Srikanth Ryali

All Publications

• Deep learning models reveal replicable, generalizable, and behaviorally relevant sex differences in human functional brain organization. Proceedings of the National Academy of Sciences of the United States of America Ryali, S., Zhang, Y., de Los Angeles, C., Supekar, K., Menon, V. 2024; 121 (9): e2310012121

  Abstract

  Sex plays a crucial role in human brain development, aging, and the manifestation of psychiatric and neurological disorders. However, our understanding of sex differences in human functional brain organization and their behavioral consequences has been hindered by inconsistent findings and a lack of replication. Here, we address these challenges using a spatiotemporal deep neural network (stDNN) model to uncover latent functional brain dynamics that distinguish male and female brains. Our stDNN model accurately differentiated male and female brains, demonstrating consistently high cross-validation accuracy (>90%), replicability, and generalizability across multisession data from the same individuals and three independent cohorts (N ~ 1,500 young adults aged 20 to 35). Explainable AI (XAI) analysis revealed that brain features associated with the default mode network, striatum, and limbic network consistently exhibited significant sex differences (effect sizes > 1.5) across sessions and independent cohorts. Furthermore, XAI-derived brain features accurately predicted sex-specific cognitive profiles, a finding that was also independently replicated. Our results demonstrate that sex differences in functional brain dynamics are not only highly replicable and generalizable but also behaviorally relevant, challenging the notion of a continuum in male-female brain organization. Our findings underscore the crucial role of sex as a biological determinant in human brain organization, have significant implications for developing personalized sex-specific biomarkers in psychiatric and neurological disorders, and provide innovative AI-based computational tools for future research.

  View details for DOI 10.1073/pnas.2310012121

  View details for PubMedID 38377194

• Robust, Generalizable, and Interpretable Artificial Intelligence-Derived Brain Fingerprints of Autism and Social Communication Symptom Severity. Biological psychiatry Supekar, K., Ryali, S., Yuan, R., Kumar, D., de Los Angeles, C., Menon, V. 2022

  Abstract

  BACKGROUND: Autism spectrum disorder (ASD) is among the most pervasive neurodevelopmental disorders, yet the neurobiology of ASD is still poorly understood because inconsistent findings from underpowered individual studies preclude the identification of robust and interpretable neurobiological markers and predictors of clinical symptoms.METHODS: We leverage multiple brain imaging cohorts and exciting recent advances in explainable artificial intelligence to develop a novel spatiotemporal deep neural network (stDNN) model, which identifies robust and interpretable dynamic brain markers that distinguish ASD from neurotypical control subjects and predict clinical symptom severity.RESULTS: stDNN achieved consistently high classification accuracies in cross-validation analysis of data from the multisite ABIDE (Autism Brain Imaging Data Exchange) cohort (n= 834). Crucially, stDNN also accurately classified data from independent Stanford (n= 202) and GENDAAR (Gender Exploration of Neurogenetics and Development to Advanced Autism Research) (n= 90) cohorts without additional training. stDNN could not distinguish attention-deficit/hyperactivity disorder from neurotypical control subjects, highlighting the model's specificity. Explainable artificial intelligence revealed that brain features associated with the posterior cingulate cortex and precuneus, dorsolateral and ventrolateral prefrontal cortex, and superior temporal sulcus, which anchor the default mode network, cognitive control, and human voice processing systems, respectively, most clearly distinguished ASD from neurotypical control subjects in the three cohorts. Furthermore, features associated with the posterior cingulate cortex and precuneus nodes of the default mode network emerged as robust predictors of the severity of core social and communication deficits but not restricted/repetitive behaviors in ASD.CONCLUSIONS: Our findings, replicated across independent cohorts, reveal robust individualized functional brain fingerprints of ASD psychopathology, which could lead to more objective and precise phenotypic characterization and targeted treatments.

  View details for DOI 10.1016/j.biopsych.2022.02.005

  View details for PubMedID 35382930

• Deep learning identifies robust gender differences in functional brain organization and their dissociable links to clinical symptoms in autism. The British journal of psychiatry : the journal of mental science Supekar, K., de Los Angeles, C., Ryali, S., Cao, K., Ma, T., Menon, V. 2022: 1-8

  Abstract

  BACKGROUND: Autism spectrum disorder (ASD) is a highly heterogeneous disorder that affects nearly 1 in 189 females and 1 in 42 males. However, the neurobiological basis of gender differences in ASD is poorly understood, as most studies have neglected females and used methods ill-suited to capture such differences.AIMS: To identify robust functional brain organisation markers that distinguish between females and males with ASD and predict symptom severity.METHOD: We leveraged multiple neuroimaging cohorts (ASD n = 773) and developed a novel spatiotemporal deep neural network (stDNN), which uses spatiotemporal convolution on functional magnetic resonance imaging data to distinguish between groups.RESULTS: stDNN achieved consistently high classification accuracy in distinguishing between females and males with ASD. Notably, stDNN trained to distinguish between females and males with ASD could not distinguish between neurotypical females and males, suggesting that there are gender differences in the functional brain organisation in ASD that differ from normative gender differences. Brain features associated with motor, language and visuospatial attentional systems reliably distinguished between females and males with ASD. Crucially, these results were observed in a large multisite cohort and replicated in a fully independent cohort. Furthermore, brain features associated with the motor network's primary motor cortex node predicted the severity of restricted/repetitive behaviours in females but not in males with ASD.CONCLUSIONS: Our replicable findings reveal that the brains of females and males with ASD are functionally organised differently, contributing to their clinical symptoms in distinct ways. They inform the development of gender-specific diagnoses and treatment strategies for ASD, and ultimately advance precision psychiatry.

  View details for DOI 10.1192/bjp.2022.13

  View details for PubMedID 35164888

• Developmental Maturation of Causal Signaling Hubs in Voluntary Control of Saccades and Their Functional Controllability. Cerebral cortex (New York, N.Y. : 1991) Zhang, Y., Ryali, S., Cai, W., Supekar, K., Pasumarthy, R., Padmanabhan, A., Luna, B., Menon, V. 1800

  Abstract

  The ability to adaptively respond to behaviorally relevant cues in the environment, including voluntary control of automatic but inappropriate responses and deployment of a goal-relevant alternative response, undergoes significant maturation from childhood to adulthood. Importantly, the maturation of voluntary control processes influences the developmental trajectories of several key cognitive domains, including executive function and emotion regulation. Understanding the maturation of voluntary control is therefore of fundamental importance, but little is known about the underlying causal functional circuit mechanisms. Here, we use state-space and control-theoretic modeling to investigate the maturation of causal signaling mechanisms underlying voluntary control over saccades. We demonstrate that directed causal interactions in a canonical saccade network undergo significant maturation between childhood and adulthood. Crucially, we show that the frontal eye field (FEF) is an immature causal signaling hub in children during control over saccades. Using control-theoretic analysis, we then demonstrate that the saccade network is less controllable in children and that greater energy is required to drive FEF dynamics in children compared to adults. Our findings provide novel evidence that strengthening of causal signaling hubs and controllability of FEF are key mechanisms underlying age-related improvements in the ability to plan and execute voluntary control over saccades.

  View details for DOI 10.1093/cercor/bhab514

  View details for PubMedID 35094063

• Dynamic causal brain circuits during working memory and their functional controllability. Nature communications Cai, W., Ryali, S., Pasumarthy, R., Talasila, V., Menon, V. 2021; 12 (1): 3314

  Abstract

  Control processes associated with working memory play a central role in human cognition, but their underlying dynamic brain circuit mechanisms are poorly understood. Here we use system identification, network science, stability analysis, and control theory to probe functional circuit dynamics during working memory task performance. Our results show that dynamic signaling between distributed brain areas encompassing the salience (SN), fronto-parietal (FPN), and default mode networks can distinguish between working memory load and predict performance. Network analysis of directed causal influences suggests the anterior insula node of the SN and dorsolateral prefrontal cortex node of the FPN are causal outflow and inflow hubs, respectively. Network controllability decreases with working memory load and SN nodes show the highest functional controllability. Our findings reveal dissociable roles of the SN and FPN in systems control and provide novel insights into dynamic circuit mechanisms by which cognitive control circuits operate asymmetrically during cognition.

