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Vince D. Calhoun

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156 papers
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156

JBHI Journal 2026 Journal Article

Group Information Guided Smooth Independent Component Analysis Method for Multi-Subject fMRI Data Analysis

  • Yuhui Du
  • Chen Huang
  • Vince D. Calhoun

Group independent component analysis (ICA) has been extensively used to extract brain functional networks (FNs) and associated neuroimaging measures from multi-subject functional magnetic resonance imaging (fMRI) data. However, the inherent noise in fMRI data can adversely affect the performance of ICA, often leading to noisy FNs and hindering the identification of network-level biomarkers. To address this challenge, we propose a novel method called group information guided smooth independent component analysis (GIG-sICA). Our method effectively generates smoother functional networks with reduced noise and enhanced functional coherence, while preserving intra-subject independence and inter-subject correspondence of FN. Importantly, GIG-sICA is capable of handling different types of noise either separately or in combination. To validate the efficacy of our approach, we conducted comprehensive experiments, comparing GIG-sICA with traditional group ICA methods on both simulated and real fMRI datasets. Experiments on five simulated datasets, generated by adding various types of noise, demonstrate that GIG-sICA produces smoother functional networks with enhanced spatial accuracy. Additionally, experiments on real fMRI data from 137 schizophrenia patients and 144 healthy controls demonstrate that GIG-sICA more effectively captures functionally meaningful brain networks and reveals clearer group differences. Overall, GIG-sICA produces smooth and precise network estimations, supporting the discovery of robust biomarkers at the network level for neuroscience research.

TMLR Journal 2026 Journal Article

SSFL: Discovering Sparse Unified Subnetworks at Initialization for Efficient Federated Learning

  • Riyasat Ohib
  • Bishal Thapaliya
  • Gintare Karolina Dziugaite
  • Jingyu Liu
  • Vince D. Calhoun
  • Sergey Plis

In this work, we propose Salient Sparse Federated Learning (SSFL), a streamlined approach for sparse federated learning with efficient communication. SSFL identifies a sparse subnetwork prior to training, leveraging parameter saliency scores computed separately on local client data in non-IID scenarios, and then aggregated, to determine a global mask. Only the sparse model weights are trained and communicated each round between the clients and the server. On standard benchmarks including CIFAR-10, CIFAR-100, and Tiny-ImageNet, SSFL consistently improves the accuracy–sparsity trade-off, achieving more than 20\% relative error reduction on CIFAR-10 compared to the strongest sparse baseline, while reducing communication costs by $2 \times$ relative to dense FL. Finally, in a real-world federated learning deployment, SSFL delivers over $2.3 \times$ faster communication time, underscoring its practical efficiency.

YNIMG Journal 2025 Journal Article

A dynamic spatiotemporal representation framework for deciphering personal brain function

  • Xuyang Wang
  • Ting Zou
  • Haofei Wang
  • Honghao Han
  • Huafu Chen
  • Vince D. Calhoun
  • Rong Li

Functional magnetic resonance imaging (fMRI) opens a window on observing spontaneous activities of the human brain in vivo. However, the high complexity of fMRI signals makes brain functional representations intractable. Here, we introduce a state decomposition method to reduce this complexity and decipher individual brain functions at multiple levels. Briefly, brain dynamics are captured by temporal first-order derivatives and spatially divided into 'state sets' at each time point based on the velocity and direction of change. This approach transforms the original signals into discrete series consisting of four fundamental states, which efficiently encode individual-specific information. Subsequently, we designed a suite of state-based metrics to quantify regional activities and network interactions. Compared with conventional representations such as resting-state fluctuation amplitude and Pearson's functional connectivity, the state-based representations serve as more discriminative 'brain fingerprints' for individuals and produce reproducible spatial patterns across heterogeneous cohorts (n = 1015). Regarding functional organization, our proposed profiles extend previous representations into nonlinear domains, revealing not only the canonical default-mode dominant pattern but also patterns dominated by the attention network and basal ganglia. Moreover, we demonstrate that personal phenotypes (such as age and gender) can be decoded from regional representations with high accuracy. The equivalence between state series outperforms other existing network representations in predicting individual fluid intelligence. Overall, this framework establishes a foundation for enriching the repertoire of brain functional representations and enhancing the power of brain-phenotype modeling.

YNICL Journal 2025 Journal Article

A multimodal Neuroimaging-Based risk score for mild cognitive impairment

  • Elaheh Zendehrouh
  • Mohammad S.E. Sendi
  • Anees Abrol
  • Ishaan Batta
  • Reihaneh Hassanzadeh
  • Vince D. Calhoun

INTRODUCTION: Alzheimer's disease (AD), the most prevalent age-related dementia, leads to significant cognitive decline. While genetic risk factors and neuroimaging biomarkers have been extensively studied, establishing a neuroimaging-based metric to assess AD risk has received less attention. This study introduces the Brain-wide Risk Score (BRS), a novel approach using multimodal neuroimaging data to assess the risk of mild cognitive impairment (MCI), a precursor to AD. METHODS: Participants from the OASIS-3 cohort (N = 1,389) were categorized into control (CN) and MCI groups. Structural MRI (sMRI) data provided gray matter (GM) segmentation maps, while resting-state functional MRI (fMRI) data yielded functional network connectivity (FNC) matrices via spatially constrained independent component analysis. Similar imaging features were computed from the UK Biobank (N = 37,780). The BRS was calculated by comparing each participant's neuroimaging features to the difference between average features of CN and MCI groups. Both GM and FNC features were used. The BRS effectively differentiated CN from MCI individuals within OASIS-3 and in an independent dataset from the ADNI cohort (N = 729), demonstrating its ability to identify MCI risk. RESULTS: Unimodal analysis revealed that sMRI provided greater differentiation than fMRI, consistent with prior research. Using the multimodal BRS, we identified two distinct groups: one with high MCI risk (negative GM and FNC BRS) and another with low MCI risk (positive GM and FNC BRS). Additionally, 46 UK Biobank participants diagnosed with AD showed FNC and GM patterns similar to the high-risk groups. CONCLUSION: Validation using the ADNI dataset confirmed our results, highlighting the potential of FNC and sMRI-based BRS in early Alzheimer's detection.

JBHI Journal 2025 Journal Article

An orthogonal semi-nonnegative matrix factorization method for dynamic functional connectivity analysis and its application to schizophrenia

  • Xingyu He
  • Vince D. Calhoun
  • Godfrey D. Pearlson
  • Peter Kochunov
  • Theo G.M. van Erp
  • Yuhui Du

Dynamic functional connectivity (dFC) analysis investigates how the functional interactions between brain regions change over time by identifying recurring connectivity patterns, known as dFC states, and tracking transitions between them. Non-negative matrix factorization (NMF) has been used in dFC analysis because it produces non-negative dFC states and coefficients, interpreting dFC states and their transitions straightforwardly. However, existing NMF-based methods are limited to processing dFC data with exclusively positive values, failing to align with the functional correlations and anti-correlations between brain regions. This paper proposes an orthogonal semi-nonnegative matrix factorization (OSemiNMF) method, extending NMF to directly handle mixed-sign dFC data. Furthermore, an orthogonality constraint on the bases (i. e. , dFC states) is incorporated to enhance the uniqueness of dFC states. For 10 simulated datasets with varying properties, our method outperforms comparison methods, supporting its superior ability to capture dFC states and state transitions. Using four resting-state fMRI datasets consisting of 708 healthy controls (HCs) and 537 schizophrenia patients (SZs), our method identifies reproducible dFC states and state transitions across datasets. Further, our findings reveal that SZs spend less time in high-connectivity states compared to HCs. Our study identifies meaningful and reproducible biomarkers of schizophrenia, mainly involving the connectivity associated with the sub-cortical domain. In summary, the OSemiNMF method facilitates the dFC analysis for understanding brain dynamics.

YNICL Journal 2025 Journal Article

Consistent frontal-limbic-occipital connections in distinguishing treatment-resistant and non-treatment-resistant schizophrenia

  • Yijie Zhang
  • Shuzhan Gao
  • Chuang Liang
  • Juan Bustillo
  • Peter Kochunov
  • Jessica A. Turner
  • Vince D. Calhoun
  • Lei Wu

BACKGROUND AND HYPOTHESIS: Treatment-resistant schizophrenia (TR-SZ) and non-treatment-resistant schizophrenia (NTR-SZ) lack specific biomarkers to distinguish from each other. This investigation aims to identify consistent dysfunctional brain connections with different atlases, multiple feature selection strategies, and several classifiers in distinguishing TR-SZ and NTR-SZ. STUDY DESIGN: 55 TR-SZs, 239 NTR-SZs, and 87 healthy controls (HCs) were recruited from the Affiliated Brain Hospital of Nanjing Medical University. Resting-state functional connection (FC) matrices were constructed from automated anatomical labeling (AAL), Yeo-Networks (YEO) and Brainnetome (BNA) atlases. Two feature selection methods (Select From Model and Recursive Feature Elimination) and four classifiers (Adaptive Boost, Bernoulli Naïve Bayes, Gradient Boosting and Random Forest) were combined to identify the consistent FCs in distinguishing TR-SZ and HC, NTR-SZ and HC, TR-SZ and NTR-SZ. STUDY RESULTS: The whole brain FCs, except the temporal-occipital FC, were consistent in distinguishing SZ and HC. Abnormal frontal-limbic, frontal-parietal and occipital-temporal FCs were consistent in distinguishing TR-SZ and NTR-SZ, that were further correlated with disease progression, symptoms and medication dosage. Moreover, the frontal-limbic and frontal-parietal FCs were highly consistent for the diagnosis of SZ (TR-SZ vs. HC, NTR-SZ vs. HC and TR-SZ vs. NTR-SZ). The BNA atlas achieved the highest classification accuracy (>90 %) comparing with AAL and YEO in the most diagnostic tasks. CONCLUSIONS: These results indicate that the frontal-limbic and the frontal-parietal FCs are the robust neural pathways in the diagnosis of SZ, whereas the frontal-limbic, frontal-parietal and occipital-temporal FCs may be informative in recognizing those TR-SZ in the clinical practice.

YNIMG Journal 2025 Journal Article

Developmental trajectory of neural activity underlying motor control differs by sequence complexity and motor stage

  • Thomas W. Ward
  • Jackson Derby
  • Jake J. Son
  • Peihan J. Huang
  • Danielle L. Rice
  • Grace C. Ende
  • Anna T. Coutant
  • Erica L. Steiner

Primary motor areas in the brain mature relatively early in development, yet the control of complex movements improves through early adulthood. Neural oscillations in higher-order regions are refined in adolescence and contribute to executive processes important for complex motor control, but the neural dynamics among these regions and primary motor cortices remain poorly understood in youth. We recorded magnetoencephalography during a motor sequencing task in 68 healthy youth from ten to 17 years of age. Significant changes in oscillatory activity relative to baseline were identified at the sensor level and source reconstructed with a beamformer. Whole-brain maps of beta (18-24 Hz) and gamma (74-84 Hz) oscillatory activity were subjected to voxel-wise repeated-measures ANCOVAs to identify brain areas in which the developmental trajectory of oscillatory power differed by sequence complexity (simple/complex) or motor stage (planning/execution). Beta activity in bilateral prefrontal cortices was weaker with age during the planning of complex movements. Across simple and complex conditions, older youth tended to have stronger beta in posterior areas during planning. Finally, gamma activity across conditions was stronger with age in occipital and weaker in temporal cortices. These results suggest that the functional refinement of association cortices may drive improvements in motor control by enabling more efficient attentional and inhibitory control during formulation of the motor plan.

YNIMG Journal 2025 Journal Article

Linking brain entropy to molecular and cellular architecture in psychosis

  • Qiang Li
  • Jingyu Liu
  • Vince D. Calhoun

Brain entropy reflects the complexity of intrinsic activity and has been linked to both cognitive function and psychiatric disorders. Yet its connection to the brain's neurochemical and cellular architecture remains poorly understood. By integrating molecular imaging with neuroimaging datasets, we show that the spatial distribution of cell types, neurotransmitter systems, and mitochondrial phenotypes is systematically related to brain entropy. We observed significant differences in entropy correlations: between healthy controls and individuals with schizophrenia for the mu-opioid and dopamine D1 receptors, and between controls and individuals with bipolar disorder for the norepinephrine transporter (NAT) and N-methyl-D-aspartate (NMDA) receptor. No significant differences emerged between schizophrenia and bipolar disorder in the neurotransmitter domain. At the cellular and metabolic level, both control-schizophrenia and control-bipolar comparisons revealed widespread alterations involving most mitochondrial markers, glial cells, and inhibitory neurons. These patterns point to disruptions in energy metabolism, neuroinflammatory processes, and inhibitory regulation within the clinical groups. Overall, the findings indicate that brain entropy is not randomly distributed but is closely tied to specific neurochemical systems and cellular features. This systems-level view helps explain how the complexity of brain activity arises from molecular architecture, and how it is altered in psychiatric disorders. It also provides a biological foundation for understanding brain entropy in the context of psychosis.

NeurIPS Conference 2025 Conference Paper

MoRE-Brain: Routed Mixture of Experts for Interpretable and Generalizable Cross-Subject fMRI Visual Decoding

  • Yuxiang Wei
  • Yanteng Zhang
  • Xi Xiao
  • Tianyang Wang
  • Xiao Wang
  • Vince D. Calhoun

Decoding visual experiences from fMRI offers a powerful avenue to understand human perception and develop advanced brain-computer interfaces. However, current progress often prioritizes maximizing reconstruction fidelity while overlooking interpretability, an essential aspect for deriving neuroscientific insight. To address this gap, we propose MoRE-Brain, a neuro-inspired framework designed for high-fidelity, adaptable, and interpretable visual reconstruction. MoRE-Brain uniquely employs a hierarchical Mixture-of-Experts architecture where distinct experts process fMRI signals from functionally related voxel groups, mimicking specialized brain networks. The experts are first trained to encode fMRI into the frozen CLIP space. A finetuned diffusion model then synthesizes images, guided by expert outputs through a novel dual-stage routing mechanism that dynamically weighs expert contributions across the diffusion process. MoRE-Brain offers three main advancements: First, it introduces a novel Mixture-of-Experts architecture grounded in brain network principles for neuro-decoding. Second, it achieves efficient cross-subject generalization by sharing core expert networks while adapting only subject-specific routers. Third, it provides enhanced mechanistic insight, as the explicit routing reveals precisely how different modeled brain regions shape the semantic and spatial attributes of the reconstructed image. Extensive experiments validate MoRE-Brain’s high reconstruction fidelity, with bottleneck analyses further demonstrating its effective utilization of fMRI signals, distinguishing genuine neural decoding from over-reliance on generative priors. Consequently, MoRE-Brain marks a substantial advance towards more generalizable and interpretable fMRI-based visual decoding.

YNICL Journal 2024 Journal Article

A whole-brain neuromark resting-state fMRI analysis of first-episode and early psychosis: Evidence of aberrant cortical-subcortical-cerebellar functional circuitry

  • Kyle M. Jensen
  • Vince D. Calhoun
  • Zening Fu
  • Kun Yang
  • Andreia V. Faria
  • Koko Ishizuka
  • Akira Sawa
  • Pablo Andrés-Camazón

Psychosis (including symptoms of delusions, hallucinations, and disorganized conduct/speech) is a main feature of schizophrenia and is frequently present in other major psychiatric illnesses. Studies in individuals with first-episode (FEP) and early psychosis (EP) have the potential to interpret aberrant connectivity associated with psychosis during a period with minimal influence from medication and other confounds. The current study uses a data-driven whole-brain approach to examine patterns of aberrant functional network connectivity (FNC) in a multi-site dataset comprising resting-state functional magnetic resonance images (rs-fMRI) from 117 individuals with FEP or EP and 130 individuals without a psychiatric disorder, as controls. Accounting for age, sex, race, head motion, and multiple imaging sites, differences in FNC were identified between psychosis and control participants in cortical (namely the inferior frontal gyrus, superior medial frontal gyrus, postcentral gyrus, supplementary motor area, posterior cingulate cortex, and superior and middle temporal gyri), subcortical (the caudate, thalamus, subthalamus, and hippocampus), and cerebellar regions. The prominent pattern of reduced cerebellar connectivity in psychosis is especially noteworthy, as most studies focus on cortical and subcortical regions, neglecting the cerebellum. The dysconnectivity reported here may indicate disruptions in cortical-subcortical-cerebellar circuitry involved in rudimentary cognitive functions which may serve as reliable correlates of psychosis.

YNIMG Journal 2024 Journal Article

Explainable spatio-temporal graph evolution learning with applications to dynamic brain network analysis during development

  • Longyun Chen
  • Chen Qiao
  • Kai Ren
  • Gang Qu
  • Vince D. Calhoun
  • Julia M. Stephen
  • Tony W. Wilson
  • Yu-Ping Wang

Modeling dynamic interactions among network components is crucial to uncovering the evolution mechanisms of complex networks. Recently, spatio-temporal graph learning methods have achieved noteworthy results in characterizing the dynamic changes of inter-node relations (INRs). However, challenges remain: The spatial neighborhood of an INR is underexploited, and the spatio-temporal dependencies in INRs' dynamic changes are overlooked, ignoring the influence of historical states and local information. In addition, the model's explainability has been understudied. To address these issues, we propose an explainable spatio-temporal graph evolution learning (ESTGEL) model to model the dynamic evolution of INRs. Specifically, an edge attention module is proposed to utilize the spatial neighborhood of an INR at multi-level, i.e., a hierarchy of nested subgraphs derived from decomposing the initial node-relation graph. Subsequently, a dynamic relation learning module is proposed to capture the spatio-temporal dependencies of INRs. The INRs are then used as adjacent information to improve the node representation, resulting in comprehensive delineation of dynamic evolution of the network. Finally, the approach is validated with real data on brain development study. Experimental results on dynamic brain networks analysis reveal that brain functional networks transition from dispersed to more convergent and modular structures throughout development. Significant changes are observed in the dynamic functional connectivity (dFC) associated with functions including emotional control, decision-making, and language processing.

YNIMG Journal 2024 Journal Article

Gray matters: ViT-GAN framework for identifying schizophrenia biomarkers linking structural MRI and functional network connectivity

  • Yuda Bi
  • Anees Abrol
  • Sihan Jia
  • Jing Sui
  • Vince D. Calhoun

Brain disorders are often associated with changes in brain structure and function, where functional changes may be due to underlying structural variations. Gray matter (GM) volume segmentation from 3D structural MRI offers vital structural information for brain disorders like schizophrenia, as it encompasses essential brain tissues such as neuronal cell bodies, dendrites, and synapses, which are crucial for neural signal processing and transmission; changes in GM volume can thus indicate alterations in these tissues, reflecting underlying pathological conditions. In addition, the use of the ICA algorithm to transform high-dimensional fMRI data into functional network connectivity (FNC) matrices serves as an effective carrier of functional information. In our study, we introduce a new generative deep learning architecture, the conditional efficient vision transformer generative adversarial network (cEViT-GAN), which adeptly generates FNC matrices conditioned on GM to facilitate the exploration of potential connections between brain structure and function. We developed a new, lightweight self-attention mechanism for our ViT-based generator, enhancing the generation of refined attention maps critical for identifying structural biomarkers based on GM. Our approach not only generates high quality FNC matrices with a Pearson correlation of 0. 74 compared to real FNC data, but also uses attention map technology to identify potential biomarkers in GM structure that could lead to functional abnormalities in schizophrenia patients. Visualization experiments within our study have highlighted these structural biomarkers, including the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DL-PFC), and cerebellum. In addition, through cross-domain analysis comparing generated and real FNC matrices, we have identified functional connections with the highest correlations to structural information, further validating the structure-function connections. This comprehensive analysis helps to understand the intricate relationship between brain structure and its functional manifestations, providing a more refined insight into the neurobiological research of schizophrenia.

YNICL Journal 2024 Journal Article

Joint multi-site domain adaptation and multi-modality feature selection for the diagnosis of psychiatric disorders

  • Yixin Ji
  • Rogers F. Silva
  • Tülay Adali
  • Xuyun Wen
  • Qi Zhu
  • Rongtao Jiang
  • Daoqiang Zhang
  • Shile Qi

Identifying biomarkers for computer-aided diagnosis (CAD) is crucial for early intervention of psychiatric disorders. Multi-site data have been utilized to increase the sample size and improve statistical power, while multi-modality classification offers significant advantages over traditional single-modality based approaches for diagnosing psychiatric disorders. However, inter-site heterogeneity and intra-modality heterogeneity present challenges to multi-site and multi-modality based classification. In this paper, brain functional and structural networks (BFNs/BSNs) from multiple sites were constructed to establish a joint multi-site multi-modality framework for psychiatric diagnosis. To do this we developed a hypergraph based multi-source domain adaptation (HMSDA) which allowed us to transform source domain subjects into a target domain. A local ordinal structure based multi-task feature selection (LOSMFS) approach was developed by integrating the transformed functional and structural connections (FCs/SCs). The effectiveness of our method was validated by evaluating diagnosis of both schizophrenia (SZ) and autism spectrum disorder (ASD). The proposed method obtained accuracies of 92.2 %±2.22 % and 84.8 %±2.68 % for the diagnosis of SZ and ASD, respectively. We also compared with 6 DA, 10 multi-modality feature selection, and 8 multi-site and multi-modality methods. Results showed the proposed HMSDA+LOSMFS effectively integrated multi-site and multi-modality data to enhance psychiatric diagnosis and identify disorder-specific diagnostic brain connections.

YNIMG Journal 2024 Journal Article

Local-structure-preservation and redundancy-removal-based feature selection method and its application to the identification of biomarkers for schizophrenia

  • Ying Xing
  • Godfrey D. Pearlson
  • Peter Kochunov
  • Vince D. Calhoun
  • Yuhui Du

Accurate diagnosis of mental disorders is expected to be achieved through the identification of reliable neuroimaging biomarkers with the help of cutting-edge feature selection techniques. However, existing feature selection methods often fall short in capturing the local structural characteristics among samples and effectively eliminating redundant features, resulting in inadequate performance in disorder prediction. To address this gap, we propose a novel supervised method named local-structure-preservation and redundancy-removal-based feature selection (LRFS), and then apply it to the identification of meaningful biomarkers for schizophrenia (SZ). LRFS method leverages graph-based regularization to preserve original sample similarity relationships during data transformation, thus retaining crucial local structure information. Additionally, it introduces redundancy-removal regularization based on interrelationships among features to exclude similar and redundant features from high-dimensional data. Moreover, LRFS method incorporates l 2, 1 sparse regularization that enables selecting a sparse and noise-robust feature subset. Experimental evaluations on eight public datasets with diverse properties demonstrate the superior performance of our method over nine popular feature selection methods in identifying discriminative features, with average classification accuracy gains ranging from 1. 30 % to 9. 11 %. Furthermore, the LRFS method demonstrates superior discriminability in four functional magnetic resonance imaging (fMRI) datasets from 708 healthy controls (HCs) and 537 SZ patients, with an average increase in classification accuracy ranging from 1. 89 % to 9. 24 % compared to other nine methods. Notably, our method reveals reproducible and significant changes in SZ patients relative to HCs across the four datasets, predominantly in the thalamus-related functional network connectivity, which exhibit a significant correlation with clinical symptoms. Convergence analysis, parameter sensitivity analysis, and ablation studies further demonstrate the effectiveness and robustness of our method. In short, our proposed feature selection method effectively identifies discriminative and reliable features that hold the potential to be biomarkers, paving the way for the elucidation of brain abnormalities and the advancement of precise diagnosis of mental disorders.

YNIMG Journal 2024 Journal Article

Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities

  • Zening Fu
  • Ishaan Batta
  • Lei Wu
  • Anees Abrol
  • Oktay Agcaoglu
  • Mustafa S Salman
  • Yuhui Du
  • Armin Iraji

A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.

YNIMG Journal 2024 Journal Article

Self-supervised multimodal learning for group inferences from MRI data: Discovering disorder-relevant brain regions and multimodal links

  • Alex Fedorov
  • Eloy Geenjaar
  • Lei Wu
  • Tristan Sylvain
  • Thomas P. DeRamus
  • Margaux Luck
  • Maria Misiura
  • Girish Mittapalle

In recent years, deep learning approaches have gained significant attention in predicting brain disorders using neuroimaging data. However, conventional methods often rely on single-modality data and supervised models, which provide only a limited perspective of the intricacies of the highly complex brain. Moreover, the scarcity of accurate diagnostic labels in clinical settings hinders the applicability of the supervised models. To address these limitations, we propose a novel self-supervised framework for extracting multiple representations from multimodal neuroimaging data to enhance group inferences and enable analysis without resorting to labeled data during pre-training. Our approach leverages Deep InfoMax (DIM), a self-supervised methodology renowned for its efficacy in learning representations by estimating mutual information without the need for explicit labels. While DIM has shown promise in predicting brain disorders from single-modality MRI data, its potential for multimodal data remains untapped. This work extends DIM to multimodal neuroimaging data, allowing us to identify disorder-relevant brain regions and explore multimodal links. We present compelling evidence of the efficacy of our multimodal DIM analysis in uncovering disorder-relevant brain regions, including the hippocampus, caudate, insula, - and multimodal links with the thalamus, precuneus, and subthalamus hypothalamus. Our self-supervised representations demonstrate promising capabilities in predicting the presence of brain disorders across a spectrum of Alzheimer's phenotypes. Comparative evaluations against state-of-the-art unsupervised methods based on autoencoders, canonical correlation analysis, and supervised models highlight the superiority of our proposed method in achieving improved classification performance, capturing joint information, and interpretability capabilities. The computational efficiency of the decoder-free strategy enhances its practical utility, as it saves compute resources without compromising performance. This work offers a significant step forward in addressing the challenge of understanding multimodal links in complex brain disorders, with potential applications in neuroimaging research and clinical diagnosis.

JBHI Journal 2023 Journal Article

A Novel Neighborhood Rough Set-Based Feature Selection Method and Its Application to Biomarker Identification of Schizophrenia

  • Ying Xing
  • Peter Kochunov
  • Theo G.M. van Erp
  • Tianzhou Ma
  • Vince D. Calhoun
  • Yuhui Du

Feature selection can disclose biomarkers of mental disorders that have unclear biological mechanisms. Although neighborhood rough set (NRS) has been applied to discover important sparse features, it has hardly ever been utilized in neuroimaging-based biomarker identification, probably due to the inadequate feature evaluation metric and incomplete information provided under a single-granularity. Here, we propose a new NRS-based feature selection method and successfully identify brain functional connectivity biomarkers of schizophrenia (SZ) using functional magnetic resonance imaging (fMRI) data. Specifically, we develop a new weighted metric based on NRS combined with information entropy to evaluate the capacity of features in distinguishing different groups. Inspired by multi-granularity information maximization theory, we further take advantage of the complementary information from different neighborhood sizes via a multi-granularity fusion to obtain the most discriminative and stable features. For validation, we compare our method with six popular feature selection methods using three public omics datasets as well as resting-state fMRI data of 393 SZ patients and 429 healthy controls. Results show that our method obtained higher classification accuracies on both omics data (100. 0%, 88. 6%, and 72. 2% for three omics datasets, respectively) and fMRI data (93. 9% for main dataset, and 76. 3% and 83. 8% for two independent datasets, respectively). Moreover, our findings reveal biologically meaningful substrates of SZ, notably involving the connectivity between the thalamus and superior temporal gyrus as well as between the postcentral gyrus and calcarine gyrus. Taken together, we propose a new NRS-based feature selection method that shows the potential of exploring effective and sparse neuroimaging-based biomarkers of mental disorders.

YNICL Journal 2023 Journal Article

Aberrant resting-state functional connectivity associated with childhood trauma among juvenile offenders

  • Corey H. Allen
  • Jenna Shold
  • J. Michael Maurer
  • Brooke L. Reynolds
  • Nathaniel E. Anderson
  • Carla L. Harenski
  • Keith A. Harenski
  • Vince D. Calhoun

Individuals with history of childhood trauma are characterized by aberrant resting-state limbic and paralimbic functional network connectivity. However, it is unclear whether specific subtypes of trauma (i.e., experienced vs observed or community) showcase differential effects. This study examined whether subtypes of childhood trauma (assessed via the Trauma Checklist [TCL] 2.0) were associated with aberrant intra-network amplitude of fluctuations and connectivity (i.e., functional coherence within a network), and inter-network connectivity across resting-state networks among incarcerated juvenile males (n = 179). Subtypes of trauma were established via principal component analysis of the TCL 2.0 and resting-state networks were identified by applying group independent component analysis to resting-state fMRI scans. We tested the association of subtypes of childhood trauma (i.e., TCL Factor 1 measuring experienced trauma and TCL Factor 2 assessing community trauma), and TCL Total scores to the aforementioned functional connectivity measures. TCL Factor 2 scores were associated with increased high-frequency fluctuations and increased intra-network connectivity in cognitive control, auditory, and sensorimotor networks, occurring primarily in paralimbic regions. TCL Total scores exhibited similar neurobiological patterns to TCL Factor 2 scores (with the addition of aberrant intra-network connectivity in visual networks), and no significant associations were found for TCL Factor 1. Consistent with previous analyses of community samples, our results suggest that childhood trauma among incarcerated juvenile males is associated with aberrant intra-network amplitude of fluctuations and connectivity across multiple networks including predominately paralimbic regions. Our results highlight the importance of accounting for traumatic loss, observed trauma, and community trauma in assessing neurobiological aberrances associated with adverse experiences in childhood, as well as the value of trained-rater trauma assessments compared to self-report.

