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All Publications

  • Mitigating head motion artifact in functional connectivity MRI. Nature protocols Ciric, R. n., Rosen, A. F., Erus, G. n., Cieslak, M. n., Adebimpe, A. n., Cook, P. A., Bassett, D. S., Davatzikos, C. n., Wolf, D. H., Satterthwaite, T. D. 2018; 13 (12): 2801–26


    Participant motion during functional magnetic resonance image (fMRI) acquisition produces spurious signal fluctuations that can confound measures of functional connectivity. Without mitigation, motion artifact can bias statistical inferences about relationships between connectivity and individual differences. To counteract motion artifact, this protocol describes the implementation of a validated, high-performance denoising strategy that combines a set of model features, including physiological signals, motion estimates, and mathematical expansions, to target both widespread and focal effects of subject movement. This protocol can be used to reduce motion-related variance to near zero in studies of functional connectivity, providing up to a 100-fold improvement over minimal-processing approaches in large datasets. Image denoising requires 40 min to 4 h of computing per image, depending on model specifications and data dimensionality. The protocol additionally includes instructions for assessing the performance of a denoising strategy. Associated software implements all denoising and diagnostic procedures, using a combination of established image-processing libraries and the eXtensible Connectivity Pipeline (XCP) software.

    View details for DOI 10.1038/s41596-018-0065-y

    View details for PubMedID 30446748

  • Contextual connectivity: A framework for understanding the intrinsic dynamic architecture of large-scale functional brain networks. Scientific reports Ciric, R., Nomi, J. S., Uddin, L. Q., Satpute, A. B. 2017; 7 (1): 6537


    Investigations of the human brain's connectomic architecture have produced two alternative models: one describes the brain's spatial structure in terms of static localized networks, and the other describes the brain's temporal structure in terms of dynamic whole-brain states. Here, we used tools from connectivity dynamics to develop a synthesis that bridges these models. Using resting fMRI data, we investigated the assumptions undergirding current models of the human connectome. Consistent with state-based models, our results suggest that static localized networks are superordinate approximations of underlying dynamic states. Furthermore, each of these localized, dynamic connectivity states is associated with global changes in the whole-brain functional connectome. By nesting localized dynamic connectivity states within their whole-brain contexts, we demonstrate the relative temporal independence of brain networks. Our assay for functional autonomy of coordinated neural systems is broadly applicable, and our findings provide evidence of structure in temporal state dynamics that complements the well-described static spatial organization of the brain.

    View details for DOI 10.1038/s41598-017-06866-w

    View details for PubMedID 28747717

    View details for PubMedCentralID PMC5529582

  • Benchmarking of participant-level confound regression strategies for the control of motion artifact in studies of functional connectivity. NeuroImage Ciric, R. n., Wolf, D. H., Power, J. D., Roalf, D. R., Baum, G. L., Ruparel, K. n., Shinohara, R. T., Elliott, M. A., Eickhoff, S. B., Davatzikos, C. n., Gur, R. C., Gur, R. E., Bassett, D. S., Satterthwaite, T. D. 2017; 154: 174–87


    Since initial reports regarding the impact of motion artifact on measures of functional connectivity, there has been a proliferation of participant-level confound regression methods to limit its impact. However, many of the most commonly used techniques have not been systematically evaluated using a broad range of outcome measures. Here, we provide a systematic evaluation of 14 participant-level confound regression methods in 393 youths. Specifically, we compare methods according to four benchmarks, including the residual relationship between motion and connectivity, distance-dependent effects of motion on connectivity, network identifiability, and additional degrees of freedom lost in confound regression. Our results delineate two clear trade-offs among methods. First, methods that include global signal regression minimize the relationship between connectivity and motion, but result in distance-dependent artifact. In contrast, censoring methods mitigate both motion artifact and distance-dependence, but use additional degrees of freedom. Importantly, less effective de-noising methods are also unable to identify modular network structure in the connectome. Taken together, these results emphasize the heterogeneous efficacy of existing methods, and suggest that different confound regression strategies may be appropriate in the context of specific scientific goals.

    View details for DOI 10.1016/j.neuroimage.2017.03.020

    View details for PubMedID 28302591

    View details for PubMedCentralID PMC5483393

  • TemplateFlow: FAIR-sharing of multi-scale, multi-species brain models. Nature methods Ciric, R., Thompson, W. H., Lorenz, R., Goncalves, M., MacNicol, E. E., Markiewicz, C. J., Halchenko, Y. O., Ghosh, S. S., Gorgolewski, K. J., Poldrack, R. A., Esteban, O. 2022; 19 (12): 1568-1571


    Reference anatomies of the brain ('templates') and corresponding atlases are the foundation for reporting standardized neuroimaging results. Currently, there is no registry of templates and atlases; therefore, the redistribution of these resources occurs either bundled within existing software or in ad hoc ways such as downloads from institutional sites and general-purpose data repositories. We introduce TemplateFlow as a publicly available framework for human and non-human brain models. The framework combines an open database with software for access, management, and vetting, allowing scientists to share their resources under FAIR-findable, accessible, interoperable, and reusable-principles. TemplateFlow enables multifaceted insights into brains across species, and supports multiverse analyses testing whether results generalize across standard references, scales, and in the long term, species.

