Measuring Daily Activity Rhythms in Young Adults at Risk of Affective Instability Using Passively Collected Smartphone Data: Observational Study.

BACKGROUND: Irregularities in circadian rhythms have been associated with adverse health outcomes. The regularity of rhythms can be quantified using passively collected smartphone data to provide clinically relevant biomarkers of routine. OBJECTIVE: This study aims to develop a metric to quantify the regularity of activity rhythms and explore the relationship between routine and mood, as well as demographic covariates, in an outpatient psychiatric cohort. METHODS: Passively sensed smartphone data from a cohort of 38 young adults from the Penn or Children's Hospital of Philadelphia Lifespan Brain Institute and Outpatient Psychiatry Clinic at the University of Pennsylvania were fitted with 2-state continuous-time hidden Markov models representing active and resting states. The regularity of routine was modeled as the hour-of-the-day random effects on the probability of state transition (ie, the association between the hour-of-the-day and state membership). A regularity score, Activity Rhythm Metric, was calculated from the continuous-time hidden Markov models and regressed on clinical and demographic covariates. RESULTS: Regular activity rhythms were associated with longer sleep durations (P=.009), older age (P=.001), and mood (P=.049). CONCLUSIONS: Passively sensed Activity Rhythm Metrics are an alternative to existing metrics but do not require burdensome survey-based assessments. Low-burden, passively sensed metrics based on smartphone data are promising and scalable alternatives to traditional measurements.

Mobile footprinting: linking individual distinctiveness in mobility patterns to mood, sleep, and brain functional connectivity.

Mapping individual differences in behavior is fundamental to personalized neuroscience, but quantifying complex behavior in real world settings remains a challenge. While mobility patterns captured by smartphones have increasingly been linked to a range of psychiatric symptoms, existing research has not specifically examined whether individuals have person-specific mobility patterns. We collected over 3000 days of mobility data from a sample of 41 adolescents and young adults (age 17-30 years, 28 female) with affective instability. We extracted summary mobility metrics from GPS and accelerometer data and used their covariance structures to identify individuals and calculated the individual identification accuracy-i.e., their "footprint distinctiveness". We found that statistical patterns of smartphone-based mobility features represented unique "footprints" that allow individual identification (p < 0.001). Critically, mobility footprints exhibited varying levels of person-specific distinctiveness (4-99%), which was associated with age and sex. Furthermore, reduced individual footprint distinctiveness was associated with instability in affect (p < 0.05) and circadian patterns (p < 0.05) as measured by environmental momentary assessment. Finally, brain functional connectivity, especially those in the somatomotor network, was linked to individual differences in mobility patterns (p < 0.05). Together, these results suggest that real-world mobility patterns may provide individual-specific signatures relevant for studies of development, sleep, and psychopathology.

Finding the needle in a high-dimensional haystack: Canonical correlation analysis for neuroscientists.

The 21st century marks the emergence of "big data" with a rapid increase in the availability of datasets with multiple measurements. In neuroscience, brain-imaging datasets are more commonly accompanied by dozens or hundreds of phenotypic subject descriptors on the behavioral, neural, and genomic level. The complexity of such "big data" repositories offer new opportunities and pose new challenges for systems neuroscience. Canonical correlation analysis (CCA) is a prototypical family of methods that is useful in identifying the links between variable sets from different modalities. Importantly, CCA is well suited to describing relationships across multiple sets of data, such as in recently available big biomedical datasets. Our primer discusses the rationale, promises, and pitfalls of CCA.

Multi-scale network regression for brain-phenotype associations.

Brain networks are increasingly characterized at different scales, including summary statistics, community connectivity, and individual edges. While research relating brain networks to behavioral measurements has yielded many insights into brain-phenotype relationships, common analytical approaches only consider network information at a single scale. Here, we designed, implemented, and deployed Multi-Scale Network Regression (MSNR), a penalized multivariate approach for modeling brain networks that explicitly respects both edge- and community-level information by assuming a low rank and sparse structure, both encouraging less complex and more interpretable modeling. Capitalizing on a large neuroimaging cohort (n = 1, 051), we demonstrate that MSNR recapitulates interpretable and statistically significant connectivity patterns associated with brain development, sex differences, and motion-related artifacts. Compared to single-scale methods, MSNR achieves a balance between prediction performance and model complexity, with improved interpretability. Together, by jointly exploiting both edge- and community-level information, MSNR has the potential to yield novel insights into brain-behavior relationships.

