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Davatzikos, C.

Publications and source records attributed to Davatzikos, C..

At least 37 records · Page 2Linked to original sources
bioRxiv2022

Multiscale functional connectivity patterns of the aging brain learned from rsfMRI data of 4,259 individuals of the multi-cohort iSTAGING study

To learn multiscale functional connectivity patterns of the aging brain, we built a brain age prediction model of functional connectivity measures at seven scales on a large fMRI dataset, consisting of resting-state fMRI scans of 4259 individuals with a wide age range (22 to 97 years, with an average of 63) from five cohorts. We computed multiscale functional connectivity measures of individual subjects using a personalized functional network computational method, harmonized the functional connectivity measures of subjects from multiple datasets in order to build a functional brain age model, and finally evaluated how functional brain age gap correlated with cognitive measures of individual subjects. Our study has revealed that functional connectivity measures at multiple scales were more informative than those at any single scale for the brain age prediction, the data harmonization significantly improved the brain age prediction performance, and harmonization in the tangent space worked better than in the original space. Moreover, brain age gap scores of individual subjects derived from the brain age prediction model were significantly correlated with clinical and cognitive measures. Overall, these results demonstrated that multiscale functional connectivity patterns learned from a large-scale multi-site rsfMRI dataset were informative for characterizing the aging brain and the derived brain age gap was associated with cognitive and clinical measures.

bioengineering↗
bioRxiv2022

Penalized Decomposition Using Residuals (PeDecURe) for Nuisance Variable Adjustment in Multivariate Pattern Analysis

SO_SCPLOWUMMARYC_SCPLOWIn neuroimaging studies, multivariate methods provide a framework for studying associations between complex patterns distributed throughout the brain and neurological, psychiatric, and behavioral phenotypes. However, mitigating the influence of nuisance variables, such as confounders, remains a critical challenge in multivariate pattern analysis (MVPA). In studies of Alzheimers Disease, for example, imbalance in disease rates across age and sex may make it difficult to distinguish between structural patterns in the brain (as measured by neuroimaging scans) attributable to disease progression and those characteristic of typical human aging or sex differences. Concerningly, when not properly adjusted for, nuisance variables can obscure interpretations and preclude the generalizability of findings from neuroimaging studies. Motivated by this critical issue, in this work we examine the impact of nuisance variables on features extracted from image decomposition methods and propose Penalized Decomposition Using Residuals (PeDecURe), a new MVPA method for obtaining nuisance variable-adjusted features. PeDecURe estimates primary directions of variation which maximize covariance between residualized imaging features and a variable of interest (e.g., Alzheimers diagnosis) while simultaneously mitigating the influence of nuisance variation through a penalty on the covariance between residualized imaging features and those variables. Using features estimated using PeDecURes first direction of variation, we train an accurate and generalizable predictive model, as evidenced by its robustness in testing samples with different underlying nuisance variable distributions. We compare PeDecURe to commonly used decomposition methods (principal component analysis (PCA) and partial least squares) as well as a confounder-adjusted variation of PCA. We find that features derived from PeDecURe offer greater accuracy and generalizability and lower partial correlations with nuisance variables compared with the other methods. While PeDecURe is primarily motivated by MVPA in the context of neuroimaging, it is broadly applicable to datasets where the dimensionality or complexity of the covariance structure calls for novel methods to handle sources of nuisance variation.

neuroscience↗
bioRxiv2021

Harmonizing Functional Connectivity Reduces Scanner Effects in Community Detection

Community detection on graphs constructed from functional magnetic resonance imaging (fMRI) data has led to important insights into brain functional organization. Large studies of brain community structure often include images acquired on multiple scanners across different studies. Differences in scanner can introduce variability into the downstream results, and these differences are often referred to as scanner effects. Such effects have been previously shown to significantly impact common network metrics. In this study, we identify scanner effects in data-driven community detection results and related network metrics. We assess a commonly employed harmonization method and propose new methodology for harmonizing functional connectivity that leverage existing knowledge about network structure as well as patterns of covariance in the data. Finally, we demonstrate that our new methods reduce scanner effects in community structure and network metrics. Our results highlight scanner effects in studies of brain functional organization and provide additional tools to address these unwanted effects. These findings and methods can be incorporated into future functional connectivity studies, potentially preventing spurious findings and improving reliability of results.