  View details for DOI 10.1038/s41467-021-23509-x

  View details for PubMedID 34188024

• Aberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism. Nature communications Supekar, K., Ryali, S., Mistry, P., Menon, V. 2021; 12 (1): 3537

  Abstract

  Restricted and repetitive behaviors (RRBs) are a defining clinical feature of autism spectrum disorders (ASD). RRBs are highly heterogeneous with variable expression of circumscribed interests (CI), insistence of sameness (IS) and repetitive motor actions (RM), which are major impediments to effective functioning in individuals with ASD; yet, the neurobiological basis of CI, IS and RM is unknown. Here we evaluate a unified functional brain circuit model of RRBs and test the hypothesis that CI and IS are associated with aberrant cognitive control circuit dynamics, whereas RM is associated with aberrant motor circuit dynamics. Using task-free fMRI data from 96 children, we first demonstrate that time-varying cross-network interactions in cognitive control circuit are significantly reduced and inflexible in children with ASD, and predict CI and IS symptoms, but not RM symptoms. Furthermore, we show that time-varying cross-network interactions in motor circuit are significantly greater in children with ASD, and predict RM symptoms, but not CI or IS symptoms. We confirmed these results using cross-validation analyses. Moreover, we show that brain-clinical symptom relations are not detected with time-averaged functional connectivity analysis. Our findings provide neurobiological support for the validity of RRB subtypes and identify dissociable brain circuit dynamics as a candidate biomarker for a key clinical feature of ASD.

  View details for DOI 10.1038/s41467-021-23822-5

  View details for PubMedID 34112791

• Intrinsic functional architecture of the human speech processing network. Cortex; a journal devoted to the study of the nervous system and behavior Abrams, D. A., Kochalka, J. n., Bhide, S. n., Ryali, S. n., Menon, V. n. 2020; 129: 41–56

  Abstract

  Speech engages distributed temporo-fronto-parietal brain regions, however a comprehensive understanding of its intrinsic functional network architecture is lacking. Here we investigate the human speech processing network using the largest sample to date, high temporal resolution resting-state fMRI data, network stability analysis, and theoretically informed models. Network consensus analysis revealed three stable functional modules encompassing: (1) superior temporal plane (STP) and Area Spt, (2) superior temporal sulcus (STS) + ventral frontoparietal cortex, and (3) dorsal frontoparietal cortex. The STS + ventral frontoparietal cortex module showed the highest participation coefficient, and a hub-like organization linking STP with frontoparietal cortical nodes. Node-wise analysis revealed key connectivity features underlying this modular architecture, including a leftward asymmetric connectivity profile, and differential connectivity of STS and STP, with frontoparietal cortex. Our findings, replicated across cohorts, reveal a tripartite functional network architecture supporting speech processing and provide a novel template for future studies.

  View details for DOI 10.1016/j.cortex.2020.03.013

  View details for PubMedID 32428761

• Uncovering hidden brain state dynamics that regulate performance and decision-making during cognition NATURE COMMUNICATIONS Taghia, J., Cai, W., Ryali, S., Kochalka, J., Nicholas, J., Chen, T., Menon, V. 2018; 9

  View details for DOI 10.1038/s41467-018-04723-6

  View details for Web of Science ID 000436540700023

• Bayesian Switching Factor Analysis for Estimating Time-varying Functional Connectivity in fMRI. NeuroImage Taghia, J., Ryali, S., Chen, T., Supekar, K., Cai, W., Menon, V. 2017

  Abstract

  There is growing interest in understanding the dynamical properties of functional interactions between distributed brain regions. However, robust estimation of temporal dynamics from functional magnetic resonance imaging (fMRI) data remains challenging due to limitations in extant multivariate methods for modeling time-varying functional interactions between multiple brain areas. Here, we develop a Bayesian generative model for fMRI time-series within the framework of hidden Markov models (HMMs). The model is a dynamic variant of the static factor analysis model (Ghahramani and Beal, 2000). We refer to this model as Bayesian switching factor analysis (BSFA) as it integrates factor analysis into a generative HMM in a unified Bayesian framework. In BSFA, brain dynamic functional networks are represented by latent states which are learnt from the data. Crucially, BSFA is a generative model which estimates the temporal evolution of brain states and transition probabilities between states as a function of time. An attractive feature of BSFA is the automatic determination of the number of latent states via Bayesian model selection arising from penalization of excessively complex models. Key features of BSFA are validated using extensive simulations on carefully designed synthetic data. We further validate BSFA using fingerprint analysis of multisession resting-state fMRI data from the Human Connectome Project (HCP). Our results show that modeling temporal dependencies in the generative model of BSFA results in improved fingerprinting of individual participants. Finally, we apply BSFA to elucidate the dynamic functional organization of the salience, central-executive, and default mode networks-three core neurocognitive systems with central role in cognitive and affective information processing (Menon, 2011). Across two HCP sessions, we demonstrate a high level of dynamic interactions between these networks and determine that the salience network has the highest temporal flexibility among the three networks. Our proposed methods provide a novel and powerful generative model for investigating dynamic brain connectivity.

  View details for DOI 10.1016/j.neuroimage.2017.02.083

  View details for PubMedID 28267626

• Temporal Dynamics and Developmental Maturation of Salience, Default and Central-Executive Network Interactions Revealed by Variational Bayes Hidden Markov Modeling PLOS COMPUTATIONAL BIOLOGY Ryali, S., Supekar, K., Chen, T., Kochalka, J., Cai, W., Nicholas, J., Padmanabhan, A., Menon, V. 2016; 12 (12)

  Abstract

  Little is currently known about dynamic brain networks involved in high-level cognition and their ontological basis. Here we develop a novel Variational Bayesian Hidden Markov Model (VB-HMM) to investigate dynamic temporal properties of interactions between salience (SN), default mode (DMN), and central executive (CEN) networks-three brain systems that play a critical role in human cognition. In contrast to conventional models, VB-HMM revealed multiple short-lived states characterized by rapid switching and transient connectivity between SN, CEN, and DMN. Furthermore, the three "static" networks occurred in a segregated state only intermittently. Findings were replicated in two adult cohorts from the Human Connectome Project. VB-HMM further revealed immature dynamic interactions between SN, CEN, and DMN in children, characterized by higher mean lifetimes in individual states, reduced switching probability between states and less differentiated connectivity across states. Our computational techniques provide new insights into human brain network dynamics and its maturation with development.

  View details for DOI 10.1371/journal.pcbi.1005138

  View details for Web of Science ID 000392126000005

  View details for PubMedID 27959921

  View details for PubMedCentralID PMC5154470

• Multivariate dynamical systems-based estimation of causal brain interactions in fMRI: Group-level validation using benchmark data, neurophysiological models and human connectome project data JOURNAL OF NEUROSCIENCE METHODS Ryali, S., Chen, T., Supekar, K., Tu, T., Kochalka, J., Cai, W., Menon, V. 2016; 268: 142-153

  Abstract

  Causal estimation methods are increasingly being used to investigate functional brain networks in fMRI, but there are continuing concerns about the validity of these methods.Multivariate Dynamical Systems (MDS) is a state-space method for estimating dynamic causal interactions in fMRI data. Here we validate MDS using benchmark simulations as well as simulations from a more realistic stochastic neurophysiological model. Finally, we applied MDS to investigate dynamic casual interactions in a fronto-cingulate-parietal control network using Human Connectome Project (HCP) data acquired during performance of a working memory task. Crucially, since the ground truth in experimental data is unknown, we conducted novel stability analysis to determine robust causal interactions within this network.MDS accurately recovered dynamic causal interactions with an area under receiver operating characteristic (AUC) above 0.7 for benchmark datasets and AUC above 0.9 for datasets generated using the neurophysiological model. In experimental fMRI data, bootstrap procedures revealed a stable pattern of causal influences from the anterior insula to other nodes of the fronto-cingulate-parietal network.MDS is effective in estimating dynamic causal interactions in both the benchmark and neurophysiological model based datasets in terms of AUC, sensitivity and false positive rates.Our findings demonstrate that MDS can accurately estimate causal interactions in fMRI data. Neurophysiological models and stability analysis provide a general framework for validating computational methods designed to estimate causal interactions in fMRI. The right anterior insula functions as a causal hub during working memory.

