Network modeling of dynamic brain interactions predicts emergence of neural information that supports human cognitive behavior.

How cognitive task behavior is generated by brain network interactions is a central question in neuroscience. Answering this question calls for the development of novel analysis tools that can firstly capture neural signatures of task information with high spatial and temporal precision (the "where and when") and then allow for empirical testing of alternative network models of brain function that link information to behavior (the "how"). We outline a novel network modeling approach suited to this purpose that is applied to noninvasive functional neuroimaging data in humans. We first dynamically decoded the spatiotemporal signatures of task information in the human brain by combining MRI-individualized source electroencephalography (EEG) with multivariate pattern analysis (MVPA). A newly developed network modeling approach-dynamic activity flow modeling-then simulated the flow of task-evoked activity over more causally interpretable (relative to standard functional connectivity [FC] approaches) resting-state functional connections (dynamic, lagged, direct, and directional). We demonstrate the utility of this modeling approach by applying it to elucidate network processes underlying sensory-motor information flow in the brain, revealing accurate predictions of empirical response information dynamics underlying behavior. Extending the model toward simulating network lesions suggested a role for the cognitive control networks (CCNs) as primary drivers of response information flow, transitioning from early dorsal attention network-dominated sensory-to-response transformation to later collaborative CCN engagement during response selection. These results demonstrate the utility of the dynamic activity flow modeling approach in identifying the generative network processes underlying neurocognitive phenomena.

Distributed network flows generate localized category selectivity in human visual cortex.

A central goal of neuroscience is to understand how function-relevant brain activations are generated. Here we test the hypothesis that function-relevant brain activations are generated primarily by distributed network flows. We focused on visual processing in human cortex, given the long-standing literature supporting the functional relevance of brain activations in visual cortex regions exhibiting visual category selectivity. We began by using fMRI data from N = 352 human participants to identify category-specific responses in visual cortex for images of faces, places, body parts, and tools. We then systematically tested the hypothesis that distributed network flows can generate these localized visual category selective responses. This was accomplished using a recently developed approach for simulating - in a highly empirically constrained manner - the generation of task-evoked brain activations by modeling activity flowing over intrinsic brain connections. We next tested refinements to our hypothesis, focusing on how stimulus-driven network interactions initialized in V1 generate downstream visual category selectivity. We found evidence that network flows directly from V1 were sufficient for generating visual category selectivity, but that additional, globally distributed (whole-cortex) network flows increased category selectivity further. Using null network architectures we also found that each region's unique intrinsic "connectivity fingerprint" was key to the generation of category selectivity. These results generalized across regions associated with all four visual categories tested (bodies, faces, places, and tools), and provide evidence that the human brain's intrinsic network organization plays a prominent role in the generation of functionally relevant, localized responses.

Acute psychosocial stress modulates neural and behavioral substrates of cognitive control.

Acute psychosocial stress affects learning, memory, and attention, but the evidence for the influence of stress on the neural processes supporting cognitive control remains mixed. We investigated how acute psychosocial stress influences performance and neural processing during the Go/NoGo task-an established cognitive control task. The experimental group underwent the Trier Social Stress Test (TSST) acute stress induction, whereas the control group completed personality questionnaires. Then, participants completed a functional magnetic resonance imaging (fMRI) Go/NoGo task, with self-report, blood pressure and salivary cortisol measurements of induced stress taken intermittently throughout the experimental session. The TSST was successful in eliciting a stress response, as indicated by significant Stress > Control between-group differences in subjective stress ratings and systolic blood pressure. We did not identify significant differences in cortisol levels, however. The stress induction also impacted subsequent Go/NoGo task performance, with participants who underwent the TSST making fewer commission errors on trials requiring the most inhibitory control (NoGo Green) relative to the control group, suggesting increased vigilance. Univariate analysis of fMRI task-evoked brain activity revealed no differences between stress and control groups for any region. However, using multivariate pattern analysis, stress and control groups were reliably differentiated by activation patterns contrasting the most demanding NoGo trials (i.e., NoGo Green trials) versus baseline in the medial intraparietal area (mIPA, affiliated with the dorsal attention network) and subregions of the cerebellum (affiliated with the default mode network). These results align with prior reports linking the mIPA and the cerebellum to visuomotor coordination, a function central to cognitive control processes underlying goal-directed behavior. This suggests that stressor-induced hypervigilance may produce a facilitative effect on response inhibition which is represented neurally by the activation patterns of cognitive control regions.