    View details for DOI 10.1038/s41592-022-01681-2

    View details for PubMedID 36456786

  • Efficient coding in the economics of human brain connectomics. Network neuroscience (Cambridge, Mass.) Zhou, D., Lynn, C. W., Cui, Z., Ciric, R., Baum, G. L., Moore, T. M., Roalf, D. R., Detre, J. A., Gur, R. C., Gur, R. E., Satterthwaite, T. D., Bassett, D. S. 2022; 6 (1): 234-274


    In systems neuroscience, most models posit that brain regions communicate information under constraints of efficiency. Yet, evidence for efficient communication in structural brain networks characterized by hierarchical organization and highly connected hubs remains sparse. The principle of efficient coding proposes that the brain transmits maximal information in a metabolically economical or compressed form to improve future behavior. To determine how structural connectivity supports efficient coding, we develop a theory specifying minimum rates of message transmission between brain regions to achieve an expected fidelity, and we test five predictions from the theory based on random walk communication dynamics. In doing so, we introduce the metric of compression efficiency, which quantifies the trade-off between lossy compression and transmission fidelity in structural networks. In a large sample of youth (n = 1,042; age 8-23 years), we analyze structural networks derived from diffusion-weighted imaging and metabolic expenditure operationalized using cerebral blood flow. We show that structural networks strike compression efficiency trade-offs consistent with theoretical predictions. We find that compression efficiency prioritizes fidelity with development, heightens when metabolic resources and myelination guide communication, explains advantages of hierarchical organization, links higher input fidelity to disproportionate areal expansion, and shows that hubs integrate information by lossy compression. Lastly, compression efficiency is predictive of behavior-beyond the conventional network efficiency metric-for cognitive domains including executive function, memory, complex reasoning, and social cognition. Our findings elucidate how macroscale connectivity supports efficient coding and serve to foreground communication processes that utilize random walk dynamics constrained by network connectivity.

    View details for DOI 10.1162/netn_a_00223

    View details for PubMedID 36605887

  • Analysis of task-based functional MRI data preprocessed with fMRIPrep. Nature protocols Esteban, O., Ciric, R., Finc, K., Blair, R. W., Markiewicz, C. J., Moodie, C. A., Kent, J. D., Goncalves, M., DuPre, E., Gomez, D. E., Ye, Z., Salo, T., Valabregue, R., Amlien, I. K., Liem, F., Jacoby, N., Stojic, H., Cieslak, M., Urchs, S., Halchenko, Y. O., Ghosh, S. S., De La Vega, A., Yarkoni, T., Wright, J., Thompson, W. H., Poldrack, R. A., Gorgolewski, K. J. 2020


    Functional magnetic resonance imaging (fMRI) is a standard tool to investigate the neural correlates of cognition. fMRI noninvasively measures brain activity, allowing identification of patterns evoked by tasks performed during scanning. Despite the long history of this technique, the idiosyncrasies of each dataset have led to the use of ad-hoc preprocessing protocols customized for nearly every different study. This approach is time consuming, error prone and unsuitable for combining datasets from many sources. Here we showcase fMRIPrep (, a robust tool to prepare human fMRI data for statistical analysis. This software instrument addresses the reproducibility concerns of the established protocols for fMRI preprocessing. By leveraging the Brain Imaging Data Structure to standardize both the input datasets (MRI data as stored by the scanner) and the outputs (data ready for modeling and analysis), fMRIPrep is capable of preprocessing a diversity of datasets without manual intervention. In support of the growing popularity of fMRIPrep, this protocol describes how to integrate the tool in a task-based fMRI investigation workflow.

    View details for DOI 10.1038/s41596-020-0327-3

    View details for PubMedID 32514178

  • Optimization of energy state transition trajectory supports the development of executive function during youth. eLife Cui, Z. n., Stiso, J. n., Baum, G. L., Kim, J. Z., Roalf, D. R., Betzel, R. F., Gu, S. n., Lu, Z. n., Xia, C. H., He, X. n., Ciric, R. n., Oathes, D. J., Moore, T. M., Shinohara, R. T., Ruparel, K. n., Davatzikos, C. n., Pasqualetti, F. n., Gur, R. E., Gur, R. C., Bassett, D. S., Satterthwaite, T. D. 2020; 9


    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.

    View details for DOI 10.7554/eLife.53060

    View details for PubMedID 32216874

  • Temporal sequences of brain activity at rest are constrained by white matter structure and modulated by cognitive demands. Communications biology Cornblath, E. J., Ashourvan, A. n., Kim, J. Z., Betzel, R. F., Ciric, R. n., Adebimpe, A. n., Baum, G. L., He, X. n., Ruparel, K. n., Moore, T. M., Gur, R. C., Gur, R. E., Shinohara, R. T., Roalf, D. R., Satterthwaite, T. D., Bassett, D. S. 2020; 3 (1): 261


    A diverse set of white matter connections supports seamless transitions between cognitive states. However, it remains unclear how these connections guide the temporal progression of large-scale brain activity patterns in different cognitive states. Here, we analyze the brain's trajectories across a set of single time point activity patterns from functional magnetic resonance imaging data acquired during the resting state and an n-back working memory task. We find that specific temporal sequences of brain activity are modulated by cognitive load, associated with age, and related to task performance. Using diffusion-weighted imaging acquired from the same subjects, we apply tools from network control theory to show that linear spread of activity along white matter connections constrains the probabilities of these sequences at rest, while stimulus-driven visual inputs explain the sequences observed during the n-back task. Overall, these results elucidate the structural underpinnings of cognitively and developmentally relevant spatiotemporal brain dynamics.

