Edge-Based General Linear Models Capture Moment-to-Moment Fluctuations in Attention.

Although we must prioritize the processing of task-relevant information to navigate life, our ability to do so fluctuates across time. Previous work has identified fMRI functional connectivity (FC) networks that predict an individual's ability to sustain attention and vary with attentional state from 1 min to the next. However, traditional dynamic FC approaches typically lack the temporal precision to capture moment-to-moment network fluctuations. Recently, researchers have "unfurled" traditional FC matrices in "edge cofluctuation time series" which measure timepoint-by-timepoint cofluctuations between regions. Here we apply event-based and parametric fMRI analyses to edge time series to capture moment-to-moment fluctuations in networks related to attention. In two independent fMRI datasets examining young adults of both sexes in which participants performed a sustained attention task, we identified a reliable set of edges that rapidly deflects in response to rare task events. Another set of edges varies with continuous fluctuations in attention and overlaps with a previously defined set of edges associated with individual differences in sustained attention. Demonstrating that edge-based analyses are not simply redundant with traditional regions-of-interest-based approaches, up to one-third of reliably deflected edges were not predicted from univariate activity patterns alone. These results reveal the large potential in combining traditional fMRI analyses with edge time series to identify rapid reconfigurations in networks across the brain.

Differences in the functional brain architecture of sustained attention and working memory in youth and adults.

Sustained attention (SA) and working memory (WM) are critical processes, but the brain networks supporting these abilities in development are unknown. We characterized the functional brain architecture of SA and WM in 9- to 11-year-old children and adults. First, we found that adult network predictors of SA generalized to predict individual differences and fluctuations in SA in youth. A WM model predicted WM performance both across and within children-and captured individual differences in later recognition memory-but underperformed in youth relative to adults. We next characterized functional connections differentially related to SA and WM in youth compared to adults. Results revealed 2 network configurations: a dominant architecture predicting performance in both age groups and a secondary architecture, more prominent for WM than SA, predicting performance in each age group differently. Thus, functional connectivity (FC) predicts SA and WM in youth, with networks predicting WM performance differing more between youths and adults than those predicting SA.

Functional connectome stability and optimality are markers of cognitive performance.

Patterns of whole-brain fMRI functional connectivity, or connectomes, are unique to individuals. Previous work has identified subsets of functional connections within these patterns whose strength predicts aspects of attention and cognition. However, overall features of these connectomes, such as how stable they are over time and how similar they are to a group-average (typical) or high-performance (optimal) connectivity pattern, may also reflect cognitive and attentional abilities. Here, we test whether individuals who express more stable, typical, optimal, and distinctive patterns of functional connectivity perform better on cognitive tasks using data from three independent samples. We find that individuals with more stable task-based functional connectivity patterns perform better on attention and working memory tasks, even when controlling for behavioral performance stability. Additionally, we find initial evidence that individuals with more typical and optimal patterns of functional connectivity also perform better on these tasks. These results demonstrate that functional connectome stability within individuals and similarity across individuals predicts individual differences in cognition.

Predicting multilingual effects on executive function and individual connectomes in children: An ABCD study.

While there is a substantial amount of work studying multilingualism's effect on cognitive functions, little is known about how the multilingual experience modulates the brain as a whole. In this study, we analyzed data of over 1,000 children from the Adolescent Brain Cognitive Development (ABCD) Study to examine whether monolinguals and multilinguals differ in executive function, functional brain connectivity, and brain-behavior associations. We observed significantly better performance from multilingual children than monolinguals in working-memory tasks. In one finding, we were able to classify multilinguals from monolinguals using only their whole-brain functional connectome at rest and during an emotional n-back task. Compared to monolinguals, the multilingual group had different functional connectivity mainly in the occipital lobe and subcortical areas during the emotional n-back task and in the occipital lobe and prefrontal cortex at rest. In contrast, we did not find any differences in behavioral performance and functional connectivity when performing a stop-signal task. As a second finding, we investigated the degree to which behavior is reflected in the brain by implementing a connectome-based behavior prediction approach. The multilingual group showed a significant correlation between observed and connectome-predicted individual working-memory performance scores, while the monolingual group did not show any correlations. Overall, our observations suggest that multilingualism enhances executive function and reliably modulates the corresponding brain functional connectome, distinguishing multilinguals from monolinguals even at the developmental stage.