Causally informed activity flow models provide mechanistic insight into network-generated cognitive activations.

Brain activity flow models estimate the movement of task-evoked activity over brain connections to help explain network-generated task functionality. Activity flow models have been shown to accurately generate task-evoked brain activations across a wide variety of brain regions and task conditions. However, these models have had limited explanatory power, given known issues with causal interpretations of the standard functional connectivity measures used to parameterize activity flow models. We show here that functional/effective connectivity (FC) measures grounded in causal principles facilitate mechanistic interpretation of activity flow models. We progress from simple to complex FC measures, with each adding algorithmic details reflecting causal principles. This reflects many neuroscientists' preference for reduced FC measure complexity (to minimize assumptions, minimize compute time, and fully comprehend and easily communicate methodological details), which potentially trades off with causal validity. We start with Pearson correlation (the current field standard) to remain maximally relevant to the field, estimating causal validity across a range of FC measures using simulations and empirical fMRI data. Finally, we apply causal-FC-based activity flow modeling to a dorsolateral prefrontal cortex region (DLPFC), demonstrating distributed causal network mechanisms contributing to its strong activation during a working memory task. Notably, this fully distributed model is able to account for DLPFC working memory effects traditionally thought to rely primarily on within-region (i.e., not distributed) recurrent processes. Together, these results reveal the promise of parameterizing activity flow models using causal FC methods to identify network mechanisms underlying cognitive computations in the human brain.

Dorsal attention network activity during perceptual organization is distinct in schizophrenia and predictive of cognitive disorganization.

Visual shape completion is a canonical perceptual organization process that integrates spatially distributed edge information into unified representations of objects. People with schizophrenia show difficulty in discriminating completed shapes, but the brain networks and functional connections underlying this perceptual difference remain poorly understood. Also unclear is whether brain network differences in schizophrenia occur in related illnesses or vary with illness features transdiagnostically. To address these topics, we scanned (functional magnetic resonance imaging, fMRI) people with schizophrenia, bipolar disorder, or no psychiatric illness during rest and during a task in which they discriminated configurations that formed or failed to form completed shapes (illusory and fragmented condition, respectively). Multivariate pattern differences were identified on the cortical surface using 360 predefined parcels and 12 functional networks composed of such parcels. Brain activity flow mapping was used to evaluate the likely involvement of resting-state connections for shape completion. Illusory/fragmented task activation differences ('modulations') in the dorsal attention network (DAN) could distinguish people with schizophrenia from the other groups (AUCs > .85) and could transdiagnostically predict cognitive disorganization severity. Activity flow over functional connections from the DAN could predict secondary visual network modulations in each group, except in schizophrenia. The secondary visual network was strongly and similarly modulated in each group. Task modulations were dispersed over more networks in patients compared to controls. In summary, DAN activity during visual perceptual organization is distinct in schizophrenia, symptomatically relevant, and potentially related to improper attention-related feedback into secondary visual areas.

Brain network mechanisms of visual shape completion.

Visual shape completion recovers object shape, size, and number from spatially segregated edges. Despite being extensively investigated, the process's underlying brain regions, networks, and functional connections are still not well understood. To shed light on the topic, we scanned (fMRI) healthy adults during rest and during a task in which they discriminated pac-man configurations that formed or failed to form completed shapes (illusory and fragmented condition, respectively). Task activation differences (illusory-fragmented), resting-state functional connectivity, and multivariate patterns were identified on the cortical surface using 360 predefined parcels and 12 functional networks composed of such parcels. Brain activity flow mapping (ActFlow) was used to evaluate the likely involvement of resting-state connections for shape completion. We identified 36 differentially-active parcels including a posterior temporal region, PH, whose activity was consistent across 95% of observers. Significant task regions primarily occupied the secondary visual network but also incorporated the frontoparietal, dorsal attention, default mode, and cingulo-opercular networks. Each parcel's task activation difference could be modeled via its resting-state connections with the remaining parcels (r=.62, p<10-9), suggesting that such connections undergird shape completion. Functional connections from the dorsal attention network were key in modelling task activation differences in the secondary visual network. Dorsal attention and frontoparietal connections could also model activations in the remaining networks. Taken together, these results suggest that shape completion relies upon a sparsely distributed but densely interconnected network coalition that is centered in the secondary visual network, coordinated by the dorsal attention network, and inclusive of at least three other networks.

Task-evoked activity quenches neural correlations and variability across cortical areas.