neuroscience↗
bioRxiv2021

Computing personalized brain functional networks from fMRI using self-supervised deep learning

A novel self-supervised deep learning (DL) method is developed for computing bias-free, personalized brain functional networks (FNs) that provide unique opportunities to better understand brain function, behavior, and disease. Specifically, convolutional neural networks with an encoder-decoder architecture are employed to compute personalized FNs from resting-state fMRI data without utilizing any external supervision by optimizing functional homogeneity of personalized FNs in a self-supervised setting. We demonstrate that a DL model trained on fMRI scans from the Human Connectome Project can identify canonical FNs and generalizes well across four different datasets. We further demonstrate that the identified personalized FNs are informative for predicting individual differences in behavior, brain development, and schizophrenia status. Taken together, self-supervised DL allows for rapid, generalizable computation of personalized FNs.

neuroscience↗
bioRxiv2021

Linking Individual Differences in Personalized Functional Network Topography to Psychopathology in Youth

The spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in association cortex that has been implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth. Capitalizing on a large sample with 27-minutes of high-quality functional MRI data (n=790, ages 8-23 years) and advances in machine learning, we examined associations between functional topography and four correlated dimensions of psychopathology (fear, psychosis, externalizing, anxious-misery) as well as an overall psychopathology factor. We found that functional topography significantly predicted individual differences in dimensions of psychopathology, driven mainly by robust associations between topography and overall psychopathology. Reduced cortical representations of association networks were among the most important features of the model. Our results emphasize the value of considering systematic differences in functional neuroanatomy for personalized diagnostics and therapeutics in psychiatry.

neuroscience↗
bioRxiv2021

Dissociable Multi-scale Patterns of Development in Personalized Brain Networks

The brain is organized into networks at multiple resolutions, or scales, yet studies of functional network development typically focus on a single scale. Here, we derived personalized functional networks across 29 scales in a large sample of youths (n=693, ages 8-23 years) to identify multi-scale patterns of network re-organization related to neurocognitive development. We found that developmental shifts in inter-network coupling systematically adhered to and strengthened a functional hierarchy of cortical organization. Furthermore, we observed that scale-dependent effects were present in lower-order, unimodal networks, but not higher-order, transmodal networks. Finally, we found that network maturation had clear behavioral relevance: the development of coupling in unimodal and transmodal networks dissociably mediated the emergence of executive function. These results delineate maturation of multi-scale brain networks, which varies according to a functional hierarchy and impacts cognitive development.

neuroscience↗
bioRxiv2021

Sex Differences in Functional Topography of Association Networks

Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here we leveraged an advanced machine learning method (sparsity-regularized nonnegative matrix factorization) to define individualized functional networks in 693 youth (ages 8-23 years) who underwent functional magnetic resonance imaging as part of the Philadelphia Neurodevelopmental Cohort. Multivariate pattern analysis using support vector machines classified participant sex based on functional topography with 83% accuracy (p<0.0001). Brain regions most effective in classifying participant sex belonged to association networks, including the ventral attention and default mode networks. Mass-univariate analyses using generalized additive models with penalized splines provided convergent results. Comparative analysis using transcriptomic data from the Allen Human Brain Atlas revealed that sex differences in multivariate patterns of functional topography correlated with the expression of genes on the X-chromosome. These results identify normative developmental sex differences in the functional topography of association networks and highlight the role of sex as a biological variable in shaping brain development in youth. SIGNIFICANCE STATEMENTWe identify normative developmental sex differences in the functional topography of personalized association networks including the ventral attention network and default mode network. Furthermore, chromosomal enrichment analyses revealed that sex differences in multivariate patterns of functional topography were spatially coupled to the expression of X-linked genes as well as astrocytic and excitatory neuronal cell-type signatures. These results highlight the role of sex as a biological variable in shaping functional brain development in youth.

