Spatial Dynamic Subspaces Encode Sex-Specific Schizophrenia Disruptions in Transient Network Overlap and Their Links to Genetic Risk.

BACKGROUND: Schizophrenia research reveals sex differences in incidence, symptoms, genetic risk factors, and brain function. However, a knowledge gap remains regarding sex-specific schizophrenia alterations in brain function. Schizophrenia is considered a dysconnectivity syndrome, but the dynamic integration and segregation of brain networks are poorly understood. Recent advances in resting-state functional magnetic resonance imaging allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. Nevertheless, estimating time-resolved networks remains challenging due to low signal-to-noise ratio, limited short-time information, and uncertain network identification. METHODS: We adapted a reference-informed network estimation technique to capture time-resolved networks and their dynamic spatial integration and segregation for 193 individuals with schizophrenia and 315 control participants. We focused on time-resolved spatial functional network connectivity, an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to genomic data. RESULTS: Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spatial functional network connectivity exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and is correlated with genetic risk for schizophrenia. This dysfunction is reflected in regions with weak functional connectivity to corresponding networks. CONCLUSIONS: Our method can effectively capture spatially dynamic networks, detect nuanced schizophrenia effects including sex-specific ones, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the clinical potential of dynamic spatial dependence and weak connectivity.

Phase and amplitude, two sides of functional connectivity.

The dynamics of the human brain can be captured by estimating time-resolved functional network connectivity (trFNC). The most used method for estimating trFNC is sliding window Pearson correlation (SWPC). Methods based on instantaneous phase synchrony, which uses phase information for estimating trFNC are being increasingly used. These two approaches are similar under specific assumptions. Prior works have focused on which of these approaches is the best. Some works argue that SWPC can capture amplitude information and therefore we believe that instantaneous phase synchrony methods and SWPC capture different aspects of connectivity since phase synchrony methods work with the phase of the signal. Here we show that these two approaches result in different time-resolved information and therefore should be viewed as complimentary views of connectivity.

Alterations in grey matter structure linked to frequency-specific cortico-subcortical connectivity in schizophrenia via multimodal data fusion.

Schizophrenia (SZ) is a complex psychiatric disorder that is currently defined by symptomatic and behavioral, rather than biological, criteria. Neuroimaging is an appealing avenue for SZ biomarker development, as several neuroimaging-based studies comparing individuals with SZ to healthy controls (HC) have shown measurable group differences in brain structure, as well as functional brain alterations in both static and dynamic functional network connectivity (sFNC and dFNC, respectively). The recently proposed filter-banked connectivity (FBC) method extends the standard dFNC sliding-window approach to estimate FNC within an arbitrary number of distinct frequency bands. The initial implementation used a set of filters spanning the full connectivity spectral range, providing a unified approach to examine both sFNC and dFNC in a single analysis. Initial FBC results found that individuals with SZ spend more time in a less structured, more disconnected low-frequency (i.e., static) FNC state than HC, as well as preferential SZ occupancy in high-frequency connectivity states, suggesting a frequency-specific component underpinning the functional dysconnectivity observed in SZ. Building on these findings, we sought to link such frequency-specific patterns of FNC to covarying data-driven structural brain networks in the context of SZ. Specifically, we employ a multi-set canonical correlation analysis + joint independent components analysis (mCCA + jICA) data fusion framework to study the connection between grey matter volume (GMV) maps and FBC states across the full connectivity frequency spectrum. Our multimodal analysis identified two joint sources that captured co-varying patterns of frequency-specific functional connectivity and alterations in GMV with significant group differences in loading parameters between the SZ group and HC. The first joint source linked frequency-modulated connections between the subcortical and sensorimotor networks and GMV alterations in the frontal and temporal lobes, while the second joint source identified a relationship between low-frequency cerebellar-sensorimotor connectivity and structural changes in both the cerebellum and motor cortex. Together, these results show a strong connection between cortico-subcortical functional connectivity at both high and low frequencies and alterations in cortical GMV that may be relevant to the pathogenesis and pathophysiology of SZ.

A Unified Framework for Modularizing and Comparing Time-Resolved Functional Connectivity Methods.

