Network analysis of discrete emotional states measured via ecological momentary assessment in schizophrenia.

Prior studies demonstrate that schizophrenia (SZ) is associated with abnormalities in positive and negative emotional experience that predict clinical presentation. However, it is unclear whether specific discrete emotions within the broader positive/negative categories are driving those symptom associations. Further, it is also unclear whether specific emotions contribute to symptoms in isolation or via networks of emotional states that dynamically interact across time. The current study used network analysis to evaluate temporally dynamic interactions among discrete emotional states experienced in the real world as assessed via Ecological Momentary Assessment (EMA). Participants included 46 outpatients with chronic SZ and 52 demographically matched healthy controls (CN) who completed 6 days of EMA that captured reports of emotional experience and symptoms derived from monetary surveys and geolocation based symptom markers of mobility and home location. Results indicated that less dense emotion networks were associated with greater severity of negative symptoms, whereas more dense emotion networks were associated with more severe positive symptoms and mania. Additionally, SZ evidenced greater centrality for shame, which was associated with greater severity of positive symptoms. These findings suggest that positive and negative symptoms are associated with distinct profiles of temporally dynamic and interactive emotion networks in SZ. Findings have implications for adapting psychosocial therapies to target specific discrete emotional states in the treatment of positive versus negative symptoms.

High-amplitude cofluctuations in cortical activity drive functional connectivity.

Resting-state functional connectivity is used throughout neuroscience to study brain organization and to generate biomarkers of development, disease, and cognition. The processes that give rise to correlated activity are, however, poorly understood. Here we decompose resting-state functional connectivity using a temporal unwrapping procedure to assess the contributions of moment-to-moment activity cofluctuations to the overall connectivity pattern. This approach temporally resolves functional connectivity at a timescale of single frames, which enables us to make direct comparisons of cofluctuations of network organization with fluctuations in the blood oxygen level-dependent (BOLD) time series. We show that surprisingly, only a small fraction of frames exhibiting the strongest cofluctuation amplitude are required to explain a significant fraction of variance in the overall pattern of connection weights as well as the network's modular structure. These frames coincide with frames of high BOLD activity amplitude, corresponding to activity patterns that are remarkably consistent across individuals and identify fluctuations in default mode and control network activity as the primary driver of resting-state functional connectivity. Finally, we demonstrate that cofluctuation amplitude synchronizes across subjects during movie watching and that high-amplitude frames carry detailed information about individual subjects (whereas low-amplitude frames carry little). Our approach reveals fine-scale temporal structure of resting-state functional connectivity and discloses that frame-wise contributions vary across time. These observations illuminate the relation of brain activity to functional connectivity and open a number of directions for future research.

Edge-centric analysis of time-varying functional brain networks with applications in autism spectrum disorder.

The interaction between brain regions changes over time, which can be characterized using time-varying functional connectivity (tvFC). The common approach to estimate tvFC uses sliding windows and offers limited temporal resolution. An alternative method is to use the recently proposed edge-centric approach, which enables the tracking of moment-to-moment changes in co-fluctuation patterns between pairs of brain regions. Here, we first examined the dynamic features of edge time series and compared them to those in the sliding window tvFC (sw-tvFC). Then, we used edge time series to compare subjects with autism spectrum disorder (ASD) and healthy controls (CN). Our results indicate that relative to sw-tvFC, edge time series captured rapid and bursty network-level fluctuations that synchronize across subjects during movie-watching. The results from the second part of the study suggested that the magnitude of peak amplitude in the collective co-fluctuations of brain regions (estimated as root sum square (RSS) of edge time series) is similar in CN and ASD. However, the trough-to-trough duration in RSS signal is greater in ASD, compared to CN. Furthermore, an edge-wise comparison of high-amplitude co-fluctuations showed that the within-network edges exhibited greater magnitude fluctuations in CN. Our findings suggest that high-amplitude co-fluctuations captured by edge time series provide details about the disruption of functional brain dynamics that could potentially be used in developing new biomarkers of mental disorders.