    View details for DOI 10.1038/s42003-020-0961-x

    View details for PubMedID 32444827

  • Development of structure-function coupling in human brain networks during youth. Proceedings of the National Academy of Sciences of the United States of America Baum, G. L., Cui, Z., Roalf, D. R., Ciric, R., Betzel, R. F., Larsen, B., Cieslak, M., Cook, P. A., Xia, C. H., Moore, T. M., Ruparel, K., Oathes, D. J., Alexander-Bloch, A. F., Shinohara, R. T., Raznahan, A., Gur, R. E., Gur, R. C., Bassett, D. S., Satterthwaite, T. D. 2019


    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.

    View details for DOI 10.1073/pnas.1912034117

    View details for PubMedID 31874926

  • Accelerated cortical thinning within structural brain networks is associated with irritability in youth NEUROPSYCHOPHARMACOLOGY Jirsaraie, R. J., Kaczkurkin, A. N., Rush, S., Piiwia, K., Adebimpe, A., Bassett, D. S., Bourque, J., Calkins, M. E., Cieslak, M., Ciric, R., Cook, P. A., Davila, D., Elliott, M. A., Leibenluft, E., Murtha, K., Roalf, D. R., Rosen, A. G., Ruparel, K., Shinohara, R. T., Sotiras, A., Wolf, D. H., Davatzikos, C., Satterthwaite, T. D. 2019; 44 (13): 2254–62


    Irritability is an important dimension of psychopathology that spans multiple clinical diagnostic categories, yet its relationship to patterns of brain development remains sparsely explored. Here, we examined how transdiagnostic symptoms of irritability relate to the development of structural brain networks. All participants (n = 137, 83 females) completed structural brain imaging with 3 Tesla MRI at two timepoints (mean age at follow-up: 21.1 years, mean inter-scan interval: 5.2 years). Irritability at follow-up was assessed using the Affective Reactivity Index, and cortical thickness was quantified using Advanced Normalization Tools software. Structural covariance networks were delineated using non-negative matrix factorization, a multivariate analysis technique. Both cross-sectional and longitudinal associations with irritability at follow-up were evaluated using generalized additive models with penalized splines. The False Discovery Rate (q < 0.05) was used to correct for multiple comparisons. Cross-sectional analysis of follow-up data revealed that 11 of the 24 covariance networks were associated with irritability, with higher levels of irritability being associated with thinner cortex. Longitudinal analyses further revealed that accelerated cortical thinning within nine networks was related to irritability at follow-up. Effects were particularly prominent in brain regions implicated in emotion regulation, including the orbitofrontal, lateral temporal, and medial temporal cortex. Collectively, these findings suggest that irritability is associated with widespread reductions in cortical thickness and accelerated cortical thinning, particularly within the frontal and temporal cortex. Aberrant structural maturation of regions important for emotional regulation may in part underlie symptoms of irritability.

    View details for DOI 10.1038/s41386-019-0508-3

    View details for Web of Science ID 000496913900017

    View details for PubMedID 31476764

    View details for PubMedCentralID PMC6897907

  • Evidence for Dissociable Linkage of Dimensions of Psychopathology to Brain Structure in Youths AMERICAN JOURNAL OF PSYCHIATRY Kaczkurkin, A. N., Park, S., Sotiras, A., Moore, T. M., Calkins, M. E., Cieslak, M., Rosen, A. G., Ciric, R., Xia, C., Cui, Z., Sharma, A., Wolf, D. H., Ruparel, K., Pine, D. S., Shinohara, R. T., Roalf, D. R., Gur, R. C., Davatzikos, C., Gur, R. E., Satterthwaite, T. D. 2019; 176 (12): 1000–1009


    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.

    View details for DOI 10.1176/appi.ajp.2019.18070835

    View details for Web of Science ID 000499693200007

    View details for PubMedID 31230463

    View details for PubMedCentralID PMC6888993

  • System-level matching of structural and functional connectomes in the human brain NEUROIMAGE Osmanhoglu, Y., Tunc, B., Parker, D., Elliott, M. A., Baum, G. L., Ciric, R., Satterthwaite, T. D., Gur, R. E., Gur, R. C., Verma, R. 2019; 199: 93–104


    The brain can be considered as an information processing network, where complex behavior manifests as a result of communication between large-scale functional systems such as visual and default mode networks. As the communication between brain regions occurs through underlying anatomical pathways, it is important to define a "traffic pattern" that properly describes how the regions exchange information. Empirically, the choice of the traffic pattern can be made based on how well the functional connectivity between regions matches the structural pathways equipped with that traffic pattern. In this paper, we present a multimodal connectomics paradigm utilizing graph matching to measure similarity between structural and functional connectomes (derived from dMRI and fMRI data) at node, system, and connectome level. Through an investigation of the brain's structure-function relationship over a large cohort of 641 healthy developmental participants aged 8-22 years, we demonstrate that communicability as the traffic pattern describes the functional connectivity of the brain best, with large-scale systems having significant agreement between their structural and functional connectivity patterns. Notably, matching between structural and functional connectivity for the functionally specialized modular systems such as visual and motor networks are higher as compared to other more integrated systems. Additionally, we show that the negative functional connectivity between the default mode network (DMN) and motor, frontoparietal, attention, and visual networks is significantly associated with its underlying structural connectivity, highlighting the counterbalance between functional activation patterns of DMN and other systems. Finally, we investigated sex difference and developmental changes in brain and observed that similarity between structure and function changes with development.