Functional connectivity predicts changes in attention observed across minutes, days, and months.

The ability to sustain attention differs across people and changes within a single person over time. Although recent work has demonstrated that patterns of functional brain connectivity predict individual differences in sustained attention, whether these same patterns capture fluctuations in attention within individuals remains unclear. Here, across five independent studies, we demonstrate that the sustained attention connectome-based predictive model (CPM), a validated model of sustained attention function, generalizes to predict attentional state from data collected across minutes, days, weeks, and months. Furthermore, the sustained attention CPM is sensitive to within-subject state changes induced by propofol as well as sevoflurane, such that individuals show functional connectivity signatures of stronger attentional states when awake than when under deep sedation and light anesthesia. Together, these results demonstrate that fluctuations in attentional state reflect variability in the same functional connectivity patterns that predict individual differences in sustained attention.

Predicting Identity-Preserving Object Transformations across the Human Ventral Visual Stream.

In everyday life, we have no trouble categorizing objects varying in position, size, and orientation. Previous fMRI research shows that higher-level object processing regions in the human lateral occipital cortex may link object responses from different affine states (i.e., size and viewpoint) through a general linear mapping function capable of predicting responses to novel objects. In this study, we extended this approach to examine the mapping for both Euclidean (e.g., position and size) and non-Euclidean (e.g., image statistics and spatial frequency) transformations across the human ventral visual processing hierarchy, including areas V1, V2, V3, V4, ventral occipitotemporal cortex, and lateral occipitotemporal cortex. The predicted pattern generated from a linear mapping function could capture a significant amount of the changes associated with the transformations throughout the ventral visual stream. The derived linear mapping functions were not category independent as performance was better for the categories included than those not included in training and better between two similar versus two dissimilar categories in both lower and higher visual regions. Consistent with object representations being stronger in higher than in lower visual regions, pattern selectivity and object category representational structure were somewhat better preserved in the predicted patterns in higher than in lower visual regions. There were no notable differences between Euclidean and non-Euclidean transformations. These findings demonstrate a near-orthogonal representation of object identity and these nonidentity features throughout the human ventral visual processing pathway with these nonidentity features largely untangled from the identity features early in visual processing.SIGNIFICANCE STATEMENT Presently we still do not fully understand how object identity and nonidentity (e.g., position, size) information are simultaneously represented in the primate ventral visual system to form invariant representations. Previous work suggests that the human lateral occipital cortex may be linking different affine states of object representations through general linear mapping functions. Here, we show that across the entire human ventral processing pathway, we could link object responses in different states of nonidentity transformations through linear mapping functions for both Euclidean and non-Euclidean transformations. These mapping functions are not identity independent, suggesting that object identity and nonidentity features are represented in a near rather than a completely orthogonal manner.

A cognitive state transformation model for task-general and task-specific subsystems of the brain connectome.

The human brain flexibly controls different cognitive behaviors, such as memory and attention, to satisfy contextual demands. Much progress has been made to reveal task-induced modulations in the whole-brain functional connectome, but we still lack a way to model context-dependent changes. Here, we present a novel connectome-to-connectome (C2C) transformation framework that enables us to model the brain's functional reorganization from one connectome state to another in response to specific task goals. Using functional magnetic resonance imaging data from the Human Connectome Project, we demonstrate that the C2C model accurately generates an individual's task-related connectomes from their task-free (resting-state) connectome with a high degree of specificity across seven different cognitive states. Moreover, the C2C model amplifies behaviorally relevant individual differences in the task-free connectome, thereby improving behavioral predictions with increased power, achieving similar performance with just a third of the subjects needed when relying on resting-state data alone. Finally, the C2C model reveals how the brain reorganizes between cognitive states. Our observations support the existence of reliable state-specific subsystems in the brain and demonstrate that we can quantitatively model how the connectome reconfigures to different cognitive states, enabling more accurate predictions of behavior with fewer subjects.

Functional Connectivity during Encoding Predicts Individual Differences in Long-Term Memory.

