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.

Edge-based general linear models capture high-frequency 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 one minute to the next. However, traditional dynamic FC approaches typically lack the temporal precision to capture moment-by-moment network fluctuations. Recently, researchers have 'unfurled' traditional FC matrices in 'edge cofluctuation time series' which measure time point-by-time point cofluctuations between regions. Here we apply event-based and parametric fMRI analyses to edge time series to capture high-frequency fluctuations in networks related to attention. In two independent fMRI datasets 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.

Associations of physical frailty with health outcomes and brain structure in 483 033 middle-aged and older adults: a population-based study from the UK Biobank.

BACKGROUND: Physical frailty is a state of increased vulnerability to stressors and is associated with serious health issues. However, how frailty affects and is affected by numerous other factors, including mental health and brain structure, remains underexplored. We aimed to investigate the mutual effects of frailty and health using large, multidimensional data. METHODS: For this population-based study, we used data from the UK Biobank to examine the pattern and direction of association between physical frailty and 325 health-related measures across multiple domains, using linear mixed-effect models and adjusting for numerous confounders. Participants were included if complete data were available for all five indicators of frailty, all covariates, and at least one health measure. We further examined the association between frailty and brain structure and the role of this association in mediating the relationship between frailty and health outcomes. FINDINGS: 483 033 participants aged 38-73 years were included in the study at baseline (between Dec 19, 2006, and Oct 1, 2010); at a median follow-up of 9 years (IQR 8-10), behavioural data were available for 46 501 participants and neuroimaging data for 40 210 participants. The severity of physical frailty was significantly associated with decreased cognitive performance (Cohen's d=0·025-0·162), increased early-life risks (d=0·026-0·111), unhealthy lifestyle (d=0·013-0·394), poor physical fitness (d=0·007-0·668), increased symptoms of poor mental health (d=0·032-0·607), severe environmental pollution (d=0·013-0·064), and adverse biochemical markers (d=0·025-0·198). Some associations were bidirectional, with the strongest effects on mental health measures. The severity of frailty correlated with increased total white matter hyperintensity and lower grey matter volume, particularly in subcortical regions (d=0·027-0·082), which significantly mediated the association between frailty and health-related outcomes, although the mediated effects were small. INTERPRETATION: Physical frailty is associated with diverse unfavourable health-related outcomes, which can be mediated by differences in brain structure. Our findings offer a framework for guiding preventative strategies targeting both frailty and psychiatric disorders. FUNDING: National Institute of Mental Health, National Science Foundation.

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.

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.

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.

Antagonistic network signature of motor function in Parkinson's disease revealed by connectome-based predictive modeling.

Motor impairment is a core clinical feature of Parkinson's disease (PD). Although the decoupled brain connectivity has been widely reported in previous neuroimaging studies, how the functional connectome is involved in motor dysfunction has not been well elucidated in PD patients. Here we developed a distributed brain signature by predicting clinical motor scores of PD patients across multicenter datasets (total n = 236). We decomposed the Pearson's correlation into accordance and discordance via a temporal discrete procedure, which can capture coupling and anti-coupling respectively. Using different profiles of functional connectivity, we trained candidate predictive models and tested them on independent and heterogeneous PD samples. We showed that the antagonistic model measured by discordance had the best sensitivity and generalizability in all validations and it was dubbed as Parkinson's antagonistic motor signature (PAMS). The PAMS was dominated by the subcortical, somatomotor, visual, cerebellum, default-mode, and frontoparietal networks, and the motor-visual stream accounted for the most part of predictive weights among network pairs. Additional stage-specific analysis showed that the predicted scores generated from the antagonistic model tended to be higher than the observed scores in the early course of PD, indicating that the functional signature may vary more sensitively with the neurodegenerative process than clinical behaviors. Together, these findings suggest that motor dysfunction of PD is represented as antagonistic interactions within multi-level brain systems. The signature shows great potential in the early motor evaluation and developing new therapeutic approaches for PD in the clinical realm.

A brain-based general measure of attention.

Attention is central to many aspects of cognition, but there is no singular neural measure of a person's overall attentional functioning across tasks. Here, using original data from 92 participants performing three different attention-demanding tasks during functional magnetic resonance imaging, we constructed a suite of whole-brain models that can predict a profile of multiple attentional components (sustained attention, divided attention and tracking, and working memory capacity) for novel individuals. Multiple brain regions across the salience, subcortical and frontoparietal networks drove accurate predictions, supporting a common (general) attention factor across tasks, distinguished from task-specific ones. Furthermore, connectome-to-connectome transformation modelling generated an individual's task-related connectomes from rest functional magnetic resonance imaging, substantially improving predictive power. Finally, combining the connectome transformation and general attention factor, we built a standardized measure that shows superior generalization across four independent datasets (total N = 495) of various attentional measures, suggesting broad utility for research and clinical applications.