YNICL Journal 2023 Journal Article

Exploring the longitudinal associations of functional network connectivity and psychiatric symptom changes in youth

  • Lorenza Dall'Aglio
  • Fernando Estévez-López
  • Mónica López-Vicente
  • Bing Xu
  • Oktay Agcaoglu
  • Elias Boroda
  • Kelvin O. Lim
  • Vince D. Calhoun

BACKGROUND: Functional connectivity has been associated with psychiatric problems, both in children and adults, but inconsistencies are present across studies. Prior research has mostly focused on small clinical samples with cross-sectional designs. METHODS: We adopted a longitudinal design with repeated assessments to investigate associations between functional network connectivity (FNC) and psychiatric problems in youth (9- to 17-year-olds, two time points) from the general population. The largest single-site study of pediatric neurodevelopment was used: Generation R (N = 3,131 with data at either time point). Psychiatric symptoms were measured with the Child Behavioral Checklist as broadband internalizing and externalizing problems, and its eight specific syndrome scales (e.g., anxious-depressed). FNC was assessed with two complementary approaches. First, static FNC (sFNC) was measured with graph theory-based metrics. Second, dynamic FNC (dFNC), where connectivity is allowed to vary over time, was summarized into 5 states that participants spent time in. Cross-lagged panel models were used to investigate the longitudinal bidirectional relationships of sFNC with internalizing and externalizing problems. Similar cross-lagged panel models were run for dFNC. RESULTS: Small longitudinal relationships between dFNC and certain syndrome scales were observed, especially for baseline syndrome scales (i.e., rule-breaking, somatic complaints, thought problems, and attention problems) predicting connectivity changes. However, no association between any of the psychiatric problems (broadband and syndrome scales) with either measure of FNC survived correction for multiple testing. CONCLUSION: We found no or very modest evidence for longitudinal associations between psychiatric problems with dynamic and static FNC in this population-based sample. Differences in findings may stem from the population drawn, study design, developmental timing, and sample sizes.

YNICL Journal 2023 Journal Article

Multi-model order spatially constrained ICA reveals highly replicable group differences and consistent predictive results from resting data: A large N fMRI schizophrenia study

  • Xing Meng
  • Armin Iraji
  • Zening Fu
  • Peter Kochunov
  • Aysenil Belger
  • Judy M. Ford
  • Sara McEwen
  • Daniel H. Mathalon

Brain functional networks identified from resting functional magnetic resonance imaging (fMRI) data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to compare across studies, and approaches that use fixed atlas-based regions can have limited sensitivity to individual sensitivity. By contrast, spatially constrained ICA (scICA) provides a hybrid, fully automated solution that can incorporate spatial network priors while also adapting to new subjects. However, scICA has thus far only been used with a single spatial scale (ICA dimensionality, i.e., ICA model order). In this work, we present an approach using multi-objective optimization scICA with reference algorithm (MOO-ICAR) to extract subject-specific intrinsic connectivity networks (ICNs) from fMRI data at multiple spatial scales, which also enables us to study interactions across spatial scales. We evaluate this approach using a large N (N > 1,600) study of schizophrenia divided into separate validation and replication sets. A multi-scale ICN template was estimated and labeled, then used as input into scICA which was computed on an individual subject level. We then performed a subsequent analysis of multiscale functional network connectivity (msFNC) to evaluate the patient data, including group differences and classification. Results showed highly consistent group differences in msFNC in regions including cerebellum, thalamus, and motor/auditory networks. Importantly, multiple msFNC pairs linking different spatial scales were implicated. The classification model built on the msFNC features obtained up to 85% F1 score, 83% precision, and 88% recall, indicating the strength of the proposed framework in detecting group differences between schizophrenia and the control group. Finally, we evaluated the relationship of the identified patterns to positive symptoms and found consistent results across datasets. The results verified the robustness of our framework in evaluating brain functional connectivity of schizophrenia at multiple spatial scales, implicated consistent and replicable brain networks, and highlighted a promising approach for leveraging resting fMRI data for brain biomarker development.

JBHI Journal 2023 Journal Article

The Individualized Prediction of Neurocognitive Function in People Living with HIV Based on Clinical and Multimodal Connectome Data

  • Xiang Li
  • Sheri L. Towe
  • Ryan P. Bell
  • Rongtao Jiang
  • Shana A. Hall
  • Vince D. Calhoun
  • Christina S. Meade
  • Jing Sui

Neurocognitive impairment continues to be common comorbidity for people living with HIV (PLWH). Given the chronic nature of HIV disease, identifying reliable biomarkers of these impairments is essential to advance our understanding of the underlying neural foundation and facilitate screening and diagnosis in clinical care. While neuroimaging provides immense potential for such biomarkers, to date, investigations in PLWH have been mostly limited to either univariate mass techniques or a single neuroimaging modality. In the present study, connectome-based predictive modeling (CPM) was proposed to predict individual differences of cognitive functioning in PLWH, using resting-state functional connectivity (FC), white matter structural connectivity (SC), and clinical relevant measures. We also adopted an efficient feature selection approach to identify the most predictive features, which achieved an optimal prediction accuracy of r = 0. 61 in the discovery dataset ( n = 102) and r = 0. 45 in an independent validation HIV cohort ( n = 88). Two brain templates and nine distinct prediction models were also tested for better modeling generalizability. Results show that combining multimodal FC and SC features enabled higher prediction accuracy of cognitive scores in PLWH, while adding clinical and demographic metrics may further improve the prediction by introducing complementary information, which may help better evaluate the individual-level cognitive performance in PLWH.

YNICL Journal 2023 Journal Article

The link between static and dynamic brain functional network connectivity and genetic risk of Alzheimer's disease

  • Mohammad S.E. Sendi
  • Elaheh Zendehrouh
  • Charles A. Ellis
  • Zening Fu
  • Jiayu Chen
  • Robyn L. Miller
  • Elizabeth C. Mormino
  • David H. Salat

Apolipoprotein E (APOE) polymorphic alleles are genetic factors associated with Alzheimer's disease (AD) risk. Although previous studies have explored the link between AD genetic risk and static functional network connectivity (sFNC), to the best of our knowledge, no previous studies have evaluated the association between dynamic FNC (dFNC) and AD genetic risk. Here, we examined the link between sFNC, dFNC, and AD genetic risk with a data-driven approach. We used rs-fMRI, demographic, and APOE data from cognitively normal individuals (N = 886) between 42 and 95 years of age (mean = 70 years). We separated individuals into low, moderate, and high-risk groups. Using Pearson correlation, we calculated sFNC across seven brain networks. We also calculated dFNC with a sliding window and Pearson correlation. The dFNC windows were partitioned into three distinct states with k-means clustering. Next, we calculated the proportion of time each subject spent in each state, called occupancy rate or OCR and frequency of visits. We compared both sFNC and dFNC features across individuals with different genetic risks and found that both sFNC and dFNC are related to AD genetic risk. We found that higher AD risk reduces within-visual sensory network (VSN) sFNC and that individuals with higher AD risk spend more time in a state with lower within-VSN dFNC. We also found that AD genetic risk affects whole-brain sFNC and dFNC in women but not men. In conclusion, we presented novel insights into the links between sFNC, dFNC, and AD genetic risk.

YNIMG Journal 2022 Journal Article

A longitudinal study of functional connectome uniqueness and its association with psychological distress in adolescence

  • Zack Y Shan
  • Abdalla Z Mohamed
  • Paul Schwenn
  • Larisa T McLoughlin
  • Amanda Boyes
  • Dashiell D Sacks
  • Christina Driver
  • Vince D. Calhoun

Each human brain has a unique functional synchronisation pattern (functional connectome) analogous to a fingerprint that underpins brain functions and related behaviours. Here we examine functional connectome (whole-brain and 13 networks) maturation by measuring its uniqueness in adolescents who underwent brain scans longitudinally from 12 years of age every four months. The uniqueness of a functional connectome is defined as its ratio of self-similarity (from the same subject at a different time point) to the maximal similarity-to-others (from a given subject and any others at a different time point). We found that the unique whole brain connectome exists in 12 years old adolescents, with 92% individuals having a whole brain uniqueness value greater than one. The cingulo-opercular network (CON; a long-acting 'brain control network' configuring information processing) demonstrated marginal uniqueness in early adolescence with 56% of individuals showing uniqueness greater than one (i.e., more similar to her/his own CON four months later than those from any other subjects) and this increased longitudinally. Notably, the low uniqueness of the CON correlates (β = -18.6, FDR-Q < < 0.001) with K10 levels at the subsequent time point. This association suggests that the individualisation of CON network is related to psychological distress levels. Our findings highlight the potential of longitudinal neuroimaging to capture mental health problems in young people who are undergoing profound neuroplasticity and environment sensitivity period.

YNICL Journal 2022 Journal Article

A resting-state fMRI pattern of spinocerebellar ataxia type 3 and comparison with 18F-FDG PET

  • Harm J. van der Horn
  • Sanne K. Meles
  • Jelmer G. Kok
  • Victor M. Vergara
  • Shile Qi
  • Vince D. Calhoun
  • Jelle R. Dalenberg
  • Jeroen C.W. Siero

F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use.

YNIMG Journal 2022 Journal Article

Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity

  • Bhim M. Adhikari
  • L. Elliot Hong
  • Zhiwei Zhao
  • Danny J.J. Wang
  • Paul M. Thompson
  • Neda Jahanshad
  • Alyssa H. Zhu
  • Stefan Holiga

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6, 285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2. 5 × 10−3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10−6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10−6). Analysis in N = 6, 285 replicated the FCVRS→ReHo effect (p = 2. 7 × 10−27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors.

YNIMG Journal 2022 Journal Article

Detecting abnormal connectivity in schizophrenia via a joint directed acyclic graph estimation model

  • Gemeng Zhang
  • Biao Cai
  • Aiying Zhang
  • Zhuozhuo Tu
  • Li Xiao
  • Julia M. Stephen
  • Tony W. Wilson
  • Vince D. Calhoun

Functional connectivity (FC) between brain region has been widely studied and linked with cognition and behavior of an individual. FC is usually defined as the correlation or partial correlation of fMRI blood oxygen level-dependent (BOLD) signals between two brain regions. Although FC has been effective to understand brain organization, it cannot reveal the direction of interactions. Many directed acyclic graph (DAG) based methods have been applied to study the directed interactions but their performance was limited by the small sample size while high dimensionality of the available data. By enforcing group regularization and utilizing samples from both case and control groups, we propose a joint DAG model to estimate the directed FC. We first demonstrate that the proposed model is efficient and accurate through a series of simulation studies. We then apply it to the case-control study of schizophrenia (SZ) with data collected from the MIND Clinical Imaging Consortium (MCIC). We have successfully identified decreased functional integration, disrupted hub structures and characteristic edges (CtEs) in SZ patients. Those findings have been confirmed by previous studies with some identified to be potential markers for SZ patients. A comparison of the results between the directed FC and undirected FC showed substantial differences in the selected features. In addition, we used the identified features based on directed FC for the classification of SZ patients and achieved better accuracy than using undirected FC or raw features, demonstrating the advantage of using directed FC for brain network analysis.

YNIMG Journal 2022 Journal Article

Eyes-closed versus eyes-open differences in spontaneous neural dynamics during development

  • Nathan M. Petro
  • Lauren R. Ott
  • Samantha H. Penhale
  • Maggie P. Rempe
  • Christine M. Embury
  • Giorgia Picci
  • Yu-Ping Wang
  • Julia M. Stephen

BACKGROUND: Assessing brain activity during rest has become a widely used approach in developmental neuroscience. Extant literature has measured resting brain activity both during eyes-open and eyes-closed conditions, but the difference between these conditions has not yet been well characterized. Studies, limited to fMRI and EEG, have suggested that eyes-open versus -closed conditions may differentially impact neural activity, especially in visual cortices. METHODS: Spontaneous cortical activity was recorded using MEG from 108 typically developing youth (9-15 years-old; 55 female) during separate sessions of eyes-open and eyes-closed rest. MEG source images were computed, and the strength of spontaneous neural activity was estimated in the canonical delta, theta, alpha, beta, and gamma bands, respectively. Power spectral density maps for eyes-open were subtracted from eyes-closed rest, and then submitted to vertex-wise regression models to identify spatially specific differences between conditions and as a function of age and sex. RESULTS: Relative alpha power was weaker in the eyes-open compared to -closed condition, but otherwise eyes-open was stronger in all frequency bands, with differences concentrated in the occipital cortex. Relative theta power became stronger in the eyes-open compared to the eyes-closed condition with increasing age in frontal cortex. No differences were observed between males and females. CONCLUSIONS: The differences in relative power from eyes-closed to -open conditions are consistent with changes observed in task-based visual sensory responses. Age differences occurred in relatively late developing frontal regions, consistent with canonical attention regions, suggesting that these differences could be reflective of developmental changes in attention processes during puberty. Taken together, resting-state paradigms using eyes-open versus -closed produce distinct results and, in fact, can help pinpoint sensory related brain activity.

YNIMG Journal 2022 Journal Article

Individual differences in amygdala volumes predict changes in functional connectivity between subcortical and cognitive control networks throughout adolescence

  • Brittany K. Taylor
  • Michaela R. Frenzel
  • Jacob A. Eastman
  • Christine M. Embury
  • Oktay Agcaoglu
  • Yu-Ping Wang
  • Julia M. Stephen
  • Vince D. Calhoun

Adolescence is a critical period of structural and functional neural maturation among regions serving the cognitive control of emotion. Evidence suggests that this process is guided by developmental changes in amygdala and striatum structure and shifts in functional connectivity between subcortical (SC) and cognitive control (CC) networks. Herein, we investigate the extent to which such developmental shifts in structure and function reciprocally predict one another over time. 179 youth (9-15 years-old) completed annual MRI scans for three years. Amygdala and striatum volumes and connectivity within and between SC and CC resting state networks were measured for each year. We tested for reciprocal predictability of within-person and between-person changes in structure and function using random-intercept cross-lagged panel models. Within-person shifts in amygdala volumes in a given year significantly and specifically predicted deviations in SC-CC connectivity in the following year, such that an increase in volume was associated with decreased SC-CC connectivity the following year. Deviations in connectivity did not predict changes in amygdala volumes over time. Conversely, broader group-level shifts in SC-CC connectivity were predictive of subsequent deviations in striatal volumes. We did not see any cross-predictability among amygdala or striatum volumes and within-network connectivity measures. Within-person shifts in amygdala structure year-to-year robustly predicted weaker SC-CC connectivity in subsequent years, whereas broader increases in SC-CC connectivity predicted smaller striatal volumes over time. These specific structure function relationships may contribute to the development of emotional control across adolescence.

YNIMG Journal 2022 Journal Article

Longitudinal changes in the neural oscillatory dynamics underlying abstract reasoning in children and adolescents

  • Brittany K. Taylor
  • Elizabeth Heinrichs-Graham
  • Jacob A. Eastman
  • Michaela R. Frenzel
  • Yu-Ping Wang
  • Vince D. Calhoun
  • Julia M. Stephen
  • Tony W. Wilson

Fluid reasoning is the ability to problem solve in the absence of prior knowledge and is commonly conceptualized as "non-verbal" intelligence. Importantly, fluid reasoning abilities rapidly develop throughout childhood and adolescence. Although numerous studies have characterized the neural underpinnings of fluid reasoning in adults, there is a paucity of research detailing the developmental trajectory of this neural processing. Herein, we examine longitudinal changes in the neural oscillatory dynamics underlying fluid intelligence in a sample of typically developing youths. A total of 34 participants age 10 to 16 years-old completed an abstract reasoning task during magnetoencephalography (MEG) on two occasions set one year apart. We found robust longitudinal optimization in theta, beta, and gamma oscillatory activity across years of the study across a distributed network commonly implicated in fluid reasoning abilities. More specifically, activity tended to decrease longitudinally in additional, compensatory areas such as the right lateral prefrontal cortex and increase in areas commonly utilized in mature adult samples (e.g., left frontal and parietal cortices). Importantly, shifts in neural activity were associated with improvements in task performance from one year to the next. Overall, the data suggest a longitudinal shift in performance that is accompanied by a reconfiguration of the functional oscillatory dynamics serving fluid reasoning during this important period of development.

YNIMG Journal 2022 Journal Article

The development of sensorimotor cortical oscillations is mediated by pubertal testosterone

  • Madison H. Fung
  • Elizabeth Heinrichs-Graham
  • Brittany K. Taylor
  • Michaela R. Frenzel
  • Jacob A. Eastman
  • Yu-Ping Wang
  • Vince D. Calhoun
  • Julia M. Stephen

Puberty is a period of substantial hormonal fluctuations, and pubertal hormones can modulate structural and functional changes in the developing brain. Many previous studies have characterized the neural oscillatory responses serving movement, which include a beta event-related desynchronization (ERD) preceding movement onset, gamma and theta responses coinciding with movement execution, and a post-movement beta-rebound (PMBR) response following movement offset. While a few studies have investigated the developmental trajectories of these neural oscillations serving motor control, the impact of pubertal hormone levels on the maturation of these dynamics has not yet been examined. Since the timing and tempo of puberty varies greatly between individuals, pubertal hormones may uniquely impact the maturation of motor cortical oscillations distinct from other developmental metrics, such as age. In the current study we quantified these oscillations using magnetoencephalography (MEG) and utilized chronological age and measures of endogenous testosterone as indices of development during the transition from childhood to adolescence in 69 youths. Mediation analyses revealed complex maturation patterns for the beta ERD, in which testosterone predicted both spontaneous baseline and ERD power through direct and indirect effects. Age, but not pubertal hormones, predicted motor-related theta, and no relationships between oscillatory responses and developmental metrics were found for gamma or PMBR responses. These findings provide novel insight into how pubertal hormones affect motor-related oscillations, and highlight the continued development of motor cortical dynamics throughout the pubertal period.

YNIMG Journal 2021 Journal Article

Dynamic state with covarying brain activity-connectivity: On the pathophysiology of schizophrenia

  • Zening Fu
  • Armin Iraji
  • Jessica A. Turner
  • Jing Sui
  • Robyn Miller
  • Godfrey D. Pearlson
  • Vince D. Calhoun

The human brain is a dynamic system that incorporates the evolution of local activities and the reconfiguration of brain interactions. Reoccurring brain patterns, regarded as "brain states", have revealed new insights into the pathophysiology of brain disorders, particularly schizophrenia. However, previous studies only focus on the dynamics of either brain activity or connectivity, ignoring the temporal co-evolution between them. In this work, we propose to capture dynamic brain states with covarying activity-connectivity and probe schizophrenia-related brain abnormalities. We find that the state-based activity and connectivity show high correspondence, where strong and antagonistic connectivity is accompanied with strong low-frequency fluctuations across the whole brain while weak and sparse connectivity co-occurs with weak low-frequency fluctuations. In addition, graphical analysis shows that connectivity network efficiency is associated with the fluctuation of brain activities and such associations are different across brain states. Compared with healthy controls, schizophrenia patients spend more time in weakly-connected and -activated brain states but less time in strongly-connected and -activated brain states. schizophrenia patients also show lower efficiency in thalamic regions within the "strong" states. Interestingly, the atypical fractional occupancy of one brain state is correlated with individual attention performance. Our findings are replicated in another independent dataset and validated using different brain parcellation schemes. These converging results suggest that the brain spontaneously reconfigures with covarying activity and connectivity and such co-evolutionary property might provide meaningful information on the mechanism of brain disorders which cannot be observed by investigating either of them alone.

YNIMG Journal 2021 Journal Article

Frequency drift in MR spectroscopy at 3T

  • Steve C.N. Hui
  • Mark Mikkelsen
  • Helge J. Zöllner
  • Vishwadeep Ahluwalia
  • Sarael Alcauter
  • Laima Baltusis
  • Deborah A. Barany
  • Laura R. Barlow

PURPOSE: field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. DISCUSSION: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

JBHI Journal 2021 Journal Article

Multi-Paradigm fMRI Fusion via Sparse Tensor Decomposition in Brain Functional Connectivity Study

  • Yipu Zhang
  • Li Xiao
  • Gemeng Zhang
  • Biao Cai
  • Julia M. Stephen
  • Tony W. Wilson
  • Vince D. Calhoun
  • Yu-Ping Wang

Functional magnetic resonance imaging (fMRI) is a powerful technique with the potential to estimate individual variations in behavioral and cognitive traits. Joint learning of multiple datasets can utilize their complementary information so as to improve learning performance, but it also gives rise to the challenge for data fusion to effectively integrate brain patterns elicited by multiple fMRI data. However, most of the current data fusion methods analyze each single dataset separately and further infer the relationship among them, which fail to utilize the multidimensional structure inherent across modalities and may ignore complex but important interactions. To address this issue, we propose a novel sparse tensor decomposition method to integrate multiple task-stimulus (paradigm) fMRI data. Seeing each paradigm fMRI as one modality, our proposed method considers the relationships across subjects and modalities simultaneously. In specific, a third-order tensor is first modeled by using the functional network connectivity (FNC) of subjects in multiple fMRI paradigms. A novel sparse tensor decomposition with the regularization terms is designed to factorize the tensor into a series of rank-one components, which can extract the shared components across modalities as the embedded features. The L 2, 1 -norm regularizer (i. e. , group sparsity) is enforced to select a few common features among multiple subjects. Validation of the proposed method is performed on realistic three paradigm fMRI datasets from the Philadelphia Neurodevelopmental Cohort (PNC) study, for the study of the relationship between the FNC and human cognitive abilities. Experimental results show our method outperforms several other competing methods in the prediction of individuals with different cognitive behaviors via the wide range achievement test (WRAT). Furthermore, our method discovers the FNC related to the cognitive behaviors, such as the connectivity associated with the default mode network (DMN) for three paradigms, and the connectivity between DMN and visual (VIS) domains within the emotion task.

YNIMG Journal 2021 Journal Article

Respiratory, cardiac, EEG, BOLD signals and functional connectivity over multiple microsleep episodes

  • Chun Siong Soon
  • Ksenia Vinogradova
  • Ju Lynn Ong
  • Vince D. Calhoun
  • Thomas Liu
  • Juan Helen Zhou
  • Kwun Kei Ng
  • Michael W.L. Chee

Falling asleep is common in fMRI studies. By using long eyelid closures to detect microsleep onset, we showed that the onset and termination of short sleep episodes invokes a systematic sequence of BOLD signal changes that are large, widespread, and consistent across different microsleep durations. The signal changes are intimately intertwined with shifts in respiration and heart rate, indicating that autonomic contributions are integral to the brain physiology evaluated using fMRI and cannot be simply treated as nuisance signals. Additionally, resting state functional connectivity (RSFC) was altered in accord with the frequency of falling asleep and in a manner that global signal regression does not eliminate. Our findings point to the need to develop a consensus among neuroscientists using fMRI on how to deal with microsleep intrusions. SIGNIFICANCE STATEMENT: Sleep, breathing and cardiac action are influenced by common brainstem nuclei. We show that falling asleep and awakening are associated with a sequence of BOLD signal changes that are large, widespread and consistent across varied durations of sleep onset and awakening. These signal changes follow closely those associated with deceleration and acceleration of respiration and heart rate, calling into question the separation of the latter signals as 'noise' when the frequency of falling asleep, which is commonplace in RSFC studies, correlates with the extent of RSFC perturbation. Autonomic and central nervous system contributions to BOLD signal have to be jointly considered when interpreting fMRI and RSFC studies.

YNIMG Journal 2021 Journal Article

Spontaneous cortical MEG activity undergoes unique age- and sex-related changes during the transition to adolescence

  • Lauren R. Ott
  • Samantha H. Penhale
  • Brittany K. Taylor
  • Brandon J. Lew
  • Yu-Ping Wang
  • Vince D. Calhoun
  • Julia M. Stephen
  • Tony W. Wilson

BACKGROUND: While numerous studies have examined the developmental trajectory of task-based neural oscillations during childhood and adolescence, far less is known about the evolution of spontaneous cortical activity during this time period. Likewise, many studies have shown robust sex differences in task-based oscillations during this developmental period, but whether such sex differences extend to spontaneous activity is not understood. METHODS: Herein, we examined spontaneous cortical activity in 111 typically-developing youth (ages 9-15 years; 55 male). Participants completed a resting state magnetoencephalographic (MEG) recording and a structural MRI. MEG data were source imaged and the power within five canonical frequency bands (delta, theta, alpha, beta, gamma) was computed. The resulting power spectral density maps were analyzed via vertex-wise ANCOVAs to identify spatially-specific effects of age, sex, and their interaction. RESULTS: We found robust increases in power with age in all frequencies except delta, which decreased over time, with findings largely confined to frontal cortices. Sex effects were distributed across frontal and temporal regions; females tended to have greater delta and beta power, whereas males had greater alpha. Importantly, there was a significant age-by-sex interaction in theta power, such that males exhibited decreasing power with age while females showed increasing power with age in the bilateral superior temporal cortices. DISCUSSION: These data suggest that the strength of spontaneous activity undergoes robust change during the transition from childhood to adolescence (i.e., puberty onset), with intriguing sex differences in some cortical areas. Future developmental studies should probe task-related oscillations and spontaneous activity in parallel.

YNIMG Journal 2021 Journal Article

Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

  • Kurt G. Schilling
  • François Rheault
  • Laurent Petit
  • Colin B. Hansen
  • Vishwesh Nath
  • Fang-Cheng Yeh
  • Gabriel Girard
  • Muhamed Barakovic

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

JBHI Journal 2020 Journal Article

Canonical Correlation Analysis of Imaging Genetics Data Based on Statistical Independence and Structural Sparsity

  • Yipu Zhang
  • Peng Peng
  • Yongfeng Ju
  • Gang Li
  • Vince D. Calhoun
  • Yu-Ping Wang

Current developments of neuroimaging and genetics promote an integrative and compressive study of schizophrenia. However, it is still difficult to explore how gene mutations are related to brain abnormalities due to the high dimension but low sample size of these data. Conventional approaches reduce the dimension of dataset separately and then calculate the correlation, but ignore the effects of the response variables and the structure of data. To improve the identification of risk genes and abnormal brain regions on schizophrenia, in this paper, we propose a novel method called Independence and Structural sparsity Canonical Correlation Analysis (ISCCA). ISCCA combines independent component analysis (ICA) and Canonical Correlation Analysis (CCA) to reduce the collinear effects, which also incorporate graph structure of the data into the model to improve the accuracy of feature selection. The results from simulation studies demonstrate its higher accuracy in discovering correlations compared with other competing methods. Moreover, applying ISCCA to a real imaging genetics dataset collected by Mind Clinical Imaging Consortium (MCIC), a set of distinct gene-ROI interactions are identified, which are verified to be both statistically and biologically significant.

YNIMG Journal 2020 Journal Article

Connectivity dynamics from wakefulness to sleep

  • Eswar Damaraju
  • Enzo Tagliazucchi
  • Helmut Laufs
  • Vince D. Calhoun

Interest in time-resolved connectivity in fMRI has grown rapidly in recent years. The most widely used technique for studying connectivity changes over time utilizes a sliding windows approach. There has been some debate about the utility of shorter versus longer windows, the use of fixed versus adaptive windows, as well as whether observed resting state dynamics during wakefulness may be predominantly due to changes in sleep state and subject head motion. In this work we use an independent component analysis (ICA)-based pipeline applied to concurrent EEG/fMRI data collected during wakefulness and various sleep stages and show: 1) connectivity states obtained from clustering sliding windowed correlations of resting state functional network time courses well classify the sleep states obtained from EEG data, 2) using shorter sliding windows instead of longer non-overlapping windows improves the ability to capture transition dynamics even at windows as short as 30 ​s, 3) motion appears to be mostly associated with one of the states rather than spread across all of them 4) a fixed tapered sliding window approach outperforms an adaptive dynamic conditional correlation approach, and 5) consistent with prior EEG/fMRI work, we identify evidence of multiple states within the wakeful condition which are able to be classified with high accuracy. Classification of wakeful only states suggest the presence of time-varying changes in connectivity in fMRI data beyond sleep state or motion. Results also inform about advantageous technical choices, and the identification of different clusters within wakefulness that are separable suggest further studies in this direction.

