Weidong Cai

All Publications

• Reduced temporal and spatial stability of neural activity patterns predict cognitive control deficits in children with ADHD. bioRxiv : the preprint server for biology Gao, Z., Duberg, K., Warren, S. L., Zheng, L., Hinshaw, S. P., Menon, V., Cai, W. 2024

  Abstract

  This study explores the neural underpinnings of cognitive control deficits in ADHD, focusing on overlooked aspects of trial-level variability of neural coding. We employed a novel computational approach to neural decoding on a single-trial basis alongside a cued stop-signal task which allowed us to distinctly probe both proactive and reactive cognitive control. Typically developing (TD) children exhibited stable neural response patterns for efficient proactive and reactive dual control mechanisms. However, neural coding was compromised in children with ADHD. Children with ADHD showed increased temporal variability and diminished spatial stability in neural responses in salience and frontal-parietal network regions, indicating disrupted neural coding during both proactive and reactive control. Moreover, this variability correlated with fluctuating task performance and with more severe symptoms of ADHD. These findings underscore the significance of modeling single-trial variability and representational similarity in understanding distinct components of cognitive control in ADHD, highlighting new perspectives on neurocognitive dysfunction in psychiatric disorders.

  View details for DOI 10.1101/2024.05.29.596493

  View details for PubMedID 38854066

  View details for PubMedCentralID PMC11160739

• Subthalamic nucleus-language network connectivity predicts dopaminergic modulation of speech function in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America Cai, W., Young, C. B., Yuan, R., Lee, B., Ryman, S., Kim, J., Yang, L., Levine, T. F., Henderson, V. W., Poston, K. L., Menon, V. 2024; 121 (22): e2316149121

  Abstract

  Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.

  View details for DOI 10.1073/pnas.2316149121

  View details for PubMedID 38768342

• Increased Temporal and Spatial Variability of TrialEvoked Brain Responses During Dynamic Inhibitory Control in Children With ADHD Gao, Z., Zheng, L., Huynh, H., Kammer, E., Menon, V., Cai, W. ELSEVIER SCIENCE INC. 2024: S133

  View details for Web of Science ID 001282811900308

• A multi-demand operating system underlying diverse cognitive tasks. Nature communications Cai, W., Taghia, J., Menon, V. 2024; 15 (1): 2185

  Abstract

  The existence of a multiple-demand cortical system with an adaptive, domain-general, role in cognition has been proposed, but the underlying dynamic mechanisms and their links to cognitive control abilities are poorly understood. Here we use a probabilistic generative Bayesian model of brain circuit dynamics to determine dynamic brain states across multiple cognitive domains, independent datasets, and participant groups, including task fMRI data from Human Connectome Project, Dual Mechanisms of Cognitive Control study and a neurodevelopment study. We discover a shared brain state across seven distinct cognitive tasks and found that the dynamics of this shared brain state predicted cognitive control abilities in each task. Our findings reveal the flexible engagement of dynamic brain processes across multiple cognitive domains and participant groups, and uncover the generative mechanisms underlying the functioning of a domain-general cognitive operating system. Our computational framework opens promising avenues for probing neurocognitive function and dysfunction.

  View details for DOI 10.1038/s41467-024-46511-5

  View details for PubMedID 38467606

  View details for PubMedCentralID 4577153

• Bayesian dynamical system analysis of the effects of methylphenidate in children with attention-deficit/hyperactivity disorder: a randomized trial. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Cai, W., Mizuno, Y., Tomoda, A., Menon, V. 2023

  Abstract

  Methylphenidate is a widely used and effective treatment for attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural mechanisms and their relationship to changes in behavior are not fully understood. Specifically, it remains unclear how methylphenidate affects brain and behavioral dynamics, and the interplay between these dynamics, in individuals with ADHD. To address this gap, we used a novel Bayesian dynamical system model to investigate the effects of methylphenidate on latent brain states in 27 children with ADHD and 49 typically developing children using a double-blind, placebo-controlled crossover design. Methylphenidate remediated greater behavioral variability on a continuous performance task in children with ADHD. Children with ADHD exhibited aberrant latent brain state dynamics compared to typically developing children, with a single latent state showing particularly abnormal dynamics, which was remediated by methylphenidate. Additionally, children with ADHD showed brain state-dependent hyper-connectivity in the default mode network, which was also remediated by methylphenidate. Finally, we found that methylphenidate-induced changes in latent brain state dynamics, as well as brain state-related functional connectivity between salience and default mode networks, were correlated with improvements in behavioral variability. Taken together, our findings reveal a novel latent brain state dynamical process and circuit mechanism underlying the therapeutic effects of methylphenidate in childhood ADHD. We suggest that Bayesian dynamical system models may be particularly useful for capturing complex nonlinear changes in neural activity and behavioral variability associated with ADHD. Our approach may be of value to clinicians and researchers investigating the neural mechanisms underlying pharmacological treatment of psychiatric disorders.

  View details for DOI 10.1038/s41386-023-01668-3

  View details for PubMedID 37491674

• Both reactive and proactive control are deficient in children with ADHD and predictive of clinical symptoms. Translational psychiatry Cai, W., Warren, S. L., Duberg, K., Yu, A., Hinshaw, S. P., Menon, V. 2023; 13 (1): 179

  Abstract

  Cognitive control deficits are a hallmark of attention deficit hyperactivity disorder (ADHD) in children. Theoretical models posit that cognitive control involves reactive and proactive control processes but their distinct roles and inter-relations in ADHD are not known, and the contributions of proactive control remain vastly understudied. Here, we investigate the dynamic dual cognitive control mechanisms associated with both proactive and reactive control in 50 children with ADHD (16F/34M) and 30 typically developing (TD) children (14F/16M) aged 9-12 years across two different cognitive controls tasks using a within-subject design. We found that while TD children were capable of proactively adapting their response strategies, children with ADHD demonstrated significant deficits in implementing proactive control strategies associated with error monitoring and trial history. Children with ADHD also showed weaker reactive control than TD children, and this finding was replicated across tasks. Furthermore, while proactive and reactive control functions were correlated in TD children, such coordination between the cognitive control mechanisms was not present in children with ADHD. Finally, both reactive and proactive control functions were associated with behavioral problems in ADHD, and multi-dimensional features derived from the dynamic dual cognitive control framework predicted inattention and hyperactivity/impulsivity clinical symptoms. Our findings demonstrate that ADHD in children is characterized by deficits in both proactive and reactive control, and suggest that multi-componential cognitive control measures can serve as robust predictors of clinical symptoms.

