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Psychiatric disorders show high rates of co-morbidity and non-specificity of presenting clinical symptoms, while at the same time demonstrating substantial heterogeneity within diagnostic categories. Notably, many of these psychiatric disorders first manifest in youth. Here we review progress and next steps in efforts to parse heterogeneity in psychiatric symptoms in youth 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 vs. categorical approaches and single-view vs. multi-view 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 youth, and discuss issues to consider when using these approaches. Finally, we end by highlighting avenues for future research.

Significance The human brain is organized into a hierarchy of functional systems that evolve in childhood and adolescence to support the dynamic control of attention and behavior. However, it remains unknown how developing white-matter architecture supports coordinated fluctuations in neural activity underlying cognition. We document marked remodeling of structure–function coupling in youth, which aligns with cortical hierarchies of functional specialization and evolutionary expansion. Further, we demonstrate that structure–function coupling in rostrolateral prefrontal cortex supports age-related improvements in executive ability. These findings have broad relevance for accounts of experience-dependent plasticity in healthy development and abnormal development associated with neuropsychiatric illness., The protracted development of structural and functional brain connectivity within distributed association networks coincides with improvements in higher-order cognitive processes such as executive function. However, it remains unclear how white-matter architecture develops during youth to directly support coordinated neural activity. Here, we characterize the development of structure–function coupling using diffusion-weighted imaging and n-back functional MRI data in a sample of 727 individuals (ages 8 to 23 y). We found that spatial variability in structure–function coupling aligned with cortical hierarchies of functional specialization and evolutionary expansion. Furthermore, hierarchy-dependent age effects on structure–function coupling localized to transmodal cortex in both cross-sectional data and a subset of participants with longitudinal data (n = 294). Moreover, structure–function coupling in rostrolateral prefrontal cortex was associated with executive performance and partially mediated age-related improvements in executive function. Together, these findings delineate a critical dimension of adolescent brain development, whereby the coupling between structural and functional connectivity remodels to support functional specialization and cognition.

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.

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.

To support brain development during youth, the brain must balance energy delivery and consumption. Previous studies in adults have demonstrated high coupling between cerebral blood flow and brain function as measured using functional neuroimaging, but how this relationship evolves over adolescence is unknown. To address this gap, we studied a sample of 831 children and adolescents (478 females, ages 8-22) from the Philadelphia Neurodevelopmental Cohort who were scanned at 3T with both arterial spin labeled (ASL) MRI and resting-state functional MRI (fMRI). Local coupling between cerebral blood flow (CBF, from ASL) and the amplitude of low frequency fluctuations (ALFF, from fMRI) was first quantified using locally weighted regressions on the cortical surface. We then used generalized additive models to evaluate how CBF-ALFF coupling was associated with age, sex, and executive function. Enrichment of effects within canonical functional networks was evaluated using spin-based permutation tests. Our analyses revealed tight CBF-ALFF coupling across the brain. Whole-brain CBF-ALFF coupling decreased with age, largely driven by coupling decreases in the inferior frontal cortex, precuneus, visual cortex, and temporoparietal cortex (pfdr pfdr pfdr SIGNIFICANCEThe functions of the human brain are metabolically expensive and reliant on coupling between cerebral blood flow and neural activity. Previous neuroimaging studies in adults demonstrate tight physiology-function coupling, but how this coupling evolves over development is unknown. Here, we examine the relationship between blood flow as measured by arterial spin labeling and the amplitude of low frequency fluctuations from resting-state magnetic resonance imaging across a large sample of youth. We demonstrate regionally specific changes in coupling over age and show that variations in coupling are related to biological sex and executive function. Our results highlight the importance of CBF-ALFF coupling throughout development; we discuss its potential as a future target for the study of neuropsychiatric diseases.

Depression is a common psychiatric illness that often begins in youth, and is sometimes associated with cognitive deficits. However, there is significant variability in cognitive dysfunction, likely reflecting biological heterogeneity. We sought to identify neurocognitive subtypes and their neurofunctional signatures in a large cross-sectional sample of depressed youth. Participants were drawn from the Philadelphia Neurodevelopmental Cohort, including 712 youth with a lifetime history of a major depressive episode and 712 typically developing (TD) youth matched on age and sex. A subset (MDD n = 368, TD n = 200) also completed neuroimaging. Cognition was assessed with the Penn Computerized Neurocognitive Battery. A recently developed semi-supervised machine learning algorithm was used to delineate neurocognitive subtypes. Subtypes were evaluated for differences in both clinical psychopathology and brain activation during an n-back working memory fMRI task. We identified three neurocognitive subtypes in the depressed group. Subtype 1 was high-performing (high accuracy, moderate speed), Subtype 2 was cognitively impaired (low accuracy, slow speed), and Subtype 3 was impulsive (low accuracy, fast speed). While subtypes did not differ in clinical psychopathology, they diverged in their activation profiles in regions critical for executive function, which mirrored differences in cognition. Taken together, these data suggest disparate mechanisms of cognitive vulnerability and resilience in depressed youth, which may inform the identification of biomarkers for prognosis and treatment response.