YNICL Journal 2020 Journal Article

Default mode network modulation by mentalizing in young adults with autism spectrum disorder or schizophrenia

  • Christopher J. Hyatt
  • Vince D. Calhoun
  • Brian Pittman
  • Silvia Corbera
  • Morris D. Bell
  • Liron Rabany
  • Kevin Pelphrey
  • Godfrey D. Pearlson

Schizophrenia and autism spectrum disorder (ASD) are nosologically distinct neurodevelopmental disorders with similar deficits in social cognition, including the ability to form mental representations of others (i.e., mentalizing). However, the extent of patient deficit overlap in underlying neural mechanisms is unclear. Our goal was to examine deficits in mentalizing task-related (MTR) activity modulation in schizophrenia and ASD and the relationship of such deficits with social functioning and psychotic symptoms in patients. Adults, ages 18-34, diagnosed with either ASD or schizophrenia, and typically developed controls (n = 30/group), performed an interactive functional MRI Domino task. Using independent component analysis, we analyzed game intervals known to stimulate mentalizing in the default mode network (DMN), i.e., medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), precuneus, and temporoparietal junction (TPJ), for group differences in MTR activity and associations between MTR activity and social and psychosis measures. Compared to controls, both schizophrenia and ASD groups showed MTR activity deficits in PCC and TPJ. In TPJ and MPFC, MTR activity modulation was associated with social communication impairments only in ASD. In precuneus, MTR activity was associated with increased self-reported fantasizing only in schizophrenia. In schizophrenia, we found no indication of over-mentalizing activity or an association between MTR activity and psychotic symptoms. Results suggest shared neural deficits between ASD and schizophrenia in mentalizing-associated DMN regions; however, neural organization might correspond to different dimensional social deficits. Our results therefore indicate the importance of examining both categorical-clinical diagnosis and social functioning dimensional constructs when examining neural deficits in schizophrenia and ASD.

YNIMG Journal 2020 Journal Article

Development and sex modulate visuospatial oscillatory dynamics in typically-developing children and adolescents

  • Abraham D. Killanin
  • Alex I. Wiesman
  • Elizabeth Heinrichs-Graham
  • Boman R. Groff
  • Michaela R. Frenzel
  • Jacob A. Eastman
  • Yu-Ping Wang
  • Vince D. Calhoun

Visuospatial processing is a cognitive function that is critical to navigating one's surroundings and begins to develop during infancy. Extensive research has examined visuospatial processing in adults, but far less work has investigated how visuospatial processing and the underlying neurophysiology changes from childhood to early adolescence, which is a critical period of human development that is marked by the onset of puberty. In the current study, we examined behavioral performance and the oscillatory dynamics serving visuospatial processing using magnetoencephalography (MEG) in a cohort of 70 children and young adolescents aged 8–15 years. All participants performed a visuospatial processing task during MEG, and the resulting oscillatory responses were imaged using a beamformer and probed for developmental and sex-related differences. Our findings indicated that reaction time on the task was negatively correlated with age, and that the amplitude of theta oscillations in the medial occipital cortices increased with age. Significant sex-by-age interactions were also detected, with female participants exhibiting increased theta oscillatory activity in the right prefrontal cortex with increasing age, while male participants exhibited theta increases in the left parietal lobe/left precuneus and left supplementary motor area with increasing age. These data indicate that different nodes of the visuospatial processing network develop earlier in males compared to females (and vice versa) in this age range, which may have major implications for the developmental trajectory of behavioral performance and executive function more generally during the transition through puberty.

YNIMG Journal 2020 Journal Article

Disambiguating the role of blood flow and global signal with partial information decomposition

  • Nigel Colenbier
  • Frederik Van de Steen
  • Lucina Q. Uddin
  • Russell A. Poldrack
  • Vince D. Calhoun
  • Daniele Marinazzo

Global signal (GS) is an ubiquitous construct in resting state functional magnetic resonance imaging (rs-fMRI), associated to nuisance, but containing by definition most of the neuronal signal. Global signal regression (GSR) effectively removes the impact of physiological noise and other artifacts, but at the same time it alters correlational patterns in unpredicted ways. Performing GSR taking into account the underlying physiology (mainly the blood arrival time) has been proven to be beneficial. From these observations we aimed to: 1) characterize the effect of GSR on network-level functional connectivity in a large dataset; 2) assess the complementary role of global signal and vessels; and 3) use the framework of partial information decomposition to further look into the joint dynamics of the global signal and vessels, and their respective influence on the dynamics of cortical areas. We observe that GSR affects intrinsic connectivity networks in the connectome in a non-uniform way. Furthermore, by estimating the predictive information of blood flow and the global signal using partial information decomposition, we observe that both signals are present in different amounts across intrinsic connectivity networks. Simulations showed that differences in blood arrival time can largely explain this phenomenon, while using hemodynamic and calcium mouse recordings we were able to confirm the presence of vascular effects, as calcium recordings lack hemodynamic information. With these results we confirm network-specific effects of GSR and the importance of taking blood flow into account for improving de-noising methods. Additionally, and beyond the mere issue of data denoising, we quantify the diverse and complementary effect of global and vessel BOLD signals on the dynamics of cortical areas.

YNICL Journal 2020 Journal Article

Distinct structural brain circuits indicate mood and apathy profiles in bipolar disorder

  • Wenhao Jiang
  • Ole A. Andreassen
  • Ingrid Agartz
  • Trine V. Lagerberg
  • Lars T. Westlye
  • Vince D. Calhoun
  • Jessica A. Turner

Bipolar disorder (BD) is a severe manic-depressive illness. Patients with BD have been shown to have gray matter (GM) deficits in prefrontal, frontal, parietal, and temporal regions; however, the relationship between structural effects and clinical profiles has proved elusive when considered on a region by region or voxel by voxel basis. In this study, we applied parallel independent component analysis (pICA) to structural neuroimaging measures and the positive and negative syndrome scale (PANSS) in 110 patients (mean age 34.9 ± 11.65) with bipolar disorder, to examine networks of brain regions that relate to symptom profiles. The pICA revealed two distinct symptom profiles and associated GM concentration alteration circuits. The first PANSS pICA profile mainly involved anxiety, depression and guilty feelings, reflecting mood symptoms. Reduced GM concentration in right temporal regions predicted worse mood symptoms in this profile. The second PANSS pICA profile generally covered blunted affect, emotional withdrawal, passive/apathetic social withdrawal, depression and active social avoidance, exhibiting a withdrawal or apathy dominating component. Lower GM concentration in bilateral parietal and frontal regions showed worse symptom severity in this profile. In summary, a pICA decomposition suggested BD patients showed distinct mood and apathy profiles differing from the original PANSS subscales, relating to distinct brain structural networks.

JBHI Journal 2020 Journal Article

Guest Editorial: Information Fusion for Medical Data: Early, Late, and Deep Fusion Methods for Multimodal Data

  • Ines Domingues
  • Henning Muller
  • Andres Ortiz
  • Belur V. Dasarathy
  • Pedro H. Abreu
  • Vince D. Calhoun

The papers in this special section examine important current topics on multimodal data fusion in the medical context. All clinical data, including genomic and proteomic, play a role in the diagnosis and in particular in the treatment planning and follow-up. This is true for all types of data analyses whether in classification, regression, retrieval, clustering, or other. The interaction between several types of information is not always well understood. Experienced clinicians automatically and even unconsciously add multiple sources of information into their decision process, but machine learning tools often concentrate on single information sources. This special issue presents five examples where several data sources are fused. The papers give several examples of fusion techniques and also the results obtained in quite different application scenarios.

YNICL Journal 2020 Journal Article

Identifying commonality and specificity across psychosis sub-groups via classification based on features from dynamic connectivity analysis

  • Yuhui Du
  • Hui Hao
  • Shuhua Wang
  • Godfrey D Pearlson
  • Vince D. Calhoun

It is difficult to distinguish schizophrenia (SZ), schizoaffective disorder (SAD), and bipolar disorder with psychosis (BPP) as their clinical diagnoses rely on symptoms that overlap. In this paper, we investigate if there is biological evidence to support the symptom-based clinical categories by looking across the three disorders using dynamic connectivity measures, and provide meaningful characteristics on which brain functional connectivity measures are commonly or uniquely impaired. Large-sample functional magnetic resonance image (fMRI) datasets from 623 subjects including 238 healthy controls (HCs), 113 SZ patients, 132 SAD patients, and 140 BPP patients were analyzed. First, we computed whole-brain dynamic functional connectivity (DFC) using a sliding-window technique, and then extracted the individual connectivity states by applying our previously proposed decomposition-based DFC analysis method. Next, with the features from the dominant connectivity state, we assessed the clinical categories by performing both four-group (SZ, SAD, BPP and healthy control groups) and pair-wise classification using a support vector machine within cross-validation. Furthermore, we comprehensively summarized the shared and unique connectivity alterations among the disorders. In terms of the classification performance, our method achieved 69% in the four-group classification and >80% in the between-group classifications for the mean overall accuracy; and yielded 66% in the four-group classification and >80% in the between-group classifications for the mean balanced accuracy. Through summarizing the features that were automatically selected in the classifications, we found that among the three symptom-related disorders, their disorder-common impairments primarily included the decreased connectivity strength between thalamus and cerebellum and the increased strength between postcentral gyrus and thalamus. The disorder-unique changes included more various brain regions, mainly in the temporal and frontal gyrus. Our work demonstrates that dynamic functional connectivity provides biological evidence that both common and unique impairments exist in psychosis sub-groups.

YNICL Journal 2020 Journal Article

In search of multimodal brain alterations in Alzheimer's and Binswanger's disease

  • Zening Fu
  • Armin Iraji
  • Arvind Caprihan
  • John C. Adair
  • Jing Sui
  • Gary A. Rosenberg
  • Vince D. Calhoun

Structural and functional brain abnormalities have been widely identified in dementia, but with variable replicability and significant overlap. Alzheimer's disease (AD) and Binswanger's disease (BD) share similar symptoms and common brain changes that can confound diagnosis. In this study, we aimed to investigate correlated structural and functional brain changes in AD and BD by combining resting-state functional magnetic resonance imaging (fMRI) and diffusion MRI. A group independent component analysis was first performed on the fMRI data to extract 49 intrinsic connectivity networks (ICNs). Then we conducted a multi-set canonical correlation analysis on three features, functional network connectivity (FNC) between ICNs, fractional anisotropy (FA) and mean diffusivity (MD). Two inter-correlated components show significant group differences. The first component demonstrates distinct brain changes between AD and BD. AD shows increased cerebellar FNC but decreased thalamic and hippocampal FNC. Such FNC alterations are linked to the decreased corpus callosum FA. AD also has increased MD in the frontal and temporal cortex, but BD shows opposite alterations. The second component demonstrates specific brain changes in BD. Increased FNC is mainly between default mode and sensory regions, while decreased FNC is mainly within the default mode domain and related to auditory regions. The FNC changes are associated with FA changes in posterior/middle cingulum cortex and visual cortex and increased MD in thalamus and hippocampus. Our findings provide evidence of linked functional and structural deficits in dementia and suggest that AD and BD have both common and distinct changes in white matter integrity and functional connectivity.

YNIMG Journal 2020 Journal Article

Independent vector analysis for common subspace analysis: Application to multi-subject fMRI data yields meaningful subgroups of schizophrenia

  • Qunfang Long
  • Suchita Bhinge
  • Vince D. Calhoun
  • Tülay Adali

The extraction of common and distinct biomedical signatures among different populations allows for a more detailed study of the group-specific as well as distinct information of different populations. A number of subspace analysis algorithms have been developed and successfully applied to data fusion, however they are limited to joint analysis of only a couple of datasets. Since subspace analysis is very promising for analysis of multi-subject medical imaging data as well, we focus on this problem and propose a new method based on independent vector analysis (IVA) for common subspace extraction (IVA-CS) for multi-subject data analysis. IVA-CS leverages the strength of IVA in identification of a complete subspace structure across multiple datasets along with an efficient solution that uses only second-order statistics. We propose a subset analysis approach within IVA-CS to mitigate issues in estimation in IVA due to high dimensionality, both in terms of components estimated and the number of datasets. We introduce a scheme to determine a desirable size for the subset that is high enough to exploit the dependence across datasets and is not affected by the high dimensionality issue. We demonstrate the success of IVA-CS in extracting complex subset structures and apply the method to analysis of functional magnetic resonance imaging data from 179 subjects and show that it successfully identifies shared and complementary brain patterns from patients with schizophrenia (SZ) and healthy controls group. Two components with linked resting-state networks are identified to be unique to the SZ group providing evidence of functional dysconnectivity. IVA-CS also identifies subgroups of SZs that show significant differences in terms of their brain networks and clinical symptoms.

YNICL Journal 2020 Journal Article

NeuroMark: An automated and adaptive ICA based pipeline to identify reproducible fMRI markers of brain disorders

  • Yuhui Du
  • Zening Fu
  • Jing Sui
  • Shuang Gao
  • Ying Xing
  • Dongdong Lin
  • Mustafa Salman
  • Anees Abrol

Many mental illnesses share overlapping or similar clinical symptoms, confounding the diagnosis. It is important to systematically characterize the degree to which unique and similar changing patterns are reflective of brain disorders. Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. However, it is still an open question on replicating and translating findings across studies. Standardized approaches for capturing reproducible and comparable imaging markers are greatly needed. Here, we propose a pipeline based on the priori-driven independent component analysis, NeuroMark, which is capable of estimating brain functional network measures from functional magnetic resonance imaging (fMRI) data that can be used to link brain network abnormalities among different datasets, studies, and disorders. NeuroMark automatically estimates features adaptable to each individual subject and comparable across datasets/studies/disorders by taking advantage of the reliable brain network templates extracted from 1828 healthy controls as guidance. Four studies including 2442 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, mild cognitive impairment, Alzheimer's disease, bipolar disorder, and major depressive disorder) to evaluate validity of the proposed pipeline from different perspectives (replication of brain abnormalities, cross-study comparison, identification of subtle brain changes, and multi-disorder classification using identified biomarkers). Our results highlight that NeuroMark effectively identified replicated brain network abnormalities of schizophrenia across different datasets; revealed interesting neural clues on the overlap and specificity between autism and schizophrenia; demonstrated brain functional impairments present to varying degrees in mild cognitive impairments and Alzheimer's disease; and captured biomarkers that achieved good performance in classifying bipolar disorder and major depressive disorder.

YNIMG Journal 2020 Journal Article

Prediction and classification of sleep quality based on phase synchronization related whole-brain dynamic connectivity using resting state fMRI

  • Zhongxing Zhou
  • Biao Cai
  • Gemeng Zhang
  • Aiying Zhang
  • Vince D. Calhoun
  • Yu-Ping Wang

Recently, functional network connectivity (FNC) has been extended from static to dynamic analysis to explore the time-varying functional organization of brain networks. Nowadays, a majority of dynamic FNC (dFNC) analysis frameworks identified recurring FNC patterns with linear correlations based on the amplitude of fMRI time series. However, the brain is a complex dynamical system and phase synchronization provides more informative measures. This paper proposes a novel framework for the prediction/classification of behaviors and cognitions based on the dFNCs derived from phase locking value. When applying to the analysis of fMRI data from Human Connectome Project (HCP), four dFNC states are identified for the study of sleep quality. State 1 exhibits most intense phase synchronization across the whole brain. States 2 and 3 have low and weak connections, respectively. State 4 exhibits strong phase synchronization in intra and inter-connections of somatomotor, visual and cognitive control networks. Through the two-sample t-test, we reveal that for the group with bad sleep quality, state 4 shows decreased phase synchronization within and between networks such as subcortical, auditory, somatomotor and visual, but increased phase synchronization within cognitive control network, and between this network and somatomotor/visual/default-mode/cerebellar networks. The networks with increased phase synchronization in state 4 behave oppositely in state 2. Group differences are absent in state 3, and weak in state 1. We establish a prediction model by linear regression of FNC against sleep quality, and adopt a support vector machine approach for the classification. We compare the performance between conventional FNC and PLV-based dFNC with cross-validation. Results show that the PLV-based dFNC significantly outperforms the conventional FNC in terms of both predictive power and classification accuracy. We also observe that combining static and dynamic features does not significantly improve the classification over using dFNC features alone. Overall, the proposed approach provides a novel means to assess dFNC, which can be used as brain fingerprints to facilitate prediction and classification.

YNICL Journal 2020 Journal Article

Preliminary prediction of individual response to electroconvulsive therapy using whole-brain functional magnetic resonance imaging data

  • Hailun Sun
  • Rongtao Jiang
  • Shile Qi
  • Katherine L. Narr
  • Benjamin SC Wade
  • Joel Upston
  • Randall Espinoza
  • Tom Jones

Electroconvulsive therapy (ECT) works rapidly and has been widely used to treat depressive disorders (DEP). However, identifying biomarkers predictive of response to ECT remains a priority to individually tailor treatment and understand treatment mechanisms. This study used a connectome-based predictive modeling (CPM) approach in 122 patients with DEP to determine if pre-ECT whole-brain functional connectivity (FC) predicts depressive rating changes and remission status after ECT (47 of 122 total subjects or 38.5% of sample), and whether pre-ECT and longitudinal changes (pre/post-ECT) in regional brain network biomarkers are associated with treatment-related changes in depression ratings. Results show the networks with the best predictive performance of ECT response were negative (anti-correlated) FC networks, which predict the post-ECT depression severity (continuous measure) with a 76.23% accuracy for remission prediction. FC networks with the greatest predictive power were concentrated in the prefrontal and temporal cortices and subcortical nuclei, and include the inferior frontal (IFG), superior frontal (SFG), superior temporal (STG), inferior temporal gyri (ITG), basal ganglia (BG), and thalamus (Tha). Several of these brain regions were also identified as nodes in the FC networks that show significant change pre-/post-ECT, but these networks were not related to treatment response. This study design has limitations regarding the longitudinal design and the absence of a control group that limit the causal inference regarding mechanism of post-treatment status. Though predictive biomarkers remained below the threshold of those recommended for potential translation, the analysis methods and results demonstrate the promise and generalizability of biomarkers for advancing personalized treatment strategies.

YNIMG Journal 2020 Journal Article

Task-induced brain connectivity promotes the detection of individual differences in brain-behavior relationships

  • Rongtao Jiang
  • Nianming Zuo
  • Judith M. Ford
  • Shile Qi
  • Dongmei Zhi
  • Chuanjun Zhuo
  • Yong Xu
  • Zening Fu

Although both resting and task-induced functional connectivity (FC) have been used to characterize the human brain and cognitive abilities, the potential of task-induced FCs in individualized prediction for out-of-scanner cognitive traits remains largely unexplored. A recent study Greene et al. (2018) predicted the fluid intelligence scores using FCs derived from rest and multiple task conditions, suggesting that task-induced brain state manipulation improved prediction of individual traits. Here, using a large dataset incorporating fMRI data from rest and 7 distinct task conditions, we replicated the original study by employing a different machine learning approach, and applying the method to predict two reading comprehension-related cognitive measures. Consistent with their findings, we found that task-based machine learning models often outperformed rest-based models. We also observed that combining multi-task fMRI improved prediction performance, yet, integrating the more fMRI conditions can not necessarily ensure better predictions. Compared with rest, the predictive FCs derived from language and working memory tasks were highlighted with more predictive power in predominantly default mode and frontoparietal networks. Moreover, prediction models demonstrated high stability to be generalizable across distinct cognitive states. Together, this replication study highlights the benefit of using task-based FCs to reveal brain-behavior relationships, which may confer more predictive power and promote the detection of individual differences of connectivity patterns underlying relevant cognitive traits, providing strong evidence for the validity and robustness of the original findings.

YNICL Journal 2020 Journal Article

The chronnectome as a model for Charcot’s ‘dynamic lesion’ in functional movement disorders

  • Ramesh S. Marapin
  • A.M. Madelein van der Stouwe
  • Bauke M. de Jong
  • Jeannette M. Gelauff
  • Victor M. Vergara
  • Vince D. Calhoun
  • Jelle R. Dalenberg
  • Yasmine E.M. Dreissen

This exploratory study set out to investigate dynamic functional connectivity (dFC) in patients with jerky and tremulous functional movement disorders (JT-FMD). The focus in this work is on dynamic brain states, which represent distinct dFC patterns that reoccur in time and across subjects. Resting-state fMRI data were collected from 17 patients with JT-FMD and 17 healthy controls (HC). Symptom severity was measured using the Clinical Global Impression-Severity scale. Depression and anxiety were measured using the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), respectively. Independent component analysis was used to extract functional brain components. After computing dFC, dynamic brain states were determined for every subject using k-means clustering. Compared to HC, patients with JT-FMD spent more time in a state that was characterized predominantly by increasing medial prefrontal, and decreasing posterior midline connectivity over time. They also tended to visit this state more frequently. In addition, patients with JT-FMD transitioned significantly more often between different states compared to HC, and incorporated a state with decreasing medial prefrontal, and increasing posterior midline connectivity in their attractor, i.e., the cyclic patterns of state transitions. Altogether, this is the first study that demonstrates altered functional brain network dynamics in JT-FMD that may support concepts of increased self-reflective processes and impaired sense of agency as driving factors in FMD.

YNIMG Journal 2019 Journal Article

A framework for linking resting-state chronnectome/genome features in schizophrenia: A pilot study

  • Barnaly Rashid
  • Jiayu Chen
  • Ishtiaque Rashid
  • Eswar Damaraju
  • Jingyu Liu
  • Robyn Miller
  • Oktay Agcaoglu
  • Theo G.M. van Erp

Multimodal, imaging-genomics techniques offer a platform for understanding genetic influences on brain abnormalities in psychiatric disorders. Such approaches utilize the information available from both imaging and genomics data and identify their association. Particularly for complex disorders such as schizophrenia, the relationship between imaging and genomic features may be better understood by incorporating additional information provided by advanced multimodal modeling. In this study, we propose a novel framework to combine features corresponding to functional magnetic resonance imaging (functional) and single nucleotide polymorphism (SNP) data from 61 schizophrenia (SZ) patients and 87 healthy controls (HC). In particular, the features for the functional and genetic modalities include dynamic (i. e. , time-varying) functional network connectivity (dFNC) features and the SNP data, respectively. The dFNC features are estimated from component time-courses, obtained using group independent component analysis (ICA), by computing sliding-window functional network connectivity, and then estimating subject specific states from this dFNC data using a k-means clustering approach. For each subject, both the functional (dFNC states) and SNP data are selected as features for a parallel ICA (pICA) based imaging-genomic framework. This analysis identified a significant association between a SNP component (defined by large clusters of functionally related SNPs statistically correlated with phenotype components) and time-varying or dFNC component (defined by clusters of related connectivity links among distant brain regions distributed across discrete dynamic states, and statistically correlated with genomic components) in schizophrenia. Importantly, the polygenetic risk score (PRS) for SZ (computed as a linearly weighted sum of the genotype profiles with weights derived from the odds ratios of the psychiatric genomics consortium (PGC)) was negatively correlated with the significant dFNC component, which were mostly present within a state that exhibited a lower occupancy rate in individuals with SZ compared with HC, hence identifying a potential dFNC imaging biomarker for schizophrenia. Taken together, the current findings provide preliminary evidence for a link between dFNC measures and genetic risk, suggesting the application of dFNC patterns as biomarkers in imaging genetic association study.

YNICL Journal 2019 Journal Article

Aberrant activity in conceptual networks underlies N400 deficits and unusual thoughts in schizophrenia

  • Michael S. Jacob
  • Judith M. Ford
  • Brian J. Roach
  • Vince D. Calhoun
  • Daniel H. Mathalon

BACKGROUND: The N400 event-related potential (ERP) is triggered by meaningful stimuli that are incongruous, or unmatched, with their semantic context. Functional magnetic resonance imaging (fMRI) studies have identified brain regions activated by semantic incongruity, but their precise links to the N400 ERP are unclear. In schizophrenia (SZ), N400 amplitude reduction is thought to reflect overly broad associations in semantic networks, but the abnormalities in brain networks underlying deficient N400 remain unknown. We utilized joint independent component analysis (JICA) to link temporal patterns in ERPs to neuroanatomical patterns from fMRI and investigate relationships between N400 amplitude and neuroanatomical activation in SZ patients and healthy controls (HC). METHODS: SZ patients (n = 24) and HC participants (n = 25) performed a picture-word matching task, in which words were either matched (APPLE→apple) by preceding pictures, or were unmatched by semantically related (in-category; IC, APPLE→lemon) or unrelated (out of category; OC, APPLE→cow) pictures, in separate ERP and fMRI sessions. A JICA "data fusion" analysis was conducted to identify the fMRI brain regions specifically associated with the ERP N400 component. SZ and HC loading weights were compared and correlations with clinical symptoms were assessed. RESULTS: JICA identified an ERP-fMRI "fused" component that captured the N400, with loading weights that were reduced in SZ. The JICA map for the IC condition showed peaks of activation in the cingulate, precuneus, bilateral temporal poles and cerebellum, whereas the JICA map from the OC condition was linked primarily to visual cortical activation and the left temporal pole. Among SZ patients, fMRI activity from the IC condition was inversely correlated with unusual thought content. CONCLUSIONS: The neural networks associated with the N400 ERP response to semantic violations depends on conceptual relatedness. These findings are consistent with a distributed network underlying neural responses to semantic incongruity including unimodal visual areas as well as integrative, transmodal areas. Unusual thoughts in SZ may reflect impaired processing in transmodal hub regions such as the precuneus, leading to overly broad semantic associations.

JBHI Journal 2019 Journal Article

Aberrant Brain Connectivity in Schizophrenia Detected via a Fast Gaussian Graphical Model

  • Aiying Zhang
  • Jian Fang
  • Faming Liang
  • Vince D. Calhoun
  • Yu-Ping Wang

Schizophrenia (SZ) is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. It has been proposed that this disorder is related to disrupted brain connectivity, which has been verified by many studies. With the development of functional magnetic resonance imaging (fMRI), further exploration of brain connectivity was made possible. Region-based networks are commonly used for mapping brain connectivity. However, they fail to illustrate the connectivity within regions of interest (ROIs) and lose precise location information. Voxel-based networks provide higher precision, but are difficult to construct and interpret due to the high dimensionality of the data. In this paper, we adopt a novel high-dimensional Gaussian graphical model – $\psi$ -learning method, which can help ease computational burden and provide more accurate inference for the underlying networks. This method has been proven to be an equivalent measure of the partial correlation coefficient and, thus, is flexible for network comparison through statistical tests. The fMRI data we used were collected by the mind clinical imaging consortium using an auditory task in which there are 92 SZ patients and 116 healthy controls. We compared the networks at three different scales by using global measurements, community structure, and edge-wise comparisons within the networks. Our results reveal, at the highest voxel resolution, sets of distinct aberrant patterns for the SZ patients, and more precise local structures are provided within ROIs for further investigation.

YNIMG Journal 2019 Journal Article

Association between the oral microbiome and brain resting state connectivity in smokers

  • Dongdong Lin
  • Kent E. Hutchison
  • Salvador Portillo
  • Victor Vegara
  • Jarrod M. Ellingson
  • Jingyu Liu
  • Kenneth S. Krauter
  • Amanda Carroll-Portillo

Recent studies have shown a critical role of the gastrointestinal microbiome in brain and behavior via the complex gut–microbiome–brain axis. However, the influence of the oral microbiome in neurological processes is much less studied, especially in response to the stimuli, such as smoking, within the oral microenvironment. Additionally, given the complex structural and functional networks in brain, our knowledge about the relationship between microbiome and brain function through specific brain circuits is still very limited. In this pilot study, we leveraged next generation sequencing for microbiome and functional neuroimaging technique to enable the delineation of microbiome-brain network links as well as their relationship to cigarette smoking. Thirty smokers and 30 age- and sex-matched nonsmokers were recruited for 16S sequencing of their oral microbial community. Among them, 56 subjects were scanned by resting-state functional magnetic resonance imaging to derive brain functional networks. Statistical analyses were performed to demonstrate the influence of smoking on the oral microbial composition, functional network connectivity, and the associations between microbial shifts and functional network connectivity alternations. Compared to nonsmokers, we found a significant decrease of beta diversity (P = 6 × 10−3) in smokers and identified several classes (Betaproteobacteria, Spirochaetia, Synergistia, and Mollicutes) with significant alterations in microbial abundance. Pathway analysis on the predicted KEGG pathways shows that the microbiota with altered abundance are mainly involved in pathways related to cell processes, DNA repair, immune system, and neurotransmitters signaling. One brain functional network connectivity component was identified to have a significant difference between smokers and nonsmokers (P = 0. 032), mainly including connectivity between brain default network and other task-positive networks. This brain functional component was also significantly associated with smoking related microbiota, suggesting a correlated cross-individual pattern between smoking-induced oral microbiome dysbiosis and brain functional connectivity alternation, possibly involving immunological and neurotransmitter signaling pathways. This work is the first attempt to link oral microbiome and brain functional networks, and provides support for future work in characterizing the role of oral microbiome in mediating smoking effects on brain activity.