  View details for DOI 10.1038/s41398-023-02471-w

  View details for PubMedID 37236924

• Methylphenidate Normalizes Aberrant Latent State Dynamics in Children With ADHD Cai, W., Mizuno, Y., Tomoda, A., Menon, V. ELSEVIER SCIENCE INC. 2023: S115-S116

  View details for Web of Science ID 000993018500276

• The Effects of Methylphenidate on Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder -Randomized Controlled Studies in Two Independent Cohorts Mizuno, Y., Cai, W., Supekar, K., Makita, K., Takiguchi, S., Silk, T. J., Tomoda, A., Menon, V. ELSEVIER SCIENCE INC. 2023: S103

  View details for Web of Science ID 000993018500245

• Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder. Biological psychiatry. Cognitive neuroscience and neuroimaging Mizuno, Y., Cai, W., Supekar, K., Makita, K., Takiguchi, S., Silk, T. J., Tomoda, A., Menon, V. 2022

  Abstract

  BACKGROUND: Methylphenidate, a first-line treatment for attention-deficit/hyperactivity disorder (ADHD), is thought to influence dopaminergic neurotransmission in the nucleus accumbens (NAc) and its associated brain circuitry, but this hypothesis has yet to be systematically tested.METHODS: We conducted a randomized, placebo-controlled, double-blind crossover trial including 27 children with ADHD. Children with ADHD were scanned twice with resting-state functional magnetic resonance imaging under methylphenidate and placebo conditions, along with assessment of sustained attention. We examined spontaneous neural activity in the NAc and the salience, frontoparietal, and default mode networks and their links to behavioral changes. Replicability of methylphenidate effects on spontaneous neural activity was examined in a second independent cohort.RESULTS: Methylphenidate increased spontaneous neural activity in the NAc and the salience and default mode networks. Methylphenidate-induced changes in spontaneous activity patterns in the default mode network were associated with improvements in intraindividual response variability during a sustained attention task. Critically, despite differences in clinical trial protocols and data acquisition parameters, the NAc and the salience and default mode networks showed replicable patterns of methylphenidate-induced changes in spontaneous activity across two independent cohorts.CONCLUSIONS: We provide reproducible evidence demonstrating that methylphenidate enhances spontaneous neural activity in NAc and cognitive control networks in children with ADHD, resulting in more stable sustained attention. Our findings identified a novel neural mechanism underlying methylphenidate treatment in ADHD to inform the development of clinically useful biomarkers for evaluating treatment outcomes.

  View details for DOI 10.1016/j.bpsc.2022.10.001

  View details for PubMedID 36717325

• Methylphenidate remediates aberrant brain network dynamics in children with attention-deficit/hyperactivity disorder: a randomized controlled trial. NeuroImage Mizuno, Y., Cai, W., Supekar, K., Makita, K., Takiguchi, S., Tomoda, A., Menon, V. 2022: 119332

  Abstract

  Methylphenidate is a widely used first-line treatment for attention deficit/hyperactivity disorder (ADHD), but the underlying circuit mechanisms are poorly understood. Here we investigate whether a single dose of osmotic release oral system methylphenidate can remediate attention deficits and aberrancies in functional circuit dynamics in cognitive control networks, which have been implicated in ADHD. In a randomized placebo-controlled double-blind crossover design, 27 children with ADHD were scanned twice with resting-state functional MRI and sustained attention was examined using a continuous performance task under methylphenidate and placebo conditions; 49 matched typically-developing (TD) children were scanned once for comparison. Dynamic time-varying cross-network interactions between the salience (SN), frontoparietal (FPN), and default mode (DMN) networks were examined in children with ADHD under both administration conditions and compared with TD children. Methylphenidate improved sustained attention on a continuous performance task in children with ADHD, when compared to the placebo condition. Children with ADHD under placebo showed aberrancies in dynamic time-varying cross-network interactions between the SN, FPN and DMN, which were remediated by methylphenidate. Multivariate classification analysis confirmed that methylphenidate remediates aberrant dynamic brain network interactions. Furthermore, dynamic time-varying network interactions under placebo conditions predicted individual differences in methylphenidate-induced improvements in sustained attention in children with ADHD. These findings suggest that a single dose of methylphenidate can remediate deficits in sustained attention and aberrant brain circuit dynamics in cognitive control circuits in children with ADHD. Findings identify a novel brain circuit mechanism underlying a first-line pharmacological treatment for ADHD, and may inform clinically useful biomarkers for evaluating treatment outcomes.

  View details for DOI 10.1016/j.neuroimage.2022.119332

  View details for PubMedID 35640787

• Methylphenidate Enhances Spontaneous Fluctuations in Reward and Cognitive Control Networks in Children With Attention-Deficit/Hyperactivity Disorder: A Randomized Control Trial Mizuno, Y., Cai, W., Supekar, K., Makita, K., Takiguchi, S., Tomoda, A., Menon, V. ELSEVIER SCIENCE INC. 2022: S110

  View details for Web of Science ID 000789022200269

• Insights from an autism imaging biomarker challenge: promises and threats to biomarker discovery. NeuroImage Traut, N., Heuer, K., Lemaître, G., Beggiato, A., Germanaud, D., Elmaleh, M., Bethegnies, A., Bonnasse-Gahot, L., Cai, W., Chambon, S., Cliquet, F., Ghriss, A., Guigui, N., de Pierrefeu, A., Wang, M., Zantedeschi, V., Boucaud, A., Bossche, J. v., Kegl, B., Delorme, R., Bourgeron, T., Toro, R., Varoquaux, G. 2022: 119171

  Abstract

  MRI has been extensively used to identify anatomical and functional differences in Autism Spectrum Disorder (ASD). Yet, many of these findings have proven difficult to replicate because studies rely on small cohorts and are built on many complex, undisclosed, analytic choices. We conducted an international challenge to predict ASD diagnosis from MRI data, where we provided preprocessed anatomical and functional MRI data from > 2,000 individuals. Evaluation of the predictions was rigorously blinded. 146 challengers submitted prediction algorithms, which were evaluated at the end of the challenge using unseen data and an additional acquisition site. On the best algorithms, we studied the importance of MRI modalities, brain regions, and sample size. We found evidence that MRI could predict ASD diagnosis: the 10 best algorithms reliably predicted diagnosis with AUC∼0.80 - far superior to what can be currently obtained using genotyping data in cohorts 20-times larger. We observed that functional MRI was more important for prediction than anatomical MRI, and that increasing sample size steadily increased prediction accuracy, providing an efficient strategy to improve biomarkers. We also observed that despite a strong incentive to generalise to unseen data, model development on a given dataset faces the risk of overfitting: performing well in cross-validation on the data at hand, but not generalising. Finally, we were able to predict ASD diagnosis on an external sample added after the end of the challenge (EU-AIMS), although with a lower prediction accuracy (AUC=0.72). This indicates that despite being based on a large multisite cohort, our challenge still produced biomarkers fragile in the face of dataset shifts.