  View details for DOI 10.1016/j.jneumeth.2016.03.010

  View details for Web of Science ID 000379104400017

  View details for PubMedID 27015792

• Distinct Global Brain Dynamics and Spatiotemporal Organization of the Salience Network PLOS BIOLOGY Chen, T., Cai, W., Ryali, S., Supekar, K., Menon, V. 2016; 14 (6)

  Abstract

  One of the most fundamental features of the human brain is its ability to detect and attend to salient goal-relevant events in a flexible manner. The salience network (SN), anchored in the anterior insula and the dorsal anterior cingulate cortex, plays a crucial role in this process through rapid detection of goal-relevant events and facilitation of access to appropriate cognitive resources. Here, we leverage the subsecond resolution of large multisession fMRI datasets from the Human Connectome Project and apply novel graph-theoretical techniques to investigate the dynamic spatiotemporal organization of the SN. We show that the large-scale brain dynamics of the SN are characterized by several distinctive and robust properties. First, the SN demonstrated the highest levels of flexibility in time-varying connectivity with other brain networks, including the frontoparietal network (FPN), the cingulate-opercular network (CON), and the ventral and dorsal attention networks (VAN and DAN). Second, dynamic functional interactions of the SN were among the most spatially varied in the brain. Third, SN nodes maintained a consistently high level of network centrality over time, indicating that this network is a hub for facilitating flexible cross-network interactions. Fourth, time-varying connectivity profiles of the SN were distinct from all other prefrontal control systems. Fifth, temporal flexibility of the SN uniquely predicted individual differences in cognitive flexibility. Importantly, each of these results was also observed in a second retest dataset, demonstrating the robustness of our findings. Our study provides fundamental new insights into the distinct dynamic functional architecture of the SN and demonstrates how this network is uniquely positioned to facilitate interactions with multiple functional systems and thereby support a wide range of cognitive processes in the human brain.

  View details for DOI 10.1371/journal.pbio.1002469

  View details for Web of Science ID 000378611200001

  View details for PubMedID 27270215

  View details for PubMedCentralID PMC4896426

• Neural circuits underlying mother's voice perception predict social communication abilities in children PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Abrams, D. A., Chen, T., Odriozola, P., Cheng, K. M., Baker, A. E., Padmanabhan, A., Ryali, S., Kochalka, J., Feinstein, C., Menon, V. 2016; 113 (22): 6295-6300

  Abstract

  The human voice is a critical social cue, and listeners are extremely sensitive to the voices in their environment. One of the most salient voices in a child's life is mother's voice: Infants discriminate their mother's voice from the first days of life, and this stimulus is associated with guiding emotional and social function during development. Little is known regarding the functional circuits that are selectively engaged in children by biologically salient voices such as mother's voice or whether this brain activity is related to children's social communication abilities. We used functional MRI to measure brain activity in 24 healthy children (mean age, 10.2 y) while they attended to brief (<1 s) nonsense words produced by their biological mother and two female control voices and explored relationships between speech-evoked neural activity and social function. Compared to female control voices, mother's voice elicited greater activity in primary auditory regions in the midbrain and cortex; voice-selective superior temporal sulcus (STS); the amygdala, which is crucial for processing of affect; nucleus accumbens and orbitofrontal cortex of the reward circuit; anterior insula and cingulate of the salience network; and a subregion of fusiform gyrus associated with face perception. The strength of brain connectivity between voice-selective STS and reward, affective, salience, memory, and face-processing regions during mother's voice perception predicted social communication skills. Our findings provide a novel neurobiological template for investigation of typical social development as well as clinical disorders, such as autism, in which perception of biologically and socially salient voices may be impaired.

  View details for DOI 10.1073/pnas.1602948113

  View details for Web of Science ID 000376784600059

  View details for PubMedID 27185915

• Combining optogenetic stimulation and fMRI to validate a multivariate dynamical systems model for estimating causal brain interactions NEUROIMAGE Ryali, S., Shih, Y. I., Chen, T., Kochalka, J., Albaugh, D., Fang, Z., Supekar, K., Lee, J. H., Menon, V. 2016; 132: 398-405

  Abstract

  State-space multivariate dynamical systems (MDS) (Ryali et al. 2011) and other causal estimation models are being increasingly used to identify directed functional interactions between brain regions. However, the validity and accuracy of such methods are poorly understood. Performance evaluation based on computer simulations of small artificial causal networks can address this problem to some extent, but they often involve simplifying assumptions that reduce biological validity of the resulting data. Here, we use a novel approach taking advantage of recently developed optogenetic fMRI (ofMRI) techniques to selectively stimulate brain regions while simultaneously recording high-resolution whole-brain fMRI data. ofMRI allows for a more direct investigation of causal influences from the stimulated site to brain regions activated downstream and is therefore ideal for evaluating causal estimation methods in vivo. We used ofMRI to investigate whether MDS models for fMRI can accurately estimate causal functional interactions between brain regions. Two cohorts of ofMRI data were acquired, one at Stanford University and the University of California Los Angeles (Cohort 1) and the other at the University of North Carolina Chapel Hill (Cohort 2). In each cohort, optical stimulation was delivered to the right primary motor cortex (M1). General linear model analysis revealed prominent downstream thalamic activation in Cohort 1, and caudate-putamen (CPu) activation in Cohort 2. MDS accurately estimated causal interactions from M1 to thalamus and from M1 to CPu in Cohort 1 and Cohort 2, respectively. As predicted, no causal influences were found in the reverse direction. Additional control analyses demonstrated the specificity of causal interactions between stimulated and target sites. Our findings suggest that MDS state-space models can accurately and reliably estimate causal interactions in ofMRI data and further validate their use for estimating causal interactions in fMRI. More generally, our study demonstrates that the combined use of optogenetics and fMRI provides a powerful new tool for evaluating computational methods designed to estimate causal interactions between distributed brain regions.

  View details for DOI 10.1016/j.neuroimage.2016.02.067

  View details for Web of Science ID 000374832200039

  View details for PubMedID 26934644

• Development and validation of consensus clustering-based framework for brain segmentation using resting fMRI. Journal of neuroscience methods Ryali, S., Chen, T., Padmanabhan, A., Cai, W., Menon, V. 2015; 240: 128-140

  Abstract

  Clustering methods are increasingly employed to segment brain regions into functional subdivisions using resting-state functional magnetic resonance imaging (rs-fMRI). However, these methods are highly sensitive to the (i) precise algorithms employed, (ii) their initializations, and (iii) metrics used for uncovering the optimal number of clusters from the data.To address these issues, we develop a novel consensus clustering evidence accumulation (CC-EAC) framework, which effectively combines multiple clustering methods for segmenting brain regions using rs-fMRI data. Using extensive computer simulations, we examine the performance of widely used clustering algorithms including K-means, hierarchical, and spectral clustering as well as their combinations. We also examine the accuracy and validity of five objective criteria for determining the optimal number of clusters: mutual information, variation of information, modified silhouette, Rand index, and probabilistic Rand index.A CC-EAC framework with a combination of base K-means clustering (KC) and hierarchical clustering (HC) with probabilistic Rand index as the criterion for choosing the optimal number of clusters, accurately uncovered the correct number of clusters from simulated datasets. In experimental rs-fMRI data, these methods reliably detected functional subdivisions of the supplementary motor area, insula, intraparietal sulcus, angular gyrus, and striatum.Unlike conventional approaches, CC-EAC can accurately determine the optimal number of stable clusters in rs-fMRI data, and is robust to initialization and choice of free parameters.A novel CC-EAC framework is proposed for segmenting brain regions, by effectively combining multiple clustering methods and identifying optimal stable functional clusters in rs-fMRI data.

