Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients-both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged the visual2 and somatomotor network connections and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p=2e-10, Hedges' g=1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, or anxiety. It had moderate test-retest reliability (ICC=.61) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC=.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

The Transdiagnostic Connectome Project: a richly phenotyped open dataset for advancing the study of brain-behavior relationships in psychiatry.

An important aim in psychiatry is the establishment of valid and reliable associations linking profiles of brain functioning to clinically relevant symptoms and behaviors across patient populations. To advance progress in this area, we introduce an open dataset containing behavioral and neuroimaging data from 241 individuals aged 18 to 70, comprising 148 individuals meeting diagnostic criteria for a broad range of psychiatric illnesses and a healthy comparison group of 93 individuals. These data include high-resolution anatomical scans, multiple resting-state, and task-based functional MRI runs. Additionally, participants completed over 50 psychological and cognitive assessments. Here, we detail available behavioral data as well as raw and processed MRI derivatives. Associations between data processing and quality metrics, such as head motion, are reported. Processed data exhibit classic task activation effects and canonical functional network organization. Overall, we provide a comprehensive and analysis-ready transdiagnostic dataset, which we hope will accelerate the identification of illness-relevant features of brain functioning, enabling future discoveries in basic and clinical neuroscience.

A shared spatial topography links the functional connectome correlates of cocaine use disorder and dopamine D2/3 receptor densities.

Background: The biological mechanisms that contribute to cocaine and other substance use disorders involve an array of cortical and subcortical systems. Prior work on the development and maintenance of substance use has largely focused on cortico-striatal circuits, with relatively less attention on alterations within and across large-scale functional brain networks, and associated aspects of the dopamine system. The brain-wide pattern of temporal co-activation between distinct brain regions, referred to as the functional connectome, underpins individual differences in behavior. Critically, the functional connectome correlates of substance use and their specificity to dopamine receptor densities relative to other metabotropic receptors classes remains to be established. Methods: We comprehensively characterized brain-wide differences in functional connectivity across multiple scales, including individual connections, regions, and networks in participants with cocaine use disorder (CUD; n=69) and healthy matched controls (n=62), Further, we studied the relationship between the observed functional connectivity signatures of CUD and the spatial distribution of a broad range of normative neurotransmitter receptor and transporter bindings as assessed through 18 different normative positron emission tomography (PET) maps. Results: Our analyses identified a widespread profile of functional connectivity differences between individuals with CUD and matched healthy comparison participants (8.8% of total edges; 8,185 edges; pFWE=0.025). We largely find lower connectivity preferentially linking default network and subcortical regions, and higher within-network connectivity in the default network in participants with CUD. Furthermore, we find consistent and replicable associations between signatures of CUD and normative spatial density of dopamine D2/3 receptors. Conclusions: Our analyses revealed a widespread profile of altered connectivity in individuals with CUD that extends across the functional connectome and implicates multiple circuits. This profile is robustly coupled with normative dopamine D2/3 receptors densities. Underscoring the translational potential of connectomic approaches for the study of in vivo brain functions, CUD-linked aspects of brain function were spatially coupled to disorder relevant neurotransmitter systems.

Distinct brain network features predict internalizing and externalizing traits in children and adults.

Internalizing and externalizing traits are two distinct classes of behaviors in psychiatry. However, whether shared or unique brain network features predict internalizing and externalizing behaviors in children and adults remain poorly understood. Using a sample of 2262 children from the Adolescent Brain Cognitive Development (ABCD) study and 752 adults from the Human Connectome Project (HCP), we show that network features predicting internalizing and externalizing behavior are, at least in part, dissociable in children, but not in adults. In ABCD children, traits within internalizing and externalizing behavioral categories are predicted by more similar network features concatenated across task and resting states than those between different categories. We did not observe this pattern in HCP adults. Distinct network features predict internalizing and externalizing behaviors in ABCD children and HCP adults. These data reveal shared and unique brain network features accounting for individual variation within broad internalizing and externalizing categories across developmental stages.

Protocol for activity flow mapping of neurocognitive computations using the Brain Activity Flow Toolbox.

Traditional cognitive neuroscience uses task-evoked activations to map neurocognitive processes (and information) to brain regions; however, how those processes are generated is unknown. We developed activity flow mapping to identify and empirically validate network mechanisms underlying the generation of neurocognitive processes. This approach models the movement of task-evoked activity over brain connections to predict task-evoked activations. We present a protocol for using the Brain Activity Flow Toolbox (https://colelab.github.io/ActflowToolbox/) to identify network mechanisms underlying neurocognitive processes of interest. For complete details on the use and execution of this protocol, please refer to Cole et al., 2021.

The Functional Relevance of Task-State Functional Connectivity.