  View details for DOI 10.1016/j.neuroimage.2022.119171

  View details for PubMedID 35413445

• Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson's disease. Brain : a journal of neurology Cai, W., Young, C. B., Yuan, R., Lee, B., Ryman, S., Kim, J., Yang, L., Henderson, V. W., Poston, K. L., Menon, V. 2022

  Abstract

  Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease (PD), but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in PD by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 msec resolution) fMRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 PD patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signaling in frontoparietal-basal ganglia circuits in PD patients OFF medication. Importantly, aberrant signaling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in PD patients. These findings were specific to causal signaling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signaling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in PD. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in PD patients OFF medication. However, dopaminergic medication in PD patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.

  View details for DOI 10.1093/brain/awac007

  View details for PubMedID 35357463

• 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

• Latent brain state dynamics and cognitive flexibility in older adults. Progress in neurobiology Lee, B., Cai, W., Young, C. B., Yuan, R., Ryman, S., Kim, J., Santini, V., Henderson, V. W., Poston, K. L., Menon, V. 2021: 102180

  Abstract

  Cognitive impairment in older adults is a rapidly growing public health concern as the elderly population dramatically grows worldwide. While it is generally assumed that cognitive deficits in older adults are associated with reduced brain flexibility, quantitative evidence has been lacking. Here, we investigate brain flexibility in healthy older adults (ages 60-85) using a novel Bayesian switching dynamical system algorithm and ultrafast temporal resolution (490msec) whole-brain fMRI data during performance of a Sternberg working memory task. We identify latent brain states and characterize their dynamic temporal properties, including state transitions, associated with encoding, maintenance, and retrieval. Crucially, we demonstrate that brain inflexibility is associated with slower and more fragmented transitions between latent brain states, and that brain inflexibility mediates the relation between age and cognitive inflexibility. Our study provides a novel neurocomputational framework for investigating latent dynamic circuit processes underlying brain flexibility and cognition in the context of aging.

  View details for DOI 10.1016/j.pneurobio.2021.102180

  View details for PubMedID 34627994

• 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

• Effects of Methylphenidate on Aberrant Brain Network Dynamics in Children With Attention-Deficit/Hyperactivity Disorder: A Randomized Controlled Clinical Trial Mizuno, Y., Cai, W., Spekar, K., Makita, K., Takiguchi, S., Tomoda, A., Menon, V. ELSEVIER SCIENCE INC. 2021: S108

  View details for Web of Science ID 000645683800257

• Latent brain state dynamics distinguish behavioral variability, impaired decision-making, and inattention. Molecular psychiatry Cai, W., Warren, S. L., Duberg, K., Pennington, B., Hinshaw, S. P., Menon, V. 2021

  Abstract

  Children with Attention Deficit Hyperactivity Disorder (ADHD) have prominent deficits in sustained attention that manifest as elevated intra-individual response variability and poor decision-making. Influential neurocognitive models have linked attentional fluctuations to aberrant brain dynamics, but these models have not been tested with computationally rigorous procedures. Here we use a Research Domain Criteria approach, drift-diffusion modeling of behavior, and a novel Bayesian Switching Dynamic System unsupervised learning algorithm, with ultrafast temporal resolution (490ms) whole-brain task-fMRI data, to investigate latent brain state dynamics of salience, frontoparietal, and default mode networks and their relation to response variability, latent decision-making processes, and inattention. Our analyses revealed that occurrence of a task-optimal latent brain state predicted decreased intra-individual response variability and increased evidence accumulation related to decision-making. In contrast, occurrence and dwell time of a non-optimal latent brain state predicted inattention symptoms and furthermore, in a categorical analysis, distinguished children with ADHD from controls. Importantly, functional connectivity between salience and frontoparietal networks predicted rate of evidence accumulation to a decision threshold, whereas functional connectivity between salience and default mode networks predicted inattention. Taken together, our computational modeling reveals dissociable latent brain state features underlying response variability, impaired decision-making, and inattentional symptoms common to ADHD. Our findings provide novel insights into the neurobiology of attention deficits in children.

  View details for DOI 10.1038/s41380-021-01022-3

  View details for PubMedID 33589738

• Seeing It Is Like Touching It: Unraveling the Effective Product Presentations on Online Apparel Purchase Decisions and Brain Activity (An fMRI Study) JOURNAL OF INTERACTIVE MARKETING Jai, T., Fang, D., Bao, F. S., James, R. N., Chen, T., Cai, W. 2021; 53: 66–79

  View details for DOI 10.1016/j.intmar.2020.04.005

  View details for Web of Science ID 000614900100005

• Microstructural organization of human insula is linked to its macrofunctional circuitry and predicts cognitive control. eLife Menon, V. n., Gallardo, G. n., Pinsk, M. A., Nguyen, V. D., Li, J. R., Cai, W. n., Wassermann, D. n. 2020; 9

  Abstract

  The human insular cortex is a heterogeneous brain structure which plays an integrative role in guiding behavior. The cytoarchitectonic organization of the human insula has been investigated over the last century using postmortem brains but there has been little progress in noninvasive in vivo mapping of its microstructure and large-scale functional circuitry. Quantitative modeling of multi-shell diffusion MRI data from 413 participants revealed that human insula microstructure differs significantly across subdivisions that serve distinct cognitive and affective functions. Insular microstructural organization was mirrored in its functionally interconnected circuits with the anterior cingulate cortex that anchors the salience network, a system important for adaptive switching of cognitive control systems. Furthermore, insular microstructural features, confirmed in Macaca mulatta, were linked to behavior and predicted individual differences in cognitive control ability. Our findings open new possibilities for probing psychiatric and neurological disorders impacted by insular cortex dysfunction, including autism, schizophrenia, and fronto-temporal dementia.