  View details for DOI 10.1016/j.jneumeth.2014.11.014

  View details for PubMedID 25450335

• Role of the anterior insular cortex in integrative causal signaling during multisensory auditory-visual attention. European journal of neuroscience Chen, T., Michels, L., Supekar, K., Kochalka, J., Ryali, S., Menon, V. 2015; 41 (2): 264-274

  Abstract

  Coordinated attention to information from multiple senses is fundamental to our ability to respond to salient environmental events, yet little is known about brain network mechanisms that guide integration of information from multiple senses. Here we investigate dynamic causal mechanisms underlying multisensory auditory-visual attention, focusing on a network of right-hemisphere frontal-cingulate-parietal regions implicated in a wide range of tasks involving attention and cognitive control. Participants performed three 'oddball' attention tasks involving auditory, visual and multisensory auditory-visual stimuli during fMRI scanning. We found that the right anterior insula (rAI) demonstrated the most significant causal influences on all other frontal-cingulate-parietal regions, serving as a major causal control hub during multisensory attention. Crucially, we then tested two competing models of the role of the rAI in multisensory attention: an 'integrated' signaling model in which the rAI generates a common multisensory control signal associated with simultaneous attention to auditory and visual oddball stimuli versus a 'segregated' signaling model in which the rAI generates two segregated and independent signals in each sensory modality. We found strong support for the integrated, rather than the segregated, signaling model. Furthermore, the strength of the integrated control signal from the rAI was most pronounced on the dorsal anterior cingulate and posterior parietal cortices, two key nodes of saliency and central executive networks respectively. These results were preserved with the addition of a superior temporal sulcus region involved in multisensory processing. Our study provides new insights into the dynamic causal mechanisms by which the AI facilitates multisensory attention.

  View details for DOI 10.1111/ejn.12764

  View details for PubMedID 25352218

• Dissociable roles of right inferior frontal cortex and anterior insula in inhibitory control: evidence from intrinsic and task-related functional parcellation, connectivity, and response profile analyses across multiple datasets. journal of neuroscience Cai, W., Ryali, S., Chen, T., Li, C. R., Menon, V. 2014; 34 (44): 14652-14667

  Abstract

  The right inferior frontal cortex (rIFC) and the right anterior insula (rAI) have been implicated consistently in inhibitory control, but their differential roles are poorly understood. Here we use multiple quantitative techniques to dissociate the functional organization and roles of the rAI and rIFC. We first conducted a meta-analysis of 70 published inhibitory control studies to generate a commonly activated right fronto-opercular cortex volume of interest (VOI). We then segmented this VOI using two types of features: (1) intrinsic brain activity; and (2) stop-signal task-evoked hemodynamic response profiles. In both cases, segmentation algorithms identified two stable and distinct clusters encompassing the rAI and rIFC. The rAI and rIFC clusters exhibited several distinct functional characteristics. First, the rAI showed stronger intrinsic and task-evoked functional connectivity with the anterior cingulate cortex, whereas the rIFC had stronger intrinsic and task-evoked functional connectivity with dorsomedial prefrontal and lateral fronto-parietal cortices. Second, the rAI showed greater activation than the rIFC during Unsuccessful, but not Successful, Stop trials, and multivoxel response profiles in the rAI, but not the rIFC, accurately differentiated between Successful and Unsuccessful Stop trials. Third, activation in the rIFC, but not rAI, predicted individual differences in inhibitory control abilities. Crucially, these findings were replicated in two independent cohorts of human participants. Together, our findings provide novel quantitative evidence for the dissociable roles of the rAI and rIFC in inhibitory control. We suggest that the rAI is particularly important for detecting behaviorally salient events, whereas the rIFC is more involved in implementing inhibitory control.

  View details for DOI 10.1523/JNEUROSCI.3048-14.2014

  View details for PubMedID 25355218

  View details for PubMedCentralID PMC4212065

• Estimation of resting-state functional connectivity using random subspace based partial correlation: A novel method for reducing global artifacts. NeuroImage Chen, T., Ryali, S., Qin, S., Menon, V. 2013; 82: 87-100

  Abstract

  Intrinsic functional connectivity analysis using resting-state functional magnetic resonance imaging (rsfMRI) has become a powerful tool for examining brain functional organization. Global artifacts such as physiological noise pose a significant problem in estimation of intrinsic functional connectivity. Here we develop and test a novel random subspace method for functional connectivity (RSMFC) that effectively removes global artifacts in rsfMRI data. RSMFC estimates the partial correlation between a seed region and each target brain voxel using multiple subsets of voxels sampled randomly across the whole brain. We evaluated RSMFC on both simulated and experimental rsfMRI data and compared its performance with standard methods that rely on global mean regression (GSReg) which are widely used to remove global artifacts. Using extensive simulations we demonstrate that RSMFC is effective in removing global artifacts in rsfMRI data. Critically, using a novel simulated dataset we demonstrate that, unlike GSReg, RSMFC does not artificially introduce anti-correlations between inherently uncorrelated networks, a result of paramount importance for reliably estimating functional connectivity. Furthermore, we show that the overall sensitivity, specificity and accuracy of RSMFC are superior to GSReg. Analysis of posterior cingulate cortex connectivity in experimental rsfMRI data from 22 healthy adults revealed strong functional connectivity in the default mode network, including more reliable identification of connectivity with left and right medial temporal lobe regions that were missed by GSReg. Notably, compared to GSReg, negative correlations with lateral fronto-parietal regions were significantly weaker in RSMFC. Our results suggest that RSMFC is an effective method for minimizing the effects of global artifacts and artificial negative correlations, while accurately recovering intrinsic functional brain networks.

  View details for DOI 10.1016/j.neuroimage.2013.05.118

  View details for PubMedID 23747287

• Salience Network-Based Classification and Prediction of Symptom Severity in Children With Autism JAMA PSYCHIATRY Uddin, L. Q., Supekar, K., Lynch, C. J., Khouzam, A., Phillips, J., Feinstein, C., Ryali, S., Menon, V. 2013; 70 (8): 869-879

  Abstract

  IMPORTANCE Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. MAIN OUTCOMES AND MEASURES Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual's salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.

  View details for DOI 10.1001/jamapsychiatry.2013.104

  View details for Web of Science ID 000322833600013

  View details for PubMedID 23803651

• Underconnectivity between voice-selective cortex and reward circuitry in children with autism PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Abrams, D. A., Lynch, C. J., Cheng, K. M., Phillips, J., Supekar, K., Ryali, S., Uddin, L. Q., Menon, V. 2013; 110 (29): 12060-12065

  Abstract

  Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.

  View details for DOI 10.1073/pnas.1302982110

  View details for Web of Science ID 000322086100085

  View details for PubMedID 23776244

• Multivariate Activation and Connectivity Patterns Discriminate Speech Intelligibility in Wernicke's, Broca's, and Geschwind's Areas CEREBRAL CORTEX Abrams, D. A., Ryali, S., Chen, T., Balaban, E., Levitin, D. J., Menon, V. 2013; 23 (7): 1703-1714

  Abstract

  The brain network underlying speech comprehension is usually described as encompassing fronto-temporal-parietal regions while neuroimaging studies of speech intelligibility have focused on a more spatially restricted network dominated by the superior temporal cortex. Here we use functional magnetic resonance imaging with a novel whole-brain multivariate pattern analysis (MVPA) to more fully characterize neural responses and connectivity to intelligible speech. Consistent with previous univariate findings, intelligible speech elicited greater activity in bilateral superior temporal cortex relative to unintelligible speech. However, MVPA identified a more extensive network that discriminated between intelligible and unintelligible speech, including left-hemisphere middle temporal gyrus, angular gyrus, inferior temporal cortex, and inferior frontal gyrus pars triangularis. These fronto-temporal-parietal areas also showed greater functional connectivity during intelligible, compared with unintelligible, speech. Our results suggest that speech intelligibly is encoded by distinct fine-grained spatial representations and within-task connectivity, rather than differential engagement or disengagement of brain regions, and they provide a more complete view of the brain network serving speech comprehension. Our findings bridge a divide between neural models of speech comprehension and the neuroimaging literature on speech intelligibility, and suggest that speech intelligibility relies on differential multivariate response and connectivity patterns in Wernicke's, Broca's, and Geschwind's areas.