Nonuniformity of Whole-Cerebral Neural Resource Allocation, a Neuromarker of the Broad-Task Attention.

The neural basis of attention is thought to involve the allocation of limited neural resources. However, the quantitative validation of this hypothesis remains challenging. Here, we provide quantitative evidence that the nonuniform allocation of neural resources across the whole cerebral gray matter reflects the broad-task process of sustained attention. We propose a neural measure for the nonuniformity of whole-cerebral allocation using functional magnetic resonance imaging. We found that this measure was significantly correlated with conventional indicators of attention level, such as task difficulty and pupil dilation. We further found that the broad-task neural correlates of the measure belong to frontoparietal and dorsal attention networks. Finally, we found that patients with attention-deficit/hyperactivity disorder showed abnormal decreases in the level of the proposed measure, reflecting the executive dysfunction. This study proposes a neuromarker suggesting that the nonuniform allocation of neural resources may be the broad-task neural basis of sustained attention.

The Gpx4NIKO Mouse Is a Versatile Model for Testing Interventions Targeting Ferroptotic Cell Death of Spinal Motor Neurons.

The degeneration and death of motor neurons lead to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Although the exact mechanism by which motor neuron degeneration occurs is not well understood, emerging evidence implicates the involvement of ferroptosis, an iron-dependent oxidative mode of cell death. We reported previously that treating Gpx4NIKO mice with tamoxifen to ablate the ferroptosis regulator glutathione peroxidase 4 (GPX4) in neurons produces a severe paralytic model resembling an accelerated form of ALS that appears to be caused by ferroptotic cell death of spinal motor neurons. In this study, in support of the role of ferroptosis in this model, we found that the paralytic symptoms and spinal motor neuron death of Gpx4NIKO mice were attenuated by a chemical inhibitor of ferroptosis. In addition, we observed that the paralytic symptoms of Gpx4NIKO mice were malleable and could be tapered by lowering the dose of tamoxifen, allowing for the generation of a mild paralytic model without a rapid onset of death. We further used both models to evaluate mitochondrial reactive oxygen species (mtROS) in the ferroptosis of spinal motor neurons and showed that overexpression of peroxiredoxin 3, a mitochondrial antioxidant defense enzyme, ameliorated symptoms of the mild but not the severe model of the Gpx4NIKO mice. Our results thus indicate that the Gpx4NIKO mouse is a versatile model for testing interventions that target ferroptotic death of spinal motor neurons in vivo.

Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice.

Oxidative damage including lipid peroxidation is widely reported in Alzheimer's disease (AD) with the peroxidation of phospholipids in membranes being the driver of ferroptosis, an iron-dependent oxidative form of cell death. However, the importance of ferroptosis in AD remains unclear. This study tested whether ferroptosis inhibition ameliorates AD. 5xFAD mice, a widely used AD mouse model with cognitive impairment and robust neurodegeneration, exhibit markers of ferroptosis including increased lipid peroxidation, elevated lyso-phospholipids, and reduced level of Gpx4, the master defender against ferroptosis. To determine if enhanced defense against ferroptosis retards disease development, we generated 5xFAD mice that overexpress Gpx4, i.e., 5xFAD/GPX4 mice. Consistent with enhanced defense against ferroptosis, neurons from 5xFAD/GPX4 mice showed an augmented capacity to reduce lipid reactive oxygen species. In addition, compared with control 5xFAD mice, 5xFAD/GPX4 mice showed significantly improved learning and memory abilities and had reduced neurodegeneration. Moreover, 5xFAD/GPX4 mice exhibited attenuated markers of ferroptosis. Our results indicate that enhanced defense against ferroptosis is effective in ameliorating cognitive impairment and decreasing neurodegeneration of 5xFAD mice. The findings support the notion that ferroptosis is a key contributor to AD pathogenesis.

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 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.

Using functional connectivity models to characterize relationships between working and episodic memory.