Many large-scale functional connectivity studies have emphasized the importance of communication through increased inter-region correlations during task states. In contrast, local circuit studies have demonstrated that task states primarily reduce correlations among pairs of neurons, likely enhancing their information coding by suppressing shared spontaneous activity. Here we sought to adjudicate between these conflicting perspectives, assessing whether co-active brain regions during task states tend to increase or decrease their correlations. We found that variability and correlations primarily decrease across a variety of cortical regions in two highly distinct data sets: non-human primate spiking data and human functional magnetic resonance imaging data. Moreover, this observed variability and correlation reduction was accompanied by an overall increase in dimensionality (reflecting less information redundancy) during task states, suggesting that decreased correlations increased information coding capacity. We further found in both spiking and neural mass computational models that task-evoked activity increased the stability around a stable attractor, globally quenching neural variability and correlations. Together, our results provide an integrative mechanistic account that encompasses measures of large-scale neural activity, variability, and correlations during resting and task states.

Predicting dysfunctional age-related task activations from resting-state network alterations.

Alzheimer's disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the illness timecourse. These fMRI correlates of unhealthy aging have been studied in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC alterations associated with AD disrupt the flow of activations between brain regions, leading to aberrant task activations. We apply this activity flow model in a large sample of clinically normal older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) AD risk factors. Modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy (at-risk) aged activations. This enabled reliable prediction of at-risk AD task activations, and these predicted activations were related to individual differences in task behavior. These results support activity flow over altered intrinsic functional connections as a mechanism underlying Alzheimer's-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights, this approach raises clinical potential by enabling prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks.

From connectome to cognition: The search for mechanism in human functional brain networks.

Recent developments in functional connectivity research have expanded the scope of human neuroimaging, from identifying changes in regional activation amplitudes to detailed mapping of large-scale brain networks. However, linking network processes to a clear role in cognition demands advances in the theoretical frameworks, algorithms, and experimental approaches applied. This would help evolve the field from a descriptive to an explanatory state, by targeting network interactions that can mechanistically account for cognitive effects. In the present review, we provide an explicit framework to aid this search for "network mechanisms", which anchors recent methodological advances in functional connectivity estimation to a renewed emphasis on careful experimental design. We emphasize how this framework can address specific questions in network neuroscience. These span ambiguity over the cognitive relevance of resting-state networks, how to characterize task-evoked and spontaneous network dynamics, how to identify directed or "effective" connections, and how to apply multivariate pattern analysis at the network level. In parallel, we apply the framework to highlight the mechanistic interaction of network components that remain "stable" across task domains and more "flexible" components associated with on-task reconfiguration. By emphasizing the need to structure the use of diverse analytic approaches with sound experimentation, our framework promotes an explanatory mapping between the workings of the cognitive mind and the large-scale network mechanisms of the human brain.

Empirical validation of directed functional connectivity.

Mapping directions of influence in the human brain connectome represents the next phase in understanding its functional architecture. However, a host of methodological uncertainties have impeded the application of directed connectivity methods, which have primarily been validated via "ground truth" connectivity patterns embedded in simulated functional MRI (fMRI) and magneto-/electro-encephalography (MEG/EEG) datasets. Such simulations rely on many generative assumptions, and we hence utilized a different strategy involving empirical data in which a ground truth directed connectivity pattern could be anticipated with confidence. Specifically, we exploited the established "sensory reactivation" effect in episodic memory, in which retrieval of sensory information reactivates regions involved in perceiving that sensory modality. Subjects performed a paired associate task in separate fMRI and MEG sessions, in which a ground truth reversal in directed connectivity between auditory and visual sensory regions was instantiated across task conditions. This directed connectivity reversal was successfully recovered across different algorithms, including Granger causality and Bayes network (IMAGES) approaches, and across fMRI ("raw" and deconvolved) and source-modeled MEG. These results extend simulation studies of directed connectivity, and offer practical guidelines for the use of such methods in clarifying causal mechanisms of neural processing.

Differentiating the functional contributions of resting connectivity networks to memory decision-making: fMRI support for multistage control processes.