  View details for DOI 10.1093/cercor/bhs165

  View details for Web of Science ID 000321163700020

  View details for PubMedID 22693339

  View details for PubMedCentralID PMC3673181

• Inter-subject synchronization of brain responses during natural music listening. European journal of neuroscience Abrams, D. A., Ryali, S., Chen, T., Chordia, P., Khouzam, A., Levitin, D. J., Menon, V. 2013; 37 (9): 1458-1469

  Abstract

  Music is a cultural universal and a rich part of the human experience. However, little is known about common brain systems that support the processing and integration of extended, naturalistic 'real-world' music stimuli. We examined this question by presenting extended excerpts of symphonic music, and two pseudomusical stimuli in which the temporal and spectral structure of the Natural Music condition were disrupted, to non-musician participants undergoing functional brain imaging and analysing synchronized spatiotemporal activity patterns between listeners. We found that music synchronizes brain responses across listeners in bilateral auditory midbrain and thalamus, primary auditory and auditory association cortex, right-lateralized structures in frontal and parietal cortex, and motor planning regions of the brain. These effects were greater for natural music compared to the pseudo-musical control conditions. Remarkably, inter-subject synchronization in the inferior colliculus and medial geniculate nucleus was also greater for the natural music condition, indicating that synchronization at these early stages of auditory processing is not simply driven by spectro-temporal features of the stimulus. Increased synchronization during music listening was also evident in a right-hemisphere fronto-parietal attention network and bilateral cortical regions involved in motor planning. While these brain structures have previously been implicated in various aspects of musical processing, our results are the first to show that these regions track structural elements of a musical stimulus over extended time periods lasting minutes. Our results show that a hierarchical distributed network is synchronized between individuals during the processing of extended musical sequences, and provide new insight into the temporal integration of complex and biologically salient auditory sequences.

  View details for DOI 10.1111/ejn.12173

  View details for PubMedID 23578016

• A parcellation scheme based on von Mises-Fisher distributions and Markov random fields for segmenting brain regions using resting-state fMRI NEUROIMAGE Ryali, S., Chen, T., Supekar, K., Menon, V. 2013; 65: 83-96

  Abstract

  Understanding the organization of the human brain requires identification of its functional subdivisions. Clustering schemes based on resting-state functional magnetic resonance imaging (fMRI) data are rapidly emerging as non-invasive alternatives to cytoarchitectonic mapping in postmortem brains. Here, we propose a novel spatio-temporal probabilistic parcellation scheme that overcomes major weaknesses of existing approaches by (i) modeling the fMRI time series of a voxel as a von Mises-Fisher distribution, which is widely used for clustering high dimensional data; (ii) modeling the latent cluster labels as a Markov random field, which provides spatial regularization on the cluster labels by penalizing neighboring voxels having different cluster labels; and (iii) introducing a prior on the number of labels, which helps in uncovering the number of clusters automatically from the data. Cluster labels and model parameters are estimated by an iterative expectation maximization procedure wherein, given the data and current estimates of model parameters, the latent cluster labels, are computed using α-expansion, a state of the art graph cut, method. In turn, given the current estimates of cluster labels, model parameters are estimated by maximizing the pseudo log-likelihood. The performance of the proposed method is validated using extensive computer simulations. Using novel stability analysis we examine the sensitivity of our methods to parameter initialization and demonstrate that the method is robust to a wide range of initial parameter values. We demonstrate the application of our methods by parcellating spatially contiguous as well as non-contiguous brain regions at both the individual participant and group levels. Notably, our analyses yield new data on the posterior boundaries of the supplementary motor area and provide new insights into functional organization of the insular cortex. Taken together, our findings suggest that our method is a powerful tool for investigating functional subdivisions in the human brain.

  View details for DOI 10.1016/j.neuroimage.2012.09.067

  View details for Web of Science ID 000312283900008

  View details for PubMedID 23041530

  View details for PubMedCentralID PMC3513676

• Hippocampal-Prefrontal Engagement and Dynamic Causal Interactions in the Maturation of Children's Fact Retrieval JOURNAL OF COGNITIVE NEUROSCIENCE Cho, S., Metcalfe, A. W., Young, C. B., Ryali, S., Geary, D. C., Menon, V. 2012; 24 (9): 1849-1866

  Abstract

  Children's gains in problem-solving skills during the elementary school years are characterized by shifts in the mix of problem-solving approaches, with inefficient procedural strategies being gradually replaced with direct retrieval of domain-relevant facts. We used a well-established procedure for strategy assessment during arithmetic problem solving to investigate the neural basis of this critical transition. We indexed behavioral strategy use by focusing on the retrieval frequency and examined changes in brain activity and connectivity associated with retrieval fluency during arithmetic problem solving in second- and third-grade (7- to 9-year-old) children. Children with higher retrieval fluency showed elevated signal in the right hippocampus, parahippocampal gyrus (PHG), lingual gyrus (LG), fusiform gyrus (FG), left ventrolateral PFC (VLPFC), bilateral dorsolateral PFC (DLPFC), and posterior angular gyrus. Critically, these effects were not confounded by individual differences in problem-solving speed or accuracy. Psychophysiological interaction analysis revealed significant effective connectivity of the right hippocampus with bilateral VLPFC and DLPFC during arithmetic problem solving. Dynamic causal modeling analysis revealed strong bidirectional interactions between the hippocampus and the left VLPFC and DLPFC. Furthermore, causal influences from the left VLPFC to the hippocampus served as the main top-down component, whereas causal influences from the hippocampus to the left DLPFC served as the main bottom-up component of this retrieval network. Our study highlights the contribution of hippocampal-prefrontal circuits to the early development of retrieval fluency in arithmetic problem solving and provides a novel framework for studying dynamic developmental processes that accompany children's development of problem-solving skills.

  View details for Web of Science ID 000307045400004

  View details for PubMedID 22621262

• Estimation of functional connectivity in fMRI data using stability selection-based sparse partial correlation with elastic net penalty NEUROIMAGE Ryali, S., Chen, T., Supekar, K., Menon, V. 2012; 59 (4): 3852-3861

  Abstract

  Characterizing interactions between multiple brain regions is important for understanding brain function. Functional connectivity measures based on partial correlation provide an estimate of the linear conditional dependence between brain regions after removing the linear influence of other regions. Estimation of partial correlations is, however, difficult when the number of regions is large, as is now increasingly the case with a growing number of large-scale brain connectivity studies. To address this problem, we develop novel methods for estimating sparse partial correlations between multiple regions in fMRI data using elastic net penalty (SPC-EN), which combines L1- and L2-norm regularization We show that L1-norm regularization in SPC-EN provides sparse interpretable solutions while L2-norm regularization improves the sensitivity of the method when the number of possible connections between regions is larger than the number of time points, and when pair-wise correlations between brain regions are high. An issue with regularization-based methods is choosing the regularization parameters which in turn determine the selection of connections between brain regions. To address this problem, we deploy novel stability selection methods to infer significant connections between brain regions. We also compare the performance of SPC-EN with existing methods which use only L1-norm regularization (SPC-L1) on simulated and experimental datasets. Detailed simulations show that the performance of SPC-EN, measured in terms of sensitivity and accuracy is superior to SPC-L1, especially at higher rates of feature prevalence. Application of our methods to resting-state fMRI data obtained from 22 healthy adults shows that SPC-EN reveals a modular architecture characterized by strong inter-hemispheric links, distinct ventral and dorsal stream pathways, and a major hub in the posterior medial cortex - features that were missed by conventional methods. Taken together, our findings suggest that SPC-EN provides a powerful tool for characterizing connectivity involving a large number of correlated regions that span the entire brain.