YNICL Journal 2019 Journal Article

Brain function, structure and genomic data are linked but show different sensitivity to duration of illness and disease stage in schizophrenia

  • Na Luo
  • Lin Tian
  • Vince D. Calhoun
  • Jiayu Chen
  • Dongdong Lin
  • Victor M. Vergara
  • Shuquan Rao
  • Jian Yang

The progress of schizophrenia at various stages is an intriguing question, which has been explored to some degree using single-modality brain imaging data, e.g. gray matter (GM) or functional connectivity (FC). However it remains unclear how those changes from different modalities are correlated with each other and if the sensitivity to duration of illness and disease stages across modalities is different. In this work, we jointly analyzed FC, GM volume and single nucleotide polymorphisms (SNPs) data of 159 individuals including healthy controls (HC), drug-naïve first-episode schizophrenia (FESZ) and chronic schizophrenia patients (CSZ), aiming to evaluate the links among SNP, FC and GM patterns, and their sensitivity to duration of illness and disease stages in schizophrenia. Our results suggested: 1) both GM and FC highlighted impairments in hippocampal, temporal gyrus and cerebellum in schizophrenia, which were significantly correlated with genes like SATB2, GABBR2, PDE4B, CACNA1C etc. 2) GM and FC presented gradually decrease trend (HC > FESZ>CSZ), while SNP indicated a non-gradual variation trend with un-significant group difference observed between FESZ and CSZ; 3) Group difference between HC and FESZ of FC was more remarkable than GM, and FC presented a stronger negative correlation with duration of illness than GM (p = 0.0006). Collectively, these results highlight the benefit of leveraging multimodal data and provide additional clues regarding the impact of mental illness at various disease stages.

YNIMG Journal 2019 Journal Article

Decentralized temporal independent component analysis: Leveraging fMRI data in collaborative settings

  • Bradley T. Baker
  • Anees Abrol
  • Rogers F. Silva
  • Eswar Damaraju
  • Anand D. Sarwate
  • Vince D. Calhoun
  • Sergey M. Plis

The field of neuroimaging has recently witnessed a strong shift towards data sharing; however, current collaborative research projects may be unable to leverage institutional architectures that collect and store data in local, centralized data centers. Additionally, though research groups are willing to grant access for collaborations, they often wish to maintain control of their data locally. These concerns may stem from research culture as well as privacy and accountability concerns. In order to leverage the potential of these aggregated larger data sets, we require tools that perform joint analyses without transmitting the data. Ideally, these tools would have similar performance and ease of use as their current centralized counterparts. In this paper, we propose and evaluate a new Algorithm, decentralized joint independent component analysis (djICA), which meets these technical requirements. djICA shares only intermediate statistics about the data, plausibly retaining privacy of the raw information to local sites, thus making it amenable to further privacy protections, for example via differential privacy. We validate our method on real functional magnetic resonance imaging (fMRI) data and show that it enables collaborative large-scale temporal ICA of fMRI, a rich vein of analysis as of yet largely unexplored, and which can benefit from the larger-N studies enabled by a decentralized approach. We show that djICA is robust to different distributions of data over sites, and that the temporal components estimated with djICA show activations similar to the temporal functional modes analyzed in previous work, thus solidifying djICA as a new, decentralized method oriented toward the frontiers of temporal independent component analysis.

YNICL Journal 2019 Journal Article

Dynamic functional connectivity in schizophrenia and autism spectrum disorder: Convergence, divergence and classification

  • Liron Rabany
  • Sophy Brocke
  • Vince D. Calhoun
  • Brian Pittman
  • Silvia Corbera
  • Bruce E. Wexler
  • Morris D. Bell
  • Kevin Pelphrey

BACKGROUND: Over the recent years there has been a growing debate regarding the extent and nature of the overlap in neuropathology between schizophrenia (SZ) and autism spectrum disorder (ASD). Dynamic functional network connectivity (dFNC) is a recent analysis method that explores temporal patterns of functional connectivity (FC). We compared resting-state dFNC in SZ, ASD and healthy controls (HC), characterized the associations between temporal patterns and symptoms, and performed a three-way classification analysis based on dFNC indices. METHODS: Resting-state fMRI was collected from 100 young adults: 33 SZ, 33 ASD, 34 HC. Independent component analysis (ICA) was performed, followed by dFNC analysis (window = 33 s, step = 1TR, k-means clustering). Temporal patterns were compared between groups, correlated with symptoms, and classified via cross-validated three-way discriminant analysis. RESULTS: Both clinical groups displayed an increased fraction of time (FT) spent in a state of weak, intra-network connectivity [p < .001] and decreased FT in a highly-connected state [p < .001]. SZ further showed decreased number of transitions between states [p < .001], decreased FT in a widely-connected state [p < .001], increased dwell time (DT) in the weakly-connected state [p < .001], and decreased DT in the highly-connected state [p = .001]. Social behavior scores correlated with DT in the widely-connected state in SZ [r = 0.416, p = .043], but not ASD. Classification correctly identified SZ at high rates (81.8%), while ASD and HC at lower rates. CONCLUSIONS: Results indicate a severe and pervasive pattern of temporal aberrations in SZ (specifically, being "stuck" in a state of weak connectivity), that distinguishes SZ participants from both ASD and HC, and is associated with clinical symptoms.

YNIMG Journal 2019 Journal Article

Efficacy of different dynamic functional connectivity methods to capture cognitively relevant information

  • Hua Xie
  • Charles Y. Zheng
  • Daniel A. Handwerker
  • Peter A. Bandettini
  • Vince D. Calhoun
  • Sunanda Mitra
  • Javier Gonzalez-Castillo

Given the dynamic nature of the human brain, there has been an increasing interest in investigating short-term temporal changes in functional connectivity, also known as dynamic functional connectivity (dFC), i. e. , the time-varying inter-regional statistical dependence of blood oxygenation level-dependent (BOLD) signal within the constraints of a single scan. Numerous methodologies have been proposed to characterize dFC during rest and task, but few studies have compared them in terms of their efficacy to capture behavioral and clinically relevant dynamics. This is mostly due to lack of a well-defined ground truth, especially for rest scans. In this study, with a multitask dataset (rest, memory, video, and math) serving as ground truth, we investigated the efficacy of several dFC estimation techniques at capturing cognitively relevant dFC modulation induced by external tasks. We evaluated two framewise methods (dFC estimates for a single time point): dynamic conditional correlation (DCC) and jackknife correlation (JC); and five window-based methods: sliding window correlation (SWC), sliding window correlation with L1-regularization (SWC_L1), a combination of DCC and SWC called moving average DCC (DCC_MA), multiplication of temporal derivatives (MTD), and a variant of jackknife correlation called delete-d jackknife correlation (dJC). The efficacy is defined as each dFC metric's ability to successfully subdivide multitask scans into cognitively homogenous segments (even if those segments are not temporally continuous). We found that all window-based dFC methods performed well for commonly used window lengths (WL ≥ 30sec), with sliding window methods (SWC, SWC_L1) as well as the hybrid DCC_MA approach performing slightly better. For shorter window lengths (WL ≤ 15sec), DCC_MA and dJC produced the best results. Neither framewise method (i. e. , DCC and JC) led to dFC estimates with high accuracy.

YNICL Journal 2019 Journal Article

Group ICA for identifying biomarkers in schizophrenia: ‘Adaptive’ networks via spatially constrained ICA show more sensitivity to group differences than spatio-temporal regression

  • Mustafa S. Salman
  • Yuhui Du
  • Dongdong Lin
  • Zening Fu
  • Alex Fedorov
  • Eswar Damaraju
  • Jing Sui
  • Jiayu Chen

Brain functional networks identified from fMRI data can provide potential biomarkers for brain disorders. Group independent component analysis (GICA) is popular for extracting brain functional networks from multiple subjects. In GICA, different strategies exist for reconstructing subject-specific networks from the group-level networks. However, it is unknown whether these strategies have different sensitivities to group differences and abilities in distinguishing patients. Among GICA, spatio-temporal regression (STR) and spatially constrained ICA approaches such as group information guided ICA (GIG-ICA) can be used to propagate components (indicating networks) to a new subject that is not included in the original subjects. In this study, based on the same a priori network maps, we reconstructed subject-specific networks using these two methods separately from resting-state fMRI data of 151 schizophrenia patients (SZs) and 163 healthy controls (HCs). We investigated group differences in the estimated functional networks and the functional network connectivity (FNC) obtained by each method. The networks were also used as features in a cross-validated support vector machine (SVM) for classifying SZs and HCs. We selected features using different strategies to provide a comprehensive comparison between the two methods. GIG-ICA generally showed greater sensitivity in statistical analysis and better classification performance (accuracy 76.45 ± 8.9%, sensitivity 0.74 ± 0.11, specificity 0.79 ± 0.11) than STR (accuracy 67.45 ± 8.13%, sensitivity 0.65 ± 0.11, specificity 0.71 ± 0.11). Importantly, results were also consistent when applied to an independent dataset including 82 HCs and 82 SZs. Our work suggests that the functional networks estimated by GIG-ICA are more sensitive to group differences, and GIG-ICA is promising for identifying image-derived biomarkers of brain disease.

YNIMG Journal 2019 Journal Article

Neural dynamics of verbal working memory processing in children and adolescents

  • Christine M. Embury
  • Alex I. Wiesman
  • Amy L. Proskovec
  • Mackenzie S. Mills
  • Elizabeth Heinrichs-Graham
  • Yu-Ping Wang
  • Vince D. Calhoun
  • Julia M. Stephen

Development of cognitive functions and the underlying neurophysiology is evident throughout childhood and adolescence, with higher order processes such as working memory (WM) being some of the last cognitive faculties to fully mature. Previous functional neuroimaging studies of the neurodevelopment of WM have largely focused on overall regional activity levels rather than the temporal dynamics of neural component recruitment. In this study, we used magnetoencephalography (MEG) to examine the neural dynamics of WM in a large cohort of children and adolescents who were performing a high-load, modified verbal Sternberg WM task. Consistent with previous studies in adults, our findings indicated left-lateralized activity throughout the task period, beginning in the occipital cortices and spreading anterior to include temporal and prefrontal cortices during later encoding and into maintenance. During maintenance, the occipital alpha increase that has been widely reported in adults was found to be relatively weak in this developmental sample, suggesting continuing development of this component of neural processing, which was supported by correlational analyses. Intriguingly, we also found sex-specific developmental effects in alpha responses in the right inferior frontal region during encoding and in parietal and occipital cortices during maintenance. These findings suggested a developmental divergence between males and females in the maturation of neural circuitry serving WM during the transition from childhood to adolescence.

YNICL Journal 2019 Journal Article

Resting-state fMRI dynamic functional network connectivity and associations with psychopathy traits

  • Flor A. Espinoza
  • Nathaniel E. Anderson
  • Victor M. Vergara
  • Carla L. Harenski
  • Jean Decety
  • Srinivas Rachakonda
  • Eswar Damaraju
  • Michael Koenigs

Studies have used resting-state functional magnetic resonance imaging (rs-fMRI) to examine associations between psychopathy and brain connectivity in selected regions of interest as well as networks covering the whole-brain. One of the limitations of these approaches is that brain connectivity is modeled as a constant state through the scan duration. To address this limitation, we apply group independent component analysis (GICA) and dynamic functional network connectivity (dFNC) analysis to uncover whole-brain, time-varying functional network connectivity (FNC) states in a large forensic sample. We then examined relationships between psychopathic traits (PCL-R total scores, Factor 1 and Factor 2 scores) and FNC states obtained from dFNC analysis. FNC over the scan duration was better represented by five states rather than one state previously shown in static FNC analysis. Consistent with prior findings, psychopathy was associated with networks from paralimbic regions (amygdala and insula). In addition, whole-brain FNC identified 15 networks from nine functional domains (subcortical, auditory, sensorimotor, cerebellar, visual, salience, default mode network, executive control and attentional) related to psychopathy traits (Factor 1 and PCL-R scores). Results also showed that individuals with higher Factor 1 scores (affective and interpersonal traits) spend more time in a state with weaker connectivity overall, and changed states less frequently compared to those with lower Factor 1 scores. On the other hand, individuals with higher Factor 2 scores (impulsive and antisocial behaviors) showed more dynamism (changes to and from different states) than those with lower scores.

YNIMG Journal 2019 Journal Article

Sex-related differences in intrinsic brain dynamism and their neurocognitive correlates

  • Nina de Lacy
  • Elizabeth McCauley
  • J. Nathan Kutz
  • Vince D. Calhoun

The application of dynamic or time-varying connectivity techniques to neuroimaging data represents a new and complementary method to traditional static (time-averaged) methods, capturing additional patterns of variation in human brain function. Dynamic connectivity and related measures of brain dynamism have been detailed in neurotypical brain function, during human development and across neuropsychiatric disorders, and linked to cognitive control and executive function abilities. Despite this large and growing body of work, little is known about whether sex-related differences are present in dynamic connectivity and brain dynamism, a question pertinent to our understanding of brain function in both health and disease, given the sex bias observed in the prevalence of neuropsychiatric disorders, and well-demonstrated sex-related differences in the performance of certain neurocognitive tasks. We present the first analyses of sex-related effects in dynamic connectivity and brain dynamism referenced to neurocognitive function, in a large sample of sex-, age- and motion-matched subjects in 24- and 51-network whole brain functional parcellations. We demonstrate that sexual dimorphism is present in human dynamic connectivity and in multiple high-order measures of brain dynamism, as well as validating prior work that sex-related differences exist in static intrinsic connectivity. We also provide the first evidence suggesting a link between differential neurocognitive performance by males and females and brain functional dynamics. Reduced dynamism in females, who spend more time in certain brain states and switch states less frequently, may provide a ‘stickier’ functional substrate associated with slower response inhibition, whereas males exhibit greater dynamic fluidity, change between certain states more often and range over a larger state space, achieving superior performance in mental rotation, which demands an iterative visualization and problem-solving approach. We conclude that sex is an important variable to consider in functional MRI experiments and the analysis of dynamic connectivity and brain dynamism.

YNIMG Journal 2019 Journal Article

The developmental trajectory of sensorimotor cortical oscillations

  • Michael P. Trevarrow
  • Max J. Kurz
  • Timothy J. McDermott
  • Alex I. Wiesman
  • Mackenzie S. Mills
  • Yu-Ping Wang
  • Vince D. Calhoun
  • Julia M. Stephen

Numerous studies of motor control have confirmed beta and gamma oscillations in the primary motor cortices during basic movements. These responses include a robust beta decrease that precedes and extends through movement onset, a transient gamma response that coincides with the movement, and a post-movement beta rebound (PMBR) response that occurs after movement offset. While the existence of these responses has been confirmed by many studies, very few studies have examined their developmental trajectory. In the current study, we utilized magnetoencephalography (MEG) to investigate age-related changes in sensorimotor cortical oscillations in a large cross-section of children and adolescents (n = 94; age range = 9 -15 years-old). All participants performed a stimulus detection task with their right finger and the resulting MEG data were examined using oscillatory analysis methods and imaged using a beamformer. Consistent with adult studies, these youth participants exhibited characteristic beta (16–24 Hz) decreases prior to and during movement, as well as PMBR responses following movement offset, and a transient gamma (74–84 Hz) response during movement execution. Our primary findings were that the strength of the PMBR increased with age, while the strength of the gamma synchronization decreased with chronological age. In addition, the strength of each motor-related oscillatory response was significantly correlated with the power of spontaneous activity in the same frequency range and same voxel. This was the case for all three oscillatory responses. In conclusion, we investigated motor-related oscillatory activity in the largest cohort of children and adolescents reported to date, and our results indicated that beta and gamma cortical oscillations continue to develop as children transition into adolescents, and that these responses may not be fully matured until young to middle adulthood.

YNIMG Journal 2019 Journal Article

The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

  • Enrico Premi
  • Vince D. Calhoun
  • Matteo Diano
  • Stefano Gazzina
  • Maura Cosseddu
  • Antonella Alberici
  • Silvana Archetti
  • Donata Paternicò

Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on resting-state magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials.

YNICL Journal 2018 Journal Article

Age of gray matters: Neuroprediction of recidivism

  • Kent A. Kiehl
  • Nathaniel E. Anderson
  • Eyal Aharoni
  • J.Michael Maurer
  • Keith A. Harenski
  • Vikram Rao
  • Eric D. Claus
  • Carla Harenski

Age is one of the best predictors of antisocial behavior. Risk models of recidivism often combine chronological age with demographic, social and psychological features to aid in judicial decision-making. Here we use independent component analyses (ICA) and machine learning techniques to demonstrate the utility of using brain-based measures of cerebral aging to predict recidivism. First, we developed a brain-age model that predicts chronological age based on structural MRI data from incarcerated males (n = 1332). We then test the model's ability to predict recidivism in a new sample of offenders with longitudinal outcome data (n = 93). Consistent with hypotheses, inclusion of brain-age measures of the inferior frontal cortex and anterior-medial temporal lobes (i. e. , amygdala) improved prediction models when compared with models using chronological age; and models that combined psychological, behavioral, and neuroimaging measures provided the most robust prediction of recidivism. These results verify the utility of brain measures in predicting future behavior, and suggest that brain-based data may more precisely account for important variation when compared with traditional proxy measures such as chronological age. This work also identifies new brain systems that contribute to recidivism which has clinical implications for treatment development.

YNIMG Journal 2018 Journal Article

Connectome-based individualized prediction of temperament trait scores

  • Rongtao Jiang
  • Vince D. Calhoun
  • Nianming Zuo
  • Dongdong Lin
  • Jin Li
  • Lingzhong Fan
  • Shile Qi
  • Hailun Sun

Temperament consists of multi-dimensional traits that affect various domains of human life. Evidence has shown functional connectome-based predictive models are powerful predictors of cognitive abilities. Putatively, individuals' innate temperament traits may be predictable by unique patterns of brain functional connectivity (FC) as well. However, quantitative prediction for multiple temperament traits at the individual level has not yet been studied. Therefore, we were motivated to realize the individualized prediction of four temperament traits (novelty seeking [NS], harm avoidance [HA], reward dependence [RD] and persistence [PS]) using whole-brain FC. Specifically, a multivariate prediction framework integrating feature selection and sparse regression was applied to resting-state fMRI data from 360 college students, resulting in 4 connectome-based predictive models that enabled prediction of temperament scores for unseen subjects in cross-validation. More importantly, predictive models for HA and NS could be successfully generalized to two relevant personality traits for unseen individuals, i. e. , neuroticism and extraversion, in an independent dataset. In four temperament trait predictions, brain connectivities that show top contributing power commonly concentrated on the hippocampus, prefrontal cortex, basal ganglia, amygdala, and cingulate gyrus. Finally, across independent datasets and multiple traits, we show person's temperament traits can be reliably predicted using functional connectivity strength within frontal-subcortical circuits, indicating that human social and behavioral performance can be characterized by specific brain connectivity profile.

YNIMG Journal 2018 Journal Article

Dynamic functional connectivity impairments in early schizophrenia and clinical high-risk for psychosis

  • Yuhui Du
  • Susanna L. Fryer
  • Zening Fu
  • Dongdong Lin
  • Jing Sui
  • Jiayu Chen
  • Eswar Damaraju
  • Eva Mennigen

Individuals at clinical high-risk (CHR) for psychosis are characterized by attenuated psychotic symptoms. Only a minority of CHR individuals convert to full-blown psychosis. Therefore, there is a strong interest in identifying neurobiological abnormalities underlying the psychosis risk syndrome. Dynamic functional connectivity (DFC) captures time-varying connectivity over short time scales, and has the potential to reveal complex brain functional organization. Based on resting-state functional magnetic resonance imaging (fMRI) data from 70 healthy controls (HCs), 53 CHR individuals, and 58 early illness schizophrenia (ESZ) patients, we applied a novel group information guided ICA (GIG-ICA) to estimate inherent connectivity states from DFC, and then investigated group differences. We found that ESZ patients showed more aberrant connectivities and greater alterations than CHR individuals. Results also suggested that disease-related connectivity states occurred in CHR and ESZ groups. Regarding the dominant state with the highest contribution to dynamic connectivity, ESZ patients exhibited greater impairments than CHR individuals primarily in the cerebellum, frontal cortex, thalamus and temporal cortex, while CHR and ESZ populations shared common aberrances mainly in the supplementary motor area, parahippocampal gyrus and postcentral cortex. CHR-specific changes were also found in the connections between the superior frontal gyrus and calcarine cortex in the dominant state. Our findings suggest that CHR individuals generally show an intermediate functional connectivity pattern between HCs and SZ patients but also have unique connectivity alterations.

YNICL Journal 2018 Journal Article

Dynamic functional network connectivity discriminates mild traumatic brain injury through machine learning

  • Victor M. Vergara
  • Andrew R. Mayer
  • Kent A. Kiehl
  • Vince D. Calhoun

Mild traumatic brain injury (mTBI) can result in symptoms that affect a person's cognitive and social abilities. Improvements in diagnostic methodologies are necessary given that current clinical techniques have limited accuracy and are solely based on self-reports. Recently, resting state functional network connectivity (FNC) has shown potential as an important imaging modality for the development of mTBI biomarkers. The present work explores the use of dynamic functional network connectivity (dFNC) for mTBI detection. Forty eight mTBI patients (24 males) and age-gender matched healthy controls were recruited. We identified a set of dFNC states and looked at the possibility of using each state to classify subjects in mTBI patients and healthy controls. A linear support vector machine was used for classification and validated using leave-one-out cross validation. One of the dFNC states achieved a high classification performance of 92% using the area under the curve method. A series of t-test analysis revealed significant dFNC increases between cerebellum and sensorimotor networks. This significant increase was detected in the same dFNC state useful for classification. Results suggest that dFNC can be used to identify optimal dFNC states for classification excluding those that does not contain useful features.

YNICL Journal 2018 Journal Article

Identifying functional network changing patterns in individuals at clinical high-risk for psychosis and patients with early illness schizophrenia: A group ICA study

  • Yuhui Du
  • Susanna L. Fryer
  • Dongdong Lin
  • Jing Sui
  • Qingbao Yu
  • Jiayu Chen
  • Barbara Stuart
  • Rachel L. Loewy

Although individuals at clinical high risk (CHR) for psychosis exhibit a psychosis-risk syndrome involving attenuated forms of the positive symptoms typical of schizophrenia (SZ), it remains unclear whether their resting-state brain intrinsic functional networks (INs) show attenuated or qualitatively distinct patterns of functional dysconnectivity relative to SZ patients. Based on resting-state functional magnetic imaging data from 70 healthy controls (HCs), 53 CHR individuals (among which 41 subjects were antipsychotic medication-naive), and 58 early illness SZ (ESZ) patients (among which 53 patients took antipsychotic medication) within five years of illness onset, we estimated subject-specific INs using a novel group information guided independent component analysis (GIG-ICA) and investigated group differences in INs. We found that when compared to HCs, both CHR and ESZ groups showed significant differences, primarily in default mode, salience, auditory-related, visuospatial, sensory-motor, and parietal INs. Our findings suggest that widespread INs were diversely impacted. More than 25% of voxels in the identified significant discriminative regions (obtained using all 19 possible changing patterns excepting the no-difference pattern) from six of the 15 interrogated INs exhibited monotonically decreasing Z-scores (in INs) from the HC to CHR to ESZ, and the related regions included the left lingual gyrus of two vision-related networks, the right postcentral cortex of the visuospatial network, the left thalamus region of the salience network, the left calcarine region of the fronto-occipital network and fronto-parieto-occipital network. Compared to HCs and CHR individuals, ESZ patients showed both increasing and decreasing connectivity, mainly hypo-connectivity involving 15% of the altered voxels from four INs. The left supplementary motor area from the sensory-motor network and the right inferior occipital gyrus in the vision-related network showed a common abnormality in CHR and ESZ groups. Some brain regions also showed a CHR-unique alteration (primarily the CHR-increasing connectivity). In summary, CHR individuals generally showed intermediate connectivity between HCs and ESZ patients across multiple INs, suggesting that some dysconnectivity patterns evident in ESZ predate psychosis in attenuated form during the psychosis risk stage. Hence, these connectivity measures may serve as possible biomarkers to predict schizophrenia progression.

YNICL Journal 2018 Journal Article

Neural correlates of cognitive function and symptoms in attention-deficit/hyperactivity disorder in adults

  • Kuaikuai Duan
  • Jiayu Chen
  • Vince D. Calhoun
  • Dongdong Lin
  • Wenhao Jiang
  • Barbara Franke
  • Jan K. Buitelaar
  • Martine Hoogman

While gray matter (GM) anomalies have been reported for attention-deficit/hyperactivity disorder (ADHD), investigating their associations with cognitive deficits and individual symptom domains can help pinpoint the neural underpinnings critical for the pathology of ADHD, particularly the persist form of ADHD. In this work, we performed both independent component analysis and voxel-based morphometry analysis on whole brain GM of 486 adults including 214 patients, 96 unaffected siblings, and 176 healthy controls, in relation to cognition and symptoms. Independent component analysis revealed that higher GM volume in inferior semilunar lobule, inferior frontal gyri, and superior and middle frontal gyri was associated with better working memory performance, and lower GM volume in cerebellar tonsil and culmen was associated with more severe inattention symptoms. Consistently, voxel-based morphometry analysis showed that higher GM volume in multiple regions of frontal lobe, cerebellum and temporal lobe was related to better working memory performance. Focusing on the networks derived from ICA, our results integrated prefrontal regions and cerebellar regions through associations with working memory and inattention symptoms, lending support for the theory of 'cool'-cognition dysfunction being mediated by inferior fronto-striato-cerebellar networks in ADHD. Siblings showed intermediate cognitive impairments between patients and controls but presented GM anomalies in unique focal regions, suggesting they are a separate group potentially affected by the shared genetic and environmental risks with ADHD patients.

YNIMG Journal 2018 Journal Article

Reading the (functional) writing on the (structural) wall: Multimodal fusion of brain structure and function via a deep neural network based translation approach reveals novel impairments in schizophrenia

  • Sergey M. Plis
  • Md Faijul Amin
  • Adam Chekroud
  • Devon Hjelm
  • Eswar Damaraju
  • Hyo Jong Lee
  • Juan R. Bustillo
  • Kyunghyun Cho

This work presents a novel approach to finding linkage/association between multimodal brain imaging data, such as structural MRI (sMRI) and functional MRI (fMRI). Motivated by the machine translation domain, we employ a deep learning model, and consider two different imaging views of the same brain like two different languages conveying some common facts. That analogy enables finding linkages between two modalities. The proposed translation-based fusion model contains a computing layer that learns “alignments” (or links) between dynamic connectivity features from fMRI data and static gray matter patterns from sMRI data. The approach is evaluated on a multi-site dataset consisting of eyes-closed resting state imaging data collected from 298 subjects (age- and gender matched 154 healthy controls and 144 patients with schizophrenia). Results are further confirmed on an independent dataset consisting of eyes-open resting state imaging data from 189 subjects (age- and gender matched 91 healthy controls and 98 patients with schizophrenia). We used dynamic functional connectivity (dFNC) states as the functional features and ICA-based sources from gray matter densities as the structural features. The dFNC states characterized by weakly correlated intrinsic connectivity networks (ICNs) were found to have stronger association with putamen and insular gray matter pattern, while the dFNC states of profuse strongly correlated ICNs exhibited stronger links with the gray matter pattern in precuneus, posterior cingulate cortex (PCC), and temporal cortex. Further investigation with the estimated link strength (or alignment score) showed significant group differences between healthy controls and patients with schizophrenia in several key regions including temporal lobe, and linked these to connectivity states showing less occupancy in healthy controls. Moreover, this novel approach revealed significant correlation between a cognitive score (attention/vigilance) and the function/structure alignment score that was not detected when data modalities were considered separately.

YNIMG Journal 2018 Journal Article

Whole-brain connectivity dynamics reflect both task-specific and individual-specific modulation: A multitask study

  • Hua Xie
  • Vince D. Calhoun
  • Javier Gonzalez-Castillo
  • Eswar Damaraju
  • Robyn Miller
  • Peter A. Bandettini
  • Sunanda Mitra

Functional connectivity (FC) has been widely used to study the functional organization of temporally correlated and spatially distributed brain regions. Recent studies of FC dynamics, quantified by windowed correlations, provide new insights to analyze dynamic, context-dependent reconfiguration of brain networks. A set of reoccurring whole-brain connectivity patterns at rest, referred to as FC states, have been identified, hypothetically reflecting underlying cognitive processes or mental states. We posit that the mean FC information for a given subject represents a significant contribution to the group-level FC dynamics. We show that the subject-specific FC profile, termed as FC individuality, can be removed to increase sensitivity to cognitively relevant FC states. To assess the impact of the FC individuality and task-specific FC modulation on the group-level FC dynamics analysis, we generate and analyze group studies of four subjects engaging in four cognitive conditions (rest, simple math, two-back memory, and visual attention task). We also propose a model to quantitatively evaluate the effect of two factors, namely, subject-specific and task-specific modulation on FC dynamics. We show that FC individuality is a predominant factor in group-level FC variability, and the embedded cognitively relevant FC states are clearly visible after removing the individual’s connectivity profile. Our results challenge the current understanding of FC states and emphasize the importance of individual heterogeneity in connectivity dynamics analysis.