  View details for DOI 10.7554/eLife.53470

  View details for PubMedID 32496190

• Anxiety and Stress Alter Decision-Making Dynamics and Causal Amygdala-Dorsolateral Prefrontal Cortex Circuits During Emotion Regulation in Children. Biological psychiatry Warren, S. L., Zhang, Y. n., Duberg, K. n., Mistry, P. n., Cai, W. n., Qin, S. n., Bostan, S. N., Padmanabhan, A. n., Carrion, V. G., Menon, V. n. 2020

  Abstract

  Anxiety and stress reactivity are risk factors for the development of affective disorders. However, the behavioral and neurocircuit mechanisms that potentiate maladaptive emotion regulation are poorly understood. Neuroimaging studies have implicated the amygdala and dorsolateral prefrontal cortex (DLPFC) in emotion regulation, but how anxiety and stress alter their context-specific causal circuit interactions is not known. Here, we use computational modeling to inform affective pathophysiology, etiology, and neurocircuit targets for early intervention.Forty-five children (10-11 years of age; 25 boys) reappraised aversive stimuli during functional magnetic resonance imaging scanning. Clinical measures of anxiety and stress were acquired for each child. Drift-diffusion modeling of behavioral data and causal circuit analysis of functional magnetic resonance imaging data, with a National Institute of Mental Health Research Domain Criteria approach, were used to characterize latent behavioral and neurocircuit decision-making dynamics driving emotion regulation.Children successfully reappraised negative responses to aversive stimuli. Drift-diffusion modeling revealed that emotion regulation was characterized by increased initial bias toward positive reactivity during viewing of aversive stimuli and increased drift rate, which captured evidence accumulation during emotion evaluation. Crucially, anxiety and stress reactivity impaired latent behavioral dynamics associated with reappraisal and decision making. Anxiety and stress increased dynamic casual influences from the right amygdala to DLPFC. In contrast, DLPFC, but not amygdala, reactivity was correlated with evidence accumulation and decision making during emotion reappraisal.Our findings provide new insights into how anxiety and stress in children impact decision making and amygdala-DLPFC signaling during emotion regulation, and uncover latent behavioral and neurocircuit mechanisms of early risk for psychopathology.

  View details for DOI 10.1016/j.biopsych.2020.02.011

  View details for PubMedID 32331823

• Inhibition-related modulation of salience and frontoparietal networks predicts cognitive control ability and inattention symptoms in children with ADHD. Molecular psychiatry Cai, W., Griffiths, K., Korgaonkar, M. S., Williams, L. M., Menon, V. 2019

  Abstract

  Attention-deficit hyperactivity disorder (ADHD) is associated with pervasive impairments in attention and cognitive control. Although brain circuits underlying these impairments have been extensively investigated with resting-state fMRI, little is known about task-evoked functional brain circuits and their relation to cognitive control deficits and inattention symptoms in children with ADHD. Children with ADHD and age, gender and head motion matched typically developing (TD) children completed a Go/NoGo fMRI task. We used multivariate and dimensional analyses to investigate impairments in two core cognitive control systems: (i) cingulo-opercular "salience" network (SN) anchored in the right anterior insula, dorsal anterior cingulate cortex (rdACC), and ventrolateral prefrontal cortex (rVLPFC) and (ii) dorsal frontoparietal "central executive" (FPN) network anchored in right dorsolateral prefrontal cortex (rDLPFC) and posterior parietal cortex (rPPC). We found that multivariate patterns of task-evoked effective connectivity between brain regions in SN and FPN distinguished the ADHD and TD groups, with rDLPFC-rPPC connectivity emerging as the most distinguishing link. Task-evoked rdACC-rVLPFC connectivity was positively correlated with NoGo accuracy, and negatively correlated with severity of inattention symptoms. Brain-behavior relationships were robust against potential age, gender, and head motion confounds. Our findings highlight aberrancies in task-evoked modulation of SN and FPN connectivity in children with ADHD. Crucially, cingulo-frontal connectivity was a common locus of deficits in cognitive control and clinical measures of inattention symptoms. Our study provides insights into a parsimonious systems neuroscience model of cognitive control deficits in ADHD, and suggests specific circuit biomarkers for predicting treatment outcomes in childhood ADHD.

  View details for DOI 10.1038/s41380-019-0564-4

  View details for PubMedID 31664176

• Hyperdirect insula-basal-ganglia pathway and adult-like maturity of global brain responses predict inhibitory control in children. Nature communications Cai, W., Duberg, K., Padmanabhan, A., Rehert, R., Bradley, T., Carrion, V., Menon, V. 2019; 10 (1): 4798

  Abstract

  Inhibitory control is fundamental to children's self-regulation and cognitive development. Here we investigate cortical-basal ganglia pathways underlying inhibitory control in children and their adult-like maturity. We first conduct a comprehensive meta-analysis of extant neurodevelopmental studies of inhibitory control and highlight important gaps in the literature. Second, we examine cortical-basal ganglia activation during inhibitory control in children ages 9-12 and demonstrate the formation of an adult-like inhibitory control network by late childhood. Third, we develop a neural maturation index (NMI), which assesses the similarity of brain activation patterns between children and adults, and demonstrate that higher NMI in children predicts better inhibitory control. Fourth, we show that activity in the subthalamic nucleus and its effective connectivity with the right anterior insula predicts children's inhibitory control. Fifth, we replicate our findings across multiple cohorts. Our findings provide insights into cortical-basal ganglia circuits and global brain organization underlying the development of inhibitory control.

  View details for DOI 10.1038/s41467-019-12756-8

  View details for PubMedID 31641118

• Dysregulated Brain Dynamics in a Triple-Network Saliency Model of Schizophrenia and Its Relation to Psychosis BIOLOGICAL PSYCHIATRY Supekar, K., Cai, W., Krishnadas, R., Palaniyappan, L., Menon, V. 2019; 85 (1): 60–69

  View details for DOI 10.1016/j.biopsych.2018.07.020

  View details for Web of Science ID 000451916700010

• Dopamine-related dissociation of cortical and subcortical brain activations in cognitively unimpaired Parkinson's disease patients OFF and ON medications NEUROPSYCHOLOGIA Kim, J., Zhang, K., Cai, W., YorkWilliams, S., Cruadhlaoich, M., Llanes, S., Menon, V., Poston, K. L. 2018; 119: 24–33

  View details for DOI 10.1016/j.neuropsychologia.2018.07.024

  View details for Web of Science ID 000450543800003

• 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 (1): 2505

  Abstract

  Human cognition is influenced not only by external task demands but also latent mental processes and brain states that change over time. Here, we use novel Bayesian switching dynamical systems algorithm to identify hidden brain states and determine that these states are only weakly aligned with external task conditions. We compute state transition probabilities and demonstrate how dynamic transitions between hidden states allow flexible reconfiguration of functional brain circuits. Crucially, we identify latent transient brain states and dynamic functional circuits that are optimal for cognition and show that failure to engage these states in a timely manner is associated with poorer task performance and weaker decision-making dynamics. We replicate findings in a large sample (N=122) and reveal a robust link between cognition and flexible latent brain state dynamics. Our study demonstrates the power of switching dynamical systems models for investigating hidden dynamic brain states and functional interactions underlying human cognition.