Functional connectivity is a widely used measure for finding the relationships between functional entities of the brain. Recently, more focus has been put on the methods that aim to estimate these relationships in a time-resolved fashion. However, the similarities and differences between these methods are not always clear and can result in unfair and incorrect comparisons. Here, we present a framework that provides a unified, systematic view for some of the more well-known methods. Using the proposed unified framework, we explain different methodologies using a unified language and show how they are similar and different conceptually. We give examples how this framework exposes important assumptions made by various methods, which can help clarify differences in results and facilitate reproducibility. We also show how such a framework will enable us to develop methods that improve upon previous methods.

Multi-spatial-scale dynamic interactions between functional sources reveal sex-specific changes in schizophrenia.

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.

Cue-induced craving and negative emotion disrupt response inhibition in methamphetamine use disorder: Behavioral and fMRI results from a mixed Go/No-Go task.

BACKGROUND: Drug-related cue-reactivity, dysfunctional negative emotion processing, and response-disinhibition constitute three core aspects of methamphetamine use disorder (MUD). These phenomena have been studied independently, but the neuroscientific literature on their interaction in addictive disorders remains scant. METHODS: 62 individuals with MUD were scanned when responding to the geometric Go or No-Go cues superimposed over blank, neutral, negative-emotional and drug-related background images. Neural correlates of drug and negative-emotional cue-reactivity, response-inhibition and their interactions were estimated, and methamphetamine cue-reactivity was compared between individuals with MUD and 23 healthy controls. Relationships between behavioral characteristics and observed activations were investigated. RESULTS: Individuals with MUD had longer reaction times and more errors in drug and negative-emotional compared to blank blocks, and more omission errors in drug compared to neutral blocks. They showed higher drug cue-reactivity than controls across prefrontal, fusiform, and visual regions (Z > 3.1, p-corrected<0.05). Response-inhibition was associated with precuneal, inferior parietal, anterior cingulate, temporal, and inferior frontal activations (Z > 3.1, p-corrected<0.05). Response-inhibition in drug cue blocks coincided with higher activations in the visual cortex and lower activations in the paracentral lobule and superior and inferior frontal gyri, while inhibition during negative-emotional blocks led to higher superior parietal, fusiform, and lateral occipital activations (Z > 3.1, p-corrected<0.05). CONCLUSION: Drug cue-reactivity may impair response inhibition partly through activating dis-inhibitory regions, while temporal and parietal activations associated with response-inhibition in negative blocks suggest compensatory activity. Results suggest that drug and negative-emotional cue-reactivity influence response-inhibition, and the study of these interactions may aid mechanistic understanding of methamphetamine use disorder.

Modular and state-relevant functional network connectivity in high-frequency eyes open vs eyes closed resting fMRI data.

BACKGROUND: Resting-state fMRI (rs-fMRI) is employed to assess "functional connections" of signal between brain regions. However, multiple rs-fMRI paradigms and data-filtering strategies have been used, highlighting the need to explore BOLD signal across the spectrum. Rs-fMRI data is typically filtered at frequencies ranging between 0.008∼0.2 Hz to mitigate nuisance signal (e.g. cardiac, respiratory) and maximize neuronal BOLD signal. However, some argue neuronal BOLD signal may be parsed at higher frequencies. NEW METHOD: To assess the contributions of rs-fMRI along the BOLD spectra on functional network connectivity (FNC) matrices, a spatially constrained independent component analysis (ICA) was performed at seven different frequency "bins", after which FNC values and FNC measures of matrix-randomness were assessed using linear mixed models. RESULTS: Results show FNCs at higher-frequency bins display similar randomness to those from the typical frequency bins (0.01-0.15), while the largest values are in the 0.31-0.46 Hz bin. Eyes open (EO) vs eyes closed (EC) comparison found EC was less random than EO across most frequency bins. Further, FNC was greater in EC across auditory and cognitive control pairings while EO values were greater in somatomotor, visual, and default mode FNC. COMPARISON WITH EXISTING METHODS: Effect sizes of frequency and resting-state paradigm vary from small to large, but the most notable results are specific to frequency ranges and resting-state paradigm with artifacts like motion displaying negligible effect sizes. CONCLUSIONS: These suggest unique information may be derived from FNC matrices across frequencies and paradigms, but additional data is necessary prior to any definitive conclusions.