YNICL Journal 2017 Journal Article

A joint time-frequency analysis of resting-state functional connectivity reveals novel patterns of connectivity shared between or unique to schizophrenia patients and healthy controls

  • Maziar Yaesoubi
  • Robyn L. Miller
  • Juan Bustillo
  • Kelvin O. Lim
  • Jatin Vaidya
  • Vince D. Calhoun

Functional connectivity of the resting-state (RS) brain is a vehicle to study brain dysconnectivity aspects of diseases such as schizophrenia and bipolar. Methods that are developed to measure functional connectivity are based on the underlying hypotheses regarding the actual nature of RS-connectivity including evidence of temporally dynamic versus static RS-connectivity and evidence of frequency-specific versus hemodynamically-driven connectivity over a wide frequency range. This study is derived by these observations of variation of RS-connectivity in temporal and frequency domains and evaluates such characteristics of RS-connectivity in clinical population and jointly in temporal and frequency domains (the spectro-temporal domain). We base this study on the hypothesis that by studying functional connectivity of schizophrenia patients and comparing it to the one of healthy controls in the spectro-temporal domain we might be able to make new observations regarding the differences and similarities between diseased and healthy brain connectivity and such observations could be obscured by studies which investigate such characteristics separately. Interestingly, our results include, but are not limited to, a spectrally localized (mostly mid-range frequencies) modular dynamic connectivity pattern in which sensory motor networks are anti-correlated with visual, auditory and sub-cortical networks in schizophrenia, as well as evidence of lagged dependence between default-mode and sensory networks in schizophrenia. These observations are unique to the proposed augmented domain of connectivity analysis. We conclude this study by arguing not only resting-state connectivity has structured spectro-temporal variability, but also that studying properties of connectivity in this joint domain reveals distinctive group-based differences and similarities between clinical and healthy populations.

JBHI Journal 2017 Journal Article

A Realistic Framework for Investigating Decision Making in the Brain With High Spatiotemporal Resolution Using Simultaneous EEG/fMRI and Joint ICA

  • Sreenath P. Kyathanahally
  • Ana Franco-Watkins
  • Xiaoxia Zhang
  • Vince D. Calhoun
  • Gopikrishna Deshpande

Human decision making is a multidimensional construct, driven by a complex interplay between external factors, internal biases, and computational capacity constraints. Here, we propose a layered approach to experimental design in which multiple tasks—from simple to complex—with additional layers of complexity introduced at each stage are incorporated for investigating decision making. This is demonstrated using tasks involving intertemporal choice between immediate and future prospects. Previous functional magnetic resonance imaging (fMRI) and electroencephalographic (EEG) studies have separately investigated the spatial and temporal neural substrates, respectively, of specific factors underlying decision making. In contrast, we performed simultaneous acquisition of EEG/fMRI data and fusion of both modalities using joint independent component analysis such that: 1) the native temporal/spatial resolutions of either modality is not compromised and 2) fast temporal dynamics of decision making as well as involved deeper striatal structures can be characterized. We show that spatiotemporal neural substrates underlying our proposed complex intertemporal task simultaneously incorporating rewards, costs, and uncertainty of future outcomes can be predicted (using a linear model) from neural substrates of each of these factors, which were separately obtained by simpler tasks. This was not the case for spatial and temporal features obtained separately from fMRI and EEG, respectively. However, certain prefrontal activations in the complex task could not be predicted from activations in simpler tasks, indicating that the assumption of pure insertion has limited validity. Overall, our approach provides a realistic and novel framework for investigating the neural substrates of decision making with high spatiotemporal resolution.

YNIMG Journal 2017 Journal Article

Chronnectomic patterns and neural flexibility underlie executive function

  • Jason S. Nomi
  • Shruti Gopal Vij
  • Dina R. Dajani
  • Rosa Steimke
  • Eswar Damaraju
  • Srinivas Rachakonda
  • Vince D. Calhoun
  • Lucina Q. Uddin

Despite extensive research into executive function (EF), the precise relationship between brain dynamics and flexible cognition remains unknown. Using a large, publicly available dataset (189 participants), we find that functional connections measured throughout 56min of resting state fMRI data comprise five distinct connectivity states. Elevated EF performance as measured outside of the scanner was associated with greater episodes of more frequently occurring connectivity states, and fewer episodes of less frequently occurring connectivity states. Frequently occurring states displayed metastable properties, where cognitive flexibility may be facilitated by attenuated correlations and greater functional connection variability. Less frequently occurring states displayed properties consistent with low arousal and low vigilance. These findings suggest that elevated EF performance may be associated with the propensity to occupy more frequently occurring brain configurations that enable cognitive flexibility, while avoiding less frequently occurring brain configurations related to low arousal/vigilance states. The current findings offer a novel framework for identifying neural processes related to individual differences in executive function.

YNIMG Journal 2017 Journal Article

Machine learning of structural magnetic resonance imaging predicts psychopathic traits in adolescent offenders

  • Vaughn R. Steele
  • Vikram Rao
  • Vince D. Calhoun
  • Kent A. Kiehl

Classification models are becoming useful tools for finding patterns in neuroimaging data sets that are not observable to the naked eye. Many of these models are applied to discriminating clinical groups such as schizophrenic patients from healthy controls or from patients with bipolar disorder. A more nuanced model might be to discriminate between levels of personality traits. Here, as a proof of concept, we take an initial step toward developing prediction models to differentiate individuals based on a personality disorder: psychopathy. We included three groups of adolescent participants: incarcerated youth with elevated psychopathic traits (i. e. , callous and unemotional traits and conduct disordered traits; n =71), incarcerated youth with low psychopathic traits (n =72), and non-incarcerated youth as healthy controls (n =21). Support vector machine (SVM) learning models were developed to separate these groups using an out-of-sample cross-validation method on voxel-based morphometry (VBM) data. Regions of interest from the paralimbic system, identified in an independent forensic sample, were successful in differentiating youth groups. Models seeking to classify incarcerated individuals to have high or low psychopathic traits achieved 69. 23% overall accuracy. As expected, accuracy increased in models differentiating healthy controls from individuals with high psychopathic traits (82. 61%) and low psychopathic traits (80. 65%). Here we have laid the foundation for using neural correlates of personality traits to identify group membership within and beyond psychopathy. This is only the first step, of many, toward prediction models using neural measures as a proxy for personality traits. As these methods are improved, prediction models with neural measures of personality traits could have far-reaching impact on diagnosis, treatment, and prediction of future behavior.

YNIMG Journal 2017 Journal Article

Magnetoencephalographic and functional MRI connectomics in schizophrenia via intra- and inter-network connectivity

  • Jon M. Houck
  • Mustafa S. Çetin
  • Andrew R. Mayer
  • Juan R. Bustillo
  • Julia Stephen
  • Cheryl Aine
  • Jose Cañive
  • Nora Perrone-Bizzozero

Examination of intrinsic functional connectivity using functional MRI (fMRI) has provided important findings regarding dysconnectivity in schizophrenia. Extending these results using a complementary neuroimaging modality, magnetoencephalography (MEG), we present the first direct comparison of functional connectivity between schizophrenia patients and controls, using these two modalities combined. We developed a novel MEG approach for estimation of networks using MEG that incorporates spatial independent component analysis (ICA) and pairwise correlations between independent component timecourses, to estimate intra- and intern-network connectivity. This analysis enables group-level inference and testing of between-group differences. Resting state MEG and fMRI data were acquired from a large sample of healthy controls (n=45) and schizophrenia patients (n=46). Group spatial ICA was performed on fMRI and MEG data to extract intrinsic fMRI and MEG networks and to compensate for signal leakage in MEG. Similar, but not identical spatial independent components were detected for MEG and fMRI. Analysis of functional network connectivity (FNC; i. e. , pairwise correlations in network (ICA component) timecourses) revealed a differential between-modalities pattern, with greater connectivity among occipital networks in fMRI and among frontal networks in MEG. Most importantly, significant differences between controls and patients were observed in both modalities. MEG FNC results in particular indicated dysfunctional hyperconnectivity within frontal and temporal networks in patients, while in fMRI FNC was always greater for controls than for patients. This is the first study to apply group spatial ICA as an approach to leakage correction, and as such our results may be biased by spatial leakage effects. Results suggest that combining these two neuroimaging modalities reveals additional disease-relevant patterns of connectivity that were not detectable with fMRI or MEG alone.

YNIMG Journal 2017 Journal Article

Multimodal neural correlates of cognitive control in the Human Connectome Project

  • Dov B. Lerman-Sinkoff
  • Jing Sui
  • Srinivas Rachakonda
  • Sridhar Kandala
  • Vince D. Calhoun
  • Deanna M. Barch

Cognitive control is a construct that refers to the set of functions that enable decision-making and task performance through the representation of task states, goals, and rules. The neural correlates of cognitive control have been studied in humans using a wide variety of neuroimaging modalities, including structural MRI, resting-state fMRI, and task-based fMRI. The results from each of these modalities independently have implicated the involvement of a number of brain regions in cognitive control, including dorsal prefrontal cortex, and frontal parietal and cingulo-opercular brain networks. However, it is not clear how the results from a single modality relate to results in other modalities. Recent developments in multimodal image analysis methods provide an avenue for answering such questions and could yield more integrated models of the neural correlates of cognitive control. In this study, we used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) to identify multimodal patterns of variation related to cognitive control. We used two independent cohorts of participants from the Human Connectome Project, each of which had data from four imaging modalities. We replicated the findings from the first cohort in the second cohort using both independent and predictive analyses. The independent analyses identified a component in each cohort that was highly similar to the other and significantly correlated with cognitive control performance. The replication by prediction analyses identified two independent components that were significantly correlated with cognitive control performance in the first cohort and significantly predictive of performance in the second cohort. These components identified positive relationships across the modalities in neural regions related to both dynamic and stable aspects of task control, including regions in both the frontal-parietal and cingulo-opercular networks, as well as regions hypothesized to be modulated by cognitive control signaling, such as visual cortex. Taken together, these results illustrate the potential utility of multi-modal analyses in identifying the neural correlates of cognitive control across different indicators of brain structure and function.

YNIMG Journal 2017 Journal Article

Predicting individualized clinical measures by a generalized prediction framework and multimodal fusion of MRI data

  • Xing Meng
  • Rongtao Jiang
  • Dongdong Lin
  • Juan Bustillo
  • Thomas Jones
  • Jiayu Chen
  • Qingbao Yu
  • Yuhui Du

Neuroimaging techniques have greatly enhanced the understanding of neurodiversity (human brain variation across individuals) in both health and disease. The ultimate goal of using brain imaging biomarkers is to perform individualized predictions. Here we proposed a generalized framework that can predict explicit values of the targeted measures by taking advantage of joint information from multiple modalities. This framework also enables whole brain voxel-wise searching by combining multivariate techniques such as ReliefF, clustering, correlation-based feature selection and multiple regression models, which is more flexible and can achieve better prediction performance than alternative atlas-based methods. For 50 healthy controls and 47 schizophrenia patients, three kinds of features derived from resting-state fMRI (fALFF), sMRI (gray matter) and DTI (fractional anisotropy) were extracted and fed into a regression model, achieving high prediction for both cognitive scores (MCCB composite r =0. 7033, MCCB social cognition r =0. 7084) and symptomatic scores (positive and negative syndrome scale [PANSS] positive r =0. 7785, PANSS negative r =0. 7804). Moreover, the brain areas likely responsible for cognitive deficits of schizophrenia, including middle temporal gyrus, dorsolateral prefrontal cortex, striatum, cuneus and cerebellum, were located with different weights, as well as regions predicting PANSS symptoms, including thalamus, striatum and inferior parietal lobule, pinpointing the potential neuromarkers. Finally, compared to a single modality, multimodal combination achieves higher prediction accuracy and enables individualized prediction on multiple clinical measures. There is more work to be done, but the current results highlight the potential utility of multimodal brain imaging biomarkers to eventually inform clinical decision-making.

YNIMG Journal 2017 Journal Article

Regional and source-based patterns of [ 11 C]-(+)-PHNO binding potential reveal concurrent alterations in dopamine D 2 and D 3 receptor availability in cocaine-use disorder

  • Patrick D. Worhunsky
  • David Matuskey
  • Jean-Dominique Gallezot
  • Edward C. Gaiser
  • Nabeel Nabulsi
  • Gustavo A. Angarita
  • Vince D. Calhoun
  • Robert T. Malison

Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BP ND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BP ND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BP ND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BP ND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BP ND in the D2R-rich dorsal striatum and greater BP ND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BP ND that were correlated with regional estimates of D2R-related and D3R-related proportions of BP ND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

YNIMG Journal 2017 Journal Article

Replicability of time-varying connectivity patterns in large resting state fMRI samples

  • Anees Abrol
  • Eswar Damaraju
  • Robyn L. Miller
  • Julia M. Stephen
  • Eric D. Claus
  • Andrew R. Mayer
  • Vince D. Calhoun

The past few years have seen an emergence of approaches that leverage temporal changes in whole-brain patterns of functional connectivity (the chronnectome). In this chronnectome study, we investigate the replicability of the human brain's inter-regional coupling dynamics during rest by evaluating two different dynamic functional network connectivity (dFNC) analysis frameworks using 7 500 functional magnetic resonance imaging (fMRI) datasets. To quantify the extent to which the emergent functional connectivity (FC) patterns are reproducible, we characterize the temporal dynamics by deriving several summary measures across multiple large, independent age-matched samples. Reproducibility was demonstrated through the existence of basic connectivity patterns (FC states) amidst an ensemble of inter-regional connections. Furthermore, application of the methods to conservatively configured (statistically stationary, linear and Gaussian) surrogate datasets revealed that some of the studied state summary measures were indeed statistically significant and also suggested that this class of null model did not explain the fMRI data fully. This extensive testing of reproducibility of similarity statistics also suggests that the estimated FC states are robust against variation in data quality, analysis, grouping, and decomposition methods. We conclude that future investigations probing the functional and neurophysiological relevance of time-varying connectivity assume critical importance.

IJCAI Conference 2017 Conference Paper

See without looking: joint visualization of sensitive multi-site datasets

  • Debbrata K. Saha
  • Vince D. Calhoun
  • Sandeep R. Panta
  • Sergey M. Plis

Visualization of high dimensional large-scale datasets via an embedding into a 2D map is a powerful exploration tool for assessing latent structure in the data and detecting outliers. There are many methods developed for this task but most assume that all pairs of samples are available for common computation. Specifically, the distances between all pairs of points need to be directly computable. In contrast, we work with sensitive neuroimaging data, when local sites cannot share their samples and the distances cannot be easily computed across the sites. Yet, the desire is to let all the local data participate in collaborative computation without leaving their respective sites. In this scenario, a quality control tool that visualizes decentralized dataset in its entirety via global aggregation of local computations is especially important as it would allow screening of samples that cannot be evaluated otherwise. This paper introduces an algorithm to solve this problem: decentralized data stochastic neighbor embedding (dSNE). Based on the MNIST dataset we introduce metrics for measuring the embedding quality and use them to compare dSNE to its centralized counterpart. We also apply dSNE to a multi-site neuroimaging dataset with encouraging results.

YNIMG Journal 2017 Journal Article

Single subject prediction of brain disorders in neuroimaging: Promises and pitfalls

  • Mohammad R. Arbabshirani
  • Sergey Plis
  • Jing Sui
  • Vince D. Calhoun

Neuroimaging-based single subject prediction of brain disorders has gained increasing attention in recent years. Using a variety of neuroimaging modalities such as structural, functional and diffusion MRI, along with machine learning techniques, hundreds of studies have been carried out for accurate classification of patients with heterogeneous mental and neurodegenerative disorders such as schizophrenia and Alzheimer's disease. More than 500 studies have been published during the past quarter century on single subject prediction focused on a multiple brain disorders. In the first part of this study, we provide a survey of more than 200 reports in this field with a focus on schizophrenia, mild cognitive impairment (MCI), Alzheimer's disease (AD), depressive disorders, autism spectrum disease (ASD) and attention-deficit hyperactivity disorder (ADHD). Detailed information about those studies such as sample size, type and number of extracted features and reported accuracy are summarized and discussed. To our knowledge, this is by far the most comprehensive review of neuroimaging-based single subject prediction of brain disorders. In the second part, we present our opinion on major pitfalls of those studies from a machine learning point of view. Common biases are discussed and suggestions are provided. Moreover, emerging trends such as decentralized data sharing, multimodal brain imaging, differential diagnosis, disease subtype classification and deep learning are also discussed. Based on this survey, there is extensive evidence showing the great potential of neuroimaging data for single subject prediction of various disorders. However, the main bottleneck of this exciting field is still the limited sample size, which could be potentially addressed by modern data sharing models such as the ones discussed in this paper. Emerging big data technologies and advanced data-intensive machine learning methodologies such as deep learning have coincided with an increasing need for accurate, robust and generalizable single subject prediction of brain disorders during an exciting time. In this report, we survey the past and offer some opinions regarding the road ahead.

YNIMG Journal 2017 Journal Article

Task-specific feature extraction and classification of fMRI volumes using a deep neural network initialized with a deep belief network: Evaluation using sensorimotor tasks

  • Hojin Jang
  • Sergey M. Plis
  • Vince D. Calhoun
  • Jong-Hwan Lee

Feedforward deep neural networks (DNNs), artificial neural networks with multiple hidden layers, have recently demonstrated a record-breaking performance in multiple areas of applications in computer vision and speech processing. Following the success, DNNs have been applied to neuroimaging modalities including functional/structural magnetic resonance imaging (MRI) and positron-emission tomography data. However, no study has explicitly applied DNNs to 3D whole-brain fMRI volumes and thereby extracted hidden volumetric representations of fMRI that are discriminative for a task performed as the fMRI volume was acquired. Our study applied fully connected feedforward DNN to fMRI volumes collected in four sensorimotor tasks (i. e. , left-hand clenching, right-hand clenching, auditory attention, and visual stimulus) undertaken by 12 healthy participants. Using a leave-one-subject-out cross-validation scheme, a restricted Boltzmann machine-based deep belief network was pretrained and used to initialize weights of the DNN. The pretrained DNN was fine-tuned while systematically controlling weight-sparsity levels across hidden layers. Optimal weight-sparsity levels were determined from a minimum validation error rate of fMRI volume classification. Minimum error rates (mean±standard deviation; %) of 6. 9 (±3. 8) were obtained from the three-layer DNN with the sparsest condition of weights across the three hidden layers. These error rates were even lower than the error rates from the single-layer network (9. 4±4. 6) and the two-layer network (7. 4±4. 1). The estimated DNN weights showed spatial patterns that are remarkably task-specific, particularly in the higher layers. The output values of the third hidden layer represented distinct patterns/codes of the 3D whole-brain fMRI volume and encoded the information of the tasks as evaluated from representational similarity analysis. Our reported findings show the ability of the DNN to classify a single fMRI volume based on the extraction of hidden representations of fMRI volumes associated with tasks across multiple hidden layers. Our study may be beneficial to the automatic classification/diagnosis of neuropsychiatric and neurological diseases and prediction of disease severity and recovery in (pre-) clinical settings using fMRI volumes without requiring an estimation of activation patterns or ad hoc statistical evaluation.

YNIMG Journal 2017 Journal Article

The effect of preprocessing pipelines in subject classification and detection of abnormal resting state functional network connectivity using group ICA

  • Victor M. Vergara
  • Andrew R. Mayer
  • Eswar Damaraju
  • Kent Hutchison
  • Vince D. Calhoun

Resting state functional network connectivity (rsFNC) derived from functional magnetic resonance (fMRI) imaging is emerging as a possible biomarker to identify several brain disorders. Recently it has been pointed out that methods used to preprocess head motion variance might not fully remove all unwanted effects in the data. Proposed processing pipelines locate the treatment of head motion effects either close to the beginning or as one of the final steps. In this work, we assess several preprocessing pipelines applied in group independent component analysis (gICA) methods to study the rsFNC of the brain. The evaluation method utilizes patient/control classification performance based on linear support vector machines and leave-one-out cross validation. In addition, we explored group tests and correlation with severity measures in the patient population. We also tested the effect of removing high frequencies via filtering. Two real data cohorts were used: one consisting of 48 mTBI and one composed of 21 smokers, both with their corresponding matched controls. A simulation procedure was designed to test the classification power of each pipeline. Results show that data preprocessing can change the classification performance. In real data, regressing motion variance before gICA produced clearer group differences and stronger correlation with nicotine dependence.

YNIMG Journal 2017 Journal Article

The real-time fMRI neurofeedback based stratification of Default Network Regulation Neuroimaging data repository

  • Amalia R. McDonald
  • Jordan Muraskin
  • Nicholas T.Van Dam
  • Caroline Froehlich
  • Benjamin Puccio
  • John Pellman
  • Clemens C.C. Bauer
  • Alexis Akeyson

This data descriptor describes a repository of openly shared data from an experiment to assess inter-individual differences in default mode network (DMN) activity. This repository includes cross-sectional functional magnetic resonance imaging (fMRI) data from the Multi Source Interference Task, to assess DMN deactivation, the Moral Dilemma Task, to assess DMN activation, a resting state fMRI scan, and a DMN neurofeedback paradigm, to assess DMN modulation, along with accompanying behavioral and cognitive measures. We report technical validation from n=125 participants of the final targeted sample of 180 participants. Each session includes acquisition of one whole-brain anatomical scan and whole-brain echo-planar imaging (EPI) scans, acquired during the aforementioned tasks and resting state. The data includes several self-report measures related to perseverative thinking, emotion regulation, and imaginative processes, along with a behavioral measure of rapid visual information processing. Technical validation of the data confirms that the tasks deactivate and activate the DMN as expected. Group level analysis of the neurofeedback data indicates that the participants are able to modulate their DMN with considerable inter-subject variability. Preliminary analysis of behavioral responses and specifically self-reported sleep indicate that as many as 73 participants may need to be excluded from an analysis depending on the hypothesis being tested. The present data are linked to the enhanced Nathan Kline Institute, Rockland Sample and builds on the comprehensive neuroimaging and deep phenotyping available therein. As limited information is presently available about individual differences in the capacity to directly modulate the default mode network, these data provide a unique opportunity to examine DMN modulation ability in relation to numerous phenotypic characteristics.

YNIMG Journal 2016 Journal Article

Classification of schizophrenia and bipolar patients using static and dynamic resting-state fMRI brain connectivity

  • Barnaly Rashid
  • Mohammad R. Arbabshirani
  • Eswar Damaraju
  • Mustafa S. Cetin
  • Robyn Miller
  • Godfrey D. Pearlson
  • Vince D. Calhoun

Recently, functional network connectivity (FNC, defined as the temporal correlation among spatially distant brain networks) has been used to examine the functional organization of brain networks in various psychiatric illnesses. Dynamic FNC is a recent extension of the conventional FNC analysis that takes into account FNC changes over short periods of time. While such dynamic FNC measures may be more informative about various aspects of connectivity, there has been no detailed head-to-head comparison of the ability of static and dynamic FNC to perform classification in complex mental illnesses. This paper proposes a framework for automatic classification of schizophrenia, bipolar and healthy subjects based on their static and dynamic FNC features. Also, we compare cross-validated classification performance between static and dynamic FNC. Results show that the dynamic FNC significantly outperforms the static FNC in terms of predictive accuracy, indicating that features from dynamic FNC have distinct advantages over static FNC for classification purposes. Moreover, combining static and dynamic FNC features does not significantly improve the classification performance over the dynamic FNC features alone, suggesting that static FNC does not add any significant information when combined with dynamic FNC for classification purposes. A three-way classification methodology based on static and dynamic FNC features discriminates individual subjects into appropriate diagnostic groups with high accuracy. Our proposed classification framework is potentially applicable to additional mental disorders.

YNIMG Journal 2016 Journal Article

COINS Data Exchange: An open platform for compiling, curating, and disseminating neuroimaging data

  • Drew Landis
  • William Courtney
  • Christopher Dieringer
  • Ross Kelly
  • Margaret King
  • Brittny Miller
  • Runtang Wang
  • Dylan Wood

Neuroimaging data collection is inherently expensive. Maximizing the return on investment in neuroimaging studies requires that neuroimaging data be re-used whenever possible. In an effort to further scientific knowledge, the COINS Data Exchange (DX) (http: //coins. mrn. org/dx) aims to make data sharing seamless and commonplace. DX takes a three-pronged approach towards improving the overall state of data sharing within the neuroscience community. The first prong is compiling data into one location that has been collected from all over the world in many different formats. The second prong is curating the data so that it can be stored in one consistent format and so that data QA/QC measures can be assured. The third prong is disseminating the data so that it is easy to consume and straightforward to interpret. This paper explains the concepts behind each prong and describes some challenges and successes that the Data Exchange has experienced.

YNIMG Journal 2016 Journal Article

Deep neural network with weight sparsity control and pre-training extracts hierarchical features and enhances classification performance: Evidence from whole-brain resting-state functional connectivity patterns of schizophrenia

  • Junghoe Kim
  • Vince D. Calhoun
  • Eunsoo Shim
  • Jong-Hwan Lee

Functional connectivity (FC) patterns obtained from resting-state functional magnetic resonance imaging data are commonly employed to study neuropsychiatric conditions by using pattern classifiers such as the support vector machine (SVM). Meanwhile, a deep neural network (DNN) with multiple hidden layers has shown its ability to systematically extract lower-to-higher level information of image and speech data from lower-to-higher hidden layers, markedly enhancing classification accuracy. The objective of this study was to adopt the DNN for whole-brain resting-state FC pattern classification of schizophrenia (SZ) patients vs. healthy controls (HCs) and identification of aberrant FC patterns associated with SZ. We hypothesized that the lower-to-higher level features learned via the DNN would significantly enhance the classification accuracy, and proposed an adaptive learning algorithm to explicitly control the weight sparsity in each hidden layer via L1-norm regularization. Furthermore, the weights were initialized via stacked autoencoder based pre-training to further improve the classification performance. Classification accuracy was systematically evaluated as a function of (1) the number of hidden layers/nodes, (2) the use of L1-norm regularization, (3) the use of the pre-training, (4) the use of framewise displacement (FD) removal, and (5) the use of anatomical/functional parcellation. Using FC patterns from anatomically parcellated regions without FD removal, an error rate of 14. 2% was achieved by employing three hidden layers and 50 hidden nodes with both L1-norm regularization and pre-training, which was substantially lower than the error rate from the SVM (22. 3%). Moreover, the trained DNN weights (i. e. , the learned features) were found to represent the hierarchical organization of aberrant FC patterns in SZ compared with HC. Specifically, pairs of nodes extracted from the lower hidden layer represented sparse FC patterns implicated in SZ, which was quantified by using kurtosis/modularity measures and features from the higher hidden layer showed holistic/global FC patterns differentiating SZ from HC. Our proposed schemes and reported findings attained by using the DNN classifier and whole-brain FC data suggest that such approaches show improved ability to learn hidden patterns in brain imaging data, which may be useful for developing diagnostic tools for SZ and other neuropsychiatric disorders and identifying associated aberrant FC patterns.

YNIMG Journal 2016 Journal Article

Neuroimaging measures of error-processing: Extracting reliable signals from event-related potentials and functional magnetic resonance imaging

  • Vaughn R. Steele
  • Nathaniel E. Anderson
  • Eric D. Claus
  • Edward M. Bernat
  • Vikram Rao
  • Michal Assaf
  • Godfrey D. Pearlson
  • Vince D. Calhoun

Error-related brain activity has become an increasingly important focus of cognitive neuroscience research utilizing both event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). Given the significant time and resources required to collect these data, it is important for researchers to plan their experiments such that stable estimates of error-related processes can be achieved efficiently. Reliability of error-related brain measures will vary as a function of the number of error trials and the number of participants included in the averages. Unfortunately, systematic investigations of the number of events and participants required to achieve stability in error-related processing are sparse, and none have addressed variability in sample size. Our goal here is to provide data compiled from a large sample of healthy participants (n=180) performing a Go/NoGo task, resampled iteratively to demonstrate the relative stability of measures of error-related brain activity given a range of sample sizes and event numbers included in the averages. We examine ERP measures of error-related negativity (ERN/Ne) and error positivity (Pe), as well as event-related fMRI measures locked to False Alarms. We find that achieving stable estimates of ERP measures required four to six error trials and approximately 30 participants; fMRI measures required six to eight trials and approximately 40 participants. Fewer trials and participants were required for measures where additional data reduction techniques (i. e. , principal component analysis and independent component analysis) were implemented. Ranges of reliability statistics for various sample sizes and numbers of trials are provided. We intend this to be a useful resource for those planning or evaluating ERP or fMRI investigations with tasks designed to measure error-processing.