  View details for PubMedID 29950686

• Aberrant Time-Varying Cross-Network Interactions in Children With Attention-Deficit/Hyperactivity Disorder and the Relationto Attention Deficits. Biological psychiatry. Cognitive neuroscience and neuroimaging Cai, W., Chen, T., Szegletes, L., Supekar, K., Menon, V. 2018; 3 (3): 263–73

  Abstract

  BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is thought to stem from aberrancies in large-scale cognitive control networks. However, the exact nature of aberrant brain circuit dynamics involving these control networks is poorly understood. Using a saliency-based triple-network model of cognitive control, we tested the hypothesis that dynamic cross-network interactions among the salience, central executive, and default mode networks are dysregulated in children with ADHD, and we investigated how these dysregulations contribute to inattention.METHODS: Using functional magnetic resonance imaging data from 140 children with ADHD and typically developing children from two cohorts (primary cohort= 80 children, replication cohort= 60 children) in a case-control design, we examined both time-averaged and dynamic time-varying cross-network interactions in each cohort separately.RESULTS: Time-averaged measures of salience network-centered cross-network interactions were significantly lower in children with ADHD compared with typically developing children and were correlated with severity of inattention symptoms. Children with ADHD displayed more variable dynamic cross-network interaction patterns, including less persistent brain states, significantly shorter mean lifetimes of brain states, and intermittently weaker cross-network interactions. Importantly, dynamic time-varying measures of cross-network interactions were more strongly correlated with inattention symptoms than with time-averaged measures of functional connectivity. Crucially, we replicated these findings in the two independent cohorts of children with ADHD and typically developing children.CONCLUSIONS: Aberrancies in time-varying engagement of the salience network with the central executive network and default mode network are a robust and clinically relevant neurobiological signature of childhood ADHD symptoms. The triple-network neurocognitive model provides a novel, replicable, and parsimonious dynamical systems neuroscience framework for characterizing childhood ADHD and inattention.

  View details for PubMedID 29486868

• Aberrant Time-Varying Cross-Network Interactions in Children With Attention-Deficit/Hyperactivity Disorder and the Relation to Attention Deficits BIOLOGICAL PSYCHIATRY-COGNITIVE NEUROSCIENCE AND NEUROIMAGING Cai, W., Chen, T., Szegletes, L., Supekar, K., Menon, V. 2018; 3 (3): 263–73

  View details for DOI 10.1016/j.bpsc.2017.10.005

  View details for Web of Science ID 000494340900012

• 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

• Dissociable Fronto-Operculum-Insula Control Signals for Anticipation and Detection of Inhibitory Sensory Cue. Cerebral cortex Cai, W., Chen, T., Ide, J. S., Li, C. R., Menon, V. 2016: -?

  Abstract

  The ability to anticipate and detect behaviorally salient stimuli is important for virtually all adaptive behaviors, including inhibitory control that requires the withholding of prepotent responses when instructed by external cues. Although right fronto-operculum-insula (FOI), encompassing the anterior insular cortex (rAI) and inferior frontal cortex (rIFC), involvement in inhibitory control is well established, little is known about signaling mechanisms underlying their differential roles in detection and anticipation of salient inhibitory cues. Here we use 2 independent functional magnetic resonance imaging data sets to investigate dynamic causal interactions of the rAI and rIFC, with sensory cortex during detection and anticipation of inhibitory cues. Across 2 different experiments involving auditory and visual inhibitory cues, we demonstrate that primary sensory cortex has a stronger causal influence on rAI than on rIFC, suggesting a greater role for the rAI in detection of salient inhibitory cues. Crucially, a Bayesian prediction model of subjective trial-by-trial changes in inhibitory cue anticipation revealed that the strength of causal influences from rIFC to rAI increased significantly on trials in which participants had higher anticipation of inhibitory cues. Together, these results demonstrate the dissociable bottom-up and top-down roles of distinct FOI regions in detection and anticipation of behaviorally salient cues across multiple sensory modalities.

  View details for PubMedID 27473319

• 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

• Causal Interactions Within a Frontal-Cingulate-Parietal Network During Cognitive Control: Convergent Evidence from a Multisite-Multitask Investigation. Cerebral cortex Cai, W., Chen, T., Ryali, S., Kochalka, J., Li, C. R., Menon, V. 2016; 26 (5): 2140-2153

  Abstract

  Cognitive control plays an important role in goal-directed behavior, but dynamic brain mechanisms underlying it are poorly understood. Here, using multisite fMRI data from over 100 participants, we investigate causal interactions in three cognitive control tasks within a core Frontal-Cingulate-Parietal network. We found significant causal influences from anterior insula (AI) to dorsal anterior cingulate cortex (dACC) in all three tasks. The AI exhibited greater net causal outflow than any other node in the network. Importantly, a similar pattern of causal interactions was uncovered by two different computational methods for causal analysis. Furthermore, the strength of causal interaction from AI to dACC was greater on high, compared with low, cognitive control trials and was significantly correlated with individual differences in cognitive control abilities. These results emphasize the importance of the AI in cognitive control and highlight its role as a causal hub in the Frontal-Cingulate-Parietal network. Our results further suggest that causal signaling between the AI and dACC plays a fundamental role in implementing cognitive control and are consistent with a two-stage cognitive control model in which the AI first detects events requiring greater access to cognitive control resources and then signals the dACC to execute load-specific cognitive control processes.

  View details for DOI 10.1093/cercor/bhv046

  View details for PubMedID 25778346

• Compensatory neural mechanisms in cognitively unimpaired Parkinson disease. Annals of neurology Poston, K. L., YorkWilliams, S., Zhang, K., Cai, W., Everling, D., Tayim, F. M., Llanes, S., Menon, V. 2016; 79 (3): 448-463

  Abstract

  Cognitive impairments in Parkinson's disease (PD) are thought to be caused in part by dopamine dysregulation. However, even when nigrostriatal dopamine neuron loss is severe enough to cause motor symptoms, many patients remain cognitively unimpaired. It is unclear what brain mechanisms allow these patients to remain cognitively unimpaired despite substantial dopamine dysregulation.31 cognitively unimpaired PD participants OFF dopaminergic-medications were scanned using fMRI while they performed a working memory task, along with 23 controls. We first compared the PD_OFF medication group with controls to determine whether PD participants engage compensatory frontostriatal mechanisms during working memory. We then studied the same PD participants ON dopaminergic-medications to determine whether these compensatory brain changes are altered with dopamine.Controls and PD showed working memory load-dependent activation in the bilateral putamen, anterior-dorsal insula, supplementary motor area, and anterior cingulate cortex. Compared to controls, PD_OFF showed compensatory hyper-activation of bilateral putamen and posterior insula, and machine learning algorithms identified robust differences in putamen activation patterns. Compared to PD_OFF, PD_ON showed reduced compensatory activation in the putamen. Loss of compensatory hyper-activation ON dopaminergic-medication correlated with slower performance on the working memory task and slower cognitive speed on the Symbol Digit Modality Test.Our results provide novel evidence that PD patients maintain normal cognitive performance through compensatory hyper-activation of the putamen. Dopaminergic-medication down-regulates this hyper-activation and the degree of down-regulation predicts behavior. Identifying cognitive compensatory mechanisms in PD is important for understanding how some patients maintain intact cognitive performance, despite nigrostriatal dopamine loss. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ana.24585