  View details for DOI 10.1016/j.neuroimage.2011.11.054

  View details for Web of Science ID 000301090100078

  View details for PubMedID 22155039

  View details for PubMedCentralID PMC3288428

• Decoding Subject-Driven Cognitive States with Whole-Brain Connectivity Patterns CEREBRAL CORTEX SHIRER, W. R., RYALI, S., Rykhlevskaia, E., Menon, V., Greicius, M. D. 2012; 22 (1): 158-165

  Abstract

  Decoding specific cognitive states from brain activity constitutes a major goal of neuroscience. Previous studies of brain-state classification have focused largely on decoding brief, discrete events and have required the timing of these events to be known. To date, methods for decoding more continuous and purely subject-driven cognitive states have not been available. Here, we demonstrate that free-streaming subject-driven cognitive states can be decoded using a novel whole-brain functional connectivity analysis. Ninety functional regions of interest (ROIs) were defined across 14 large-scale resting-state brain networks to generate a 3960 cell matrix reflecting whole-brain connectivity. We trained a classifier to identify specific patterns of whole-brain connectivity as subjects rested quietly, remembered the events of their day, subtracted numbers, or (silently) sang lyrics. In a leave-one-out cross-validation, the classifier identified these 4 cognitive states with 84% accuracy. More critically, the classifier achieved 85% accuracy when identifying these states in a second, independent cohort of subjects. Classification accuracy remained high with imaging runs as short as 30-60 s. At all temporal intervals assessed, the 90 functionally defined ROIs outperformed a set of 112 commonly used structural ROIs in classifying cognitive states. This approach should enable decoding a myriad of subject-driven cognitive states from brief imaging data samples.

  View details for DOI 10.1093/cercor/bhr099

  View details for Web of Science ID 000298190500014

  View details for PubMedID 21616982

  View details for PubMedCentralID PMC3236795

• Dynamic Reconfiguration of Structural and Functional Connectivity Across Core Neurocognitive Brain Networks with Development JOURNAL OF NEUROSCIENCE Uddin, L. Q., Supekar, K. S., Ryali, S., Menon, V. 2011; 31 (50): 18578-18589

  Abstract

  Brain structural and functional development, throughout childhood and into adulthood, underlies the maturation of increasingly sophisticated cognitive abilities. High-level attentional and cognitive control processes rely on the integrity of, and dynamic interactions between, core neurocognitive networks. The right fronto-insular cortex (rFIC) is a critical component of a salience network (SN) that mediates interactions between large-scale brain networks involved in externally oriented attention [central executive network (CEN)] and internally oriented cognition [default mode network (DMN)]. How these systems reconfigure and mature with development is a critical question for cognitive neuroscience, with implications for neurodevelopmental pathologies affecting brain connectivity. Using functional and effective connectivity measures applied to fMRI data, we examine interactions within and between the SN, CEN, and DMN. We find that functional coupling between key network nodes is stronger in adults than in children, as are causal links emanating from the rFIC. Specifically, the causal influence of the rFIC on nodes of the SN and CEN was significantly greater in adults compared with children. Notably, these results were entirely replicated on an independent dataset of matched children and adults. Developmental changes in functional and effective connectivity were related to structural connectivity along these links. Diffusion tensor imaging tractography revealed increased structural integrity in adults compared with children along both within- and between-network pathways associated with the rFIC. These results suggest that structural and functional maturation of rFIC pathways is a critical component of the process by which human brain networks mature during development to support complex, flexible cognitive processes in adulthood.

  View details for DOI 10.1523/JNEUROSCI.4465-11.2011

  View details for Web of Science ID 000298055600032

  View details for PubMedID 22171056

  View details for PubMedCentralID PMC3641286

• How does a child solve 7+8? Decoding brain activity patterns associated with counting and retrieval strategies DEVELOPMENTAL SCIENCE Cho, S., Ryali, S., Geary, D. C., Menon, V. 2011; 14 (5): 989-1001

  Abstract

  Cognitive development and learning are characterized by diminished reliance on effortful procedures and increased use of memory-based problem solving. Here we identify the neural correlates of this strategy shift in 7-9-year-old children at an important developmental period for arithmetic skill acquisition. Univariate and multivariate approaches were used to contrast brain responses between two groups of children who relied primarily on either retrieval or procedural counting strategies. Children who used retrieval strategies showed greater responses in the left ventrolateral prefrontal cortex; notably, this was the only brain region which showed univariate differences in signal intensity between the two groups. In contrast, multivariate analysis revealed distinct multivoxel activity patterns in bilateral hippocampus, posterior parietal cortex and left ventrolateral prefrontal cortex regions between the two groups. These results demonstrate that retrieval and counting strategies during early learning are characterized by distinct patterns of activity in a distributed network of brain regions involved in arithmetic problem solving and controlled retrieval of arithmetic facts. Our findings suggest that the reorganization and refinement of neural activity patterns in multiple brain regions plays a dominant role in the transition to memory-based arithmetic problem solving. Our findings further demonstrate how multivariate approaches can provide novel insights into fine-scale developmental changes in the brain. More generally, our study illustrates how brain imaging and developmental research can be integrated to investigate fundamental aspects of neurocognitive development.

  View details for DOI 10.1111/j.1467-7687.2011.01055.x

  View details for Web of Science ID 000294181600007

  View details for PubMedID 21884315

  View details for PubMedCentralID PMC3193275

• Decoding Temporal Structure in Music and Speech Relies on Shared Brain Resources but Elicits Different Fine-Scale Spatial Patterns CEREBRAL CORTEX Abrams, D. A., Bhatara, A., Ryali, S., Balaban, E., Levitin, D. J., Menon, V. 2011; 21 (7): 1507-1518

  Abstract

  Music and speech are complex sound streams with hierarchical rules of temporal organization that become elaborated over time. Here, we use functional magnetic resonance imaging to measure brain activity patterns in 20 right-handed nonmusicians as they listened to natural and temporally reordered musical and speech stimuli matched for familiarity, emotion, and valence. Heart rate variability and mean respiration rates were simultaneously measured and were found not to differ between musical and speech stimuli. Although the same manipulation of temporal structure elicited brain activation level differences of similar magnitude for both music and speech stimuli, multivariate classification analysis revealed distinct spatial patterns of brain responses in the 2 domains. Distributed neuronal populations that included the inferior frontal cortex, the posterior and anterior superior and middle temporal gyri, and the auditory brainstem classified temporal structure manipulations in music and speech with significant levels of accuracy. While agreeing with previous findings that music and speech processing share neural substrates, this work shows that temporal structure in the 2 domains is encoded differently, highlighting a fundamental dissimilarity in how the same neural resources are deployed.

  View details for DOI 10.1093/cercor/bhq198

  View details for Web of Science ID 000291750400005

  View details for PubMedID 21071617

  View details for PubMedCentralID PMC3116734

• Multivariate dynamical systems models for estimating causal interactions in fMRI NEUROIMAGE Ryali, S., Supekar, K., Chen, T., Menon, V. 2011; 54 (2): 807-823

  Abstract

  Analysis of dynamical interactions between distributed brain areas is of fundamental importance for understanding cognitive information processing. However, estimating dynamic causal interactions between brain regions using functional magnetic resonance imaging (fMRI) poses several unique challenges. For one, fMRI measures Blood Oxygenation Level Dependent (BOLD) signals, rather than the underlying latent neuronal activity. Second, regional variations in the hemodynamic response function (HRF) can significantly influence estimation of causal interactions between them. Third, causal interactions between brain regions can change with experimental context over time. To overcome these problems, we developed a novel state-space Multivariate Dynamical Systems (MDS) model to estimate intrinsic and experimentally-induced modulatory causal interactions between multiple brain regions. A probabilistic graphical framework is then used to estimate the parameters of MDS as applied to fMRI data. We show that MDS accurately takes into account regional variations in the HRF and estimates dynamic causal interactions at the level of latent signals. We develop and compare two estimation procedures using maximum likelihood estimation (MLE) and variational Bayesian (VB) approaches for inferring model parameters. Using extensive computer simulations, we demonstrate that, compared to Granger causal analysis (GCA), MDS exhibits superior performance for a wide range of signal to noise ratios (SNRs), sample length and network size. Our simulations also suggest that GCA fails to uncover causal interactions when there is a conflict between the direction of intrinsic and modulatory influences. Furthermore, we show that MDS estimation using VB methods is more robust and performs significantly better at low SNRs and shorter time series than MDS with MLE. Our study suggests that VB estimation of MDS provides a robust method for estimating and interpreting causal network interactions in fMRI data.