Approaches to Defining Common and Dissociable Neurobiological Deficits Associated With Psychopathology in Youth.

Psychiatric disorders show high rates of comorbidity and nonspecificity of presenting clinical symptoms, while demonstrating substantial heterogeneity within diagnostic categories. Notably, many of these psychiatric disorders first manifest in youth. We review progress and next steps in efforts to parse heterogeneity in psychiatric symptoms in youths by identifying abnormalities within neural circuits. To address this fundamental challenge in psychiatry, a number of methods have been proposed. We provide an overview of these methods, broadly organized into dimensional versus categorical approaches and single-view versus multiview approaches. Dimensional approaches including factor analysis and canonical correlation analysis aim to capture dimensional associations between psychopathology and brain measures across a continuous spectrum from health to disease. In contrast, categorical approaches, such as clustering and community detection, aim to identify subtypes of individuals within a class of symptoms or brain features. We highlight several studies that apply these methods to samples of youths and discuss issues to consider when using these approaches. Finally, we end by highlighting avenues for future research.

Alterations in white matter microstructure in individuals at persistent risk for psychosis.

Abnormalities in brain white matter (WM) are reported in youth at-risk for psychosis. Yet, the neurodevelopmental time course of these abnormalities remains unclear. Thus, longitudinal diffusion-weighted imaging (DWI) was used to investigate WM abnormalities in youth at-risk for psychosis. A subset of individuals from the Philadelphia Neurodevelopmental Cohort (PNC) completed two DWI scans approximately 20 months apart. Youths were identified through structured interview as having subthreshold persistent psychosis risk symptoms (n = 46), and were compared to healthy typically developing participants (TD; n = 98). Analyses were conducted at voxelwise and regional levels. Nonlinear developmental patterns were examined using penalized splines within a generalized additive model. Compared to TD, youth with persistent psychosis risk symptoms had lower whole-brain WM fractional anisotropy (FA) and higher radial diffusivity (RD). Voxelwise analyses revealed clusters of significant WM abnormalities within the temporal and parietal lobes. Lower FA within the cingulum bundle of hippocampus and cerebrospinal tracts were the most robust deficits in individuals with persistent psychosis symptoms. These findings were consistent over two visits. Thus, it appears that WM abnormalities are present early in youth with persistent psychosis risk symptoms, however, there is little evidence to suggest that these features emerge in late adolescence or early adulthood. Future studies should seek to characterize WM abnormalities in younger individuals and follow individuals as subthreshold psychotic symptoms emerge.

Unifying the Notions of Modularity and Core-Periphery Structure in Functional Brain Networks during Youth.

At rest, human brain functional networks display striking modular architecture in which coherent clusters of brain regions are activated. The modular account of brain function is pervasive, reliable, and reproducible. Yet, a complementary perspective posits a core-periphery or rich-club account of brain function, where hubs are densely interconnected with one another, allowing for integrative processing. Unifying these two perspectives has remained difficult due to the fact that the methodological tools to identify modules are entirely distinct from the methodological tools to identify core-periphery structure. Here, we leverage a recently-developed model-based approach-the weighted stochastic block model-that simultaneously uncovers modular and core-periphery structure, and we apply it to functional magnetic resonance imaging data acquired at rest in 872 youth of the Philadelphia Neurodevelopmental Cohort. We demonstrate that functional brain networks display rich mesoscale organization beyond that sought by modularity maximization techniques. Moreover, we show that this mesoscale organization changes appreciably over the course of neurodevelopment, and that individual differences in this organization predict individual differences in cognition more accurately than module organization alone. Broadly, our study provides a unified assessment of modular and core-periphery structure in functional brain networks, offering novel insights into their development and implications for behavior.

Evidence for Dissociable Linkage of Dimensions of Psychopathology to Brain Structure in Youths.