neuroscience↗
bioRxiv2021

Multi-scale semi-supervised clustering of brain images: deriving disease subtypes

Disease heterogeneity is a significant obstacle to understanding pathological processes and delivering precision diagnostics and treatment. Clustering methods have gained popularity for stratifying patients into subpopulations (i.e., subtypes) of brain diseases using imaging data. However, unsupervised clustering approaches are often confounded by anatomical and functional variations not related to a disease or pathology of interest. Semi-supervised clustering techniques have been proposed to overcome this and, therefore, capture disease-specific patterns more effectively. An additional limitation of both unsupervised and semi-supervised conventional machine learning methods is that they typically model, learn and infer from data using a basis of feature sets pre-defined at a fixed anatomical or functional scale (e.g., atlas-based regions of interest). Herein we propose a novel method, "Multi-scAle heteroGeneity analysIs and Clustering" (MAGIC), to depict the multi-scale presentation of disease heterogeneity, which builds on a previously proposed semi-supervised clustering method, HYDRA. It derives multi-scale and clinically interpretable feature representations and exploits a double-cyclic optimization procedure to effectively drive identification of inter-scale-consistent disease subtypes. More importantly, to understand the conditions under which the clustering model can estimate true heterogeneity related to diseases, we conducted extensive and systematic semi-simulated experiments to evaluate the proposed method on a sizeable healthy control sample from the UK Biobank (N=4403). We then applied MAGIC to imaging data from Alzheimers disease (ADNI, N=1728) and schizophrenia (PHENOM, N=1166) patients to demonstrate its potential and challenges in dissecting the neuroanatomical heterogeneity of common brain diseases. Taken together, we aim to provide guidance regarding when such analyses can succeed or should be taken with caution. The code of the proposed method is publicly available at https://github.com/anbai106/MAGIC. HighlightsO_LIWe propose a novel multi-scale semi-supervised clustering method, termed MAGIC, to disentangle the heterogeneity of brain diseases. C_LIO_LIWe perform extensive semi-simulated experiments on large control samples (UK Biobank, N=4403) to precisely quantify performance under various conditions, including varying degrees of brain atrophy, different levels of heterogeneity, overlapping disease subtypes, class imbalance, and varying sample sizes. C_LIO_LIWe apply MAGIC to MCI and Alzheimers disease (ADNI, N=1728) and schizophrenia (PHENOM, N=1166) patients to dissect their neuroanatomical heterogeneity, providing guidance regarding the use of the semi-simulated experiments to validate the subtypes found in actual clinical applications. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/440501v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@2769e9org.highwire.dtl.DTLVardef@19a691borg.highwire.dtl.DTLVardef@6a9264org.highwire.dtl.DTLVardef@b0e686_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗
bioRxiv2020

Multi-Modal Biomarkers of Cerebral Edema in Low Resolution MRI

A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images (MRI). These methods, however, may not translate to low resolution images acquired on MRI scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria were imaged using low-field 0.35 Tesla MRI. We integrate multi-atlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to cerebral malaria.

neuroscience↗
bioRxiv2020

QSIPrep: An integrative platform for preprocessing and reconstructing diffusion MRI

Diffusion-weighted magnetic resonance imaging (dMRI) has become the primary method for non-invasively studying the organization of white matter in the human brain. While many dMRI acquisition sequences have been developed, they all sample q-space in order to characterize water diffusion. Numerous software platforms have been developed for processing dMRI data, but most work on only a subset of sampling schemes or implement only parts of the processing workflow. Reproducible research and comparisons across dMRI methods are hindered by incompatible software, diverse file formats, and inconsistent naming conventions. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing upon a diverse set of software suites to capitalize upon their complementary strengths, QSIPrep automatically applies best practices for dMRI preprocessing, including denoising, distortion correction, head motion correction, coregistration, and spatial normalization. Throughout, QSIPrep provides both visual and quantitative measures of data quality as well as "glass-box" methods reporting. Taken together, these features facilitate easy implementation of best practices for processing of diffusion images while simultaneously ensuring reproducibility.