Executive function develops during adolescence, yet it remains unknown how structural brain networks mature to facilitate activation of the fronto-parietal system, which is critical for executive function. In a sample of 946 human youths (ages 8-23y) who completed diffusion imaging, we capitalized upon recent advances in linear dynamical network control theory to calculate the energetic cost necessary to activate the fronto-parietal system through the control of multiple brain regions given existing structural network topology. We found that the energy required to activate the fronto-parietal system declined with development, and the pattern of regional energetic cost predicts unseen individuals’ brain maturity. Finally, energetic requirements of the cingulate cortex were negatively correlated with executive performance, and partially mediated the development of executive performance with age. Our results reveal a mechanism by which structural networks develop during adolescence to reduce the theoretical energetic costs of transitions to activation states necessary for executive function., eLife digest Adolescents are known for taking risks, from driving too fast to experimenting with drugs and alcohol. Such behaviors tend to decrease as individuals move into adulthood. Most people in their mid-twenties have greater self-control than they did as teenagers. They are also often better at planning, sustaining attention, and inhibiting impulsive behaviors. These skills, which are known as executive functions, develop over the course of adolescence. Executive functions rely upon a series of brain regions distributed across the frontal lobe and the lobe that sits just behind it, the parietal lobe. Fiber tracts connect these regions to form a fronto-parietal network. These fiber tracts are also referred to as white matter due to the whitish fatty material that surrounds and insulates them. Cui et al. now show that changes in white matter networks have implications for teen behavior. Almost 950 healthy young people aged between 8 and 23 years underwent a type of brain scan called diffusion-weighted imaging that visualizes white matter. The scans revealed that white matter networks in the frontal and parietal lobes mature over adolescence. This makes it easier for individuals to activate their fronto-parietal networks by decreasing the amount of energy required. Cui et al. show that a computer model can predict the maturity of a person's brain based on the energy needed to activate their fronto-parietal networks. These changes help explain why executive functions improve during adolescence. This in turn explains why behaviors such as risk-taking tend to decrease with age. That said, adults with various psychiatric disorders, such as ADHD and psychosis, often show impaired executive functions. In the future, it may be possible to reduce these impairments by applying magnetic fields to the scalp to reduce the activity of specific brain regions. The techniques used in the current study could help reveal which brain regions to target with this approach.

NeuroImage: a journal of brain function 216, 116745 (2020). doi:10.1016/j.neuroimage.2020.116745, Published by Academic Press, Orlando, Fla

Human brain mapping 41(10), 2553-2566 (2020). doi:10.1002/hbm.24982, Published by Wiley-Liss, New York, NY

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 due to the complex, dynamic, and multivariate nature of interactions between brain regions. Network neuroscience provides a theoretical framework and mathematical toolset to address these difficulties. Building on areas of mathematics such as graph theory, network neuroscience 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. Here we review evidence supporting the utility of network neuroscience in understanding psychiatric disorders, with a particular 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 network neuroscience 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 network neuroscience to better understand the normative development of brain networks, and alterations in that development that accompany or foreshadow psychiatric disease.

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., Co-morbidity and symptom overlap make it difficult to associate psychiatric disorders with unique neural signatures. Here, the authors use a data-driven approach to show that the symptom dimensions of mood, psychosis, fear and externalizing behavior exhibit unique patterns of functional dysconnectivity.

Multiple studies have shown that data quality is a critical confound in the construction of brain networks derived from functional MRI. This problem is particularly relevant for studies of human brain development where important variables (such as participant age) are correlated with data quality. Nevertheless, the impact of head motion on estimates of structural connectivity derived from diffusion tractography methods remains poorly characterized. Here, we evaluated the impact of in-scanner head motion on structural connectivity using a sample of 949 participants (ages 8-23 years old) who passed a rigorous quality assessment protocol for diffusion magnetic resonance imaging (dMRI) acquired as part of the Philadelphia Neurodevelopmental Cohort. Structural brain networks were constructed for each participant using both deterministic and probabilistic tractography. We hypothesized that subtle variation in head motion would systematically bias estimates of structural connectivity and confound developmental inference, as observed in previous studies of functional connectivity. Even following quality assurance and retrospective correction for head motion, eddy currents, and field distortions, in-scanner head motion significantly impacted the strength of structural connectivity in a consistency- and length-dependent manner. Specifically, increased head motion was associated with reduced estimates of structural connectivity for network edges with high inter-subject consistency, which included both short- and long-range connections. In contrast, motion inflated estimates of structural connectivity for low-consistency network edges that were primarily shorter-range. Finally, we demonstrate that age-related differences in head motion can both inflate and obscure developmental inferences on structural connectivity. Taken together, these data delineate the systematic impact of head motion on structural connectivity, and provide a critical context for identifying motion-related confounds in studies of structural brain network 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.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

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.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.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.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.

Spatial extent inference (SEI) is widely used across neuroimaging modalities to adjust for multiple comparisons when studying brain-phenotype associations that inform our understanding of disease. Recent studies have shown that Gaussian random field (GRF)-based tools can have inflated family-wise error rates (FWERs). This has led to substantial controversy as to which processing choices are necessary to control the FWER using GRF-based SEI. The failure of GRF-based methods is due to unrealistic assumptions about the spatial covariance function of the imaging data. A permutation procedure is the most robust SEI tool because it estimates the spatial covariance function from the imaging data. However, the permutation procedure can fail because its assumption of exchangeability is violated in many imaging modalities. Here, we propose the (semi-) parametric bootstrap joint (PBJ; sPBJ) testing procedures that are designed for SEI of multilevel imaging data. The sPBJ procedure uses a robust estimate of the spatial covariance function, which yields consistent estimates of standard errors, even if the covariance model is misspecified. We use the methods to study the association between performance and executive functioning in a working memory functional magnetic resonance imaging study. The sPBJ has similar or greater power to the PBJ and permutation procedures while maintaining the nominal type 1 error rate in reasonable sample sizes. We provide an R package to perform inference using the PBJ and sPBJ procedures.

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.