Brain Density Clustering Analysis: A New Approach to Brain Functional Dynamics.

BACKGROUND: A number of studies in recent years have explored whole-brain dynamic connectivity using pairwise approaches. There has been less focus on trying to analyze brain dynamics in higher dimensions over time. METHODS: We introduce a new approach that analyzes time series trajectories to identify high traffic nodes in a high dimensional space. First, functional magnetic resonance imaging (fMRI) data are decomposed using spatial ICA to a set of maps and their associated time series. Next, density is calculated for each time point and high-density points are clustered to identify a small set of high traffic nodes. We validated our method using simulations and then implemented it on a real data set. RESULTS: We present a novel approach that captures dynamics within a high dimensional space and also does not use any windowing in contrast to many existing approaches. The approach enables one to characterize and study the time series in a potentially high dimensional space, rather than looking at each component pair separately. Our results show that schizophrenia patients have a lower dynamism compared to healthy controls. In addition, we find patients spend more time in nodes associated with the default mode network and less time in components strongly correlated with auditory and sensorimotor regions. Interestingly, we also found that subjects oscillate between state pairs that show opposite spatial maps, suggesting an oscillatory pattern. CONCLUSION: Our proposed method provides a novel approach to analyze the data in its native high dimensional space and can possibly provide new information that is undetectable using other methods.

A unified approach for characterizing static/dynamic connectivity frequency profiles using filter banks.

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.

Tools of the trade: estimating time-varying connectivity patterns from fMRI data.

Given the dynamic nature of the brain, there has always been a motivation to move beyond 'static' functional connectivity, which characterizes functional interactions over an extended period of time. Progress in data acquisition and advances in analytical neuroimaging methods now allow us to assess the whole brain's dynamic functional connectivity (dFC) and its network-based analog, dynamic functional network connectivity at the macroscale (mm) using fMRI. This has resulted in the rapid growth of analytical approaches, some of which are very complex, requiring technical expertise that could daunt researchers and neuroscientists. Meanwhile, making real progress toward understanding the association between brain dynamism and brain disorders can only be achieved through research conducted by domain experts, such as neuroscientists and psychiatrists. This article aims to provide a gentle introduction to the application of dFC. We first explain what dFC is and the circumstances under which it can be used. Next, we review two major categories of analytical approaches to capture dFC. We discuss caveats and considerations in dFC analysis. Finally, we walk readers through an openly accessible toolbox to capture dFC properties and briefly review some of the dynamic metrics calculated using this toolbox.

Weighted average of shared trajectory: A new estimator for dynamic functional connectivity efficiently estimates both rapid and slow changes over time.

BACKGROUND: Dynamic functional network connectivity (dFNC) of the brain has attracted considerable attention recently. Many approaches have been suggested to study dFNC with sliding window Pearson correlation (SWPC) being the most well-known. SWPC needs a relatively large sample size to reach a robust estimation but using large window sizes prevents us to detect rapid changes in dFNC. NEW METHOD: Here we first calculate the gradients of each time series pair and use the magnitude of these gradients to calculate weighted average of shared trajectory (WAST) as a new estimator for dFNC. RESULTS: Using WAST to compare healthy control and schizophrenia patients using a large dataset, we show disconnectivity between different regions associated with schizophrenia. In addition, WAST results reveals patients with schizophrenia stay longer in a connectivity state with negative connectivity between motor and sensory regions than do healthy controls. COMPARISON WITH EXISTING METHODS: We compare WAST with SWPC and multiplication of temporal derivatives (MTD) using different simulation scenarios. We show that WAST enables us to detect very rapid changes in dFNC (undetected by SWPC) while MTD performance is generally lower. CONCLUSIONS: As large window sizes are unable to detect short states, using shorter window size is desirable if the estimator is robust enough. We provide evidence that WAST requires fewer samples (compared to SWPC) to reach a robust estimation. As a result, we were able to identify rapidly varying dFNC patterns undetected by SWPC while still being able to robustly estimate slower dFNC patterns.

Brain Development Includes Linear and Multiple Nonlinear Trajectories: A Cross-Sectional Resting-State Functional Magnetic Resonance Imaging Study.