What is the neural basis of individual differences in the ability to hold information in long-term memory (LTM)? Here, we first characterize two whole-brain functional connectivity networks based on fMRI data acquired during an n-back task that robustly predict individual differences in two important forms of LTM, recognition and recollection. We then focus on the recognition memory model and contrast it with a working memory model. Although functional connectivity during the n-back task also predicts working memory performance and the two networks have some shared components, they are also largely distinct from each other: The recognition memory model performance remains robust when we control for working memory, and vice versa. Functional connectivity only within regions traditionally associated with LTM formation, such as the medial temporal lobe and those that show univariate subsequent memory effect, have little predictive power for both forms of LTM. Interestingly, the interactions between these regions and other brain regions play a more substantial role in predicting recollection memory than recognition memory. These results demonstrate that individual differences in LTM are dependent on the configuration of a whole-brain functional network including but not limited to regions associated with LTM during encoding and that such a network is separable from what supports the retention of information in working memory.

Searching through functional space reveals distributed visual, auditory, and semantic coding in the human brain.

The extent to which brain functions are localized or distributed is a foundational question in neuroscience. In the human brain, common fMRI methods such as cluster correction, atlas parcellation, and anatomical searchlight are biased by design toward finding localized representations. Here we introduce the functional searchlight approach as an alternative to anatomical searchlight analysis, the most commonly used exploratory multivariate fMRI technique. Functional searchlight removes any anatomical bias by grouping voxels based only on functional similarity and ignoring anatomical proximity. We report evidence that visual and auditory features from deep neural networks and semantic features from a natural language processing model, as well as object representations, are more widely distributed across the brain than previously acknowledged and that functional searchlight can improve model-based similarity and decoding accuracy. This approach provides a new way to evaluate and constrain computational models with brain activity and pushes our understanding of human brain function further along the spectrum from strict modularity toward distributed representation.

Distributed Patterns of Functional Connectivity Predict Working Memory Performance in Novel Healthy and Memory-impaired Individuals.

Individual differences in working memory relate to performance differences in general cognitive ability. The neural bases of such individual differences, however, remain poorly understood. Here, using a data-driven technique known as connectome-based predictive modeling, we built models to predict individual working memory performance from whole-brain functional connectivity patterns. Using n-back or rest data from the Human Connectome Project, connectome-based predictive models significantly predicted novel individuals' 2-back accuracy. Model predictions also correlated with measures of fluid intelligence and, with less strength, sustained attention. Separate fluid intelligence models predicted working memory score, as did sustained attention models, again with less strength. Anatomical feature analysis revealed significant overlap between working memory and fluid intelligence models, particularly in utilization of prefrontal and parietal regions, and less overlap in predictive features between working memory and sustained attention models. Furthermore, showing the generality of these models, the working memory model developed from Human Connectome Project data generalized to predict memory in an independent data set of 157 older adults (mean age = 69 years; 48 healthy, 54 amnestic mild cognitive impairment, 55 Alzheimer disease). The present results demonstrate that distributed functional connectivity patterns predict individual variation in working memory capability across the adult life span, correlating with constructs including fluid intelligence and sustained attention.

Connectome-based neurofeedback: A pilot study to improve sustained attention.

Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback is a non-invasive, non-pharmacological therapeutic tool that may be useful for training behavior and alleviating clinical symptoms. Although previous work has used rt-fMRI to target brain activity in or functional connectivity between a small number of brain regions, there is growing evidence that symptoms and behavior emerge from interactions between a number of distinct brain areas. Here, we propose a new method for rt-fMRI, connectome-based neurofeedback, in which intermittent feedback is based on the strength of complex functional networks spanning hundreds of regions and thousands of functional connections. We first demonstrate the technical feasibility of calculating whole-brain functional connectivity in real-time and provide resources for implementing connectome-based neurofeedback. We next show that this approach can be used to provide accurate feedback about the strength of a previously defined connectome-based model of sustained attention, the saCPM, during task performance. Although, in our initial pilot sample, neurofeedback based on saCPM strength did not improve performance on out-of-scanner attention tasks, future work characterizing effects of network target, training duration, and amount of feedback on the efficacy of rt-fMRI can inform experimental or clinical trial designs.

General Transformations of Object Representations in Human Visual Cortex.