  View details for DOI 10.1016/j.neuroimage.2010.09.052

  View details for Web of Science ID 000285486000009

  View details for PubMedID 20884354

  View details for PubMedCentralID PMC2997172

• Dynamic reconfiguration of structural and functional connectivity across core neurocognitive brain networks with development. Journal of Neuroscience Lucina Uddin, K., Srikanth Ryali, Vinod Menon 2011
• Discriminatory Learning based Performance Monitoring of Batch Processes American Control Conference, USA Yelchuru, R., Srikanth Ryali, Patel, Shailesh, Gudi, Ravindra 2011
• Sparse logistic regression for whole-brain classification of fMRI data NEUROIMAGE Ryali, S., Supekar, K., Abrams, D. A., Menon, V. 2010; 51 (2): 752-764

  Abstract

  Multivariate pattern recognition methods are increasingly being used to identify multiregional brain activity patterns that collectively discriminate one cognitive condition or experimental group from another, using fMRI data. The performance of these methods is often limited because the number of regions considered in the analysis of fMRI data is large compared to the number of observations (trials or participants). Existing methods that aim to tackle this dimensionality problem are less than optimal because they either over-fit the data or are computationally intractable. Here, we describe a novel method based on logistic regression using a combination of L1 and L2 norm regularization that more accurately estimates discriminative brain regions across multiple conditions or groups. The L1 norm, computed using a fast estimation procedure, ensures a fast, sparse and generalizable solution; the L2 norm ensures that correlated brain regions are included in the resulting solution, a critical aspect of fMRI data analysis often overlooked by existing methods. We first evaluate the performance of our method on simulated data and then examine its effectiveness in discriminating between well-matched music and speech stimuli. We also compared our procedures with other methods which use either L1-norm regularization alone or support vector machine-based feature elimination. On simulated data, our methods performed significantly better than existing methods across a wide range of contrast-to-noise ratios and feature prevalence rates. On experimental fMRI data, our methods were more effective in selectively isolating a distributed fronto-temporal network that distinguished between brain regions known to be involved in speech and music processing. These findings suggest that our method is not only computationally efficient, but it also achieves the twin objectives of identifying relevant discriminative brain regions and accurately classifying fMRI data.

  View details for DOI 10.1016/j.neuroimage.2010.02.040

  View details for Web of Science ID 000277141200026

  View details for PubMedID 20188193

  View details for PubMedCentralID PMC2856747

• Development, validation, and comparison of ICA-based gradient artifact reduction algorithms for simultaneous EEG-spiral in/out and echo-planar fMRI recordings NEUROIMAGE Ryali, S., Glover, G. H., Chang, C., Menon, V. 2009; 48 (2): 348-361

  Abstract

  EEG data acquired in an MRI scanner are heavily contaminated by gradient artifacts that can significantly compromise signal quality. We developed two new methods based on independent component analysis (ICA) for reducing gradient artifacts from spiral in-out and echo-planar pulse sequences at 3 T, and compared our algorithms with four other commonly used methods: average artifact subtraction (Allen, P., Josephs, O., Turner, R., 2000. A method for removing imaging artifact from continuous EEG recorded during functional MRI. NeuroImage 12, 230-239.), principal component analysis (Niazy, R., Beckmann, C., Iannetti, G., Brady, J., Smith, S., 2005. Removal of FMRI environment artifacts from EEG data using optimal basis sets. NeuroImage 28, 720-737.), Taylor series ( Wan, X., Iwata, K., Riera, J., Kitamura, M., Kawashima, R., 2006. Artifact reduction for simultaneous EEG/fMRI recording: adaptive FIR reduction of imaging artifacts. Clin. Neurophysiol. 117, 681-692.) and a conventional temporal ICA algorithm. Models of gradient artifacts were derived from simulations as well as a water phantom and performance of each method was evaluated on datasets constructed using visual event-related potentials (ERPs) as well as resting EEG. Our new methods recovered ERPs and resting EEG below the beta band (<12.5 Hz) with high signal-to-noise ratio (SNR>4). Our algorithms outperformed all of these methods on resting EEG in the theta and alpha bands (SNR>4); however, for all methods, signal recovery was modest (SNR approximately 1) in the beta band and poor (SNR<0.3) in the gamma band and above. We found that the conventional ICA algorithm performed poorly with uniformly low SNR (<0.1). Taken together, our new ICA-based methods offer a more robust technique for gradient artifact reduction when scanning at 3 T using spiral in-out and echo-planar pulse sequences. We provide new insights into the strengths and weaknesses of each method using a unified subspace framework.

  View details for DOI 10.1016/j.neuroimage.2009.06.072

  View details for Web of Science ID 000274723900005

  View details for PubMedID 19580873

• Aging and the Interaction of Sensory Cortical Function and Structure HUMAN BRAIN MAPPING Peiffer, A. M., Hugenschimidt, C. E., Maldjian, J. A., Casanova, R., Srikanth, R., Hayasaka, S., Burdette, J. H., Kraft, R. A., Laurienti, P. J. 2009; 30 (1): 228-240

  Abstract

  Even the healthiest older adults experience changes in cognitive and sensory function. Studies show that older adults have reduced neural responses to sensory information. However, it is well known that sensory systems do not act in isolation but function cooperatively to either enhance or suppress neural responses to individual environmental stimuli. Very little research has been dedicated to understanding how aging affects the interactions between sensory systems, especially cross-modal deactivations or the ability of one sensory system (e.g., audition) to suppress the neural responses in another sensory system cortex (e.g., vision). Such cross-modal interactions have been implicated in attentional shifts between sensory modalities and could account for increased distractibility in older adults. To assess age-related changes in cross-modal deactivations, functional MRI studies were performed in 61 adults between 18 and 80 years old during simple auditory and visual discrimination tasks. Results within visual cortex confirmed previous findings of decreased responses to visual stimuli for older adults. Age-related changes in the visual cortical response to auditory stimuli were, however, much more complex and suggested an alteration with age in the functional interactions between the senses. Ventral visual cortical regions exhibited cross-modal deactivations in younger but not older adults, whereas more dorsal aspects of visual cortex were suppressed in older but not younger adults. These differences in deactivation also remained after adjusting for age-related reductions in brain volume of sensory cortex. Thus, functional differences in cortical activity between older and younger adults cannot solely be accounted for by differences in gray matter volume.

  View details for DOI 10.1002/hbm.20497

  View details for Web of Science ID 000262397000020

  View details for PubMedID 18072271

• The impact of temporal regularization on estimates of the BOLD hemodynamic response function: A comparative analysis NEUROIMAGE Casanova, R., Ryali, S., Serences, J., Yang, L., Kraft, R., Laurienti, P. J., Maldjian, J. A. 2008; 40 (4): 1606-1618

  Abstract

  In fMRI data analysis it has been shown that for a wide range of situations the hemodynamic response function (HRF) can be reasonably characterized as the impulse response function of a linear and time invariant system. An accurate and robust extraction of the HRF is essential to infer quantitative information about the relative timing of the neuronal events in different brain regions. When no assumptions are made about the HRF shape, it is most commonly estimated using time windowed averaging or a least squares estimated general linear model based on either Fourier or delta basis functions. Recently, regularization methods have been employed to increase the estimation efficiency of the HRF; typically these methods produce more accurate HRF estimates than the least squares approach [Goutte, C., Nielsen, F.A., Hansen, L.K., 2000. Modeling the Haemodynamic Response in fMRI Using Smooth FIR Filters. IEEE Trans. Med. Imag. 19(12), 1188-1201.]. Here, we use simulations to clarify the relative merit of temporal regularization based methods compared to the least squares methods with respect to the accuracy of estimating certain characteristics of the HRF such as time to peak (TTP), height (HR) and width (W) of the response. We implemented a Bayesian approach proposed by Marrelec et al. [Marrelec, G., Benali, H., Ciuciu, P., Pelegrini-Issac, M., Poline, J.-B., 2003. Robust Estimation of the Hemodynamic Response Function in Event-Related BOLD fMRI Using Basic Physiological Information. Hum. Brain Mapp. 19, 1-17., Marrelec, G., Benali, H., Ciuciu, P., Poline, J.B. Bayesian estimation of the hemodynamic of the hemodynamic response function in functional MRI. In: R. F, editor; 2001; Melville. p 229-247.] and its deterministic counterpart based on a combination of Tikhonov regularization [Tikhonov, A.N., Arsenin, V.Y., 1977. Solution of ill-posed problems. Washington DC: W.H. Winston.] and generalized cross-validation (GCV) [Wahba, G., 1990. Spline Models for Observational Data. Philadelphia: SIAM.] for selecting the regularization parameter. The performance of both methods is compared with least square estimates as a function of temporal resolution, color and strength of the noise, and the type of stimulus sequences used. In almost all situations, under the considered assumptions (e.g. linearity, time invariance and smooth HRF), the regularization-based techniques more accurately characterize the HRF compared to the least-squares method. Our results clarify the effects of temporal resolution, noise color, and experimental design on the accuracy of HRF estimation.