OBJECTIVE: High comorbidity among psychiatric disorders suggests that they may share underlying neurobiological deficits. Abnormalities in cortical thickness and volume have been demonstrated in clinical samples of adults, but less is known when these structural differences emerge in youths. The purpose of this study was to examine the association between dimensions of psychopathology and brain structure. METHODS: The authors studied 1,394 youths who underwent brain imaging as part of the Philadelphia Neurodevelopmental Cohort. Dimensions of psychopathology were constructed using a bifactor model of symptoms. Cortical thickness and volume were quantified using high-resolution 3-T MRI. Structural covariance networks were derived using nonnegative matrix factorization and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear age-related effects. RESULTS: Fear symptoms were associated with reduced cortical thickness in most networks, and overall psychopathology was associated with globally reduced gray matter volume across all networks. Structural covariance networks predicted psychopathology symptoms above and beyond demographic characteristics and cognitive performance. CONCLUSIONS: The results suggest a dissociable relationship whereby fear is most strongly linked to reduced cortical thickness and overall psychopathology is most strongly linked to global reductions in gray matter volume. Such results have implications for understanding how abnormalities of brain development may be associated with divergent dimensions of psychopathology.

Gestational Age is Dimensionally Associated with Structural Brain Network Abnormalities Across Development.

Prematurity is associated with diverse developmental abnormalities, yet few studies relate cognitive and neurostructural deficits to a dimensional measure of prematurity. Leveraging a large sample of children, adolescents, and young adults (age 8-22 years) studied as part of the Philadelphia Neurodevelopmental Cohort, we examined how variation in gestational age impacted cognition and brain structure later in development. Participants included 72 preterm youth born before 37 weeks' gestation and 206 youth who were born at term (37 weeks or later). Using a previously-validated factor analysis, cognitive performance was assessed in three domains: (1) executive function and complex reasoning, (2) social cognition, and (3) episodic memory. All participants completed T1-weighted neuroimaging at 3 T to measure brain volume. Structural covariance networks were delineated using non-negative matrix factorization, an advanced multivariate analysis technique. Lower gestational age was associated with both deficits in executive function and reduced volume within 11 of 26 structural covariance networks, which included orbitofrontal, temporal, and parietal cortices as well as subcortical regions including the hippocampus. Notably, the relationship between lower gestational age and executive dysfunction was accounted for in part by structural network deficits. Together, these findings emphasize the durable impact of prematurity on cognition and brain structure, which persists across development.

Linked dimensions of psychopathology and connectivity in functional brain networks.

Neurobiological abnormalities associated with psychiatric disorders do not map well to existing diagnostic categories. High co-morbidity suggests dimensional circuit-level abnormalities that cross diagnoses. Here we seek to identify brain-based dimensions of psychopathology using sparse canonical correlation analysis in a sample of 663 youths. This analysis reveals correlated patterns of functional connectivity and psychiatric symptoms. We find that four dimensions of psychopathology - mood, psychosis, fear, and externalizing behavior - are associated (r = 0.68-0.71) with distinct patterns of connectivity. Loss of network segregation between the default mode network and executive networks emerges as a common feature across all dimensions. Connectivity linked to mood and psychosis becomes more prominent with development, and sex differences are present for connectivity related to mood and fear. Critically, findings largely replicate in an independent dataset (n = 336). These results delineate connectivity-guided dimensions of psychopathology that cross clinical diagnostic categories, which could serve as a foundation for developing network-based biomarkers in psychiatry.

Understanding the Emergence of Neuropsychiatric Disorders With Network Neuroscience.

Major neuropsychiatric disorders such as psychosis are increasingly acknowledged to be disorders of brain connectivity. Yet tools to map, model, predict, and change connectivity are difficult to develop, largely because of the complex, dynamic, and multivariate nature of interactions between brain regions. Network neuroscience (NN) provides a theoretical framework and mathematical toolset to address these difficulties. Building on areas of mathematics such as graph theory, NN in its simplest form summarizes neuroimaging data by treating brain regions as nodes in a graph and by treating interactions or connections between nodes as edges in the graph. Network metrics can then be used to quantitatively describe the architecture of the graph, which in turn reflects the network's function. We review evidence supporting the utility of NN in understanding psychiatric disorders, with a focus on normative brain network development and abnormalities associated with psychosis. We also emphasize relevant methodological challenges, such as motion artifact correction, which are particularly important to consider when applying network tools to developmental neuroimaging data. We close with a discussion of several emerging frontiers of NN in psychiatry, including generative network modeling and network control theory. We aim to offer an accessible introduction to this emerging field and motivate further work that uses NN to better understand the normative development of brain networks and alterations in that development that accompany or foreshadow psychiatric disease.