INTRODUCTION: Working memory is a critical cognitive ability that affects our daily functioning and relates to many cognitive processes and clinical conditions. Episodic memory is vital because it enables individuals to form and maintain their self-identities. Our study analyzes the extent to which whole-brain functional connectivity observed during completion of an N-back memory task, a common measure of working memory, can predict both working memory and episodic memory. METHODS: We used connectome-based predictive models (CPMs) to predict 502 Human Connectome Project (HCP) participants' in-scanner 2-back memory test scores and out-of-scanner working memory test (List Sorting) and episodic memory test (Picture Sequence and Penn Word) scores based on functional magnetic resonance imaging (fMRI) data collected both during rest and N-back task performance. We also analyzed the functional brain connections that contributed to prediction for each of these models. RESULTS: Functional connectivity observed during N-back task performance predicted out-of-scanner List Sorting scores and to a lesser extent out-of-scanner Picture Sequence scores, but did not predict out-of-scanner Penn Word scores. Additionally, the functional connections predicting 2-back scores overlapped to a greater degree with those predicting List Sorting scores than with those predicting Picture Sequence or Penn Word scores. Functional connections with the insula, including connections between insular and parietal regions, predicted scores across the 2-back, List Sorting, and Picture Sequence tasks. CONCLUSIONS: Our findings validate functional connectivity observed during the N-back task as a measure of working memory, which generalizes to predict episodic memory to a lesser extent. By building on our understanding of the predictive power of N-back task functional connectivity, this work enhances our knowledge of relationships between working memory and episodic memory.

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.

An information network flow approach for measuring functional connectivity and predicting behavior.

INTRODUCTION: Connectome-based predictive modeling (CPM) is a recently developed machine-learning-based framework to predict individual differences in behavior from functional brain connectivity (FC). In these models, FC was operationalized as Pearson's correlation between brain regions' fMRI time courses. However, Pearson's correlation is limited since it only captures linear relationships. We developed a more generalized metric of FC based on information flow. This measure represents FC by abstracting the brain as a flow network of nodes that send bits of information to each other, where bits are quantified through an information theory statistic called transfer entropy. METHODS: With a sample of individuals performing a sustained attention task and resting during functional magnetic resonance imaging (fMRI) (n = 25), we use the CPM framework to build machine-learning models that predict attention from FC patterns measured with information flow. Models trained on n - 1 participants' task-based patterns were applied to an unseen individual's resting-state pattern to predict task performance. For further validation, we applied our model to two independent datasets that included resting-state fMRI data and a measure of attention (Attention Network Task performance [n = 41] and stop-signal task performance [n = 72]). RESULTS: Our model significantly predicted individual differences in attention task performance across three different datasets. CONCLUSIONS: Information flow may be a useful complement to Pearson's correlation as a measure of FC because of its advantages for nonlinear analysis and network structure characterization.

Brain-State Extraction Algorithm Based on the State Transition (BEST): A Dynamic Functional Brain Network Analysis in fMRI Study.

Spatial pattern of the brain network changes dynamically. This change is closely linked to the brain-state transition, which vary depending on a dynamic stream of thoughts. To date, many dynamic methods have been developed for decoding brain-states. However, most of them only consider changes over time, not the brain-state transition itself. Here, we propose a novel dynamic functional connectivity analysis method, brain-state extraction algorithm based on state transition (BEST), which constructs connectivity matrices from the duration of brain-states and decodes the proper number of brain-states in a data-driven way. To set the duration of each brain-state, we detected brain-state transition time-points using spatial standard deviation of the brain activity pattern that changes over time. Furthermore, we also used Bayesian information criterion to the clustering method to estimate and extract the number of brain-states. Through validations, it was proved that BEST could find brain-state transition time-points and could estimate the proper number of brain-states without any a priori knowledge. It has also shown that BEST can be applied to resting state fMRI data and provide stable and consistent results.

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.

Highly efficient genome editing by CRISPR-Cpf1 using CRISPR RNA with a uridinylate-rich 3'-overhang.

Genome editing has been harnessed through the development of CRISPR system, and the CRISPR from Prevotella and Francisella 1 (Cpf1) system has emerged as a promising alternative to CRISPR-Cas9 for use in various circumstances. Despite the inherent multiple advantages of Cpf1 over Cas9, the adoption of Cpf1 has been unsatisfactory because of target-dependent insufficient indel efficiencies. Here, we report an engineered CRISPR RNA (crRNA) for highly efficient genome editing by Cpf1, which includes a 20-base target-complementary sequence and a uridinylate-rich 3'-overhang. When the crRNA is transcriptionally produced, crRNA with a 20-base target-complementary sequence plus a U4AU4 3'-overhang is the optimal configuration. U-rich crRNA also maximizes the utility of the AsCpf1 mutants and multiplexing genome editing using mRNA as the source of multiple crRNAs. Furthermore, U-rich crRNA enables a highly safe and specific genome editing using Cpf1 in human cells, contributing to the enhancement of a genome-editing toolbox.