  View details for DOI 10.1016/j.neuroimage.2008.01.011

  View details for Web of Science ID 000255347100018

  View details for PubMedID 18329292

• Prediction of Batch Quality Indices Using Functional Space Approximation and Partial Least Squares American Control Conference, USA. Yelchuru, R., Patel, Shailesh, Srikanth Ryali, Gudi, Ravindra 2008
• Biological parametric mapping: A statistical toolbox for multimodality brain image analysis NEUROIMAGE Casanova, R., Srikanth, R., Baer, A., Laurienti, P. J., Burdett, J. H., Hayasaka, S., Flowers, L., Wood, F., Maldjian, J. A. 2007; 34 (1): 137-143

  Abstract

  In recent years, multiple brain MR imaging modalities have emerged; however, analysis methodologies have mainly remained modality-specific. In addition, when comparing across imaging modalities, most researchers have been forced to rely on simple region-of-interest type analyses, which do not allow the voxel-by-voxel comparisons necessary to answer more sophisticated neuroscience questions. To overcome these limitations, we developed a toolbox for multimodal image analysis called biological parametric mapping (BPM), based on a voxel-wise use of the general linear model. The BPM toolbox incorporates information obtained from other modalities as regressors in a voxel-wise analysis, thereby permitting investigation of more sophisticated hypotheses. The BPM toolbox has been developed in Matlab with a user-friendly interface for performing analyses, including voxel-wise multimodal correlation, ANCOVA, and multiple regression. It has a high degree of integration with the SPM (statistical parametric mapping) software relying on it for visualization and statistical inference. Furthermore, statistical inference for a correlation field, rather than a widely used T-field, has been implemented in the correlation analysis for more accurate results. An example with in vivo data is presented, demonstrating the potential of the BPM methodology as a tool for multimodal image analysis.

  View details for DOI 10.1016/j.neuroimage.2006.09.011

  View details for Web of Science ID 000242735300014

  View details for PubMedID 17070709

• Estimation of false discovery rates for wavelet-denoised statistical parametric maps NEUROIMAGE Srikanth, R., Casanova, R., Laurienti, P. J., Peiffer, A. M., Maldjian, J. A. 2006; 33 (1): 72-84

  Abstract

  Correction for multiple comparisons in neuroimaging data is an important area of research. Recently, wavelet-based methods have gained popularity and have been reported to achieve better sensitivity compared to spatial domain methods. However, these techniques produce smoothed statistical maps which are difficult to interpret. The generated maps have to be thresholded again in the spatial domain to delineate active from inactive regions. The selection of a proper threshold satisfying the required error rate control is not straightforward. In this paper, a framework is proposed for thresholding wavelet-denoised maps in which a rejection region is fixed, and the achieved false discovery rate (FDR) is estimated. This approach provides a meaningful strategy to choose thresholds for wavelet-denoised statistical parametric maps (SPMs). Two FDR estimation algorithms were used to assess the achieved error rate control when thresholding wavelet filtered SPMs at various rejection regions. Their performance was evaluated using both simulated and resting fMRI data. The proposed framework was also applied on in vivo data.

  View details for DOI 10.1016/j.neuroimage.2006.06.033

  View details for Web of Science ID 000241209800010

  View details for PubMedID 16919480

• Wavelet-based estimation of hemodynamic response function from fMRI data INTERNATIONAL JOURNAL OF NEURAL SYSTEMS Srikanth, R., Ramakrshnan, A. G. 2006; 16 (2): 125-138

  Abstract

  We present a new algorithm to estimate hemodynamic response function (HRF) and drift components of fMRI data in wavelet domain. The HRF is modeled by both parametric and nonparametric models. The functional Magnetic resonance Image (fMRI) noise is modeled as a fractional brownian motion (fBm). The HRF parameters are estimated in wavelet domain by exploiting the property that wavelet transforms with a sufficient number of vanishing moments decorrelates a fBm process. Using this property, the noise covariance matrix in wavelet domain can be assumed to be diagonal whose entries are estimated using the sample variance estimator at each scale. We study the influence of the sampling rate of fMRI time series and shape assumption of HRF on the estimation performance. Results are presented by adding synthetic HRFs on simulated and null fMRI data. We also compare these methods with an existing method,(1) where correlated fMRI noise is modeled by a second order polynomial functions.

  View details for Web of Science ID 000237787200004

  View details for PubMedID 16688852

• Polarization-rich continuous wave direct imaging: modeling and visualization Applied Optics R. S. Umesh, A. G. Ramakrishnan, R. Srikanth, R. Hema, S. Divya 2006; 45 (18): 4344-4354
• Contextual encoding in uniform and adaptive mesh-based lossless compression of MR images IEEE TRANSACTIONS ON MEDICAL IMAGING Srikanth, R., Ramakrishnan, A. G. 2005; 24 (9): 1199-1206

  Abstract

  We propose and evaluate a number of novel improvements to the mesh-based coding scheme for 3-D brain magnetic resonance images. This includes: 1) elimination of the clinically irrelevant background leading to meshing of only the brain part of the image; 2) content-based (adaptive) mesh generation using spatial edges and optical flow between two consecutive slices; 3) a simple solution for the aperture problem at the edges, where an accurate estimation of motion vectors is not possible; and 4) context-based entropy coding of the residues after motion compensation using affine transformations. We address only lossless coding of the images, and compare the performance of uniform and adaptive mesh-based schemes. The bit rates achieved (about 2 bits per voxel) by these schemes are comparable to those of the state-of-the-art three-dimensional (3-D) wavelet-based schemes. The mesh-based schemes have been shown to be effective for the compression of 3-D brain computed tomography data also. Adaptive mesh-based schemes perform marginally better than the uniform mesh-based methods, at the expense of increased complexity.

  View details for DOI 10.1109/TMI.2005.853638

  View details for Web of Science ID 000231636400010

  View details for PubMedID 16156357

• Region of Interest Coding of 2-D and 3-D Magnetic Resonance Images ICVGIP Srikanth Ryali, A.G. Ramakrishnan 2004
• Shape Adaptive Integer Wavelet Transform based coding scheme for 2-D/3-D MR Images Data Compression Conference, Snowbird, Utah, USA, Abhishek Mehrotra, Srikanth Ryali, A.G.Ramakrishnan 2004
• Modeling and on-line recognition of PD signal buried in excessive noise Signal processing Shetty PK, Srikanth R, Ramu TS 2004; 84 (12): 2389-2401
• Wavelet-based Coding of 2-D and 3-D coding of MR images IEEE-TENCON Srikanth Ryali, A.G. Ramakrishnan 2003
• Parameter Estimation of HRF and Classification of fMRI data using Probabilistic PCA Modeling ICAPR Srikanth Ryali, A.G.Ramakrishnan 2003
• Model based Bayesian approach for MR Image Segmentation ICAPR Niranjan Joshi, Srikanth Ryali, A.G.Ramakrishnan 2003
• MR Image Coding using Content-based Mesh and Context", International Symposium on Signal Processing and Applications Srikanth Ryali, A.G. Ramakrishnan 2003
• Parameter Estimation of HRF and Classification of fMRI data using Probabilistic PCA Modeling ICAPR Srikanth Ryali, A.G.Ramakrishnan 2003
• Multivariate searchlight classification of structural MRI in children and adolescents with autism. Biological Psychiatry Uddin, L. Q, Menon, V., Young, C. B., Ryali, S., Chen, T., Khouzam, A., Minshew, N. J. & Hardan