Resting-state functional connectivity has provided substantial insight into intrinsic brain network organization, yet the functional importance of task-related change from that intrinsic network organization remains unclear. Indeed, such task-related changes are known to be small, suggesting they may have only minimal functional relevance. Alternatively, despite their small amplitude, these task-related changes may be essential for the ability of the human brain to adaptively alter its functionality via rapid changes in inter-regional relationships. We used activity flow mapping-an approach for building empirically derived network models-to quantify the functional importance of task-state functional connectivity (above and beyond resting-state functional connectivity) in shaping cognitive task activations in the (female and male) human brain. We found that task-state functional connectivity could be used to better predict independent fMRI activations across all 24 task conditions and all 360 cortical regions tested. Further, we found that prediction accuracy was strongly driven by individual-specific functional connectivity patterns, while functional connectivity patterns from other tasks (task-general functional connectivity) still improved predictions beyond resting-state functional connectivity. Additionally, since activity flow models simulate how task-evoked activations (which underlie behavior) are generated, these results may provide mechanistic insight into why prior studies found correlations between task-state functional connectivity and individual differences in behavior. These findings suggest that task-related changes to functional connections play an important role in dynamically reshaping brain network organization, shifting the flow of neural activity during task performance.SIGNIFICANCE STATEMENT Human cognition is highly dynamic, yet the functional network organization of the human brain is highly similar across rest and task states. We hypothesized that, despite this overall network stability, task-related changes from the intrinsic (resting-state) network organization of the brain strongly contribute to brain activations during cognitive task performance. Given that cognitive task activations emerge through network interactions, we leveraged connectivity-based models to predict independent cognitive task activations using resting-state versus task-state functional connectivity. This revealed that task-related changes in functional network organization increased prediction accuracy of cognitive task activations substantially, demonstrating their likely functional relevance for dynamic cognitive processes despite the small size of these task-related network changes.

Flexible Coordinator and Switcher Hubs for Adaptive Task Control.

Functional connectivity (FC) studies have identified at least two large-scale neural systems that constitute cognitive control networks, the frontoparietal network (FPN) and cingulo-opercular network (CON). Control networks are thought to support goal-directed cognition and behavior. It was previously shown that the FPN flexibly shifts its global connectivity pattern according to task goal, consistent with a "flexible hub" mechanism for cognitive control. Our aim was to build on this finding to develop a functional cartography (a multimetric profile) of control networks in terms of dynamic network properties. We quantified network properties in (male and female) humans using a high-control-demand cognitive paradigm involving switching among 64 task sets. We hypothesized that cognitive control is enacted by the FPN and CON via distinct but complementary roles reflected in network dynamics. Consistent with a flexible "coordinator" mechanism, FPN connections were varied across tasks, while maintaining within-network connectivity to aid cross-region coordination. Consistent with a flexible "switcher" mechanism, CON regions switched to other networks in a task-dependent manner, driven primarily by reduced within-network connections to other CON regions. This pattern of results suggests FPN acts as a dynamic, global coordinator of goal-relevant information, while CON transiently disbands to lend processing resources to other goal-relevant networks. This cartography of network dynamics reveals a dissociation between two prominent cognitive control networks, suggesting complementary mechanisms underlying goal-directed cognition.SIGNIFICANCE STATEMENT Cognitive control supports a variety of behaviors requiring flexible cognition, such as rapidly switching between tasks. Furthermore, cognitive control is negatively impacted in a variety of mental illnesses. We used tools from network science to characterize the implementation of cognitive control by large-scale brain systems. This revealed that two systems, the frontoparietal (FPN) and cingulo-opercular (CON) networks, have distinct but complementary roles in controlling global network reconfigurations. The FPN exhibited properties of a flexible coordinator (orchestrating task changes), while CON acted as a flexible switcher (switching specific regions to other systems to lend processing resources). These findings reveal an underlying distinction in cognitive processes that may be applicable to clinical, educational, and machine learning work targeting cognitive flexibility.

Discovering the Computational Relevance of Brain Network Organization.

Understanding neurocognitive computations will require not just localizing cognitive information distributed throughout the brain but also determining how that information got there. We review recent advances in linking empirical and simulated brain network organization with cognitive information processing. Building on these advances, we offer a new framework for understanding the role of connectivity in cognition: network coding (encoding/decoding) models. These models utilize connectivity to specify the transfer of information via neural activity flow processes, successfully predicting the formation of cognitive representations in empirical neural data. The success of these models supports the possibility that localized neural functions mechanistically emerge (are computed) from distributed activity flow processes that are specified primarily by connectivity patterns.

Task activations produce spurious but systematic inflation of task functional connectivity estimates.

Most neuroscientific studies have focused on task-evoked activations (activity amplitudes at specific brain locations), providing limited insight into the functional relationships between separate brain locations. Task-state functional connectivity (FC) - statistical association between brain activity time series during task performance - moves beyond task-evoked activations by quantifying functional interactions during tasks. However, many task-state FC studies do not remove the first-order effect of task-evoked activations prior to estimating task-state FC. It has been argued that this results in the ambiguous inference "likely active or interacting during the task", rather than the intended inference "likely interacting during the task". Utilizing a neural mass computational model, we verified that task-evoked activations substantially and inappropriately inflate task-state FC estimates, especially in functional MRI (fMRI) data. Various methods attempting to address this problem have been developed, yet the efficacies of these approaches have not been systematically assessed. We found that most standard approaches for fitting and removing mean task-evoked activations were unable to correct these inflated correlations. In contrast, methods that flexibly fit mean task-evoked response shapes effectively corrected the inflated correlations without reducing effects of interest. Results with empirical fMRI data confirmed the model's predictions, revealing activation-induced task-state FC inflation for both Pearson correlation and psychophysiological interaction (PPI) approaches. These results demonstrate that removal of mean task-evoked activations using an approach that flexibly models task-evoked response shape is an important preprocessing step for valid estimation of task-state FC.