Neural substrates of memory control are engaged when participants encounter unexpected mnemonic stimuli (e.g., a new word when told to expect an old word). The present fMRI study (n = 18) employed the likelihood cueing recognition task to elucidate the role of functional connectivity (fcMRI) networks in supporting memory control processes engaged by these unexpected events. Conventional task-evoked BOLD analyses recovered a memory control network similar to that previously reported, comprising medial prefrontal, lateral prefrontal, and inferior parietal regions. These were split by their differential affiliation to distinct fcMRI networks ("conflict detection" and "confirmatory retrieval" networks). Subsequent ROI analyses clarified the functional significance of this connectivity differentiation, with "conflict" network-affiliated regions specifically sensitive to cue strength, but not to response confidence, and "retrieval" network-affiliated regions showing the opposite pattern. BOLD time course analyses corroborated the segregation of memory control regions into "early" conflict detection and "late" retrieval analysis, with both processes underlying the allocation of memory control. Response specificity and time course findings were generalized beyond task-recruited ROIs to clusters within the large-scale fcMRI networks, suggesting that this connectivity architecture could underlie efficient processing of distinct processes within cognitive tasks. The findings raise important parallels between prevailing theories of memory and cognitive control.

Question format shifts bias away from the emphasised response in tests of recognition memory.

The question asked to interrogate memory has potential to influence response bias at retrieval, yet has not been systematically investigated. According to framing effects in the field of eyewitness testimony, retrieval cueing effects in cognitive psychology and the acquiescence bias in questionnaire responding, the question should establish a confirmatory bias. Conversely, according to findings from the rewarded decision-making literature involving mixed incentives, the question should establish a disconfirmatory bias. Across three experiments (ns=90 [online], 29 [laboratory] and 29 [laboratory]) we demonstrate a disconfirmatory bias - "old?" decreased old responding. This bias is underpinned by a goal-driven mechanism wherein participants seek to maximise emphasised response accuracy at the expense of frequency. Moreover, we demonstrate that disconfirmatory biases can be generated without explicit reference to the goal state. We conclude that subtle aspects of the test environment influence retrieval to a greater extent than has been previously considered.

Neural representation dynamics reveal computational principles of cognitive task learning.

During cognitive task learning, neural representations must be rapidly constructed for novel task performance, then optimized for robust practiced task performance. How the geometry of neural representations changes to enable this transition from novel to practiced performance remains unknown. We hypothesized that practice involves a shift from compositional representations (task-general activity patterns that can be flexibly reused across tasks) to conjunctive representations (task-specific activity patterns specialized for the current task). Functional MRI during learning of multiple complex tasks substantiated this dynamic shift from compositional to conjunctive representations, which was associated with reduced cross-task interference (via pattern separation) and behavioral improvement. Further, we found that conjunctions originated in subcortex (hippocampus and cerebellum) and slowly spread to cortex, extending multiple memory systems theories to encompass task representation learning. The formation of conjunctive representations hence serves as a computational signature of learning, reflecting cortical-subcortical dynamics that optimize task representations in the human brain.

Structural MRI and functional connectivity features predict current clinical status and persistence behavior in prescription opioid users.

Prescription opioid use disorder (POUD) has reached epidemic proportions in the United States, raising an urgent need for diagnostic biological tools that can improve predictions of disease characteristics. The use of neuroimaging methods to develop such biomarkers have yielded promising results when applied to neurodegenerative and psychiatric disorders, yet have not been extended to prescription opioid addiction. With this long-term goal in mind, we conducted a preliminary study in this understudied clinical group. Univariate and multivariate approaches to distinguishing between POUD (n = 26) and healthy controls (n = 21) were investigated, on the basis of structural MRI (sMRI) and resting-state functional connectivity (restFC) features. Univariate approaches revealed reduced structural integrity in the subcortical extent of a previously reported addiction-related network in POUD subjects. No reliable univariate between-group differences in cortical structure or edgewise restFC were observed. Contrasting these mixed univariate results, multivariate machine learning classification approaches recovered more statistically reliable group differences, especially when sMRI and restFC features were combined in a multi-modal model (classification accuracy = 66.7%, p < .001). The same multivariate multi-modal approach also yielded reliable prediction of individual differences in a clinically relevant behavioral measure (persistence behavior; predicted-to-actual overlap r = 0.42, p = .009). Our findings suggest that sMRI and restFC measures can be used to reliably distinguish the neural effects of long-term opioid use, and that this endeavor numerically benefits from multivariate predictive approaches and multi-modal feature sets. This can serve as theoretical proof-of-concept for future longitudinal modeling of prognostic POUD characteristics from neuroimaging features, which would have clearer clinical utility.

Activity flow underlying abnormalities in brain activations and cognition in schizophrenia.