The brain actively represents incoming information, but these representations are only useful to the extent that they flexibly reflect changes in the environment. How does the brain transform representations across changes, such as in size or viewing angle? We conducted a fMRI experiment and a magnetoencephalography experiment in humans (both sexes) in which participants viewed objects before and after affine viewpoint changes (rotation, translation, enlargement). We used a novel approach, representational transformation analysis, to derive transformation functions that linked the distributed patterns of brain activity evoked by an object before and after an affine change. Crucially, transformations derived from one object could predict a postchange representation for novel objects. These results provide evidence of general operations in the brain that are distinct from neural representations evoked by particular objects and scenes.SIGNIFICANCE STATEMENT The dominant focus in cognitive neuroscience has been on how the brain represents information, but these representations are only useful to the extent that they flexibly reflect changes in the environment. How does the brain transform representations, such as linking two states of an object, for example, before and after an object undergoes a physical change? We used a novel method to derive transformations between the brain activity evoked by an object before and after an affine viewpoint change. We show that transformations derived from one object undergoing a change generalized to a novel object undergoing the same change. This result shows that there are general perceptual operations that transform object representations from one state to another.

Multivariate approaches improve the reliability and validity of functional connectivity and prediction of individual behaviors.

Brain functional connectivity features can predict cognition and behavior at the level of the individual. Most studies measure univariate signals, correlating timecourses from the average of constituent voxels in each node. While straightforward, this approach overlooks the spatial patterns of voxel-wise signals within individual nodes. Given that multivariate spatial activity patterns across voxels can improve fMRI measures of mental representations, here we asked whether using voxel-wise timecourses can better characterize region-by-region interactions relative to univariate approaches. Using two fMRI datasets, the Human Connectome Project sample and a local test-retest sample, we measured multivariate functional connectivity with multivariate distance correlation and univariate connectivity with Pearson's correlation. We compared multivariate and univariate connectivity estimates, demonstrating that relative to univariate estimates, multivariate estimates exhibited higher reliability at both the edge-level and connectome-level, stronger prediction of individual differences, and greater sensitivity to brain states within individuals. Our findings suggest that multivariate estimates reliably provide more powerful information about an individual's functional brain organization and its relation to cognitive skills.

Dynamic functional connectivity during task performance and rest predicts individual differences in attention across studies.

Dynamic functional connectivity (DFC) aims to maximize resolvable information from functional brain scans by considering temporal changes in network structure. Recent work has demonstrated that static, i.e. time-invariant resting-state and task-based FC predicts individual differences in behavior, including attention. Here, we show that DFC predicts attention performance across individuals. Sliding-window FC matrices were generated from fMRI data collected during rest and attention task performance by calculating Pearson's r between every pair of nodes of a whole-brain atlas within overlapping 10-60s time segments. Next, variance in r values across windows was taken to quantify temporal variability in the strength of each connection, resulting in a DFC connectome for each individual. In a leave-one-subject-out-cross-validation approach, partial-least-square-regression (PLSR) models were then trained to predict attention task performance from DFC matrices. Predicted and observed attention scores were significantly correlated, indicating successful out-of-sample predictions across rest and task conditions. Combining DFC and static FC features numerically improves predictions over either model alone, but the improvement was not statistically significant. Moreover, dynamic and combined models generalized to two independent data sets (participants performing the Attention Network Task and the stop-signal task). Edges with significant PLSR coefficients concentrated in visual, motor, and executive-control brain networks; moreover, most of these coefficients were negative. Thus, better attention may rely on more stable, i.e. less variable, information flow between brain regions.

Connectome-based Models Predict Separable Components of Attention in Novel Individuals.

Although we typically talk about attention as a single process, it comprises multiple independent components. But what are these components, and how are they represented in the functional organization of the brain? To investigate whether long-studied components of attention are reflected in the brain's intrinsic functional organization, here we apply connectome-based predictive modeling (CPM) to predict the components of Posner and Petersen's influential model of attention: alerting (preparing and maintaining alertness and vigilance), orienting (directing attention to a stimulus), and executive control (detecting and resolving cognitive conflict) [Posner, M. I., & Petersen, S. E. The attention system of the human brain. Annual Review of Neuroscience, 13, 25-42, 1990]. Participants performed the Attention Network Task (ANT), which measures these three factors, and rested during fMRI scanning. CPMs tested with leave-one-subject-out cross-validation successfully predicted novel individual's overall ANT accuracy, RT variability, and executive control scores from functional connectivity observed during ANT performance. CPMs also generalized to predict participants' alerting scores from their resting-state functional connectivity alone, demonstrating that connectivity patterns observed in the absence of an explicit task contain a signature of the ability to prepare for an upcoming stimulus. Suggesting that significant variance in ANT performance is also explained by an overall sustained attention factor, the sustained attention CPM, a model defined in prior work to predict sustained attentional abilities, predicted accuracy, RT variability, and executive control from task-based data and predicted RT variability from resting-state data. Our results suggest that, whereas executive control may be closely related to sustained attention, the infrastructure that supports alerting is distinct and can be measured at rest. In the future, CPM may be applied to elucidate additional independent components of attention and relationships between the functional brain networks that predict them.

