additionally, significant development of intraconnectivity in the subcortical areas emerges in early adolescence, whereas development of cerebellum emerges in the very end of adolescence. These insights offer valuable contributions to our understanding of the dynamic neural processes underlying emotion regulation during adolescence.

Graph-theoretical methods have been widely used to study human brain networks in psychiatric disorders. However, the focus has primarily been on global graphic metrics with little attention to the information contained in paths connecting brain regions. Details of disruption of these paths may be highly informative for understanding disease mechanisms. To detect the absence or addition of multistep paths in the patient group, we provide an algorithm estimating edges that contribute to these paths with reference to the control group. We next examine where pairs of nodes were connected through paths in both groups by using a covariance decomposition method. We apply our method to study resting-state fMRI data in schizophrenia versus controls. Results show several disconnectors in schizophrenia within and between functional domains, particularly within the default mode and cognitive control networks. Additionally, we identify new edges generating additional paths. Moreover, although paths exist in both groups, these paths take unique trajectories and have a significant contribution to the decomposition. The proposed path analysis provides a way to characterize individuals by evaluating changes in paths, rather than just focusing on the pairwise relationships. Our results show promise for identifying path-based metrics in neuroimaging data.

We introduce an extension of independent component analysis (ICA), called multiscale ICA, and design an approach to capture dynamic functional source interactions within and between multiple spatial scales. Multiscale ICA estimates functional sources at multiple spatial scales without imposing direct constraints on the size of functional sources, overcomes the limitation of using fixed anatomical locations, and eliminates the need for model-order selection in ICA analysis. We leveraged this approach to study sex-specific and sex-common connectivity patterns in schizophrenia. Results show dynamic reconfiguration and interaction within and between multi-spatial scales. Sex-specific differences occur (a) within the subcortical domain, (b) between the somatomotor and cerebellum domains, and (c) between the temporal domain and several others, including the subcortical, visual, and default mode domains. Most of the sex-specific differences belong to between-spatial-scale functional interactions and are associated with a dynamic state with strong functional interactions between the visual, somatomotor, and temporal domains and their anticorrelation patterns with the rest of the brain. We observed significant correlations between multi-spatial-scale functional interactions and symptom scores, highlighting the importance of multiscale analyses to identify potential biomarkers for schizophrenia. As such, we recommend such analyses as an important option for future functional connectivity studies. Author Summary Brain function can be modeled as the dynamic interactions between functional sources (e.g., intrinsic connectivity networks, ICNs) at different spatial scales. Each spatial scale contains its own functional sources with unique information. For example, the default mode (DM)-ICNs from lower order independent component analysis (ICA) are not a simple union of DM-ICNs from a higher order. Furthermore, dynamic functional interactions occur both within and between different spatial scales, which has been underrepresented. Here, we introduce multiscale ICA to capture functional sources and their interactions across multiple spatial scales. We leveraged this approach to study sex-specific changes in schizophrenia. Most sex-specific differences occur in between-model order, highlighting the benefit of multi-spatial-scale analysis. In sum, studying multi-spatial-scale functional sources provides us with a wealth of information to better characterize brain function.

Static and dynamic functional network connectivity (FNC) are typically studied separately, which makes us unable to see the full spectrum of connectivity in each analysis. Here, we propose an approach called filter-banked connectivity (FBC) to estimate connectivity while preserving its full frequency range and subsequently examine both static and dynamic connectivity in one unified approach. First, we demonstrate that FBC can estimate connectivity across multiple frequencies missed by a sliding-window approach. Next, we use FBC to estimate FNC in a resting-state fMRI dataset including schizophrenia patients (SZ) and typical controls (TC). The FBC results are clustered into different network states. Some states showed weak low-frequency strength and as such were not captured in the window-based approach. Additionally, we found that SZs tend to spend more time in states exhibiting higher frequencies compared with TCs who spent more time in lower frequency states. Finally, we show that FBC enables us to analyze static and dynamic connectivity in a unified way. In summary, FBC offers a novel way to unify static and dynamic connectivity analyses and can provide additional information about the frequency profile of connectivity patterns.