YNIMG Journal 2016 Journal Article

Sample-poor estimation of order and common signal subspace with application to fusion of medical imaging data

  • Yuri Levin-Schwartz
  • Yang Song
  • Peter J. Schreier
  • Vince D. Calhoun
  • Tülay Adalı

Due to their data-driven nature, multivariate methods such as canonical correlation analysis (CCA) have proven very useful for fusion of multimodal neurological data. However, being able to determine the degree of similarity between datasets and appropriate order selection are crucial to the success of such techniques. The standard methods for calculating the order of multimodal data focus only on sources with the greatest individual energy and ignore relations across datasets. Additionally, these techniques as well as the most widely-used methods for determining the degree of similarity between datasets assume sufficient sample support and are not effective in the sample-poor regime. In this paper, we propose to jointly estimate the degree of similarity between datasets and their order when few samples are present using principal component analysis and canonical correlation analysis (PCA-CCA). By considering these two problems simultaneously, we are able to minimize the assumptions placed on the data and achieve superior performance in the sample-poor regime compared to traditional techniques. We apply PCA-CCA to the pairwise combinations of functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (sMRI), and electroencephalogram (EEG) data drawn from patients with schizophrenia and healthy controls while performing an auditory oddball task. The PCA-CCA results indicate that the fMRI and sMRI datasets are the most similar, whereas the sMRI and EEG datasets share the least similarity. We also demonstrate that the degree of similarity obtained by PCA-CCA is highly predictive of the degree of significance found for components generated using CCA.

YNIMG Journal 2016 Journal Article

SchizConnect: Mediating neuroimaging databases on schizophrenia and related disorders for large-scale integration

  • Lei Wang
  • Kathryn I. Alpert
  • Vince D. Calhoun
  • Derin J. Cobia
  • David B. Keator
  • Margaret D. King
  • Alexandr Kogan
  • Drew Landis

SchizConnect (www. schizconnect. org) is built to address the issues of multiple data repositories in schizophrenia neuroimaging studies. It includes a level of mediation—translating across data sources—so that the user can place one query, e. g. for diffusion images from male individuals with schizophrenia, and find out from across participating data sources how many datasets there are, as well as downloading the imaging and related data. The current version handles the Data Usage Agreements across different studies, as well as interpreting database-specific terminologies into a common framework. New data repositories can also be mediated to bring immediate access to existing datasets. Compared with centralized, upload data sharing models, SchizConnect is a unique, virtual database with a focus on schizophrenia and related disorders that can mediate live data as information is being updated at each data source. It is our hope that SchizConnect can facilitate testing new hypotheses through aggregated datasets, promoting discovery related to the mechanisms underlying schizophrenic dysfunction.

YNIMG Journal 2016 Journal Article

The connectivity domain: Analyzing resting state fMRI data using feature-based data-driven and model-based methods

  • Armin Iraji
  • Vince D. Calhoun
  • Natalie M. Wiseman
  • Esmaeil Davoodi-Bojd
  • Mohammad R.N. Avanaki
  • E. Mark Haacke
  • Zhifeng Kou

Spontaneous fluctuations of resting state functional MRI (rsfMRI) have been widely used to understand the macro-connectome of the human brain. However, these fluctuations are not synchronized among subjects, which leads to limitations and makes utilization of first-level model-based methods challenging. Considering this limitation of rsfMRI data in the time domain, we propose to transfer the spatiotemporal information of the rsfMRI data to another domain, the connectivity domain, in which each value represents the same effect across subjects. Using a set of seed networks and a connectivity index to calculate the functional connectivity for each seed network, we transform data into the connectivity domain by generating connectivity weights for each subject. Comparison of the two domains using a data-driven method suggests several advantages in analyzing data using data-driven methods in the connectivity domain over the time domain. We also demonstrate the feasibility of applying model-based methods in the connectivity domain, which offers a new pathway for the use of first-level model-based methods on rsfMRI data. The connectivity domain, furthermore, demonstrates a unique opportunity to perform first-level feature-based data-driven and model-based analyses. The connectivity domain can be constructed from any technique that identifies sets of features that are similar across subjects and can greatly help researchers in the study of macro-connectome brain function by enabling us to perform a wide range of model-based and data-driven approaches on rsfMRI data, decreasing susceptibility of analysis techniques to parameters that are not related to brain connectivity information, and evaluating both static and dynamic functional connectivity of the brain from a new perspective.

YNIMG Journal 2016 Journal Article

The Function Biomedical Informatics Research Network Data Repository

  • David B. Keator
  • Theo G.M. van Erp
  • Jessica A. Turner
  • Gary H. Glover
  • Bryon A. Mueller
  • Thomas T. Liu
  • James T. Voyvodic
  • Jerod Rasmussen

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1. 5 to 4T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data.

YNIMG Journal 2015 Journal Article

A group ICA based framework for evaluating resting fMRI markers when disease categories are unclear: application to schizophrenia, bipolar, and schizoaffective disorders

  • Yuhui Du
  • Godfrey D. Pearlson
  • Jingyu Liu
  • Jing Sui
  • Qingbao Yu
  • Hao He
  • Eduardo Castro
  • Vince D. Calhoun

Schizophrenia (SZ), bipolar disorder (BP) and schizoaffective disorder (SAD) share some common symptoms, and there is still a debate about whether SAD is an independent category. To the best of our knowledge, no study has been done to differentiate these three disorders or to investigate the distinction of SAD as an independent category using fMRI data. This study is aimed to explore biomarkers from resting-state fMRI networks for differentiating these disorders and investigate the relationship among these disorders based on fMRI networks with an emphasis on SAD. Firstly, a novel group ICA method, group information guided independent component analysis (GIG-ICA), was applied to extract subject-specific brain networks from fMRI data of 20 healthy controls (HC), 20 SZ patients, 20 BP patients, 20 patients suffering from SAD with manic episodes (SADM), and 13 patients suffering from SAD with depressive episodes exclusively (SADD). Then, five-level one-way analysis of covariance and multiclass support vector machine recursive feature elimination were employed to identify discriminative regions from the networks. Subsequently, the t-distributed stochastic neighbor embedding (t-SNE) projection and the hierarchical clustering were implemented to investigate the relationship among those groups. Finally, to evaluate the generalization ability, 16 new subjects were classified based on the found regions and the trained model using original 93 subjects. Results show that the discriminative regions mainly included frontal, parietal, precuneus, cingulate, supplementary motor, cerebellar, insula and supramarginal cortices, which performed well in distinguishing different groups. SADM and SADD were the most similar to each other, although SADD had greater similarity to SZ compared to other groups, which indicates that SAD may be an independent category. BP was closer to HC compared with other psychotic disorders. In summary, resting-state fMRI brain networks extracted via GIG-ICA provide a promising potential to differentiate SZ, BP, and SAD.

YNIMG Journal 2015 Journal Article

Assessing dynamic brain graphs of time-varying connectivity in fMRI data: Application to healthy controls and patients with schizophrenia

  • Qingbao Yu
  • Erik B. Erhardt
  • Jing Sui
  • Yuhui Du
  • Hao He
  • Devon Hjelm
  • Mustafa S. Cetin
  • Srinivas Rachakonda

Graph theory-based analysis has been widely employed in brain imaging studies, and altered topological properties of brain connectivity have emerged as important features of mental diseases such as schizophrenia. However, most previous studies have focused on graph metrics of stationary brain graphs, ignoring that brain connectivity exhibits fluctuations over time. Here we develop a new framework for accessing dynamic graph properties of time-varying functional brain connectivity in resting-state fMRI data and apply it to healthy controls (HCs) and patients with schizophrenia (SZs). Specifically, nodes of brain graphs are defined by intrinsic connectivity networks (ICNs) identified by group independent component analysis (ICA). Dynamic graph metrics of the time-varying brain connectivity estimated by the correlation of sliding time-windowed ICA time courses of ICNs are calculated. First- and second-level connectivity states are detected based on the correlation of nodal connectivity strength between time-varying brain graphs. Our results indicate that SZs show decreased variance in the dynamic graph metrics. Consistent with prior stationary functional brain connectivity works, graph measures of identified first-level connectivity states show lower values in SZs. In addition, more first-level connectivity states are disassociated with the second-level connectivity state which resembles the stationary connectivity pattern computed by the entire scan. Collectively, the findings provide new evidence about altered dynamic brain graphs in schizophrenia, which may underscore the abnormal brain performance in this mental illness.

YNIMG Journal 2015 Journal Article

Comparison of PCA approaches for very large group ICA

  • Vince D. Calhoun
  • Rogers F. Silva
  • Tülay Adalı
  • Srinivas Rachakonda

Large data sets are becoming more common in fMRI and, with the advent of faster pulse sequences, memory efficient strategies for data reduction via principal component analysis (PCA) turn out to be extremely useful, especially for widely used approaches like group independent component analysis (ICA). In this commentary, we discuss results and limitations from a recent paper on the topic and attempt to provide a more complete perspective on available approaches as well as discussing various issues to consider related to PCA for very large group ICA. We also provide an analysis of computation time, memory use, and number of dataloads for a variety of approaches under multiple scenarios of small and extremely large data sets.

YNIMG Journal 2015 Journal Article

Dynamic coherence analysis of resting fMRI data to jointly capture state-based phase, frequency, and time-domain information

  • Maziar Yaesoubi
  • Elena A. Allen
  • Robyn L. Miller
  • Vince D. Calhoun

Many approaches for estimating functional connectivity among brain regions or networks in fMRI have been considered in the literature. More recently, studies have shown that connectivity which is usually estimated by calculating correlation between time series or by estimating coherence as a function of frequency has a dynamic nature, during both task and resting conditions. Sliding-window methods have been commonly used to study these dynamic properties although other approaches such as instantaneous phase synchronization have also been used for similar purposes. Some studies have also suggested that spectral analysis can be used to separate the distinct contributions of motion, respiration and neurophysiological activity from the observed correlation. Several recent studies have merged analysis of coherence with study of temporal dynamics of functional connectivity though these have mostly been limited to a few selected brain regions and frequency bands. Here we propose a novel data-driven framework to estimate time-varying patterns of whole-brain functional network connectivity of resting state fMRI combined with the different frequencies and phase lags at which these patterns are observed. We show that this analysis identifies both broad-band cluster centroids that summarize connectivity patterns observed in many frequency bands, as well as clusters consisting only of functional network connectivity (FNC) from a narrow range of frequencies along with associated phase profiles. The value of this approach is demonstrated by its ability to reveal significant group differences in males versus females regarding occupancy rates of cluster that would not be separable without considering the frequencies and phase lags. The method we introduce provides a novel and informative framework for analyzing time-varying and frequency specific connectivity which can be broadly applied to the study of the healthy and diseased human brain.

YNIMG Journal 2015 Journal Article

Mutually temporally independent connectivity patterns: A new framework to study the dynamics of brain connectivity at rest with application to explain group difference based on gender

  • Maziar Yaesoubi
  • Robyn L. Miller
  • Vince D. Calhoun

Functional connectivity analysis of the human brain is an active area in fMRI research. It focuses on identifying meaningful brain networks that have coherent activity either during a task or in the resting state. These networks are generally identified either as collections of voxels whose time series correlate strongly with a pre-selected region or voxel, or using data-driven methodologies such as independent component analysis (ICA) that compute sets of maximally spatially independent voxel weightings (component spatial maps (SMs)), each associated with a single time course (TC). Studies have shown that regardless of the way these networks are defined, the activity coherence among them has a dynamic nature which is hard to estimate with global coherence analysis such as correlation or mutual information. Sliding window analyses in which functional network connectivity (FNC) is estimated separately at each time window is one of the more widely employed approaches to studying the dynamic nature of functional network connectivity (dFNC). Observed FNC patterns are summarized and replaced with a smaller set of prototype connectivity patterns (“states” or “components”), and then a dynamical analysis is applied to the resulting sequences of prototype states. In this work we are looking for a small set of connectivity patterns whose weighted contributions to the dynamically changing dFNCs are independent of each other in time. We discuss our motivation for this work and how it differs from existing approaches. Also, in a group analysis based on gender we show that males significantly differ from females by occupying significantly more combinations of these connectivity patterns over the course of the scan.

YNIMG Journal 2014 Journal Article

A multiple kernel learning approach to perform classification of groups from complex-valued fMRI data analysis: Application to schizophrenia

  • Eduardo Castro
  • Vanessa Gómez-Verdejo
  • Manel Martínez-Ramón
  • Kent A. Kiehl
  • Vince D. Calhoun

FMRI data are acquired as complex-valued spatiotemporal images. Despite the fact that several studies have identified the presence of novel information in the phase images, they are usually discarded due to their noisy nature. Several approaches have been devised to incorporate magnitude and phase data, but none of them has performed between-group inference or classification. Multiple kernel learning (MKL) is a powerful field of machine learning that finds an automatic combination of kernel functions that can be applied to multiple data sources. By analyzing this combination of kernels, the most informative data sources can be found, hence providing a better understanding of the analyzed learning task. This paper presents a methodology based on a new MKL algorithm (ν-MKL) capable of achieving a tunable sparse selection of features' sets (brain regions' patterns) that improves the classification accuracy rate of healthy controls and schizophrenia patients by 5% when phase data is included. In addition, the proposed method achieves accuracy rates that are equivalent to those obtained by the state of the art lp -norm MKL algorithm on the schizophrenia dataset and we argue that it better identifies the brain regions that show discriminative activation between groups. This claim is supported by the more accurate detection achieved by ν-MKL of the degree of information present on regions of spatial maps extracted from a simulated fMRI dataset. In summary, we present an MKL-based methodology that improves schizophrenia characterization by using both magnitude and phase fMRI data and is also capable of detecting the brain regions that convey most of the discriminative information between patients and controls.

YNIMG Journal 2014 Journal Article

A statistically motivated framework for simulation of stochastic data fusion models applied to multimodal neuroimaging

  • Rogers F. Silva
  • Sergey M. Plis
  • Tülay Adalı
  • Vince D. Calhoun

Multimodal fusion is becoming more common as it proves to be a powerful approach to identify complementary information from multimodal datasets. However, simulation of joint information is not straightforward. Published approaches mostly employ limited, provisional designs that often break the link between the model assumptions and the data for the sake of demonstrating properties of fusion techniques. This work introduces a new approach to synthetic data generation which allows full-compliance between data and model while still representing realistic spatiotemporal features in accordance with the current neuroimaging literature. The focus is on the simulation of joint information for the verification of stochastic linear models, particularly those used in multimodal data fusion of brain imaging data. Our first goal is to obtain a benchmark ground-truth in which estimation errors due to model mismatch are minimal or none. Then we move on to assess how estimation is affected by gradually increasing model discrepancies toward a more realistic dataset. The key aspect of our approach is that it permits complete control over the type and level of model mismatch, allowing for more educated inferences about the limitations and caveats of select stochastic linear models. As a result, impartial comparison of models is possible based on their performance in multiple different scenarios. Our proposed method uses the commonly overlooked theory of copulas to enable full control of the type and level of dependence/association between modalities, with no occurrence of spurious multimodal associations. Moreover, our approach allows for arbitrary single-modality marginal distributions for any fixed choice of dependence/association between multimodal features. Using our simulation framework, we can rigorously challenge the assumptions of several existing multimodal fusion approaches. Our study brings a new perspective to the problem of simulating multimodal data that can be used for ground-truth verification of various stochastic multimodal models available in the literature, and reveals some important aspects that are not captured or are overlooked by ad hoc simulations that lack a firm statistical motivation.

YNIMG Journal 2014 Journal Article

A three-way parallel ICA approach to analyze links among genetics, brain structure and brain function

  • Victor M. Vergara
  • Alvaro Ulloa
  • Vince D. Calhoun
  • David Boutte
  • Jiayu Chen
  • Jingyu Liu

Multi-modal data analysis techniques, such as the Parallel Independent Component Analysis (pICA), are essential in neuroscience, medical imaging and genetic studies. The pICA algorithm allows the simultaneous decomposition of up to two data modalities achieving better performance than separate ICA decompositions and enabling the discovery of links between modalities. However, advances in data acquisition techniques facilitate the collection of more than two data modalities from each subject. Examples of commonly measured modalities include genetic information, structural magnetic resonance imaging (MRI) and functional MRI. In order to take full advantage of the available data, this work extends the pICA approach to incorporate three modalities in one comprehensive analysis. Simulations demonstrate the three-way pICA performance in identifying pairwise links between modalities and estimating independent components which more closely resemble the true sources than components found by pICA or separate ICA analyses. In addition, the three-way pICA algorithm is applied to real experimental data obtained from a study that investigate genetic effects on alcohol dependence. Considered data modalities include functional MRI (contrast images during alcohol exposure paradigm), gray matter concentration images from structural MRI and genetic single nucleotide polymorphism (SNP). The three-way pICA approach identified links between a SNP component (pointing to brain function and mental disorder associated genes, including BDNF, GRIN2B and NRG1), a functional component related to increased activation in the precuneus area, and a gray matter component comprising part of the default mode network and the caudate. Although such findings need further verification, the simulation and in-vivo results validate the three-way pICA algorithm presented here as a useful tool in biomedical data fusion applications.

YNIMG Journal 2014 Journal Article

Dynamic changes of spatial functional network connectivity in healthy individuals and schizophrenia patients using independent vector analysis

  • Sai Ma
  • Vince D. Calhoun
  • Ronald Phlypo
  • Tülay Adalı

Recent work on both task-induced and resting-state functional magnetic resonance imaging (fMRI) data suggests that functional connectivity may fluctuate, rather than being stationary during an entire scan. Most dynamic studies are based on second-order statistics between fMRI time series or time courses derived from blind source separation, e. g. , independent component analysis (ICA), to investigate changes of temporal interactions among brain regions. However, fluctuations related to spatial components over time are of interest as well. In this paper, we examine higher-order statistical dependence between pairs of spatial components, which we define as spatial functional network connectivity (sFNC), and changes of sFNC across a resting-state scan. We extract time-varying components from healthy controls and patients with schizophrenia to represent brain networks using independent vector analysis (IVA), which is an extension of ICA to multiple data sets and enables one to capture spatial variations. Based on mutual information among IVA components, we perform statistical analysis and Markov modeling to quantify the changes in spatial connectivity. Our experimental results suggest significantly more fluctuations in patient group and show that patients with schizophrenia have more variable patterns of spatial concordance primarily between the frontoparietal, cerebellar and temporal lobe regions. This study extends upon earlier studies showing temporal connectivity differences in similar areas on average by providing evidence that the dynamic spatial interplay between these regions is also impacted by schizophrenia.

YNIMG Journal 2014 Journal Article

Functional and effective connectivity of stopping

  • René J. Huster
  • Sergey M. Plis
  • Christina F. Lavallee
  • Vince D. Calhoun
  • Christoph S. Herrmann

Behavioral inhibition often is studied by comparing the electroencephalographic responses to stop and to go signals. Most studies simply assess amplitude differences of the N200 and P300 event-related potentials, which seem to best correspond to increased activity in the theta and delta frequency bands, respectively. However, neither have reliable indicators for successful behavioral inhibition been identified nor have the causal dependencies of stop-related neurocognitive processes been addressed yet. By studying functional and effective connectivity underlying stopping behavior, this study opens new directions for the investigation of behavioral inhibition. Group independent component analysis was used to infer functionally coherent networks from electroencephalographic data, which were recorded from healthy human participants during processing of a stop signal task. Then, the temporal dynamics of causal dependencies between independent components were identified by means of Bayesian network estimations. The mean clustering coefficient and the characteristic path length measure indicated time windows between 130 and 180ms and between 420 and 500ms to express significantly different connectivity profiles between conditions. Three components showed significant correlations between 120 and 260ms with stop signal reaction times and the number of failed stops. Two of these components acted as sources of causal flow, one capturing P300/delta characteristics while the other was characterized by alpha power depletion putatively representing the evaluation or processing of stimulus features. Although results suggest that the P300 and associated delta activity seem to be statistically dependent on earlier processes associated with behavioral inhibition, the time window critical for inhibition coincides with early changes in causal patterns and largely precedes peak amplitude differences between go and stop trials. Altogether, utilizing the analysis of stopping-related connectivity, previously undetected patterns emerged that warrant further investigation.

YNIMG Journal 2014 Journal Article

Function–structure associations of the brain: Evidence from multimodal connectivity and covariance studies

  • Jing Sui
  • Rene Huster
  • Qingbao Yu
  • Judith M. Segall
  • Vince D. Calhoun

Despite significant advances in multimodal imaging techniques and analysis approaches, unimodal studies are still the predominant way to investigate brain changes or group differences, including structural magnetic resonance imaging (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI) and electroencephalography (EEG). Multimodal brain studies can be used to understand the complex interplay of anatomical, functional and physiological brain alterations or development, and to better comprehend the biological significance of multiple imaging measures. To examine the function–structure associations of the brain in a more comprehensive and integrated manner, we reviewed a number of multimodal studies that combined two or more functional (fMRI and/or EEG) and structural (sMRI and/or DTI) modalities. In this review paper, we specifically focused on multimodal neuroimaging studies on cognition, aging, disease and behavior. We also compared multiple analysis approaches, including univariate and multivariate methods. The possible strengths and limitations of each method are highlighted, which can guide readers when selecting a method based on a given research question. In particular, we believe that multimodal fusion approaches will shed further light on the neuronal mechanisms underlying the major structural and functional pathophysiological features of both the healthy brain (e. g. development) or the diseased brain (e. g. mental illness) and, in the latter case, may provide a more sensitive measure than unimodal imaging for disease classification, e. g. multimodal biomarkers, which potentially can be used to support clinical diagnosis based on neuroimaging techniques.

YNIMG Journal 2014 Journal Article

High-order interactions observed in multi-task intrinsic networks are dominant indicators of aberrant brain function in schizophrenia

  • Sergey M. Plis
  • Jing Sui
  • Terran Lane
  • Sushmita Roy
  • Vincent P. Clark
  • Vamsi K. Potluru
  • Rene J. Huster
  • Andrew Michael

Identifying the complex activity relationships present in rich, modern neuroimaging data sets remains a key challenge for neuroscience. The problem is hard because (a) the underlying spatial and temporal networks may be nonlinear and multivariate and (b) the observed data may be driven by numerous latent factors. Further, modern experiments often produce data sets containing multiple stimulus contexts or tasks processed by the same subjects. Fusing such multi-session data sets may reveal additional structure, but raises further statistical challenges. We present a novel analysis method for extracting complex activity networks from such multifaceted imaging data sets. Compared to previous methods, we choose a new point in the trade-off space, sacrificing detailed generative probability models and explicit latent variable inference in order to achieve robust estimation of multivariate, nonlinear group factors (“network clusters”). We apply our method to identify relationships of task-specific intrinsic networks in schizophrenia patients and control subjects from a large fMRI study. After identifying network-clusters characterized by within- and between-task interactions, we find significant differences between patient and control groups in interaction strength among networks. Our results are consistent with known findings of brain regions exhibiting deviations in schizophrenic patients. However, we also find high-order, nonlinear interactions that discriminate groups but that are not detected by linear, pairwise methods. We additionally identify high-order relationships that provide new insights into schizophrenia but that have not been found by traditional univariate or second-order methods. Overall, our approach can identify key relationships that are missed by existing analysis methods, without losing the ability to find relationships that are known to be important.

YNIMG Journal 2014 Journal Article

Impact of autocorrelation on functional connectivity

  • Mohammad R. Arbabshirani
  • Eswar Damaraju
  • Ronald Phlypo
  • Sergey Plis
  • Elena Allen
  • Sai Ma
  • Daniel Mathalon
  • Adrian Preda

Although the impact of serial correlation (autocorrelation) in residuals of general linear models for fMRI time-series has been studied extensively, the effect of autocorrelation on functional connectivity studies has been largely neglected until recently. Some recent studies based on results from economics have questioned the conventional estimation of functional connectivity and argue that not correcting for autocorrelation in fMRI time-series results in “spurious” correlation coefficients. In this paper, first we assess the effect of autocorrelation on Pearson correlation coefficient through theoretical approximation and simulation. Then we present this effect on real fMRI data. To our knowledge this is the first work comprehensively investigating the effect of autocorrelation on functional connectivity estimates. Our results show that although FC values are altered, even following correction for autocorrelation, results of hypothesis testing on FC values remain very similar to those before correction. In real data we show this is true for main effects and also for group difference testing between healthy controls and schizophrenia patients. We further discuss model order selection in the context of autoregressive processes, effects of frequency filtering and propose a preprocessing pipeline for connectivity studies.

YNIMG Journal 2014 Journal Article

Restricted Boltzmann machines for neuroimaging: An application in identifying intrinsic networks

  • R. Devon Hjelm
  • Vince D. Calhoun
  • Ruslan Salakhutdinov
  • Elena A. Allen
  • Tulay Adali
  • Sergey M. Plis

Matrix factorization models are the current dominant approach for resolving meaningful data-driven features in neuroimaging data. Among them, independent component analysis (ICA) is arguably the most widely used for identifying functional networks, and its success has led to a number of versatile extensions to group and multimodal data. However there are indications that ICA may have reached a limit in flexibility and representational capacity, as the majority of such extensions are case-driven, custom-made solutions that are still contained within the class of mixture models. In this work, we seek out a principled and naturally extensible approach and consider a probabilistic model known as a restricted Boltzmann machine (RBM). An RBM separates linear factors from functional brain imaging data by fitting a probability distribution model to the data. Importantly, the solution can be used as a building block for more complex (deep) models, making it naturally suitable for hierarchical and multimodal extensions that are not easily captured when using linear factorizations alone. We investigate the capability of RBMs to identify intrinsic networks and compare its performance to that of well-known linear mixture models, in particular ICA. Using synthetic and real task fMRI data, we show that RBMs can be used to identify networks and their temporal activations with accuracy that is equal or greater than that of factorization models. The demonstrated effectiveness of RBMs supports its use as a building block for deeper models, a significant prospect for future neuroimaging research.

YNIMG Journal 2014 Journal Article

Thalamus and posterior temporal lobe show greater inter-network connectivity at rest and across sensory paradigms in schizophrenia

  • Mustafa S. Çetin
  • Fletcher Christensen
  • Christopher C. Abbott
  • Julia M. Stephen
  • Andrew R. Mayer
  • José M. Cañive
  • Juan R. Bustillo
  • Godfrey D. Pearlson

Although a number of recent studies have examined functional connectivity at rest, few have assessed differences between connectivity both during rest and across active task paradigms. Therefore, the question of whether cortical connectivity patterns remain stable or change with task engagement continues to be unaddressed. We collected multi-scan fMRI data on healthy controls (N =53) and schizophrenia patients (N =42) during rest and across paradigms arranged hierarchically by sensory load. We measured functional network connectivity among 45 non-artifactual distinct brain networks. Then, we applied a novel analysis to assess cross paradigm connectivity patterns applied to healthy controls and patients with schizophrenia. To detect these patterns, we fit a group by task full factorial ANOVA model to the group average functional network connectivity values. Our approach identified both stable (static effects) and state-based differences (dynamic effects) in brain connectivity providing a better understanding of how individuals' reactions to simple sensory stimuli are conditioned by the context within which they are presented. Our findings suggest that not all group differences observed during rest are detectable in other cognitive states. In addition, the stable differences of heightened connectivity between multiple brain areas with thalamus across tasks underscore the importance of the thalamus as a gateway to sensory input and provide new insight into schizophrenia.

YNIMG Journal 2013 Journal Article

Dynamic functional connectivity: Promise, issues, and interpretations

  • R. Matthew Hutchison
  • Thilo Womelsdorf
  • Elena A. Allen
  • Peter A. Bandettini
  • Vince D. Calhoun
  • Maurizio Corbetta
  • Stefania Della Penna
  • Jeff H. Duyn

The brain must dynamically integrate, coordinate, and respond to internal and external stimuli across multiple time scales. Non-invasive measurements of brain activity with fMRI have greatly advanced our understanding of the large-scale functional organization supporting these fundamental features of brain function. Conclusions from previous resting-state fMRI investigations were based upon static descriptions of functional connectivity (FC), and only recently studies have begun to capitalize on the wealth of information contained within the temporal features of spontaneous BOLD FC. Emerging evidence suggests that dynamic FC metrics may index changes in macroscopic neural activity patterns underlying critical aspects of cognition and behavior, though limitations with regard to analysis and interpretation remain. Here, we review recent findings, methodological considerations, neural and behavioral correlates, and future directions in the emerging field of dynamic FC investigations.