Connectome-based predictive modeling of attention: Comparing different functional connectivity features and prediction methods across datasets.

Connectome-based predictive modeling (CPM; Finn et al., 2015; Shen et al., 2017) was recently developed to predict individual differences in traits and behaviors, including fluid intelligence (Finn et al., 2015) and sustained attention (Rosenberg et al., 2016a), from functional brain connectivity (FC) measured with fMRI. Here, using the CPM framework, we compared the predictive power of three different measures of FC (Pearson's correlation, accordance, and discordance) and two different prediction algorithms (linear and partial least square [PLS] regression) for attention function. Accordance and discordance are recently proposed FC measures that respectively track in-phase synchronization and out-of-phase anti-correlation (Meskaldji et al., 2015). We defined connectome-based models using task-based or resting-state FC data, and tested the effects of (1) functional connectivity measure and (2) feature-selection/prediction algorithm on individualized attention predictions. Models were internally validated in a training dataset using leave-one-subject-out cross-validation, and externally validated with three independent datasets. The training dataset included fMRI data collected while participants performed a sustained attention task and rested (N = 25; Rosenberg et al., 2016a). The validation datasets included: 1) data collected during performance of a stop-signal task and at rest (N = 83, including 19 participants who were administered methylphenidate prior to scanning; Farr et al., 2014a; Rosenberg et al., 2016b), 2) data collected during Attention Network Task performance and rest (N = 41, Rosenberg et al., in press), and 3) resting-state data and ADHD symptom severity from the ADHD-200 Consortium (N = 113; Rosenberg et al., 2016a). Models defined using all combinations of functional connectivity measure (Pearson's correlation, accordance, and discordance) and prediction algorithm (linear and PLS regression) predicted attentional abilities, with correlations between predicted and observed measures of attention as high as 0.9 for internal validation, and 0.6 for external validation (all p's < 0.05). Models trained on task data outperformed models trained on rest data. Pearson's correlation and accordance features generally showed a small numerical advantage over discordance features, while PLS regression models were usually better than linear regression models. Overall, in addition to correlation features combined with linear models (Rosenberg et al., 2016a), it is useful to consider accordance features and PLS regression for CPM.

Lower Parietal Encoding Activation Is Associated with Sharper Information and Better Memory.

Mean fMRI activation in ventral posterior parietal cortex (vPPC) during memory encoding often negatively predicts successful remembering. A popular interpretation of this phenomenon is that vPPC reflects "off-task" processing. However, recent fMRI studies considering distributed patterns of activity suggest that vPPC actively represents encoded material. Here, we assessed the relationships between pattern-based content representations in vPPC, mean activation in vPPC, and subsequent remembering. We analyzed data from two fMRI experiments where subjects studied then recalled word-face or word-scene associations. For each encoding trial, we measured 1) mean univariate activation within vPPC and 2) the strength of face/scene information as indexed by pattern analysis. Mean activation in vPPC negatively predicted subsequent remembering, but the strength of pattern-based information in the same vPPC voxels positively predicted later memory. Indeed, univariate amplitude averaged across vPPC voxels negatively correlated with pattern-based information strength. This dissociation reflected a tendency for univariate reductions to maximally occur in voxels that were not strongly tuned for the category of encoded stimuli. These results indicate that vPPC activity patterns reflect the content and quality of memory encoding and constitute a striking example of lower univariate activity corresponding to stronger pattern-based information.

Methylphenidate Modulates Functional Network Connectivity to Enhance Attention.