    View details for DOI 10.1016/j.neuroimage.2019.05.064

    View details for Web of Science ID 000478780200009

    View details for PubMedID 31141738

    View details for PubMedCentralID PMC6688960

  • Unifying the Notions of Modularity and Core-Periphery Structure in Functional Brain Networks during Youth. Cerebral cortex (New York, N.Y. : 1991) Gu, S., Xia, C. H., Ciric, R., Moore, T. M., Gur, R. C., Gur, R. E., Satterthwaite, T. D., Bassett, D. S. 2019


    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.

    View details for DOI 10.1093/cercor/bhz150

    View details for PubMedID 31504253

  • Motion artifact in studies of functional connectivity: Characteristics and mitigation strategies HUMAN BRAIN MAPPING Satterthwaite, T. D., Ciric, R., Roalf, D. R., Davatzikos, C., Bassett, D. S., Wolf, D. H. 2019; 40 (7): 2033–51


    Motion artifacts are now recognized as a major methodological challenge for studies of functional connectivity. As in-scanner motion is frequently correlated with variables of interest such as age, clinical status, cognitive ability, and symptom severity, in-scanner motion has the potential to introduce systematic bias. In this article, we describe how motion-related artifacts influence measures of functional connectivity and discuss the relative strengths and weaknesses of commonly used denoising strategies. Furthermore, we illustrate how motion can bias inference, using a study of brain development as an example. Finally, we highlight directions of ongoing and future research, and provide recommendations for investigators in the field. Hum Brain Mapp, 40:2033-2051, 2019. © 2017 Wiley Periodicals, Inc.

    View details for DOI 10.1002/hbm.23665

    View details for Web of Science ID 000463153200003

    View details for PubMedID 29091315

    View details for PubMedCentralID PMC5930165

  • Associations between Neighborhood SES and Functional Brain Network Development. Cerebral cortex (New York, N.Y. : 1991) Tooley, U. A., Mackey, A. P., Ciric, R., Ruparel, K., Moore, T. M., Gur, R. C., Gur, R. E., Satterthwaite, T. D., Bassett, D. S. 2019


    Higher socioeconomic status (SES) in childhood is associated with stronger cognitive abilities, higher academic achievement, and lower incidence of mental illness later in development. While prior work has mapped the associations between neighborhood SES and brain structure, little is known about the relationship between SES and intrinsic neural dynamics. Here, we capitalize upon a large cross-sectional community-based sample (Philadelphia Neurodevelopmental Cohort, ages 8-22years, n=1012) to examine associations between age, SES, and functional brain network topology. We characterize this topology using a local measure of network segregation known as the clustering coefficient and find that it accounts for a greater degree of SES-associated variance than mesoscale segregation captured by modularity. High-SES youth displayed stronger positive associations between age and clustering than low-SES youth, and this effect was most pronounced for regions in the limbic, somatomotor, and ventral attention systems. The moderating effect of SES on positive associations between age and clustering was strongest for connections of intermediate length and was consistent with a stronger negative relationship between age and local connectivity in these regions in low-SES youth. Our findings suggest that, in late childhood and adolescence, neighborhood SES is associated with variation in the development of functional network structure in the human brain.

    View details for DOI 10.1093/cercor/bhz066

    View details for PubMedID 31220218

  • Evaluation of confound regression strategies for the mitigation of micromovement artifact in studies of dynamic resting-state functional connectivity and multilayer network modularity NETWORK NEUROSCIENCE Lydon-Staley, D. M., Ciric, R., Satterthwaite, T. D., Bassett, D. S. 2019; 3 (2): 427–54


    Dynamic functional connectivity reflects the spatiotemporal organization of spontaneous brain activity in health and disease. Dynamic functional connectivity may be susceptible to artifacts induced by participant motion. This report provides a systematic evaluation of 12 commonly used participant-level confound regression strategies designed to mitigate the effects of micromovements in a sample of 393 youths (ages 8-22 years). Each strategy was evaluated according to a number of benchmarks, including (a) the residual association between participant motion and edge dispersion, (b) distance-dependent effects of motion on edge dispersion, (c) the degree to which functional subnetworks could be identified by multilayer modularity maximization, and (d) measures of module reconfiguration, including node flexibility and node promiscuity. Results indicate variability in the effectiveness of the evaluated pipelines across benchmarks. Methods that included global signal regression were the most consistently effective de-noising strategies.