bioinformatics↗
bioRxiv2019

Harmonization of large multi-site imaging datasets: Application to 10,232 MRIs for the analysis of imaging patterns of structural brain change throughout the lifespan

As medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,232 structural brain MRI scans from participants without known neuropsychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive normative age trends of brain structure through the lifespan (3 to 96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this normative reference of brain development and aging, and to examine deviations from normative ranges, potentially related to disease.

bioinformatics↗
bioRxiv2019

Neurocognitive and Functional Heterogeneity in Depressed Youth

OBJECTIVEDepression is a common psychiatric illness that often begins in youth, and is associated with cognitive symptoms. However, there is significant variability in the cognitive burden, likely reflecting biological heterogeneity. This study sought to identify neurocognitive subtypes in a large sample of depressed youth, and evaluated the neural signatures of these subtypes.\n\nMETHODSParticipants 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 (n=368, TD=200) also completed neuroimaging. Cognition was assessed with the Penn Computerized Neurocognitive Battery. A semi-supervised machine-learning algorithm, HYDRA (Heterogeneity through Discriminative Analysis), 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.\n\nRESULTSHYDRA identified three neurocognitive subtypes in the depressed group. Overall, Subtype 1 had better performance than TD comparators across many cognitive tasks (high accuracy, moderate speed), Subtype 2 was cognitively impaired (low accuracy, slow speed), whereas 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.\n\nCONCLUSIONSUsing a data-driven approach, three neurocognitive subtypes of depression were identified that differed in neural signatures despite similar clinical psychopathology. These data suggest disparate mechanisms of cognitive vulnerability and resilience in depression, which may inform the identification of biomarkers for prognosis and treatment response.

neuroscience↗
bioRxiv2019

Individual Variation in Control Network Topography Supports Executive Function in Youth

The spatial distribution of large-scale functional networks on the anatomic cortex differs between individuals, and is particularly variable in networks responsible for executive function. However, it remains unknown how this functional topography evolves in development and supports cognition. Capitalizing upon advances in machine learning and a large sample of youth (n=693, ages 8-23y) imaged with 27 minutes of high-quality fMRI data, we delineate how functional topography evolves during youth. We found that the functional topography of association networks is refined with age, allowing accurate prediction of an unseen individuals brain maturity. Furthermore, the cortical representation of executive networks predicts individual differences in executive function. Finally, variability of functional topography is associated with fundamental properties of brain organization including evolutionary expansion, cortical myelination, and cerebral blood flow. Our results emphasize the importance of considering both the plasticity and diversity of functional neuroanatomy during development, and suggest advances in personalized therapeutics.

neuroscience↗
bioRxiv2019

Multimodal parameters of brain structure and function related to sex differences in cognitive performance.

The Parieto-Frontal Integration Theory (PFIT) identified a fronto-parietal network of regions where individual differences in brain parameters most strongly relate to cognitive performance. PFIT was supported and extended in adult samples, but not in youths or within single-scanner well-powered multimodal studies. We performed multimodal neuroimaging in 1601 youths age 8-22 on the same 3-Tesla scanner with contemporaneous neurocognitive assessment, measuring volume, gray matter density (GMD), mean diffusivity (MD), cerebral blood flow (CBF), resting-state functional MRI measures of amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo), and activation to a working memory and a social cognition task. Across age and sex groups, better performance was associated with higher volumes, greater GMD, lower MD, lower CBF, higher ALFF and ReHo and greater activation for the working memory task in PFIT regions. However, additional cortical, striatal, limbic and cerebellar regions showed comparable effects, hence PFIT needs expansion into an Extended PFIT (ExtPFIT) network incorporating nodes that support motivation and affect. Associations of brain parameters became stronger with advancing age group from childhood to adolescence to young adulthood, effects occurring earlier in females. This ExtPFIT network is developmentally fine-tuned, optimizing abundance and integrity of neural tissue while maintaining low resting energy state.