UNLABELLED: Recent work has demonstrated that human whole-brain functional connectivity patterns measured with fMRI contain information about cognitive abilities, including sustained attention. To derive behavioral predictions from connectivity patterns, our group developed a connectome-based predictive modeling (CPM) approach (Finn et al., 2015; Rosenberg et al., 2016). Previously using CPM, we defined a high-attention network, comprising connections positively correlated with performance on a sustained attention task, and a low-attention network, comprising connections negatively correlated with performance. Validating the networks as generalizable biomarkers of attention, models based on network strength at rest predicted attention-deficit/hyperactivity disorder (ADHD) symptoms in an independent group of individuals (Rosenberg et al., 2016). To investigate whether these networks play a causal role in attention, here we examined their strength in healthy adults given methylphenidate (Ritalin), a common ADHD treatment, compared with unmedicated controls. As predicted, individuals given methylphenidate showed patterns of connectivity associated with better sustained attention: higher high-attention and lower low-attention network strength than controls. There was significant overlap between the high-attention network and a network with greater strength in the methylphenidate group, and between the low-attention network and a network with greater strength in the control group. Network strength also predicted behavior on a stop-signal task, such that participants with higher go response rates showed higher high-attention and lower low-attention network strength. These results suggest that methylphenidate acts by modulating functional brain networks related to sustained attention, and that changing whole-brain connectivity patterns may help improve attention. SIGNIFICANCE STATEMENT: Recent work identified a promising neuromarker of sustained attention based on whole-brain functional connectivity networks. To investigate the causal role of these networks in attention, we examined their response to a dose of methylphenidate, a common and effective treatment for attention-deficit/hyperactivity disorder, in healthy adults. As predicted, individuals on methylphenidate showed connectivity signatures of better sustained attention: higher high-attention and lower low-attention network strength than controls. These results suggest that methylphenidate acts by modulating strength in functional brain networks related to attention, and that changing whole-brain connectivity patterns may improve attention.

Opponent Identity Influences Value Learning in Simple Games.

Context plays a pivotal role in many decision-making scenarios, including social interactions wherein the identities and strategies of other decision makers often shape our behaviors. However, the neural mechanisms for tracking such contextual information are poorly understood. Here, we investigated how opponent identity affects human reinforcement learning during a simulated competitive game against two independent computerized opponents. We found that strategies of participants were affected preferentially by the outcomes of the previous interactions with the same opponent. In addition, reinforcement signals from the previous trial were less discriminable throughout the brain after the opponent changed, compared with when the same opponent was repeated. These opponent-selective reinforcement signals were particularly robust in right rostral anterior cingulate and right lingual regions, where opponent-selective reinforcement signals correlated with a behavioral measure of opponent-selective reinforcement learning. Therefore, when choices involve multiple contextual frames, such as different opponents in a game, decision making and its neural correlates are influenced by multithreaded histories of reinforcement. Overall, our findings are consistent with the availability of temporally overlapping, context-specific reinforcement signals. SIGNIFICANCE STATEMENT: In real-world decision making, context plays a strong role in determining the value of an action. Similar choices take on different values depending on setting. We examined the contextual dependence of reward-based learning and reinforcement signals using a simple two-choice matching-pennies game played by humans against two independent computer opponents that were randomly interleaved. We found that human subjects' strategies were highly dependent on opponent context in this game, a fact that was reflected in select brain regions' activity (rostral anterior cingulate and lingual cortex). These results indicate that human reinforcement histories are highly dependent on contextual factors, a fact that is reflected in neural correlates of reinforcement signals.

Neural Discriminability of Object Features Predicts Perceptual Organization.

How does the neural representation of simple visual features affect perceptual operations, such as perceptual grouping? If the strength of feature representations in the brain is indicative of how the perceptual system partitions information into visual elements, then identifying the underlying neural representation may determine why things look the way they do. During functional MRI, participants viewed objects that varied along three feature dimensions: shape, color, and orientation. Afterward, participants performed an independent perceptual-grouping task outside the scanner to measure the strength of feature grouping. In lateral occipital cortex, neural feature discriminability, characterized using functional MRI multivariate pattern classification, positively predicted feature grouping strength: The more distinct the neural representations of a particular feature, the stronger the grouping was for that feature outside the scanner. Thus, variation in neural feature representation can be quantified to predict perceptual organization.