YNIMG Journal 2013 Journal Article

Guided exploration of genomic risk for gray matter abnormalities in schizophrenia using parallel independent component analysis with reference

  • Jiayu Chen
  • Vince D. Calhoun
  • Godfrey D. Pearlson
  • Nora Perrone-Bizzozero
  • Jing Sui
  • Jessica A. Turner
  • Juan R. Bustillo
  • Stefan Ehrlich

One application of imaging genomics is to explore genetic variants associated with brain structure and function, presenting a new means of mapping genetic influences on mental disorders. While there is growing interest in performing genome-wide searches for determinants, it remains challenging to identify genetic factors of small effect size, especially in limited sample sizes. In an attempt to address this issue, we propose to take advantage of a priori knowledge, specifically to extend parallel independent component analysis (pICA) to incorporate a reference (pICA-R), aiming to better reveal relationships between hidden factors of a particular attribute. The new approach was first evaluated on simulated data for its performance under different configurations of effect size and dimensionality. Then pICA-R was applied to a 300-participant (140 schizophrenia (SZ) patients versus 160 healthy controls) dataset consisting of structural magnetic resonance imaging (sMRI) and single nucleotide polymorphism (SNP) data. Guided by a reference SNP set derived from ANK3, a gene implicated by the Psychiatric Genomic Consortium SZ study, pICA-R identified one pair of SNP and sMRI components with a significant loading correlation of 0. 27 (p=1. 64×10−6). The sMRI component showed a significant group difference in loading parameters between patients and controls (p=1. 33×10−15), indicating SZ-related reduction in gray matter concentration in prefrontal and temporal regions. The linked SNP component also showed a group difference (p=0. 04) and was predominantly contributed to by 1030 SNPs. The effect of these top contributing SNPs was verified using association test results of the Psychiatric Genomic Consortium SZ study, where the 1030 SNPs exhibited significant SZ enrichment compared to the whole genome. In addition, pathway analyses indicated the genetic component majorly relating to neurotransmitter and nervous system signaling pathways. Given the simulation and experiment results, pICA-R may prove a promising multivariate approach for use in imaging genomics to discover reliable genetic risk factors under a scenario of relatively high dimensionality and small effect size.

YNIMG Journal 2013 Journal Article

Mind over chatter: Plastic up-regulation of the fMRI salience network directly after EEG neurofeedback

  • Tomas Ros
  • Jean Théberge
  • Paul A. Frewen
  • Rosemarie Kluetsch
  • Maria Densmore
  • Vince D. Calhoun
  • Ruth A. Lanius

Neurofeedback (NFB) involves a brain–computer interface that allows users to learn to voluntarily control their cortical oscillations, reflected in the electroencephalogram (EEG). Although NFB is being pioneered as a noninvasive tool for treating brain disorders, there is insufficient evidence on the mechanism of its impact on brain function. Furthermore, the dominant rhythm of the human brain is the alpha oscillation (8–12Hz), yet its behavioral significance remains multifaceted and largely correlative. In this study with 34 healthy participants, we examined whether during the performance of an attentional task, the functional connectivity of distinct fMRI networks would be plastically altered after a 30-min session of voluntary reduction of alpha rhythm (n=17) versus a sham-feedback condition (n=17). We reveal that compared to sham-feedback, NFB induced an increase of connectivity within regions of the salience network involved in intrinsic alertness (dorsal anterior cingulate), which was detectable 30min after termination of training. The increase in salience network (default-mode network) connectivity was negatively (positively) correlated with changes in ‘on task’ mind-wandering as well as resting state alpha rhythm. Crucially, we observed a causal dependence between alpha rhythm synchronization during NFB and its subsequent change at resting state, not exhibited by the SHAM group. Our findings provide neurobehavioral evidence for the brain's exquisite functional plasticity, and for a temporally direct impact of NFB on a key cognitive control network, suggesting a promising basis for its use to treat cognitive disorders under physiological conditions.

YNIMG Journal 2013 Journal Article

Task-related concurrent but opposite modulations of overlapping functional networks as revealed by spatial ICA

  • Jiansong Xu
  • Sheng Zhang
  • Vince D. Calhoun
  • John Monterosso
  • Chiang-shan R. Li
  • Patrick D. Worhunsky
  • Michael Stevens
  • Godfrey D. Pearlson

Animal studies indicate that different functional networks (FNs), each with a unique timecourse, may overlap at common brain regions. For understanding how different FNs overlap in the human brain and how the timecourses of overlapping FNs are modulated by cognitive tasks, we applied spatial independent component analysis (sICA) to functional magnetic resonance imaging (fMRI) data. These data were acquired from healthy participants while they performed a visual task with parametric loads of attention and working memory. sICA identified a total of 14 FNs, and they showed different extents of overlap at a majority of brain regions exhibiting any functional activity. More FNs overlapped at the higher-order association cortex including the anterior and posterior cingulate, precuneus, insula, and lateral and medial frontoparietal cortices (FPCs) than at the primary sensorimotor cortex. Furthermore, overlapping FNs exhibited concurrent but different task-related modulations of timecourses. FNs showing task-related up- vs. down-modulation of timecourses overlapped at both the lateral and medial FPCs and subcortical structures including the thalamus, striatum, and midbrain ventral tegmental area (VTA). Such task-related, concurrent, but opposite changes in timecourses in the same brain regions may not be detected by current analyses based on General-Linear-Model (GLM). The present findings indicate that multiple cognitive processes may associate with common brain regions and exhibit simultaneous but different modulations in timecourses during cognitive tasks.

YNIMG Journal 2013 Journal Article

The spatiospectral characterization of brain networks: Fusing concurrent EEG spectra and fMRI maps

  • David A. Bridwell
  • Lei Wu
  • Tom Eichele
  • Vince D. Calhoun

Different imaging modalities capture different aspects of brain activity. Functional magnetic resonance imaging (fMRI) reveals intrinsic networks whose BOLD signals have periods from 100s (0. 01Hz) to about 10s (0. 1Hz). Electroencephalographic (EEG) recordings, in contrast, commonly reflect cortical electrical fluctuations with periods up to 20ms (50Hz) or above. We examined the correspondence between intrinsic fMRI and EEG network activity at rest in order to characterize brain networks both spatially (with fMRI) and spectrally (with EEG). Brain networks were separately identified within the concurrently recorded fMRI and EEG at the aggregate group level with group independent component analysis and the association between spatial fMRI and frequency by spatial EEG sources was examined by deconvolving their component time courses. The two modalities are considered linked if the estimated impulse response function (IRF) is significantly non-zero at biologically plausible delays. We found that negative associations were primarily present within two of five alpha components, which highlights the importance of considering multiple alpha sources in EEG–fMRI. Positive associations were primarily present within the lower (e. g. delta and theta) and higher (e. g. upper beta and lower gamma) spectral regions, sometimes within the same fMRI components. Collectively, the results demonstrate a promising approach to characterize brain networks spatially and spectrally, and reveal that positive and negative associations appear within partially distinct regions of the EEG spectrum.

YNIMG Journal 2013 Journal Article

Three-way (N-way) fusion of brain imaging data based on mCCA+jICA and its application to discriminating schizophrenia

  • Jing Sui
  • Hao He
  • Godfrey D. Pearlson
  • Tülay Adali
  • Kent A. Kiehl
  • Qingbao Yu
  • Vince P. Clark
  • Eduardo Castro

Multimodal fusion is an effective approach to better understand brain diseases. However, most such instances have been limited to pair-wise fusion; because there are often more than two imaging modalities available per subject, there is a need for approaches that can combine multiple datasets optimally. In this paper, we extended our previous two-way fusion model called “multimodal CCA+joint ICA”, to three or N-way fusion, that enables robust identification of correspondence among N data types and allows one to investigate the important question of whether certain disease risk factors are shared or distinct across multiple modalities. We compared “mCCA+jICA” with its alternatives in a 3-way fusion simulation and verified its advantages in both decomposition accuracy and modal linkage detection. We also applied it to real functional Magnetic Resonance Imaging (fMRI)–Diffusion Tensor Imaging (DTI) and structural MRI fusion to elucidate the abnormal architecture underlying schizophrenia (n=97) relative to healthy controls (n=116). Both modality-common and modality-unique abnormal regions were identified in schizophrenia. Specifically, the visual cortex in fMRI, the anterior thalamic radiation (ATR) and forceps minor in DTI, and the parietal lobule, cuneus and thalamus in sMRI were linked and discriminated between patients and controls. One fMRI component with regions of activity in motor cortex and superior temporal gyrus individually discriminated schizophrenia from controls. Finally, three components showed significant correlation with duration of illness (DOI), suggesting that lower gray matter volumes in parietal, frontal, and temporal lobes and cerebellum are associated with increased DOI, along with white matter disruption in ATR and cortico-spinal tracts. Findings suggest that the identified fractional anisotropy changes may relate to the corresponding functional/structural changes in the brain that are thought to play a role in the clinical expression of schizophrenia. The proposed “mCCA+jICA” method showed promise for elucidating the joint or coupled neuronal abnormalities underlying mental illnesses and improves our understanding of the disease process.

YNIMG Journal 2012 Journal Article

A large scale multivariate parallel ICA method reveals novel imaging–genetic relationships for Alzheimer's disease in the ADNI cohort

  • Shashwath A. Meda
  • Balaji Narayanan
  • Jingyu Liu
  • Nora I. Perrone-Bizzozero
  • Michael C. Stevens
  • Vince D. Calhoun
  • David C. Glahn
  • Li Shen

The underlying genetic etiology of late onset Alzheimer's disease (LOAD) remains largely unknown, likely due to its polygenic architecture and a lack of sophisticated analytic methods to evaluate complex genotype–phenotype models. The aim of the current study was to overcome these limitations in a bi-multivariate fashion by linking intermediate magnetic resonance imaging (MRI) phenotypes with a genome-wide sample of common single nucleotide polymorphism (SNP) variants. We compared associations between 94 different brain regions of interest derived from structural MRI scans and 533, 872 genome-wide SNPs using a novel multivariate statistical procedure, parallel-independent component analysis, in a large, national multi-center subject cohort. The study included 209 elderly healthy controls, 367 subjects with amnestic mild cognitive impairment and 181 with mild, early-stage LOAD, all of them Caucasian adults, from the Alzheimer's Disease Neuroimaging Initiative cohort. Imaging was performed on comparable 1. 5T scanners at over 50 sites in the USA/Canada. Four primary “genetic components” were associated significantly with a single structural network including all regions involved neuropathologically in LOAD. Pathway analysis suggested that each component included several genes already known to contribute to LOAD risk (e. g. APOE4) or involved in pathologic processes contributing to the disorder, including inflammation, diabetes, obesity and cardiovascular disease. In addition significant novel genes identified included ZNF673, VPS13, SLC9A7, ATP5G2 and SHROOM2. Unlike conventional analyses, this multivariate approach identified distinct groups of genes that are plausibly linked in physiologic pathways, perhaps epistatically. Further, the study exemplifies the value of this novel approach to explore large-scale data sets involving high-dimensional gene and endophenotype data.

YNIMG Journal 2012 Journal Article

Capturing inter-subject variability with group independent component analysis of fMRI data: A simulation study

  • Elena A. Allen
  • Erik B. Erhardt
  • Yonghua Wei
  • Tom Eichele
  • Vince D. Calhoun

A key challenge in functional neuroimaging is the meaningful combination of results across subjects. Even in a sample of healthy participants, brain morphology and functional organization exhibit considerable variability, such that no two individuals have the same neural activation at the same location in response to the same stimulus. This inter-subject variability limits inferences at the group-level as average activation patterns may fail to represent the patterns seen in individuals. A promising approach to multi-subject analysis is group independent component analysis (GICA), which identifies group components and reconstructs activations at the individual level. GICA has gained considerable popularity, particularly in studies where temporal response models cannot be specified. However, a comprehensive understanding of the performance of GICA under realistic conditions of inter-subject variability is lacking. In this study we use simulated functional magnetic resonance imaging (fMRI) data to determine the capabilities and limitations of GICA under conditions of spatial, temporal, and amplitude variability. Simulations, generated with the SimTB toolbox, address questions that commonly arise in GICA studies, such as: (1) How well can individual subject activations be estimated and when will spatial variability preclude estimation? (2) Why does component splitting occur and how is it affected by model order? (3) How should we analyze component features to maximize sensitivity to intersubject differences? Overall, our results indicate an excellent capability of GICA to capture between-subject differences and we make a number of recommendations regarding analytic choices for application to functional imaging data.

YNIMG Journal 2012 Journal Article

Joint ICA of ERP and fMRI during error-monitoring

  • Bethany G. Edwards
  • Vince D. Calhoun
  • Kent A. Kiehl

The anterior cingulate cortex (ACC) is commonly separated into two functional divisions: the cognitive division, which lies in the caudal region and the affective division, which lies in the rostral region of the ACC. Both regions of the ACC are engaged during error-monitoring tasks; however, little is known about the temporal sequencing associated with cognition and affective processes during error-monitoring. Here we use joint Independent Component Analysis (jICA) to couple event-related potential (ERP) time courses and functional magnetic resonance imaging (fMRI) spatial maps to examine the spatio-temporal stages of engagement in the two divisions of the ACC during error-monitoring. Consistent with hypotheses, two of the five significant spatio-temporal components identified by jICA revealed that the error-related negativity (ERN) ERP was associated with distinct spatial fMRI patterns in the ACC. The ERN1 was associated with activity in the caudal ACC and lateral prefrontal cortex (lPFC) while the ERN2 was associated with activity in the rostral ACC. These results suggest that during error-monitoring the caudal ACC and lPFC engage prior to the rostral ACC. These results suggest that cognition precedes affect during error-monitoring.

YNIMG Journal 2012 Journal Article

Modulations of functional connectivity in the healthy and schizophrenia groups during task and rest

  • Sai Ma
  • Vince D. Calhoun
  • Tom Eichele
  • Wei Du
  • Tülay Adalı

Connectivity analysis using functional magnetic resonance imaging (fMRI) data is an important area, useful for the identification of biomarkers for various mental disorders, including schizophrenia. Most studies to date have focused on resting data, while the study of functional connectivity during task and the differences between task and rest are of great interest as well. In this work, we examine the graph-theoretical properties of the connectivity maps constructed using spatial components derived from independent component analysis (ICA) for healthy controls and patients with schizophrenia during an auditory oddball task (AOD) and at extended rest. We estimate functional connectivity using the higher-order statistical dependence, i. e. , mutual information among the ICA spatial components, instead of the typically used temporal correlation. We also define three novel topological metrics based on the modules of brain networks obtained using a clustering approach. Our experimental results show that although the schizophrenia patients preserve the small-world property, they present a significantly lower small-worldness during both AOD task and rest when compared to the healthy controls, indicating a consistent tendency towards a more random organization of brain networks. In addition, the task-induced modulations to topological measures of several components involving motor, cerebellum and parietal regions are altered in patients relative to controls, providing further evidence for the aberrant connectivity in schizophrenia.

YNIMG Journal 2012 Journal Article

Multifaceted genomic risk for brain function in schizophrenia

  • Jiayu Chen
  • Vince D. Calhoun
  • Godfrey D. Pearlson
  • Stefan Ehrlich
  • Jessica A. Turner
  • Beng-Choon Ho
  • Thomas H. Wassink
  • Andrew M. Michael

Recently, deriving candidate endophenotypes from brain imaging data has become a valuable approach to study genetic influences on schizophrenia (SZ), whose pathophysiology remains unclear. In this work we utilized a multivariate approach, parallel independent component analysis, to identify genomic risk components associated with brain function abnormalities in SZ. 5157 candidate single nucleotide polymorphisms (SNPs) were derived from genome-wide array based on their possible connections with SZ and further investigated for their associations with brain activations captured with functional magnetic resonance imaging (fMRI) during a sensorimotor task. Using data from 92 SZ patients and 116 healthy controls, we detected a significant correlation (r=0. 29; p=2. 41×10−5) between one fMRI component and one SNP component, both of which significantly differentiated patients from controls. The fMRI component mainly consisted of precentral and postcentral gyri, the major activated regions in the motor task. On average, higher activation in these regions was observed in participants with higher loadings of the linked SNP component, predominantly contributed to by 253 SNPs. 138 identified SNPs were from known coding regions of 100 unique genes. 31 identified SNPs did not differ between groups, but moderately correlated with some other group-discriminating SNPs, indicating interactions among alleles contributing toward elevated SZ susceptibility. The genes associated with the identified SNPs participated in four neurotransmitter pathways: GABA receptor signaling, dopamine receptor signaling, neuregulin signaling and glutamate receptor signaling. In summary, our work provides further evidence for the complexity of genomic risk to the functional brain abnormality in SZ and suggests a pathological role of interactions between SNPs, genes and multiple neurotransmitter pathways.

YNIMG Journal 2012 Journal Article

SimTB, a simulation toolbox for fMRI data under a model of spatiotemporal separability

  • Erik B. Erhardt
  • Elena A. Allen
  • Yonghua Wei
  • Tom Eichele
  • Vince D. Calhoun

We introduce SimTB, a MATLAB toolbox designed to simulate functional magnetic resonance imaging (fMRI) datasets under a model of spatiotemporal separability. The toolbox meets the increasing need of the fMRI community to more comprehensively understand the effects of complex processing strategies by providing a ground truth that estimation methods may be compared against. SimTB captures the fundamental structure of real data, but data generation is fully parameterized and fully controlled by the user, allowing for accurate and precise comparisons. The toolbox offers a wealth of options regarding the number and configuration of spatial sources, implementation of experimental paradigms, inclusion of tissue-specific properties, addition of noise and head movement, and much more. A straightforward data generation method and short computation time (3–10 seconds for each dataset) allow a practitioner to simulate and analyze many datasets to potentially understand a problem from many angles. Beginning MATLAB users can use the SimTB graphical user interface (GUI) to design and execute simulations while experienced users can write batch scripts to automate and customize this process. The toolbox is freely available at http: //mialab. mrn. org/software together with sample scripts and tutorials.

YNIMG Journal 2012 Journal Article

TDCS guided using fMRI significantly accelerates learning to identify concealed objects

  • Vincent P. Clark
  • Brian A. Coffman
  • Andy R. Mayer
  • Michael P. Weisend
  • Terran D.R. Lane
  • Vince D. Calhoun
  • Elaine M. Raybourn
  • Christopher M. Garcia

The accurate identification of obscured and concealed objects in complex environments was an important skill required for survival during human evolution, and is required today for many forms of expertise. Here we used transcranial direct current stimulation (tDCS) guided using neuroimaging to increase learning rate in a novel, minimally guided discovery-learning paradigm. Ninety-six subjects identified threat-related objects concealed in naturalistic virtual surroundings used in real-world training. A variety of brain networks were found using functional magnetic resonance imaging (fMRI) data collected at different stages of learning, with two of these networks focused in right inferior frontal and right parietal cortex. Anodal 2. 0mA tDCS performed for 30min over these regions in a series of single-blind, randomized studies resulted in significant improvements in learning and performance compared with 0. 1mA tDCS. This difference in performance increased to a factor of two after a one-hour delay. A dose–response effect of current strength on learning was also found. Taken together, these brain imaging and stimulation studies suggest that right frontal and parietal cortex are involved in learning to identify concealed objects in naturalistic surroundings. Furthermore, they suggest that the application of anodal tDCS over these regions can greatly increase learning, resulting in one of the largest effects on learning yet reported. The methods developed here may be useful to decrease the time required to attain expertise in a variety of settings.

YNIMG Journal 2011 Journal Article

Characterization of groups using composite kernels and multi-source fMRI analysis data: Application to schizophrenia

  • Eduardo Castro
  • Manel Martínez-Ramón
  • Godfrey Pearlson
  • Jing Sui
  • Vince D. Calhoun

Pattern classification of brain imaging data can enable the automatic detection of differences in cognitive processes of specific groups of interest. Furthermore, it can also give neuroanatomical information related to the regions of the brain that are most relevant to detect these differences by means of feature selection procedures, which are also well-suited to deal with the high dimensionality of brain imaging data. This work proposes the application of recursive feature elimination using a machine learning algorithm based on composite kernels to the classification of healthy controls and patients with schizophrenia. This framework, which evaluates nonlinear relationships between voxels, analyzes whole-brain fMRI data from an auditory task experiment that is segmented into anatomical regions and recursively eliminates the uninformative ones based on their relevance estimates, thus yielding the set of most discriminative brain areas for group classification. The collected data was processed using two analysis methods: the general linear model (GLM) and independent component analysis (ICA). GLM spatial maps as well as ICA temporal lobe and default mode component maps were then input to the classifier. A mean classification accuracy of up to 95% estimated with a leave-two-out cross-validation procedure was achieved by doing multi-source data classification. In addition, it is shown that the classification accuracy rate obtained by using multi-source data surpasses that reached by using single-source data, hence showing that this algorithm takes advantage of the complimentary nature of GLM and ICA.

YNIMG Journal 2011 Journal Article

Discriminating schizophrenia and bipolar disorder by fusing fMRI and DTI in a multimodal CCA+ joint ICA model

  • Jing Sui
  • Godfrey Pearlson
  • Arvind Caprihan
  • Tülay Adali
  • Kent A. Kiehl
  • Jingyu Liu
  • Jeremy Yamamoto
  • Vince D. Calhoun

Diverse structural and functional brain alterations have been identified in both schizophrenia and bipolar disorder, but with variable replicability, significant overlap and often in limited number of subjects. In this paper, we aimed to clarify differences between bipolar disorder and schizophrenia by combining fMRI (collected during an auditory oddball task) and diffusion tensor imaging (DTI) data. We proposed a fusion method, “multimodal CCA+ joint ICA”, which increases flexibility in statistical assumptions beyond existing approaches and can achieve higher estimation accuracy. The data collected from 164 participants (62 healthy controls, 54 schizophrenia and 48 bipolar) were extracted into “features” (contrast maps for fMRI and fractional anisotropy (FA) for DTI) and analyzed in multiple facets to investigate the group differences for each pair-wised groups and each modality. Specifically, both patient groups shared significant dysfunction in dorsolateral prefrontal cortex and thalamus, as well as reduced white matter (WM) integrity in anterior thalamic radiation and uncinate fasciculus. Schizophrenia and bipolar subjects were separated by functional differences in medial frontal and visual cortex, as well as WM tracts associated with occipital and frontal lobes. Both patients and controls showed similar spatial distributions in motor and parietal regions, but exhibited significant variations in temporal lobe. Furthermore, there were different group trends for age effects on loading parameters in motor cortex and multiple WM regions, suggesting that brain dysfunction and WM disruptions occurred in identified regions for both disorders. Most importantly, we can visualize an underlying function–structure network by evaluating the joint components with strong links between DTI and fMRI. Our findings suggest that although the two patient groups showed several distinct brain patterns from each other and healthy controls, they also shared common abnormalities in prefrontal thalamic WM integrity and in frontal brain mechanisms.

YNIMG Journal 2011 Journal Article

Dynamic modeling of neuronal responses in fMRI using cubature Kalman filtering

  • Martin Havlicek
  • Karl J. Friston
  • Jiri Jan
  • Milan Brazdil
  • Vince D. Calhoun

This paper presents a new approach to inverting (fitting) models of coupled dynamical systems based on state-of-the-art (cubature) Kalman filtering. Crucially, this inversion furnishes posterior estimates of both the hidden states and parameters of a system, including any unknown exogenous input. Because the underlying generative model is formulated in continuous time (with a discrete observation process) it can be applied to a wide variety of models specified with either ordinary or stochastic differential equations. These are an important class of models that are particularly appropriate for biological time-series, where the underlying system is specified in terms of kinetics or dynamics (i. e. , dynamic causal models). We provide comparative evaluations with generalized Bayesian filtering (dynamic expectation maximization) and demonstrate marked improvements in accuracy and computational efficiency. We compare the schemes using a series of difficult (nonlinear) toy examples and conclude with a special focus on hemodynamic models of evoked brain responses in fMRI. Our scheme promises to provide a significant advance in characterizing the functional architectures of distributed neuronal systems, even in the absence of known exogenous (experimental) input; e. g. , resting state fMRI studies and spontaneous fluctuations in electrophysiological studies. Importantly, unlike current Bayesian filters (e. g. DEM), our scheme provides estimates of time-varying parameters, which we will exploit in future work on the adaptation and enabling of connections in the brain.

YNIMG Journal 2011 Journal Article

Wavelet-based fMRI analysis: 3-D denoising, signal separation, and validation metrics

  • Siddharth Khullar
  • Andrew Michael
  • Nicolle Correa
  • Tulay Adali
  • Stefi A. Baum
  • Vince D. Calhoun

We present a novel integrated wavelet-domain based framework (w-ICA) for 3-D denoising functional magnetic resonance imaging (fMRI) data followed by source separation analysis using independent component analysis (ICA) in the wavelet domain. We propose the idea of a 3-D wavelet-based multi-directional denoising scheme where each volume in a 4-D fMRI data set is sub-sampled using the axial, sagittal and coronal geometries to obtain three different slice-by-slice representations of the same data. The filtered intensity value of an arbitrary voxel is computed as an expected value of the denoised wavelet coefficients corresponding to the three viewing geometries for each sub-band. This results in a robust set of denoised wavelet coefficients for each voxel. Given the de-correlated nature of these denoised wavelet coefficients, it is possible to obtain more accurate source estimates using ICA in the wavelet domain. The contributions of this work can be realized as two modules: First, in the analysis module we combine a new 3-D wavelet denoising approach with signal separation properties of ICA in the wavelet domain. This step helps obtain an activation component that corresponds closely to the true underlying signal, which is maximally independent with respect to other components. Second, we propose and describe two novel shape metrics for post-ICA comparisons between activation regions obtained through different frameworks. We verified our method using simulated as well as real fMRI data and compared our results against the conventional scheme (Gaussian smoothing+spatial ICA: s-ICA). The results show significant improvements based on two important features: (1) preservation of shape of the activation region (shape metrics) and (2) receiver operating characteristic curves. It was observed that the proposed framework was able to preserve the actual activation shape in a consistent manner even for very high noise levels in addition to significant reduction in false positive voxels.

YNIMG Journal 2010 Journal Article

A CCA+ICA based model for multi-task brain imaging data fusion and its application to schizophrenia

  • Jing Sui
  • Tülay Adali
  • Godfrey Pearlson
  • Honghui Yang
  • Scott R. Sponheim
  • Tonya White
  • Vince D. Calhoun

Collection of multiple-task brain imaging data from the same subject has now become common practice in medical imaging studies. In this paper, we propose a simple yet effective model, “CCA+ICA”, as a powerful tool for multi-task data fusion. This joint blind source separation (BSS) model takes advantage of two multivariate methods: canonical correlation analysis and independent component analysis, to achieve both high estimation accuracy and to provide the correct connection between two datasets in which sources can have either common or distinct between-dataset correlation. In both simulated and real fMRI applications, we compare the proposed scheme with other joint BSS models and examine the different modeling assumptions. The contrast images of two tasks: sensorimotor (SM) and Sternberg working memory (SB), derived from a general linear model (GLM), were chosen to contribute real multi-task fMRI data, both of which were collected from 50 schizophrenia patients and 50 healthy controls. When examining the relationship with duration of illness, CCA+ICA revealed a significant negative correlation with temporal lobe activation. Furthermore, CCA+ICA located sensorimotor cortex as the group-discriminative regions for both tasks and identified the superior temporal gyrus in SM and prefrontal cortex in SB as task-specific group-discriminative brain networks. In summary, we compared the new approach to some competitive methods with different assumptions, and found consistent results regarding each of their hypotheses on connecting the two tasks. Such an approach fills a gap in existing multivariate methods for identifying biomarkers from brain imaging data.

YNIMG Journal 2010 Journal Article

A pilot multivariate parallel ICA study to investigate differential linkage between neural networks and genetic profiles in schizophrenia

  • Shashwath A. Meda
  • Kanchana Jagannathan
  • Joel Gelernter
  • Vince D. Calhoun
  • Jingyu Liu
  • Michael C. Stevens
  • Godfrey D. Pearlson

Understanding genetic influences on both healthy and disordered brain function is a major focus in psychiatric neuroimaging. We utilized task-related imaging findings from an fMRI auditory oddball task known to be robustly associated with abnormal activation in schizophrenia, to investigate genomic factors derived from multiple single nucleotide polymorphisms (SNPs) from genes previously shown to be associated with schizophrenia. Our major aim was to investigate the relationship of these genomic factors to normal/abnormal brain functionality between controls and schizophrenia patients. We studied a Caucasian-only sample of 35 healthy controls and 31 schizophrenia patients. All subjects performed an auditory oddball task, which consists of detecting an infrequent sound within a series of frequent sounds. Each subject was characterized on 24 different SNP markers spanning multiple risk genes previously associated with schizophrenia. We used a recently developed technique named parallel independent component analysis (para-ICA) to analyze this multimodal data set (Liu et al. , 2008). The method aims to identify simultaneously independent components of each modality (functional imaging, genetics) and the relationships between them. We detected three fMRI components significantly correlated with two distinct gene components. The fMRI components, along with their significant genetic profile (dominant SNP) correlations were as follows: (1) Inferior frontal–anterior/posterior cingulate–thalamus–caudate with SNPs from Brain derived neurotropic factor (BDNF) and dopamine transporter (DAT) [r =-0. 51; p <0. 0001], (2) superior/middle temporal gyrus–cingulate–premotor with SLC6A4_PR and SLC6A4_PR_AG (serotonin transporter promoter; 5HTTLPR) [r =0. 27; p =0. 03], and (3) default mode-fronto-temporal gyrus with Brain derived neurotropic factor and dopamine transporter (BDNF, DAT) [r =-0. 25; p =0. 04]. Functional components comprised task-relevant regions (including PFC, ACC, STG and MTG) frequently identified as abnormal in schizophrenia. Further, gene–fMRI combinations 1 (Z =1. 75; p =0. 03), 2 (Z =1. 84; p =0. 03) and 3 (Z =1. 67; p =0. 04) listed above showed significant differences between controls and patients, based on their correlated loading coefficients. We demonstrate a framework to identify interactions between “clusters” of brain function and of genetic information. Our results reveal the effect/influence of specific interactions, (perhaps epistastatic in nature), between schizophrenia risk genes on imaging endophenotypes representing attention/working memory and goal directed related brain function, thus establishing a useful methodology to probe multivariate genotype–phenotype relationships.