neuroscience↗
bioRxiv2019

Neurostructural Heterogeneity in Youth with Internalizing Symptoms

Internalizing disorders such as anxiety and depression are the most common psychiatric disorders, frequently begin in youth, and exhibit marked heterogeneity in treatment response and clinical course. It is increasingly recognized that symptom-based classification approaches to internalizing disorders do not align with underlying neurobiology. An alternative to classifying psychopathology based on clinical symptoms is to identify neurobiologically-informed subtypes based on brain imaging data. We used a recently developed semi-supervised machine learning method (HYDRA) to delineate patterns of neurobiological heterogeneity within youth with internalizing symptoms using structural imaging data collected at 3T from a large community-based sample of 1,141 youth. Using volume and cortical thickness, cross-validation methods indicated a highly stable solution (ARI=.66; permutation-based pfdr < .001) and identified two subtypes of internalizing youth. Subtype 1, defined by smaller brain volumes and reduced cortical thickness, was marked by impaired cognitive performance and higher levels of psychopathology than both Subtype 2 and typically developing youth. Using resting-state fMRI and diffusion images not considered during clustering, we found that Subtype 1 also showed reduced amplitudes of low-frequency fluctuations in fronto-limbic regions at rest, as well as reduced fractional anisotropy in white matter tracts such as the parahippocampal cingulum bundle and the uncinate fasciculus. In contrast, Subtype 2 showed intact cognitive performance, greater volume, cortical thickness, and amplitudes during rest compared to Subtype 1 and typically developing youth, despite still showing clinically significant levels of psychopathology. Identification of biologically-grounded subtypes of internalizing disorders may assist in targeting early interventions and assessing longitudinal prognosis.

neuroscience↗
bioRxiv2019

Accelerated Cortical Thinning within Structural Brain Networks is Associated with Irritability in Youth

BackgroundIrritability 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 trans-diagnostic symptoms of irritability relate to the development of structural brain networks.\n\nMethodsAll participants (n=144, 87 females) completed structural brain imaging with 3 Tesla MRI at two timepoints (mean age at follow-up: 20.9 years, mean inter-scan interval: 5.1 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.\n\nResultsCross-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 9 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.\n\nConclusionsCollectively, these findings suggest that irritability is associated with widespread cortical thickness reductions and accelerated cortical thinning, particularly within frontal and temporal cortex. Aberrant structural maturation of regions important for emotional regulation may in part underlie symptoms of irritability.

neuroscience↗
bioRxiv2018

Optimization of Energy State Transition Trajectory Supports the Development of Executive Function During Youth

Executive function develops rapidly during adolescence, and failures of executive function are associated with both risk-taking behaviors and psychopathology. However, it remains relatively unknown how structural brain networks mature during this critical period to facilitate energetically demanding transitions to activate the frontoparietal system, which is critical for executive function. In a sample of 946 human youths (ages 8-23 yr) who completed diffusion imaging as part of the Philadelphia Neurodevelopment Cohort, we capitalized upon recent advances in network control theory in order to calculate the control energy necessary to activate the frontoparietal system given the existing structural network topology. We found that the control energy required to activate the frontoparietal system declined with development. Moreover, we found that this control energy pattern contains sufficient information to make accurate predictions about individuals brain maturity. Finally, the control energy costs of the cingulate cortex were negatively correlated with executive performance, and partially mediated the development of executive performance with age. These results could not be explained by changes in general network control properties or in network modularity. Taken together, our results reveal a mechanism by which structural networks develop during adolescence to facilitate the instantiation of activation states necessary for executive function.\n\nSIGNIFICANCE STATEMENTExecutive function undergoes protracted development during youth, but it is unknown how structural brain networks mature to facilitate the activation of the frontoparietal cortex that is critical for executive processes. Here, we leverage recent advances in network control theory to establish that structural brain networks evolve in adolescence to lower the energetic cost of activating the frontoparietal system. Our results suggest a new mechanistic framework for understanding how brain network maturation supports cognition, with clear implications for disorders marked by executive dysfunction, such as ADHD and psychosis.

neuroscience↗