Modularity maximization as a flexible and generic framework for brain network exploratory analysis.

The modular structure of brain networks supports specialized information processing, complex dynamics, and cost-efficient spatial embedding. Inter-individual variation in modular structure has been linked to differences in performance, disease, and development. There exist many data-driven methods for detecting and comparing modular structure, the most popular of which is modularity maximization. Although modularity maximization is a general framework that can be modified and reparamaterized to address domain-specific research questions, its application to neuroscientific datasets has, thus far, been narrow. Here, we highlight several strategies in which the "out-of-the-box" version of modularity maximization can be extended to address questions specific to neuroscience. First, we present approaches for detecting "space-independent" modules and for applying modularity maximization to signed matrices. Next, we show that the modularity maximization frame is well-suited for detecting task- and condition-specific modules. Finally, we highlight the role of multi-layer models in detecting and tracking modules across time, tasks, subjects, and modalities. In summary, modularity maximization is a flexible and general framework that can be adapted to detect modular structure resulting from a wide range of hypotheses. This article highlights multiple frontiers for future research and applications.

Space-independent community and hub structure of functional brain networks.

Coordinated brain activity reflects underlying cognitive processes and can be modeled as a network of inter-regional functional connections. The most costly connections in the network are long-distance correlations that, in the absence of underlying structural connections, are maintained by sustained energetic inputs. Here, we present a spatial modeling approach that amplifies contributions made by long-distance functional connections to whole-brain network architecture, while simultaneously suppressing contributions made by short-range connections. We use this method to characterize the long-distance architecture of functional networks and to identify aspects of community and hub structure that are driven by long-distance correlations and that, we argue, are of greater functional significance. We find that based only on patterns of long-distance connectivity, primary sensory cortices occupy increasingly central positions and appear more "hub-like". Additionally, we show that the community structure of long-distance connections spans multiple topological levels and differs from the community structure detected in networks that include both short-range and long-distance connections. In summary, these findings highlight the complex relationship between the brain's physical layout and its functional architecture. The results presented here inform future analyses of community structure and network hubs in health, across development, and in the case of neuropsychiatric disorders.

Modular subgraphs in large-scale connectomes underpin spontaneous co-fluctuation events in mouse and human brains.

Previous studies have adopted an edge-centric framework to study fine-scale network dynamics in human fMRI. To date, however, no studies have applied this framework to data collected from model organisms. Here, we analyze structural and functional imaging data from lightly anesthetized mice through an edge-centric lens. We find evidence of "bursty" dynamics and events - brief periods of high-amplitude network connectivity. Further, we show that on a per-frame basis events best explain static FC and can be divided into a series of hierarchically-related clusters. The co-fluctuation patterns associated with each cluster centroid link distinct anatomical areas and largely adhere to the boundaries of algorithmically detected functional brain systems. We then investigate the anatomical connectivity undergirding high-amplitude co-fluctuation patterns. We find that events induce modular bipartitions of the anatomical network of inter-areal axonal projections. Finally, we replicate these same findings in a human imaging dataset. In summary, this report recapitulates in a model organism many of the same phenomena observed in previously edge-centric analyses of human imaging data. However, unlike human subjects, the murine nervous system is amenable to invasive experimental perturbations. Thus, this study sets the stage for future investigation into the causal origins of fine-scale brain dynamics and high-amplitude co-fluctuations. Moreover, the cross-species consistency of the reported findings enhances the likelihood of future translation.

Markov chain analysis indicates that positive and negative emotions have abnormal temporal interactions during daily life in schizophrenia.