  View details for PubMedID 26696272

• 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

• Evidence Supports Specific Braking Function for Inferior PFC. Trends in cognitive sciences Aron, A. R., Cai, W. n., Badre, D. n., Robbins, T. W. 2015

  View details for PubMedID 26482801

• 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 Web of Science ID 000345220100015

  View details for PubMedCentralID PMC4212065

• Sensorimotor-independent prefrontal activity during response inhibition HUMAN BRAIN MAPPING Cai, W., Cannistraci, C. J., Gore, J. C., Leung, H. 2014; 35 (5): 2119-2136

  Abstract

  A network of brain regions involving the ventral inferior frontal gyrus/anterior insula (vIFG/AI), presupplementary motor area (pre-SMA) and basal ganglia has been implicated in stopping impulsive, unwanted responses. However, whether this network plays an equal role in response inhibition under different sensorimotor contexts has not been tested systematically. Here, we conducted an fMRI experiment using the stop signal task, a sensorimotor task requiring occasional withholding of the planned response upon the presentation of a stop signal. We manipulated both the sensory modality of the stop signal (visual versus auditory) and the motor response modality (hand versus eye). Results showed that the vIFG/AI and the preSMA along with the right middle frontal gyrus were commonly activated in response inhibition across the various sensorimotor conditions. Our findings provide direct evidence for a common role of these frontal areas, but not striatal areas in response inhibition independent of the sensorimotor contexts. Nevertheless, these three frontal regions exhibited different activation patterns during successful and unsuccessful stopping. Together with the existing evidence, we suggest that the vIFG/AI is involved in the early stages of stopping such as triggering the stop process while the preSMA may play a role in regulating other cortical and subcortical regions involved in stopping.

  View details for DOI 10.1002/hbm.22315

  View details for Web of Science ID 000334012100023

  View details for PubMedID 23798325

• Proactive Selective Response Suppression Is Implemented via the Basal Ganglia JOURNAL OF NEUROSCIENCE Majid, D. S., Cai, W., Corey-Bloom, J., Aron, A. R. 2013; 33 (33): 13259-13269

  Abstract

  In the welter of everyday life, people can stop particular response tendencies without affecting others. A key requirement for such selective suppression is that subjects know in advance which responses need stopping. We hypothesized that proactively setting up and implementing selective suppression relies on the basal ganglia and, specifically, regions consistent with the inhibitory indirect pathway for which there is scant functional evidence in humans. Consistent with this hypothesis, we show, first, that the degree of proactive motor suppression when preparing to stop selectively (indexed by transcranial magnetic stimulation) corresponds to striatal, pallidal, and frontal activation (indexed by functional MRI). Second, we demonstrate that greater striatal activation at the time of selective stopping correlates with greater behavioral selectivity. Third, we show that people with striatal and pallidal volume reductions (those with premanifest Huntington's disease) have both absent proactive motor suppression and impaired behavioral selectivity when stopping. Thus, stopping goals are used to proactively set up specific basal ganglia channels that may then be triggered to implement selective suppression. By linking this suppression to the striatum and pallidum, these results provide compelling functional evidence in humans of the basal ganglia's inhibitory indirect pathway.

  View details for DOI 10.1523/JNEUROSCI.5651-12.2013

  View details for Web of Science ID 000323155700002

  View details for PubMedID 23946385

  View details for PubMedCentralID PMC3742918

• The role of the right presupplementary motor area in stopping action: two studies with event-related transcranial magnetic stimulation JOURNAL OF NEUROPHYSIOLOGY Cai, W., George, J. S., Verbruggen, F., Chambers, C. D., Aron, A. R. 2012; 108 (2): 380-389

  Abstract

  Rapidly stopping action engages a network in the brain including the right presupplementary motor area (preSMA), the right inferior frontal gyrus, and the basal ganglia. Yet the functional role of these different regions within the overall network still remains unclear. Here we focused on the role of the right preSMA in behavioral stopping. We hypothesized that the underlying neurocognitive function of this region is one or more of setting up a stopping rule in advance, modulating response tendencies (e.g., slowing down in anticipation of stopping), and implementing stopping when the stop signal occurs. We performed two experiments with magnetic resonance imaging (MRI)-guided, event-related, transcranial magnetic stimulation(TMS), during the performance of variants of the stop signal task. In experiment 1 we show that stimulation of the right preSMA versus vertex (control site) slowed the implementation of stopping (measured via stop signal reaction time) but had no influence on modulation of response tendencies. In experiment 2, we showed that stimulation of the right preSMA slowed implementation of stopping in a mechanistically selective form of stopping but had no influence on setting up stopping rules. The results go beyond the replication of prior findings by showing that TMS of the right preSMA impairs stopping behavior (including a behaviorally selective form of stopping) through a specific disruption of the implementation of stopping. Future studies are required to establish whether this was due to stimulation of the right preSMA itself or because of remote effects on the wider stopping network.

  View details for DOI 10.1152/jn.00132.2012

  View details for Web of Science ID 000306416400002

  View details for PubMedID 22514296

  View details for PubMedCentralID PMC3404792

• Stimulating deep cortical structures with the batwing coil: How to determine the intensity for transcranial magnetic stimulation using coil-cortex distance JOURNAL OF NEUROSCIENCE METHODS Cai, W., George, J. S., Chambers, C. D., Stokes, M. G., Verbruggen, F., Aron, A. R. 2012; 204 (2): 238-241

  Abstract

  Transcranial magnetic stimulation (TMS) is increasingly used in cognitive neuroscience to probe non-motor cortical regions. A key question for such studies is the choice of stimulation intensity. Early studies used a simple metric such as 115% of motor threshold (MT) for non-motor regions; where MT is the stimulation intensity required to elicit a particular amplitude of motor evoked potential or visible muscle twitch when the coil is placed over primary motor cortex. Recently, however, it was demonstrated that this simple metric for stimulation of non-motor regions is inadequate - it could lead to over or under-stimulation depending on the distance between the coil and the cortex. Instead, a method was developed to scale the motor threshold based on coil-cortex distance, at least for standard figure-of-eight stimulating coils. Here we validate the same method for a 'batwing coil', which is designed to stimulate deeper cortical structures such as the medial frontal cortex. We modulated coil-cortex distance within-participant by inserting spacers of different thickness between coil and scalp. We then measured MT at each spacer. We show that for every millimeter between coil and scalp an additional 1.4% of TMS output is required to induce an equivalent level of brain stimulation at the motor cortex. Using this parameter we describe a linear function to adjust MT for future studies of non-motor regions-of-interest using the batwing coil. This is the first study to demonstrate the effects of coil-cortical distance on stimulation efficiency via a monophasic system using a batwing coil.