Studies of brain structure have shown that the cortex matures in both a linear and nonlinear manner depending on the time window and specific region studied. In addition, it has been shown that socioeconomic status can impact brain development throughout childhood. However, very few studies have evaluated these patterns using functional measures. To this end, in this study we used cross-sectional resting-state functional magnetic resonance imaging data of 368 subjects, age 3-21 years, to examine the linear and nonlinear development of brain connectivity. We employed a clustering approach to characterize these developmental patterns into different linear and nonlinear groups. Our results showed that functional brain development exhibits multiple types of linear and nonlinear patterns, and assuming that brain connectivity values reach a stable state after a specific age might be misleading.

Characterizing Whole Brain Temporal Variation of Functional Connectivity via Zero and First Order Derivatives of Sliding Window Correlations.

Brain functional connectivity has been shown to change over time during resting state fMRI experiments. Close examination of temporal changes have revealed a small set of whole-brain connectivity patterns called dynamic states. Dynamic functional network connectivity (dFNC) studies have demonstrated that it is possible to replicate the dynamic states across several resting state experiments. However, estimation of states and their temporal dynamicity still suffers from noisy and imperfect estimations. In regular dFNC implementations, states are estimated by comparing connectivity patterns through the data without considering time, in other words only zero order changes are examined. In this work we propose a method that includes first order variations of dFNC in the searching scheme of dynamic connectivity patterns. Our approach, referred to as temporal variation of functional network connectivity (tvFNC), estimates the derivative of dFNC, and then searches for reoccurring patterns of concurrent dFNC states and their derivatives. The tvFNC method is first validated using a simulated dataset and then applied to a resting-state fMRI sample including healthy controls (HC) and schizophrenia (SZ) patients and compared to the standard dFNC approach. Our dynamic approach reveals extra patterns in the connectivity derivatives complementing the already reported state patterns. State derivatives consist of additional information about increment and decrement of connectivity among brain networks not observed by the original dFNC method. The tvFNC shows more sensitivity than regular dFNC by uncovering additional FNC differences between the HC and SZ groups in each state. In summary, the tvFNC method provides a new and enhanced approach to examine time-varying functional connectivity.

Changing brain connectivity dynamics: From early childhood to adulthood.

Brain maturation through adolescence has been the topic of recent studies. Previous works have evaluated changes in morphometry and also changes in functional connectivity. However, most resting-state fMRI studies have focused on static connectivity. Here we examine the relationship between age/maturity and the dynamics of brain functional connectivity. Utilizing a resting fMRI dataset comprised 421 subjects ages 3-22 from the PING study, we first performed group ICA to extract independent components and their time courses. Next, dynamic functional network connectivity (dFNC) was calculated via a sliding window followed by clustering of connectivity patterns into 5 states. Finally, we evaluated the relationship between age and the amount of time each participant spent in each state as well as the transitions among different states. Results showed that older participants tend to spend more time in states which reflect overall stronger connectivity patterns throughout the brain. In addition, the relationship between age and state transition is symmetric. This can mean individuals change functional connectivity through time within a specific set of states. On the whole, results indicated that dynamic functional connectivity is an important factor to consider when examining brain development across childhood.

Functional neuroimaging for addiction medicine: From mechanisms to practical considerations.

During last 20 years, neuroimaging with functional magnetic resonance imaging (fMRI) in people with drug addictions has introduced a wide range of quantitative biomarkers from brain's regional or network level activities during different cognitive functions. These quantitative biomarkers could be potentially used for assessment, planning, prediction, and monitoring for "addiction medicine" during screening, acute intoxication, admission to a program, completion of an acute program, admission to a long-term program, and postgraduation follow-up. In this chapter, we have briefly reviewed main neurocognitive targets for fMRI studies associated with addictive behaviors, main study types using fMRI among drug dependents, and potential applications for fMRI in addiction medicine. Main challenges and limitations for extending fMRI studies and evidences aiming at clinical applications in addiction medicine are also discussed. There is still a significant gap between available evidences from group-based fMRI studies and personalized decisions during daily practices in addiction medicine. It will be important to fill this gap with large-scale clinical trials and longitudinal studies using fMRI measures with a well-defined strategic plan for the future.