Cognitive dysfunction is a core feature of many brain disorders, including schizophrenia (SZ), and has been linked to aberrant brain activations. However, it is unclear how these activation abnormalities emerge. We propose that aberrant flow of brain activity across functional connectivity (FC) pathways leads to altered activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping, an approach that models the movement of task-related activity between brain regions as a function of FC. Using functional magnetic resonance imaging data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in patients. Our results suggest that dysfunctional task-evoked activity flow is a large-scale network mechanism contributing to cognitive dysfunction in SZ.

Global connectivity of the fronto-parietal cognitive control network is related to depression symptoms in the general population.

We all vary in our mental health, even among people not meeting diagnostic criteria for mental illness. Understanding this individual variability may reveal factors driving the risk for mental illness, as well as factors driving subclinical problems that still adversely affect quality of life. To better understand the large-scale brain network mechanisms underlying this variability, we examined the relationship between mental health symptoms and resting-state functional connectivity patterns in cognitive control systems. One such system is the fronto-parietal cognitive control network (FPN). Changes in FPN connectivity may impact mental health by disrupting the ability to regulate symptoms in a goal-directed manner. Here we test the hypothesis that FPN dysconnectivity relates to mental health symptoms even among individuals who do not meet formal diagnostic criteria but may exhibit meaningful symptom variation. We found that depression symptoms severity negatively correlated with between-network global connectivity (BGC) of the FPN. This suggests that decreased connectivity between the FPN and the rest of the brain is related to increased depression symptoms in the general population. These findings complement previous clinical studies to support the hypothesis that global FPN connectivity contributes to the regulation of mental health symptoms across both health and disease.

Advancing functional connectivity research from association to causation.

Cognition and behavior emerge from brain network interactions, such that investigating causal interactions should be central to the study of brain function. Approaches that characterize statistical associations among neural time series-functional connectivity (FC) methods-are likely a good starting point for estimating brain network interactions. Yet only a subset of FC methods ('effective connectivity') is explicitly designed to infer causal interactions from statistical associations. Here we incorporate best practices from diverse areas of FC research to illustrate how FC methods can be refined to improve inferences about neural mechanisms, with properties of causal neural interactions as a common ontology to facilitate cumulative progress across FC approaches. We further demonstrate how the most common FC measures (correlation and coherence) reduce the set of likely causal models, facilitating causal inferences despite major limitations. Alternative FC measures are suggested to immediately start improving causal inferences beyond these common FC measures.

Cognitive task information is transferred between brain regions via resting-state network topology.

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach-information transfer mapping-to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here, we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

Pupil dilation during recognition memory: Isolating unexpected recognition from judgment uncertainty.

Optimally discriminating familiar from novel stimuli demands a decision-making process informed by prior expectations. Here we demonstrate that pupillary dilation (PD) responses during recognition memory decisions are modulated by expectations, and more specifically, that pupil dilation increases for unexpected compared to expected recognition. Furthermore, multi-level modeling demonstrated that the time course of the dilation during each individual trial contains separable early and late dilation components, with the early amplitude capturing unexpected recognition, and the later trailing slope reflecting general judgment uncertainty or effort. This is the first demonstration that the early dilation response during recognition is dependent upon observer expectations and that separate recognition expectation and judgment uncertainty components are present in the dilation time course of every trial. The findings provide novel insights into adaptive memory-linked orienting mechanisms as well as the general cognitive underpinnings of the pupillary index of autonomic nervous system activity.

The hippocampus and entorhinal cortex encode the path and Euclidean distances to goals during navigation.

BACKGROUND: Despite decades of research on spatial memory, we know surprisingly little about how the brain guides navigation to goals. While some models argue that vectors are represented for navigational guidance, other models postulate that the future path is computed. Although the hippocampal formation has been implicated in processing spatial goal information, it remains unclear whether this region processes path- or vector-related information. RESULTS: We report neuroimaging data collected from subjects navigating London's Soho district; these data reveal that both the path distance and the Euclidean distance to the goal are encoded by the medial temporal lobe during navigation. While activity in the posterior hippocampus was sensitive to the distance along the path, activity in the entorhinal cortex was correlated with the Euclidean distance component of a vector to the goal. During travel periods, posterior hippocampal activity increased as the path to the goal became longer, but at decision points, activity in this region increased as the path to the goal became closer and more direct. Importantly, sensitivity to the distance was abolished in these brain areas when travel was guided by external cues. CONCLUSIONS: The results indicate that the hippocampal formation contains representations of both the Euclidean distance and the path distance to goals during navigation. These findings argue that the hippocampal formation houses a flexible guidance system that changes how it represents distance to the goal depending on the fluctuating demands of navigation.