YNIMG Journal 2010 Journal Article

Abnormal functional connectivity of default mode sub-networks in autism spectrum disorder patients

  • Michal Assaf
  • Kanchana Jagannathan
  • Vince D. Calhoun
  • Laura Miller
  • Michael C. Stevens
  • Robert Sahl
  • Jacqueline G. O'Boyle
  • Robert T. Schultz

Autism spectrum disorders (ASDs) are characterized by deficits in social and communication processes. Recent data suggest that altered functional connectivity (FC), i. e. synchronous brain activity, might contribute to these deficits. Of specific interest is the FC integrity of the default mode network (DMN), a network active during passive resting states and cognitive processes related to social deficits seen in ASD, e. g. Theory of Mind. We investigated the role of altered FC of default mode sub-networks (DM-SNs) in 16 patients with high-functioning ASD compared to 16 matched healthy controls of short resting fMRI scans using independent component analysis (ICA). ICA is a multivariate data-driven approach that identifies temporally coherent networks, providing a natural measure of FC. Results show that compared to controls, patients showed decreased FC between the precuneus and medial prefrontal cortex/anterior cingulate cortex, DMN core areas, and other DM-SNs areas. FC magnitude in these regions inversely correlated with the severity of patients' social and communication deficits as measured by the Autism Diagnostic Observational Schedule and the Social Responsiveness Scale. Importantly, supplemental analyses suggest that these results were independent of treatment status. These results support the hypothesis that DM-SNs under-connectivity contributes to the core deficits seen in ASD. Moreover, these data provide further support for the use of data-driven analysis with resting-state data for illuminating neural systems that differ between groups. This approach seems especially well suited for populations where compliance with and performance of active tasks might be a challenge, as it requires minimal cooperation.

YNIMG Journal 2010 Journal Article

Anomalous neural circuit function in schizophrenia during a virtual Morris water task

  • Bradley S. Folley
  • Robert Astur
  • Kanchana Jagannathan
  • Vince D. Calhoun
  • Godfrey D. Pearlson

Previous studies have reported learning and navigation impairments in schizophrenia patients during virtual reality allocentric learning tasks. The neural bases of these deficits have not been explored using functional MRI despite well-explored anatomic characterization of these paradigms in non-human animals. Our objective was to characterize the differential distributed neural circuits involved in virtual Morris water task performance using independent component analysis (ICA) in schizophrenia patients and controls. Additionally, we present behavioral data in order to derive relationships between brain function and performance, and we have included a general linear model-based analysis in order to exemplify the incremental and differential results afforded by ICA. Thirty-four individuals with schizophrenia and twenty-eight healthy controls underwent fMRI scanning during a block design virtual Morris water task using hidden and visible platform conditions. Independent components analysis was used to deconstruct neural contributions to hidden and visible platform conditions for patients and controls. We also examined performance variables, voxel-based morphometry and hippocampal subparcellation, and regional BOLD signal variation. Independent component analysis identified five neural circuits. Mesial temporal lobe regions, including the hippocampus, were consistently task-related across conditions and groups. Frontal, striatal, and parietal circuits were recruited preferentially during the visible condition for patients, while frontal and temporal lobe regions were more saliently recruited by controls during the hidden platform condition. Gray matter concentrations and BOLD signal in hippocampal subregions were associated with task performance in controls but not patients. Patients exhibited impaired performance on the hidden and visible conditions of the task, related to negative symptom severity. While controls showed coupling between neural circuits, regional neuroanatomy, and behavior, patients activated different task-related neural circuits, not associated with appropriate regional neuroanatomy. GLM analysis elucidated several comparable regions, with the exception of the hippocampus. Inefficient allocentric learning and memory in patients may be related to an inability to recruit appropriate task-dependent neural circuits.

YNIMG Journal 2010 Journal Article

Changes in fMRI magnitude data and phase data observed in block-design and event-related tasks

  • Sunil Kumar Arja
  • Zhaomei Feng
  • Zikuan Chen
  • Arvind Caprihan
  • Kent A. Kiehl
  • Tülay Adali
  • Vince D. Calhoun

Functional magnetic resonance imaging (fMRI) data are acquired as a complex image pair including magnitude and phase information. The vast majority of fMRI experiments do not attempt to take advantage of the time varying phase information. The phase of the MRI signal is related to the local magnetic field changes, suggesting it may contain useful information about the source of hemodynamic activity. Analysis of phase data acquired from different fMRI experiments has shown the presence of activity in response to various stimuli. However, there have been no studies that have examined phase data in a larger group of subjects for multiple types of fMRI tasks nor have studies examined phase changes due to event-related stimuli. In this paper, we evaluate the correspondence between the magnitude and phase changes at a group level in a block-design motor tapping task and in an event-related auditory oddball task. The results for both block-design and event-related tasks indicate the presence of task-related information in the phase data with phase-only and magnitude-only approaches showing signal changes in the expected brain regions. Although there is more overall activity detected with magnitude data, the phase-only analysis also reveals activity in regions expected to be involved in the task, some of which were not significantly activated in the magnitude-only analysis, suggesting that the phase might provide some unique information. In addition, the phase can potentially increase sensitivity within regions also showing magnitude changes. Future work should focus on additional methods for combining the magnitude and phase data.

YNIMG Journal 2010 Journal Article

Does function follow form?: Methods to fuse structural and functional brain images show decreased linkage in schizophrenia

  • Andrew M. Michael
  • Stefi A. Baum
  • Tonya White
  • Oguz Demirci
  • Nancy C. Andreasen
  • Judith M. Segall
  • Rex E. Jung
  • Godfrey Pearlson

When both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) data are collected they are typically analyzed separately and the joint information is not examined. Techniques that examine joint information can help to find hidden traits in complex disorders such as schizophrenia. The brain is vastly interconnected, and local brain morphology may influence functional activity at distant regions. In this paper we introduce three methods to identify inter-correlations among sMRI and fMRI voxels within the whole brain. We apply these methods to examine sMRI gray matter data and fMRI data derived from an auditory sensorimotor task from a large study of schizophrenia. In Method 1 the sMRI–fMRI cross-correlation matrix is reduced to a histogram and results show that healthy controls (HC) have stronger correlations than do patients with schizophrenia (SZ). In Method 2 the spatial information of sMRI–fMRI correlations is retained. Structural regions in the cerebellum and frontal regions show more positive and more negative correlations, respectively, with functional regions in HC than in SZ. In Method 3 significant sMRI–fMRI inter-regional links are detected, with regions in the cerebellum showing more significant positive correlations with functional regions in HC relative to SZ. Results from all three methods indicate that the linkage between gray matter and functional activation is stronger in HC than SZ. The methods introduced can be easily extended to comprehensively correlate large data sets.

YNIMG Journal 2010 Journal Article

Dynamic Granger causality based on Kalman filter for evaluation of functional network connectivity in fMRI data

  • Martin Havlicek
  • Jiri Jan
  • Milan Brazdil
  • Vince D. Calhoun

Increasing interest in understanding dynamic interactions of brain neural networks leads to formulation of sophisticated connectivity analysis methods. Recent studies have applied Granger causality based on standard multivariate autoregressive (MAR) modeling to assess the brain connectivity. Nevertheless, one important flaw of this commonly proposed method is that it requires the analyzed time series to be stationary, whereas such assumption is mostly violated due to the weakly nonstationary nature of functional magnetic resonance imaging (fMRI) time series. Therefore, we propose an approach to dynamic Granger causality in the frequency domain for evaluating functional network connectivity in fMRI data. The effectiveness and robustness of the dynamic approach was significantly improved by combining a forward and backward Kalman filter that improved estimates compared to the standard time-invariant MAR modeling. In our method, the functional networks were first detected by independent component analysis (ICA), a computational method for separating a multivariate signal into maximally independent components. Then the measure of Granger causality was evaluated using generalized partial directed coherence that is suitable for bivariate as well as multivariate data. Moreover, this metric provides identification of causal relation in frequency domain, which allows one to distinguish the frequency components related to the experimental paradigm. The procedure of evaluating Granger causality via dynamic MAR was demonstrated on simulated time series as well as on two sets of group fMRI data collected during an auditory sensorimotor (SM) or auditory oddball discrimination (AOD) tasks. Finally, a comparison with the results obtained from a standard time-invariant MAR model was provided.

YNIMG Journal 2010 Journal Article

Multi-set canonical correlation analysis for the fusion of concurrent single trial ERP and functional MRI

  • Nicolle M. Correa
  • Tom Eichele
  • Tülay Adalı
  • Yi-Ou Li
  • Vince D. Calhoun

Functional magnetic resonance imaging (fMRI) data and electroencephalography (EEG) data provide complementary spatio-temporal information about brain function. Methods to couple the relative strengths of these modalities usually involve two stages: first forming a feature set from each dataset based on one criterion followed by exploration of connections among the features using a second criterion. We propose a data fusion method for simultaneously acquired fMRI and EEG data that combines these steps using a single criterion for finding the cross-modality associations and performing source separation. Using multi-set canonical correlation analysis (M-CCA), we obtain a decomposition of the two modalities, into spatial maps for fMRI data and a corresponding temporal evolution for EEG data, based on trial-to-trial covariation across the two modalities. Additionally, the analysis is performed on data from a group of subjects in order to make group inferences about the covariation across modalities. Being multivariate, the proposed method facilitates the study of brain connectivity along with localization of brain function. M-CCA can be easily extended to incorporate different data types and additional modalities. We demonstrate the promise of the proposed method in finding covarying trial-to-trial amplitude modulations (AMs) in an auditory task involving implicit pattern learning. The results show approximately linear decreasing trends in AMs for both modalities and the corresponding spatial activations occur mainly in motor, frontal, temporal, inferior parietal, and orbito-frontal areas that are linked both to sensory function as well as learning and expectation—all of which match activations related to the presented paradigm.

YNIMG Journal 2010 Journal Article

Reactivity of hemodynamic responses and functional connectivity to different states of alpha synchrony: A concurrent EEG-fMRI study

  • Lei Wu
  • Tom Eichele
  • Vince D. Calhoun

Concurrent EEG-fMRI studies have provided increasing details of the dynamics of intrinsic brain activity during the resting state. Here, we investigate a prominent effect in EEG during relaxed resting, i. e. the increase of the alpha power when the eyes are closed compared to when the eyes are open. This phenomenon is related to changes in thalamo-cortical and cortico-cortical synchronization. In order to investigate possible changes to EEG-fMRI coupling and fMRI functional connectivity during the two states we adopted a data-driven approach that fuses the multimodal data on the basis of parallel ICA decompositions of the fMRI data in the spatial domain and of the EEG data in the spectral domain. The power variation of a posterior alpha component was used as a reference function to deconvolve the hemodynamic responses from occipital, frontal, temporal, and subcortical fMRI components. Additionally, we computed the functional connectivity between these components. The results showed widespread alpha hemodynamic responses and high functional connectivity during eyes-closed (EC) rest, while eyes open (EO) resting abolished many of the hemodynamic responses and markedly decreased functional connectivity. These data suggest that generation of local hemodynamic responses is highly sensitive to state changes that do not involve changes of mental effort or awareness. They also indicate the localized power differences in posterior alpha between EO and EC in resting state data are accompanied by spatially widespread amplitude changes in hemodynamic responses and inter-regional functional connectivity, i. e. low frequency hemodynamic signals display an equivalent of alpha reactivity.

YNIMG Journal 2010 Journal Article

The COMT Val108/158Met polymorphism and medial temporal lobe volumetry in patients with schizophrenia and healthy adults

  • Stefan Ehrlich
  • Eric M. Morrow
  • Joshua L. Roffman
  • Stuart R. Wallace
  • Melissa Naylor
  • H. Jeremy Bockholt
  • Antonia Lundquist
  • Anastasia Yendiki

Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2. 6% increase in right amygdala volume, a 3. 8% increase in left amygdala volume and a 2. 2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.

YNIMG Journal 2010 Journal Article

WITHDRAWN: Erratum to “Does function follow form?: Methods to fuse structural and functional brain images show decreased linkage in schizophrenia” [NeuroImage 49 (2010) 2626–2637]

  • Andrew M. Michael
  • Stefi A. Baum
  • Tonya White
  • Oguz Demirci
  • Nancy C. Andreasen
  • Judith M. Segall
  • Rex E. Jung
  • Godfrey Pearlson

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http: //www. elsevier. com/locate/withdrawalpolicy.

YNIMG Journal 2009 Journal Article

A review of group ICA for fMRI data and ICA for joint inference of imaging, genetic, and ERP data

  • Vince D. Calhoun
  • Jingyu Liu
  • Tülay Adalı

Independent component analysis (ICA) has become an increasingly utilized approach for analyzing brain imaging data. In contrast to the widely used general linear model (GLM) that requires the user to parameterize the data (e. g. the brain’s response to stimuli), ICA, by relying upon a general assumption of independence, allows the user to be agnostic regarding the exact form of the response. In addition, ICA is intrinsically a multivariate approach, and hence each component provides a grouping of brain activity into regions that share the same response pattern thus providing a natural measure of functional connectivity. There are a wide variety of ICA approaches that have been proposed, in this paper we focus upon two distinct methods. The first part of this paper reviews the use of ICA for making group inferences from fMRI data. We provide an overview of current approaches for utilizing ICA to make group inferences with a focus upon the group ICA approach implemented in the GIFT software. In the next part of this paper, we provide an overview of the use of ICA to combine or fuse multimodal data. ICA has proven particularly useful for data fusion of multiple tasks or data modalities such as single nucleotide polymorphism (SNP) data or event-related potentials. As demonstrated by a number of examples in this paper, ICA is a powerful and versatile data-driven approach for studying the brain.

YNIMG Journal 2009 Journal Article

Age-related cognitive gains are mediated by the effects of white matter development on brain network integration

  • Michael C. Stevens
  • Pawel Skudlarski
  • Godfrey D. Pearlson
  • Vince D. Calhoun

A fundamental, yet rarely tested premise of developmental cognitive neuroscience is that changes in brain activity and improvements in behavioral control across adolescent development are related to brain maturational factors that shape a more efficient, highly-interconnected brain in adulthood. We present the first multimodal neuroimaging study to empirically demonstrate that maturation of executive cognitive ability is directly associated with the relationship of white matter development and age-related changes in neural network functional integration. In this study, we identified specific white matter regions whose maturation across adolescence appears to reduce reliance on local processing in brain regions recruited for conscious, deliberate cognitive control in favor of a more widely distributed profile of functionally-integrated brain activity. Greater white matter coherence with age was associated with both increases and decreases in functional connectivity within task-engaged functional circuits. Importantly, these associations between white matter development and brain system functional integration were related to behavioral performance on tests of response inhibition, demonstrating their importance in the maturation of optimal cognitive control.

YNIMG Journal 2009 Journal Article

An ICA-based method for the identification of optimal FMRI features and components using combined group-discriminative techniques

  • Jing Sui
  • Tülay Adali
  • Godfrey D. Pearlson
  • Vince D. Calhoun

Extraction of relevant features from multitask functional MRI (fMRI) data in order to identify potential biomarkers for disease, is an attractive goal. In this paper, we introduce a novel feature-based framework, which is sensitive and accurate in detecting group differences (e. g. controls vs. patients) by proposing three key ideas. First, we integrate two goal-directed techniques: coefficient-constrained independent component analysis (CC-ICA) and principal component analysis with reference (PCA-R), both of which improve sensitivity to group differences. Secondly, an automated artifact-removal method is developed for selecting components of interest derived from CC-ICA, with an average accuracy of 91%. Finally, we propose a strategy for optimal feature/component selection, aiming to identify optimal group-discriminative brain networks as well as the tasks within which these circuits are engaged. The group-discriminating performance is evaluated on 15 fMRI feature combinations (5 single features and 10 joint features) collected from 28 healthy control subjects and 25 schizophrenia patients. Results show that a feature from a sensorimotor task and a joint feature from a Sternberg working memory (probe) task and an auditory oddball (target) task are the top two feature combinations distinguishing groups. We identified three optimal features that best separate patients from controls, including brain networks consisting of temporal lobe, default mode and occipital lobe circuits, which when grouped together provide improved capability in classifying group membership. The proposed framework provides a general approach for selecting optimal brain networks which may serve as potential biomarkers of several brain diseases and thus has wide applicability in the neuroimaging research community.

YNIMG Journal 2009 Journal Article

Biophysical modeling of phase changes in BOLD fMRI

  • Zhaomei Feng
  • Arvind Caprihan
  • Krastan B. Blagoev
  • Vince D. Calhoun

In BOLD fMRI, stimulus related phase changes have been repeatedly observed in humans. However, virtually all fMRI processing utilizes the magnitude information only, while ignoring the phase. This results in an unnecessary loss of physiological information and signal-to-noise efficiency. A widely held view is that the BOLD phase change is zero for a voxel containing randomly orientated blood vessels and that phase changes are only due to the presence of large vessels. Based on a previously developed theoretical model, we show through simulations and experimental human BOLD fMRI data that a non-zero phase change can be present in a region with randomly oriented vessels. Using simulations of the model, we first demonstrate that a spatially distributed susceptibility results in a non-zero phase distribution. Next, experimental data in a finger-tapping experiment show consistent bipolar phase distribution across multiple subjects. This model is then used to show that in theory a bipolar phase distribution can also be produced by the model. Finally, we show that the model can produce a bipolar phase pattern consistent with that observed in the experimental data. Understanding of the mechanisms behind the experimentally observed phase changes in BOLD fMRI would be an important step forward and will enable biophysical model based methods for integrating the phase and magnitude information in BOLD fMRI experiments.

YNIMG Journal 2009 Journal Article

Genetic determinants of target and novelty-related event-related potentials in the auditory oddball response

  • Jingyu Liu
  • Kent A. Kiehl
  • Godfrey Pearlson
  • Nora I. Perrone-Bizzozero
  • Tom Eichele
  • Vince D. Calhoun

Processing of novel and target stimuli in the auditory target detection or ‘oddball’ task encompasses the chronometry of perception, attention and working memory and is reflected in scalp recorded event-related potentials (ERPs). A variety of ERP components related to target and novelty processing have been described and extensively studied, and linked to deficits of cognitive processing. However, little is known about associations of genotypes with ERP endophenotypes. Here we sought to elucidate the genetic underpinnings of auditory oddball ERP components using a novel data analysis technique. A parallel independent component analysis of the electrophysiology and single nucleotide polymorphism (SNP) data was used to extract relations between patterns of ERP components and SNP associations purely based on an analysis incorporating higher order statistics. The method allows for broader associations of genotypes with phenotypes than traditional hypothesis-driven univariate correlational analyses. We show that target detection and processing of novel stimuli are both associated with a shared cluster of genes linked to the adrenergic and dopaminergic pathways. These results provide evidence of genetic influences on normal patterns of ERP generation during auditory target detection and novelty processing at the SNP association level.

YNIMG Journal 2009 Journal Article

Investigation of relationships between fMRI brain networks in the spectral domain using ICA and Granger causality reveals distinct differences between schizophrenia patients and healthy controls

  • Oguz Demirci
  • Michael C. Stevens
  • Nancy C. Andreasen
  • Andrew Michael
  • Jingyu Liu
  • Tonya White
  • Godfrey D. Pearlson
  • Vincent P. Clark

Functional network connectivity (FNC) is an approach that examines the relationships between brain networks (as opposed to functional connectivity (FC) that focuses upon the relationships between single voxels). FNC may help explain the complex relationships between distributed cerebral sites in the brain and possibly provide new understanding of neurological and psychiatric disorders such as schizophrenia. In this paper, we use independent component analysis (ICA) to extract the time courses of spatially independent components and then use these in Granger causality test (GCT) to investigate causal relationships between brain activation networks. We present results using both simulations and fMRI data of 155 subjects obtained during two different tasks. Unlike previous research, causal relationships are presented over different portions of the frequency spectrum in order to differentiate high and low-frequency effects and not merged in a scalar. The results obtained using Sternberg item recognition paradigm (SIRP) and auditory oddball (AOD) tasks showed FNC differentiations between schizophrenia and control groups, and explained how the two groups differed during these tasks. During the SIRP task, secondary visual and cerebellum activation networks served as hubs and included most complex relationships between the activated regions. Secondary visual and temporal lobe activations replaced these components during the AOD task.

YNIMG Journal 2009 Journal Article

Joint source based morphometry identifies linked gray and white matter group differences

  • Lai Xu
  • Godfrey Pearlson
  • Vince D. Calhoun

We present a multivariate approach called joint source based morphometry (jSBM), to identify linked gray and white matter regions which differ between groups. In jSBM, joint independent component analysis (jICA) is used to decompose preprocessed gray and white matter images into joint sources and statistical analysis is used to determine the significant joint sources showing group differences and their relationship to other variables of interest (e. g. age or sex). The identified joint sources are groupings of linked gray and white matter regions with common covariation among subjects. In this study, we first provide a simulation to validate the jSBM approach. To illustrate our method on real data, jSBM is then applied to structural magnetic resonance imaging (sMRI) data obtained from 120 chronic schizophrenia patients and 120 healthy controls to identify group differences. JSBM identified four joint sources as significantly associated with schizophrenia. Linked gray–white matter regions identified in each of the joint sources included: 1) temporal — corpus callosum, 2) occipital/frontal — inferior fronto-occipital fasciculus, 3) frontal/parietal/occipital/temporal — superior longitudinal fasciculus and 4) parietal/frontal — thalamus. Age effects on all four joint sources were significant, but sex effects were significant only for the third joint source. Our findings demonstrate that jSBM can exploit the natural linkage between gray and white matter by incorporating them into a unified framework. This approach is applicable to a wide variety of problems to study linked gray and white matter group differences.

YNIMG Journal 2008 Journal Article

A method for functional network connectivity among spatially independent resting-state components in schizophrenia

  • Madiha J. Jafri
  • Godfrey D. Pearlson
  • Michael Stevens
  • Vince D. Calhoun

Functional connectivity of the brain has been studied by analyzing correlation differences in time courses among seed voxels or regions with other voxels of the brain in healthy individuals as well as in patients with brain disorders. The spatial extent of strongly temporally coherent brain regions co-activated during rest has also been examined using independent component analysis (ICA). However, the weaker temporal relationships among ICA component time courses, which we operationally define as a measure of functional network connectivity (FNC), have not yet been studied. In this study, we propose an approach for evaluating FNC and apply it to functional magnetic resonance imaging (fMRI) data collected from persons with schizophrenia and healthy controls. We examined the connectivity and latency among ICA component time courses to test the hypothesis that patients with schizophrenia would show increased functional connectivity and increased lag among resting state networks compared to controls. Resting state fMRI data were collected and the inter-relationships among seven selected resting state networks (identified using group ICA) were evaluated by correlating each subject's ICA time courses with one another. Patients showed higher correlation than controls among most of the dominant resting state networks. Patients also had slightly more variability in functional connectivity than controls. We present a novel approach for quantifying functional connectivity among brain networks identified with spatial ICA. Significant differences between patient and control connectivity in different networks were revealed possibly reflecting deficiencies in cortical processing in patients.

YNIMG Journal 2008 Journal Article

A projection pursuit algorithm to classify individuals using fMRI data: Application to schizophrenia

  • Oguz Demirci
  • Vincent P. Clark
  • Vince D. Calhoun

Schizophrenia is diagnosed based largely upon behavioral symptoms. Currently, no quantitative, biologically based diagnostic technique has yet been developed to identify patients with schizophrenia. Classification of individuals into patient with schizophrenia and healthy control groups based on quantitative biologically based data is of great interest to support and refine psychiatric diagnoses. We applied a novel projection pursuit technique on various components obtained with independent component analysis (ICA) of 70 subjects’ fMRI activation maps obtained during an auditory oddball task. The validity of the technique was tested with a leave-one-out method and the detection performance varied between 80% and 90%. The findings suggest that the proposed data reduction algorithm is effective in classifying individuals into schizophrenia and healthy control groups and may eventually prove useful as a diagnostic tool.

YNIMG Journal 2008 Journal Article

Measuring brain connectivity: Diffusion tensor imaging validates resting state temporal correlations

  • Pawel Skudlarski
  • Kanchana Jagannathan
  • Vince D. Calhoun
  • Michelle Hampson
  • Beata A. Skudlarska
  • Godfrey Pearlson

Diffusion tensor imaging (DTI) and resting state temporal correlations (RSTC) are two leading techniques for investigating the connectivity of the human brain. They have been widely used to investigate the strength of anatomical and functional connections between distant brain regions in healthy subjects, and in clinical populations. Though they are both based on magnetic resonance imaging (MRI) they have not yet been compared directly. In this work both techniques were employed to create global connectivity matrices covering the whole brain gray matter. This allowed for direct comparisons between functional connectivity measured by RSTC with anatomical connectivity quantified using DTI tractography. We found that connectivity matrices obtained using both techniques showed significant agreement. Connectivity maps created for a priori defined anatomical regions showed significant correlation, and furthermore agreement was especially high in regions showing strong overall connectivity, such as those belonging to the default mode network. Direct comparison between functional RSTC and anatomical DTI connectivity, presented here for the first time, links two powerful approaches for investigating brain connectivity and shows their strong agreement. It provides a crucial multi-modal validation for resting state correlations as representing neuronal connectivity. The combination of both techniques presented here allows for further combining them to provide richer representation of brain connectivity both in the healthy brain and in clinical conditions.

YNIMG Journal 2005 Journal Article

An adaptive reflexive processing model of neurocognitive function: supporting evidence from a large scale (n = 100) fMRI study of an auditory oddball task

  • Kent A. Kiehl
  • Michael C. Stevens
  • Kristin R. Laurens
  • Godfrey Pearlson
  • Vince D. Calhoun
  • Peter F. Liddle

Recent hemodynamic imaging studies have shown that processing of low probability task-relevant target stimuli (i. e. , oddballs) and low probability task-irrelevant novel stimuli elicit widespread activity in diverse, spatially distributed cortical and subcortical systems. The nature of this distributed response supports the model that processing of salient and novel stimuli engages many brain regions regardless of whether said regions were necessary for task performance. However, these latter neuroimaging studies largely employed small sample sizes and fixed-effect analyses, limiting the characterization and inference of the results. The present study addressed these issues by collecting a large sample size (n = 100) and employed random effects statistical models. Analyses were also conducted to determine the inter-subject reliability of the hemodynamic response and the effects of gender and age on target detection and novelty processing. Group data demonstrated highly significant activation in all 34 specified regions of interest for target detection and all 24 specified regions of interest for processing of novel stimuli. Neither age nor gender systematically influenced the results. These data are discussed within the context of a model that proposes that the mammalian brain has evolved to adopt a strategy of engaging distributed neuronal systems when processing salient stimuli despite the low probability that many of these brain regions are required for successful task performance. This process may be termed ‘adaptive reflexive processing. ’ The implications of these results for interpreting functional MRI studies are discussed.

YNIMG Journal 2005 Journal Article

Hemispheric differences in hemodynamics elicited by auditory oddball stimuli

  • Michael C. Stevens
  • Vince D. Calhoun
  • Kent A. Kiehl

Evidence from neuroimaging studies suggests that the right hemisphere of the human brain might be more specialized for attention than the left hemisphere. However, differences between right and left hemisphere in the magnitude of hemodynamic activity (i. e. , ‘functional asymmetry’) rarely have been explicitly examined in previous neuroimaging studies of attention. This study used a new voxel-based comparison method to examine hemispheric differences in the amplitude of the hemodynamic response in response to infrequent target, infrequent novel, and frequent standard stimuli during an event-related fMRI auditory oddball task in 100 healthy adult participants. Processing of low probability task-relevant target stimuli, or ‘oddballs’, and low probability task-irrelevant novel stimuli is believed to engage in orienting and attentional processes. It was hypothesized that greater right-hemisphere activation compared to left would be observed to infrequent target and novel stimuli. Consistent with predictions, greater right hemisphere than left frontal, temporal, and parietal lobe activity was observed for target detection and novelty processing. Moreover, asymmetry effects did not differ with respect to age or gender of the participants. The results (1) support the proposal that the right hemisphere is differentially engaged in processing salient stimuli and (2) demonstrate the successful use of a new voxel-based laterality analysis technique for fMRI data.