    View details for DOI 10.1162/netn_a_00071

    View details for Web of Science ID 000476767200009

    View details for PubMedID 30793090

    View details for PubMedCentralID PMC6370491

  • Faster family-wise error control for neuroimaging with a parametric bootstrap BIOSTATISTICS Vandekar, S. N., Satterthwaite, T. D., Rosen, A., Ciric, R., Roalf, D. R., Ruparel, K., Gur, R. C., Gur, R. E., Shinohara, R. T. 2018; 19 (4): 497–513


    In neuroimaging, hundreds to hundreds of thousands of tests are performed across a set of brain regions or all locations in an image. Recent studies have shown that the most common family-wise error (FWE) controlling procedures in imaging, which rely on classical mathematical inequalities or Gaussian random field theory, yield FWE rates (FWER) that are far from the nominal level. Depending on the approach used, the FWER can be exceedingly small or grossly inflated. Given the widespread use of neuroimaging as a tool for understanding neurological and psychiatric disorders, it is imperative that reliable multiple testing procedures are available. To our knowledge, only permutation joint testing procedures have been shown to reliably control the FWER at the nominal level. However, these procedures are computationally intensive due to the increasingly available large sample sizes and dimensionality of the images, and analyses can take days to complete. Here, we develop a parametric bootstrap joint testing procedure. The parametric bootstrap procedure works directly with the test statistics, which leads to much faster estimation of adjusted p-values than resampling-based procedures while reliably controlling the FWER in sample sizes available in many neuroimaging studies. We demonstrate that the procedure controls the FWER in finite samples using simulations, and present region- and voxel-wise analyses to test for sex differences in developmental trajectories of cerebral blood flow.

    View details for DOI 10.1093/biostatistics/kxx051

    View details for Web of Science ID 000448373200006

    View details for PubMedID 29059370

    View details for PubMedCentralID PMC6232833

  • Linked dimensions of psychopathology and connectivity in functional brain networks NATURE COMMUNICATIONS Xia, C., Ma, Z., Ciric, R., Gu, S., Betzel, R. F., Kaczkurkin, A. N., Calkins, M. E., Cook, P. A., de la Garza, A., Vandekar, S. N., Cui, Z., Moore, T. M., Roalf, D. R., Ruparel, K., Wolf, D. H., Davatzikos, C., Gur, R. C., Gur, R. E., Shinohara, R. T., Bassett, D. S., Satterthwaite, T. D. 2018; 9: 3003


    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.

    View details for DOI 10.1038/s41467-018-05317-y

    View details for Web of Science ID 000440413500003

    View details for PubMedID 30068943

    View details for PubMedCentralID PMC6070480

  • The impact of in-scanner head motion on structural connectivity derived from diffusion MRI NEUROIMAGE Baum, G. L., Roalf, D. R., Cook, P. A., Ciric, R., Rosen, A. G., Xia, C., Elliott, M. A., Ruparel, K., Verma, R., Tunc, B., Gur, R. C., Gur, R. E., Bassett, D. S., Satterthwaite, T. D. 2018; 173: 275–86


    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.

    View details for DOI 10.1016/j.neuroimage.2018.02.041

    View details for Web of Science ID 000430366000022

    View details for PubMedID 29486323

    View details for PubMedCentralID PMC5911236

  • Quantitative assessment of structural image quality NEUROIMAGE Rosen, A. G., Roalf, D. R., Ruparel, K., Blake, J., Seelaus, K., Villa, L. P., Ciric, R., Cook, P. A., Davatzikos, C., Elliott, M. A., de La Garza, A., Gennatas, E. D., Quarmley, M., Schmitt, J., Shinohara, R. T., Tisdall, M., Craddock, R., Gur, R. E., Gur, R. C., Satterthwaite, T. D. 2018; 169: 407–18


    Data quality is increasingly recognized as one of the most important confounding factors in brain imaging research. It is particularly important for studies of brain development, where age is systematically related to in-scanner motion and data quality. Prior work has demonstrated that in-scanner head motion biases estimates of structural neuroimaging measures. However, objective measures of data quality are not available for most structural brain images. Here we sought to identify quantitative measures of data quality for T1-weighted volumes, describe how these measures relate to cortical thickness, and delineate how this in turn may bias inference regarding associations with age in youth. Three highly-trained raters provided manual ratings of 1840 raw T1-weighted volumes. These images included a training set of 1065 images from Philadelphia Neurodevelopmental Cohort (PNC), a test set of 533 images from the PNC, as well as an external test set of 242 adults acquired on a different scanner. Manual ratings were compared to automated quality measures provided by the Preprocessed Connectomes Project's Quality Assurance Protocol (QAP), as well as FreeSurfer's Euler number, which summarizes the topological complexity of the reconstructed cortical surface. Results revealed that the Euler number was consistently correlated with manual ratings across samples. Furthermore, the Euler number could be used to identify images scored "unusable" by human raters with a high degree of accuracy (AUC: 0.98-0.99), and out-performed proxy measures from functional timeseries acquired in the same scanning session. The Euler number also was significantly related to cortical thickness in a regionally heterogeneous pattern that was consistent across datasets and replicated prior results. Finally, data quality both inflated and obscured associations with age during adolescence. Taken together, these results indicate that reliable measures of data quality can be automatically derived from T1-weighted volumes, and that failing to control for data quality can systematically bias the results of studies of brain maturation.