Abnormalities in positive and negative emotional experience have been identified in laboratory-based studies in schizophrenia (SZ) and associated with poorer clinical outcomes. However, emotions are not static in daily life-they are dynamic processes that unfold across time and are characterized by temporal interactions. Whether these temporal interactions are abnormal in SZ and associated with clinical outcomes is unclear (i.e., whether the experience of positive/negative emotions at time t increases or decreases the intensity of positive/negative emotions at time t+1). In the current study, participants with SZ (n = 48) and healthy controls (CN; n = 52) completed 6 days of ecological momentary assessment (EMA) surveys that sampled state emotional experience and symptoms. The EMA emotional experience data was submitted to Markov chain analysis to evaluate transitions among combined positive and negative affective states from time t to t+1. Results indicated that: (1) In SZ, the emotion system is more likely to stay in moderate or high negative affect states, regardless of positive affect level; (2) SZ transition to co-activated emotional states more than CN, and once emotional co-activation occurs, the range of emotional states SZ transition to is more variable than CN; (3) Maladaptive transitions among emotional states were significantly correlated with greater positive symptoms and poorer functional outcome in SZ. Collectively, these findings clarify how emotional co-activation occurs in SZ and its effects on the emotion system across time, as well as how negative emotions dampen the ability to sustain positive emotions across time. Treatment implications are discussed.

Local structure-function relationships in human brain networks across the lifespan.

A growing number of studies have used stylized network models of communication to predict brain function from structure. Most have focused on a small set of models applied globally. Here, we compare a large number of models at both global and regional levels. We find that globally most predictors perform poorly. At the regional level, performance improves but heterogeneously, both in terms of variance explained and the optimal model. Next, we expose synergies among predictors by using pairs to jointly predict FC. Finally, we assess age-related differences in global and regional coupling across the human lifespan. We find global decreases in the magnitude of structure-function coupling with age. We find that these decreases are driven by reduced coupling in sensorimotor regions, while higher-order cognitive systems preserve local coupling with age. Our results describe patterns of structure-function coupling across the cortex and how this may change with age.

The diversity and multiplexity of edge communities within and between brain systems.

The human brain is composed of functionally specialized systems that support cognition. Recently, we proposed an edge-centric model for detecting overlapping communities. It remains unclear how these communities and brain systems are related. Here, we address this question using data from the Midnight Scan Club and show that all brain systems are linked via at least two edge communities. We then examine the diversity of edge communities within each system, finding that heteromodal systems are more diverse than sensory systems. Next, we cluster the entire cortex to reveal it according to the regions' edge-community profiles. We find that regions in heteromodal systems are more likely to form their own clusters. Finally, we show that edge communities are personalized. Our work reveals the pervasive overlap of edge communities across the cortex and their relationship with brain systems. Our work provides pathways for future research using edge-centric brain networks.

Network Analysis Indicates That Avolition Is the Most Central Domain for the Successful Treatment of Negative Symptoms: Evidence From the Roluperidone Randomized Clinical Trial.

A recent conceptual development in schizophrenia is to view its manifestations as interactive networks rather than individual symptoms. Negative symptoms, which are associated with poor functional outcome and reduced rates of recovery, represent a critical need in schizophrenia therapeutics. MIN101 (roluperidone), a compound in development, demonstrated efficacy in the treatment of negative symptoms in schizophrenia. However, it is unclear how the drug achieved its effect from a network perspective. The current study evaluated the efficacy of roluperidone from a network perspective. In this randomized clinical trial, participants with schizophrenia and moderate to severe negative symptoms were randomly assigned to roluperidone 32 mg (n = 78), 64 mg (n = 83), or placebo (N = 83). Macroscopic network properties were evaluated to determine whether roluperidone altered the overall density of the interconnections among symptoms. Microscopic properties were evaluated to examine which individual symptoms were most influential (ie, interconnected) on other symptoms in the network and are responsible for successful treatment effects. Participants receiving roluperidone did not differ from those randomized to placebo on macroscopic properties. However, microscopic properties (degree and closeness centrality) indicated that avolition was highly central in patients receiving placebo and that roluperidone reduced this level of centrality. These findings suggest that decoupling the influence of motivational processes from other negative symptom domains is essential for producing global improvements. The search for pathophysiological mechanisms and targeted treatment development should be focused on avolition, with the expectation of improvement in the entire constellation of negative symptoms if avolition is effectively treated.