  View details for DOI 10.1016/j.jneumeth.2011.11.020

  View details for Web of Science ID 000301612700005

  View details for PubMedID 22138632

  View details for PubMedCentralID PMC3633572

• Stopping speech suppresses the task-irrelevant hand BRAIN AND LANGUAGE Cai, W., Oldenkamp, C. L., Aron, A. R. 2012; 120 (3): 412-415

  Abstract

  Some situations require one to quickly stop an initiated response. Recent evidence suggests that rapid stopping engages a mechanism that has diffuse effects on the motor system. For example, stopping the hand dampens the excitability of the task-irrelevant leg. However, it is unclear whether this 'global suppression' could apply across wider motor modalities. Here we tested whether stopping speech leads to suppression of the task-irrelevant hand. We used Transcranial Magnetic Stimulation over the primary motor cortex with concurrent electromyography from the hand. We found that when speech was successfully stopped the motor evoked potential from the task-irrelevant hand was significantly reduced compared to when the participant failed to stop speaking, or responded on non stop signal trials, or compared to baseline. This shows that when speech is quickly stopped, there is a broad suppression across the motor system. This has implications for the neural basis of speech control and stuttering.

  View details for DOI 10.1016/j.bandl.2011.11.006

  View details for Web of Science ID 000301759100022

  View details for PubMedID 22206872

  View details for PubMedCentralID PMC3533487

• Roles for the pre-supplementary motor area and the right inferior frontal gyrus in stopping action: Electrophysiological responses and functional and structural connectivity NEUROIMAGE Swann, N. C., Cai, W., Conner, C. R., Pieters, T. A., Claffey, M. P., George, J. S., Aron, A. R., Tandon, N. 2012; 59 (3): 2860-2870

  Abstract

  Both the pre-supplementary motor area (preSMA) and the right inferior frontal gyrus (rIFG) are important for stopping action outright. These regions are also engaged when preparing to stop. We aimed to elucidate the roles of these regions by harnessing the high spatio-temporal resolution of electrocorticography (ECoG), and by using a task that engages both preparing to stop and stopping outright. First, we validated the task using fMRI in 16 healthy control participants to confirm that both the preSMA and the rIFG were active. Next, we studied a rare patient with intracranial grid coverage of both these regions, using macrostimulation, diffusion tractography, cortico-cortical evoked potentials (CCEPs) and task-based ECoG. Macrostimulation of the preSMA induced behavioral motor arrest. Diffusion tractography revealed a structural connection between the preSMA and rIFG. CCEP analysis showed that stimulation of the preSMA evoked strong local field potentials within 30 ms in rIFG. During the task, when preparing to stop, there was increased high gamma amplitude (~70-250 Hz) in both regions, with preSMA preceding rIFG by ~750 ms. For outright stopping there was also a high gamma amplitude increase in both regions, again with preSMA preceding rIFG. Further, at the time of stopping, there was an increase in beta band activity (~16 Hz) in both regions, with significantly stronger inter-regional coherence for successful vs. unsuccessful stop trials. The results complement earlier reports of a structural/functional action control network between the preSMA and rIFG. They go further by revealing between-region timing differences in the high gamma band when preparing to stop and stopping outright. They also reveal strong between-region coherence in the beta band when stopping is successful. Implications for theories of action control are discussed.

  View details for DOI 10.1016/j.neuroimage.2011.09.049

  View details for Web of Science ID 000299494000085

  View details for PubMedID 21979383

  View details for PubMedCentralID PMC3322194

• Transcranial Magnetic Stimulation Reveals Dissociable Mechanisms for Global Versus Selective Corticomotor Suppression Underlying the Stopping of Action CEREBRAL CORTEX Majid, D. S., Cai, W., George, J. S., Verbruggen, F., Aron, A. R. 2012; 22 (2): 363-371

  Abstract

  Stopping an initiated response is an essential function, investigated in many studies with go/no-go and stop-signal paradigms. These standard tests require rapid action cancellation. This appears to be achieved by a suppression mechanism that has "global" effects on corticomotor excitability (i.e., affecting task-irrelevant muscles). By contrast, stopping action in everyday life may require selectivity (i.e., targeting a specific response tendency without affecting concurrent action). We hypothesized that while standard stopping engages global suppression, behaviorally selective stopping engages a selective suppression mechanism. Accordingly, we measured corticomotor excitability of the task-irrelevant leg using transcranial magnetic stimulation while subjects stopped the hand. Experiment 1 showed that for standard (i.e., nonselective) stopping, the task-irrelevant leg was suppressed. Experiment 2 showed that for behaviorally selective stopping, there was no mean leg suppression. Experiment 3 directly compared behaviorally nonselective and selective stopping. Leg suppression occurred only in the behaviorally nonselective condition. These results argue that global and selective suppression mechanisms are dissociable. Participants may use a global suppression mechanism when speed is stressed; however, they may recruit a more selective suppression mechanism when selective stopping is behaviorally necessary and preparatory information is available. We predict that different fronto-basal-ganglia pathways underpin these different suppression mechanisms.

  View details for DOI 10.1093/cercor/bhr112

  View details for Web of Science ID 000299124400011

  View details for PubMedID 21666129

  View details for PubMedCentralID PMC3256406

• Rule-Guided Executive Control of Response Inhibition: Functional Topography of the Inferior Frontal Cortex PLOS ONE Cai, W., Leung, H. 2011; 6 (6)

  Abstract

  The human inferior frontal cortex (IFC) is a large heterogeneous structure with distinct cytoarchitectonic subdivisions and fiber connections. It has been found involved in a wide range of executive control processes from target detection, rule retrieval to response control. Since these processes are often being studied separately, the functional organization of executive control processes within the IFC remains unclear.We conducted an fMRI study to examine the activities of the subdivisions of IFC during the presentation of a task cue (rule retrieval) and during the performance of a stop-signal task (requiring response generation and inhibition) in comparison to a not-stop task (requiring response generation but not inhibition). We utilized a mixed event-related and block design to separate brain activity in correspondence to transient control processes from rule-related and sustained control processes. We found differentiation in control processes within the IFC. Our findings reveal that the bilateral ventral-posterior IFC/anterior insula are more active on both successful and unsuccessful stop trials relative to not-stop trials, suggesting their potential role in the early stage of stopping such as triggering the stop process. Direct countermanding seems to be outside of the IFC. In contrast, the dorsal-posterior IFC/inferior frontal junction (IFJ) showed transient activity in correspondence to the infrequent presentation of the stop signal in both tasks and the left anterior IFC showed differential activity in response to the task cues. The IFC subdivisions also exhibited similar but distinct patterns of functional connectivity during response control.Our findings suggest that executive control processes are distributed across the IFC and that the different subdivisions of IFC may support different control operations through parallel cortico-cortical and cortico-striatal circuits.