    View details for DOI 10.1016/j.neuroimage.2017.12.059

    View details for Web of Science ID 000427642800037

    View details for PubMedID 29278774

    View details for PubMedCentralID PMC5856621

  • Diminished Cortical Thickness Is Associated with Impulsive Choice in Adolescence JOURNAL OF NEUROSCIENCE Pehlivanova, M., Wolf, D. H., Sotiras, A., Kaczkurkin, A. N., Moore, T. M., Ciric, R., Cook, P. A., de La Garza, A., Rosen, A. G., Ruparel, K., Sharma, A., Shinohara, R. T., Roalf, D. R., Gur, R. C., Davatzikos, C., Gur, R. E., Kable, J. W., Satterthwaite, T. D. 2018; 38 (10): 2471–81


    Adolescence is characterized by both maturation of brain structure and increased risk of negative outcomes from behaviors associated with impulsive decision-making. One important index of impulsive choice is delay discounting (DD), which measures the tendency to prefer smaller rewards available soon over larger rewards delivered after a delay. However, it remains largely unknown how individual differences in structural brain development may be associated with impulsive choice during adolescence. Leveraging a unique large sample of 427 human youths (208 males and 219 females) imaged as part of the Philadelphia Neurodevelopmental Cohort, we examined associations between delay discounting and cortical thickness within structural covariance networks. These structural networks were derived using non-negative matrix factorization, an advanced multivariate technique for dimensionality reduction, and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear developmental effects. We found that impulsive choice, as measured by greater discounting, was most strongly associated with diminished cortical thickness in structural brain networks that encompassed the ventromedial prefrontal cortex, orbitofrontal cortex, temporal pole, and temporoparietal junction. Furthermore, structural brain networks predicted DD above and beyond cognitive performance. Together, these results suggest that reduced cortical thickness in regions known to be involved in value-based decision-making is a marker of impulsive choice during the critical period of adolescence.SIGNIFICANCE STATEMENT Risky behaviors during adolescence, such as initiation of substance use or reckless driving, are a major source of morbidity and mortality. In this study, we present evidence from a large sample of youths that diminished cortical thickness in specific structural brain networks is associated with impulsive choice. Notably, the strongest association between impulsive choice and brain structure was seen in regions implicated in value-based decision-making; namely, the ventromedial prefrontal and orbitofrontal cortices. Moving forward, such neuroanatomical markers of impulsivity may aid in the development of personalized interventions targeted to reduce risk of negative outcomes resulting from impulsivity during adolescence.

    View details for DOI 10.1523/JNEUROSCI.2200-17.2018

    View details for Web of Science ID 000427689100008

    View details for PubMedID 29440536

    View details for PubMedCentralID PMC5858592

  • Brain state expression and transitions are related to complex executive cognition in normative neurodevelopment NEUROIMAGE Medaglia, J. D., Satterthwaite, T. D., Kelkar, A., Ciric, R., Moore, T. M., Ruparel, K., Gur, R. C., Gur, R. E., Bassett, D. S. 2018; 166: 293–306


    Adolescence is marked by rapid development of executive function. Mounting evidence suggests that executive function in adults may be driven by dynamic control of neurophysiological processes. Yet, how these dynamics evolve over adolescence and contribute to cognitive development is unknown. In a sample of 780 youth aged 8-22 yr (42.7% male) from the Philadelphia Neurodevelopment Cohort, we use a dynamic graph approach to extract activation states in BOLD fMRI data from 264 brain regions. We construct a graph in which each observation in time is a node and the similarity in brain states at two different times is an edge. Using this graphical approach, we identify two primary brain states reminiscent of intrinsic and task-evoked systems. We show that time spent in these two states is higher in older adolescents, as is the flexibility with which the brain switches between them. Increasing time spent in primary states and flexibility among states relates to increases in a complex executive accuracy factor score over adolescence. Flexibility is more positively associated with accuracy toward early adulthood. These findings suggest that brain state dynamics are associated with complex executive function across a critical period of adolescence.

    View details for DOI 10.1016/j.neuroimage.2017.10.048

    View details for Web of Science ID 000418716800026

    View details for PubMedID 29126965

    View details for PubMedCentralID PMC5747984

  • The regulation of positive and negative emotions through instructed causal attributions in lifetime depression - A functional magnetic resonance imaging study NEUROIMAGE-CLINICAL Loeffler, L. K., Radke, S., Habel, U., Ciric, R., Satterthwaite, T. D., Schneider, F., Derntl, B. 2018; 20: 1233–45


    Adequate emotional control is essential for mental health. Deficiencies in emotion regulation are evident in many psychiatric disorders, including depression. Patients with depression show, for instance, disrupted neural emotion regulation in cognitive regulation regions such as lateral and medial prefrontal cortices. Since depressed individuals tend to attribute positive events to external circumstances and negative events to themselves, modifying this non-self-serving attributional style may represent a promising regulation strategy. Spontaneous causal attributions are generally processed in medial brain structures, particularly the precuneus. However, so far no study has investigated neural correlates of instructed causal attributions (e.g. instructing a person to intentionally relate positive events to the self) and their potential to regulate emotions. The current study therefore aimed to examine how instructed causal attributions of positive and negative events affect the emotional experience of depressed individuals as well as its neural bases. For this purpose pictures of sad and happy faces were presented to 26 patients with a lifetime major depression (MDD) and 26 healthy controls (HC) during fMRI. Participants should respond naturally ("view") or imagine that the person on the picture was sad/happy because of them ("internal attribution") or because something else happened ("external attribution"). Trait attributional style and depressive symptoms were assessed with questionnaires to examine potential influential factors on emotion regulation ability. Results revealed that patients compared to controls show a non-self-serving trait attributional style (i.e. more external attributions of positive events and more internal attributions of negative events). Intriguingly, when instructed to apply specific causal attributions during the emotion regulation task, patients and controls were similarly able to regulate positive and negative emotions. Regulating emotions through instructed attributions (internal/external attribution>view) generally engaged the precuneus, which was correlated with patients' trait attributional style (i.e. more precuneus activation during external>view was linked to a general tendency to relate positive events to external sources). Up-regulating happiness through internal (compared to external) attributions recruited the parahippocampal gyrus only in controls. The down-regulation of sadness (external>internal attribution), in contrast, engaged the superior frontal gyrus only in patients. Superior frontal gyrus activation thereby correlated with depression severity, which implies a greater need of cognitive resources for a successful regulation in more severely depressed. Patients and controls did not differ in activation in brain regions related to cognitive emotion regulation or attribution. However, results point to a disturbed processing of positive emotions in depression. Interestingly, increased precuneus resting-state connectivity with emotion regulation brain regions (inferior parietal lobule, middle frontal gyrus) was linked to healthier attributions (i.e. external attributions of negative events) in patients and controls. Adequate neural communication between these regions therefore seem to facilitate an adaptive trait attributional style. Findings of this study emphasize that despite patients' dysfunctional trait attributional style, explicitly applying causal attributions effectively regulates emotions. Future research should examine the efficacy of instructed attributions in reducing negative affect and anhedonia in depressed patients, for instance by means of attribution trainings during psychotherapy.