The brain is a complex, multiscale dynamical system composed of many interacting regions. Knowledge of the spatiotemporal organization of these interactions is critical for establishing a solid understanding of the brain’s functional architecture and the relationship between neural dynamics and cognition in health and disease. The possibility of studying these dynamics through careful analysis of neuroimaging data has catalyzed substantial interest in methods that estimate time-resolved fluctuations in functional connectivity (often referred to as “dynamic” or time-varying functional connectivity; TVFC). At the same time, debates have emerged regarding the application of TVFC analyses to resting fMRI data, and about the statistical validity, physiological origins, and cognitive and behavioral relevance of resting TVFC. These and other unresolved issues complicate interpretation of resting TVFC findings and limit the insights that can be gained from this promising new research area. This article brings together scientists with a variety of perspectives on resting TVFC to review the current literature in light of these issues. We introduce core concepts, define key terms, summarize controversies and open questions, and present a forward-looking perspective on how resting TVFC analyses can be rigorously and productively applied to investigate a wide range of questions in cognitive and systems neuroscience.

Brain functional connectivity (FC), as measured by blood oxygenation level-dependent (BOLD) signal, fluctuates at the scale of 10s of seconds. It has recently been found that whole-brain dynamic FC (dFC) patterns contain sufficient information to permit identification of ongoing tasks. Here, we hypothesize that dFC patterns carry fine-grained information that allows for tracking short-term task engagement levels (i.e., 10s of seconds long). To test this hypothesis, 25 subjects were scanned continuously for 25 min while they performed and transitioned between four different tasks: working memory, visual attention, math, and rest. First, we estimated dFC patterns by using a sliding window approach. Next, we extracted two engagement-specific FC patterns representing active engagement and passive engagement by using k -means clustering. Then, we derived three metrics from whole-brain dFC patterns to track engagement level, that is, dissimilarity between dFC patterns and engagement-specific FC patterns, and the level of brainwide integration level. Finally, those engagement markers were evaluated against windowed task performance by using a linear mixed effects model. Significant relationships were observed between abovementioned metrics and windowed task performance for the working memory task only. These findings partially confirm our hypothesis and underscore the potential of whole-brain dFC to track short-term task engagement levels. Author Summary In this study, we hypothesized that whole-brain dynamic functional connectivity (FC) patterns carry fine-grained information that allows for tracking short-term task engagement levels. We derived three task engagement markers from whole-brain dynamic FC pattern, that is, dissimilarity between dynamic FC patterns and high/low-engagement FC patterns, as well as brainwide integration level. We employed a linear mixed effects model to relate those task engagement markers with short-term task performance, and confirmed our hypothesis with the working memory task.

Author Summary Neuropsychiatric disorders represent a central field of inquiry in network neuroscience, akin to lesional analysis of complex brain system dynamics. The prevalence of these conditions increases from mid-childhood to peak in adolescence and regress thereafter, challenging our ability to disambiguate maturational and connectivity effects. ADHD is a paradigmatic example, and the most common neuropsychiatric disorder of development. Here we present the first whole-brain analysis of time-varying connectivity in ADHD. Building on leading-edge methods in dynamic connectivity, our novel approach analyses time-varying connectivity on both a global brain basis, and within local network systems. This framework demonstrates that analysis of time-varying connectivity offers additional ways to characterize group and maturational effects in ADHD that are extensible to other developmental neuropsychiatric disorders. Abstract The analysis of time-varying connectivity by using functional MRI has gained momentum given its ability to complement traditional static methods by capturing additional patterns of variation in human brain function. Attention deficit hyperactivity disorder (ADHD) is a complex, common developmental neuropsychiatric disorder associated with heterogeneous connectivity differences that are challenging to disambiguate. However, dynamic connectivity has not been examined in ADHD, and surprisingly few whole-brain analyses of static functional network connectivity (FNC) using independent component analysis (ICA) exist. We present the first analyses of time-varying connectivity and whole-brain FNC using ICA in ADHD, introducing a novel framework for comparing local and global dynamic connectivity in a 44-network model. We demonstrate that dynamic connectivity analysis captures robust motifs associated with group effects consequent on the diagnosis of ADHD, implicating increased global dynamic range, but reduced fluidity and range localized to the default mode network system. These differentiate ADHD from other major neuropsychiatric disorders of development. In contrast, static FNC based on a whole-brain ICA decomposition revealed solely age effects, without evidence of group differences. Our analysis advances current methods in time-varying connectivity analysis, providing a structured example of integrating static and dynamic connectivity analysis to further investigation into functional brain differences during development.