  View details for DOI 10.1371/journal.pone.0020840

  View details for Web of Science ID 000291356400032

  View details for PubMedID 21673969

  View details for PubMedCentralID PMC3108978

• A Proactive Mechanism for Selective Suppression of Response Tendencies JOURNAL OF NEUROSCIENCE Cai, W., Oldenkamp, C. L., Aron, A. R. 2011; 31 (16): 5965-5969

  Abstract

  While most research on stopping action examines how an initiated response is stopped when a signal occurs (i.e., reactively), everyday life also calls for a mechanism to prepare to stop a particular response tendency (i.e., proactively and selectively). We hypothesized that human subjects can prepare to stop a particular response by proactively suppressing that response representation in the brain. We tested this by using single-pulse transcranial magnetic stimulation and concurrent electromyography. This allowed us to interrogate the corticomotor excitability of specific response representations even before action ensued. We found that the motor evoked potential of the effector that might need to be stopped in the future was significantly reduced compared with when that effector was at rest. Further, this neural index of proactive and selective suppression predicted the subsequent selectivity with which the behavioral response was stopped. These results go further than earlier reports of reduced motor excitability when responses are stopped. They show that the control can be applied in advance (proactively) and also targeted at a particular response channel (selectively). This provides novel evidence for an active mechanism of suppression in the brain that is setup according to the subject's goals and even before action ensues.

  View details for DOI 10.1523/JNEUROSCI.6292-10.2011

  View details for Web of Science ID 000289769400010

  View details for PubMedID 21508221

  View details for PubMedCentralID PMC3111595

• Deep Brain Stimulation of the Subthalamic Nucleus Alters the Cortical Profile of Response Inhibition in the Beta Frequency Band: A Scalp EEG Study in Parkinson's Disease JOURNAL OF NEUROSCIENCE Swann, N., Poizner, H., Houser, M., Gould, S., Greenhouse, I., Cai, W., Strunk, J., George, J., Aron, A. R. 2011; 31 (15): 5721-5729

  Abstract

  Stopping an initiated response could be implemented by a fronto-basal-ganglia circuit, including the right inferior frontal cortex (rIFC) and the subthalamic nucleus (STN). Intracranial recording studies in humans reveal an increase in beta-band power (approximately 16-20 Hz) within the rIFC and STN when a response is stopped. This suggests that the beta-band could be important for communication in this network. If this is the case, then altering one region should affect the electrophysiological response at the other. We addressed this hypothesis by recording scalp EEG during a stop task while modulating STN activity with deep brain stimulation. We studied 15 human patients with Parkinson's disease and 15 matched healthy control subjects. Behaviorally, patients OFF stimulation were slower than controls to stop their response. Moreover, stopping speed was improved for ON compared to OFF stimulation. For scalp EEG, there was greater beta power, around the time of stopping, for patients ON compared to OFF stimulation. This effect was stronger over the right compared to left frontal cortex, consistent with the putative right lateralization of the stopping network. Thus, deep brain stimulation of the STN improved behavioral stopping performance and increased the beta-band response over the right frontal cortex. These results complement other evidence for a structurally connected functional circuit between right frontal cortex and the basal ganglia. The results also suggest that deep brain stimulation of the STN may improve task performance by increasing the fidelity of information transfer within a fronto-basal-ganglia circuit.

  View details for DOI 10.1523/JNEUROSCI.6135-10.2011

  View details for Web of Science ID 000289472400021

  View details for PubMedID 21490213

  View details for PubMedCentralID PMC3086079

• Cortical activity during manual response inhibition guided by color and orientation cues BRAIN RESEARCH Cai, W., Leung, H. 2009; 1261: 20-28

  Abstract

  It has been suggested that the right inferior frontal gyrus (IFG) plays a critical role in manual response inhibition, although neuroimaging studies of healthy adults have also reported widespread activations in other cortical regions during a variety of response inhibition tasks. We conducted a functional magnetic resonance imaging (fMRI) experiment to examine whether the activation of the IFG is dependent on the type of visuo-motor associations during response inhibition by varying the feature of the stop signal (color vs. orientation) in the stop-signal task. Results from 12 subjects showed that the bilateral ventral posterior IFG, anterior insula, inferior frontal junction (IFJ), middle temporal gyrus (MTG) and fusiform gyrus (FG) are active during response inhibition cued by both color and orientation stop signals. While only the MTG showed differential activity to the two stop signals, both MTG and FG showed significantly stronger activity during successful than unsuccessful stopping of unwanted responses cued by orientation and color, respectively. Our findings suggest that the right ventral posterior IFG may play a more general role in response inhibition regardless of the feature of the visual signal, while successful inhibition may depend on efficient processing of the signal.

  View details for DOI 10.1016/j.brainres.2008.12.073

  View details for Web of Science ID 000264693300003

  View details for PubMedID 19401178

  View details for PubMedCentralID PMC2783273

• Common and differential ventrolateral prefrontal activity during inhibition of hand and eye movements JOURNAL OF NEUROSCIENCE Leung, H., Cai, W. 2007; 27 (37): 9893-9900

  Abstract

  The inferior frontal cortex, particularly the ventrolateral prefrontal cortex (VLPFC) in the right hemisphere, has been implicated to serve as a general inhibitory mechanism in the cognitive control of behavior. Because this notion was primarily based on studies of response inhibition in manual tasks, it has yet to be validated in other response modalities. We conducted a functional magnetic resonance imaging study to examine whether the VLPFC is commonly activated during inhibition of responses by hand and by eye within the same subjects. We used the stop-signal task, a relatively pure measure of response inhibition, as the behavioral paradigm. Results from 12 subjects showed that both the right and the left caudal VLPFC and anterior insula, rostral to the premotor area, are activated during inhibition of both manual and saccadic responses. Within the posterior VLPFC, activations overlapped to a significant extent across the two response modalities, although a weaker functionally differentiation was also found along the dorsoventral axis. Other areas such as medial superior frontal gyrus (pre-supplementary motor area/supplementary eye field), dorsolateral prefrontal cortex, and inferior parietal cortex were also activated during canceling both hand and eye movements. Our findings suggest that a common VLPFC network is involved in response inhibition, although the specific control of the different response modalities may be partially segregated within the lateral prefrontal cortex.

  View details for DOI 10.1523/JNEUROSCI.2837-07.2007

  View details for Web of Science ID 000249415000010

  View details for PubMedID 17855604