    View details for DOI 10.1016/j.nicl.2018.10.025

    View details for Web of Science ID 000450799000131

    View details for PubMedID 30414987

    View details for PubMedCentralID PMC6234525

  • Common Dimensional Reward Deficits Across Mood and Psychotic Disorders: A Connectome-Wide Association Study AMERICAN JOURNAL OF PSYCHIATRY Sharma, A., Wolf, D. H., Ciric, R., Kable, J. W., Moore, T. M., Vandekar, S. N., Katchmar, N., Daldal, A., Ruparel, K., Davatzikos, C., Elliott, M. A., Calkins, M. E., Shinohara, R. T., Bassett, D. S., Satterthwaite, T. D. 2017; 174 (7): 657–66


    Anhedonia is central to multiple psychiatric disorders and causes substantial disability. A dimensional conceptualization posits that anhedonia severity is related to a transdiagnostic continuum of reward deficits in specific neural networks. Previous functional connectivity studies related to anhedonia have focused on case-control comparisons in specific disorders, using region-specific seed-based analyses. Here, the authors explore the entire functional connectome in relation to reward responsivity across a population of adults with heterogeneous psychopathology.In a sample of 225 adults from five diagnostic groups (major depressive disorder, N=32; bipolar disorder, N=50; schizophrenia, N=51; psychosis risk, N=39; and healthy control subjects, N=53), the authors conducted a connectome-wide analysis examining the relationship between a dimensional measure of reward responsivity (the reward sensitivity subscale of the Behavioral Activation Scale) and resting-state functional connectivity using multivariate distance-based matrix regression.The authors identified foci of dysconnectivity associated with reward responsivity in the nucleus accumbens, the default mode network, and the cingulo-opercular network. Follow-up analyses revealed dysconnectivity among specific large-scale functional networks and their connectivity with the nucleus accumbens. Reward deficits were associated with decreased connectivity between the nucleus accumbens and the default mode network and increased connectivity between the nucleus accumbens and the cingulo-opercular network. In addition, impaired reward responsivity was associated with default mode network hyperconnectivity and diminished connectivity between the default mode network and the cingulo-opercular network.These results emphasize the centrality of the nucleus accumbens in the pathophysiology of reward deficits and suggest that dissociable patterns of connectivity among large-scale networks are critical to the neurobiology of reward dysfunction across clinical diagnostic categories.

    View details for DOI 10.1176/appi.ajp.2016.16070774

    View details for Web of Science ID 000404473900012

    View details for PubMedID 28135847

    View details for PubMedCentralID PMC5495611

  • Modular Segregation of Structural Brain Networks Supports the Development of Executive Function in Youth CURRENT BIOLOGY Baum, G. L., Ciric, R., Roalf, D. R., Betzel, R. F., Moore, T. M., Shinohara, R. T., Kahn, A. E., Vandekar, S. N., Rupert, P. E., Quarmley, M., Cook, P. A., Elliott, M. A., Ruparel, K., Gur, R. E., Gur, R. C., Bassett, D. S., Satterthwaite, T. D. 2017; 27 (11): 1561-+


    The human brain is organized into large-scale functional modules that have been shown to evolve in childhood and adolescence. However, it remains unknown whether the underlying white matter architecture is similarly refined during development, potentially allowing for improvements in executive function. In a sample of 882 participants (ages 8-22) who underwent diffusion imaging as part of the Philadelphia Neurodevelopmental Cohort, we demonstrate that structural network modules become more segregated with age, with weaker connections between modules and stronger connections within modules. Evolving modular topology facilitates global network efficiency and is driven by age-related strengthening of hub edges present both within and between modules. Critically, both modular segregation and network efficiency are associated with enhanced executive performance and mediate the improvement of executive functioning with age. Together, results delineate a process of structural network maturation that supports executive function in youth.

    View details for DOI 10.1016/j.cub.2017.04.051

    View details for Web of Science ID 000402814600042

    View details for PubMedID 28552358

    View details for PubMedCentralID PMC5491213

  • Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood JOURNAL OF NEUROSCIENCE Gennatas, E. D., Avants, B. B., Wolf, D. H., Satterthwaite, T. D., Ruparel, K., Ciric, R., Hakonarson, H., Gur, R. E., Gur, R. C. 2017; 37 (20): 5065–73


    Developmental structural neuroimaging studies in humans have long described decreases in gray matter volume (GMV) and cortical thickness (CT) during adolescence. Gray matter density (GMD), a measure often assumed to be highly related to volume, has not been systematically investigated in development. We used T1 imaging data collected on the Philadelphia Neurodevelopmental Cohort to study age-related effects and sex differences in four regional gray matter measures in 1189 youths ranging in age from 8 to 23 years. Custom T1 segmentation and a novel high-resolution gray matter parcellation were used to extract GMD, GMV, gray matter mass (GMM; defined as GMD × GMV), and CT from 1625 brain regions. Nonlinear models revealed that each modality exhibits unique age-related effects and sex differences. While GMV and CT generally decrease with age, GMD increases and shows the strongest age-related effects, while GMM shows a slight decline overall. Females have lower GMV but higher GMD than males throughout the brain. Our findings suggest that GMD is a prime phenotype for the assessment of brain development and likely cognition and that periadolescent gray matter loss may be less pronounced than previously thought. This work highlights the need for combined quantitative histological MRI studies.SIGNIFICANCE STATEMENT This study demonstrates that different MRI-derived gray matter measures show distinct age and sex effects and should not be considered equivalent but complementary. It is shown for the first time that gray matter density increases from childhood to young adulthood, in contrast with gray matter volume and cortical thickness, and that females, who are known to have lower gray matter volume than males, have higher density throughout the brain. A custom preprocessing pipeline and a novel high-resolution parcellation were created to analyze brain scans of 1189 youths collected as part of the Philadelphia Neurodevelopmental Cohort. A clear understanding of normal structural brain development is essential for the examination of brain-behavior relationships, the study of brain disease, and, ultimately, clinical applications of neuroimaging.

    View details for DOI 10.1523/JNEUROSCI.3550-16.2017

    View details for Web of Science ID 000402804000004

    View details for PubMedID 28432144

    View details for PubMedCentralID PMC5444192

  • Evolution of brain network dynamics in neurodevelopment NETWORK NEUROSCIENCE Chai, L. R., Khambhati, A. N., Ciric, R., Moore, T. M., Gur, R. C., Gur, R. E., Satterthwaite, T. D., Bassett, D. S. 2017; 1 (1): 14–30


    Cognitive function evolves significantly over development, enabling flexible control of human behavior. Yet, how these functions are instantiated in spatially distributed and dynamically interacting networks, or graphs, that change in structure from childhood to adolescence is far from understood. Here we applied a novel machine-learning method to track continuously overlapping and time-varying subgraphs in the brain at rest within a sample of 200 healthy youth (ages 8-11 and 19-22) drawn from the Philadelphia Neurodevelopmental Cohort. We uncovered a set of subgraphs that capture surprisingly integrated and dynamically changing interactions among known cognitive systems. We observed that subgraphs that were highly expressed were especially transient, flexibly switching between high and low expression over time. This transience was particularly salient in a subgraph predominantly linking frontoparietal regions of the executive system, which increases in both expression and flexibility from childhood to young adulthood. Collectively, these results suggest that healthy development is accompanied by an increasing precedence of executive networks and a greater switching of the regions and interactions subserving these networks.

    View details for DOI 10.1162/netn_a_00001

    View details for Web of Science ID 000449587400003

    View details for PubMedID 30793068

    View details for PubMedCentralID PMC6330215

  • Elevated Amygdala Perfusion Mediates Developmental Sex Differences in Trait Anxiety BIOLOGICAL PSYCHIATRY Kaczkurkin, A. N., Moore, T. M., Ruparel, K., Ciric, R., Calkins, M. E., Shinohara, R. T., Elliott, M. A., Hopson, R., Roalf, D. R., Vandekar, S. N., Gennatas, E. D., Wolf, D. H., Scott, J., Pine, D. S., Leibenluft, E., Detre, J. A., Foa, E. B., Gur, R. E., Gur, R. C., Satterthwaite, T. D. 2016; 80 (10): 775–85


    Adolescence is a critical period for emotional maturation and is a time when clinically significant symptoms of anxiety and depression increase, particularly in females. However, few studies relate developmental differences in symptoms of anxiety and depression to brain development. Cerebral blood flow is one brain phenotype that is known to have marked developmental sex differences.We investigated whether developmental sex differences in cerebral blood flow mediated sex differences in anxiety and depression symptoms by capitalizing on a large sample of 875 youths who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. Perfusion was quantified on a voxelwise basis using arterial spin-labeled magnetic resonance imaging at 3T. Perfusion images were related to trait and state anxiety using general additive models with penalized splines, while controlling for gray matter density on a voxelwise basis. Clusters found to be related to anxiety were evaluated for interactions with age, sex, and puberty.Trait anxiety was associated with elevated perfusion in a network of regions including the amygdala, anterior insula, and fusiform cortex, even after accounting for prescan state anxiety. Notably, these relationships strengthened with age and the transition through puberty. Moreover, higher trait anxiety in postpubertal females was mediated by elevated perfusion of the left amygdala.Taken together, these results demonstrate that differences in the evolution of cerebral perfusion during adolescence may be a critical element of the affective neurobiological characteristics underlying sex differences in anxiety and mood symptoms.

    View details for DOI 10.1016/j.biopsych.2016.04.021

    View details for Web of Science ID 000385513500008

    View details for PubMedID 27395327

    View details for PubMedCentralID PMC5074881