Altered default mode network associated with pesticide exposure in Latinx children from rural farmworker families.

Pesticide exposure has been associated with adverse cognitive and neurological effects. However, neuroimaging studies aimed at examining the impacts of pesticide exposure on brain networks underlying abnormal neurodevelopment in children remain limited. It has been demonstrated that pesticide exposure in children is associated with disrupted brain anatomy in regions that make up the default mode network (DMN), a subnetwork engaged across a diverse set of cognitive processes, particularly higher-order cognitive tasks. This study tested the hypothesis that functional brain network connectivity/topology in Latinx children from rural farmworker families (FW children) would differ from urban Latinx children from non-farmworker families (NFW children). We also tested the hypothesis that probable historic childhood exposure to pesticides among FW children would be associated with network connectivity/topology in a manner that parallels differences between FW and NFW children. We used brain networks from functional magnetic resonance imaging (fMRI) data from 78 children and a mixed-effects regression framework to test our hypotheses. We found that network topology was differently associated with the connection probability between FW and NFW children in the DMN. Our results also indicated that, among 48 FW children, historic reports of exposure to pesticides from prenatal to 96 months old were significantly associated with DMN topology, as hypothesized. Although the cause of the differences in brain networks between FW and NFW children cannot be determined using a cross-sectional study design, the observed associations between network connectivity/topology and historic exposure reports in FW children provide compelling evidence for a contribution of pesticide exposure on altering the DMN network organization in this vulnerable population. Although longitudinal follow-up of the children is necessary to further elucidate the cause and reveal the ultimate neurological implications, these findings raise serious concerns about the potential adverse health consequences from developmental neurotoxicity associated with pesticide exposure in this vulnerable population.

Uncovering shape signatures of resting-state functional connectivity by geometric deep learning on Riemannian manifold.

Functional neural activities manifest geometric patterns, as evidenced by the evolving network topology of functional connectivities (FC) even in the resting state. In this work, we propose a novel manifold-based geometric neural network for functional brain networks (called "Geo-Net4Net" for short) to learn the intrinsic low-dimensional feature representations of resting-state brain networks on the Riemannian manifold. This tool allows us to answer the scientific question of how the spontaneous fluctuation of FC supports behavior and cognition. We deploy a set of positive maps and rectified linear unit (ReLU) layers to uncover the intrinsic low-dimensional feature representations of functional brain networks on the Riemannian manifold taking advantage of the symmetric positive-definite (SPD) form of the correlation matrices. Due to the lack of well-defined ground truth in the resting state, existing learning-based methods are limited to unsupervised methodologies. To go beyond this boundary, we propose to self-supervise the feature representation learning of resting-state functional networks by leveraging the task-based counterparts occurring before and after the underlying resting state. With this extra heuristic, our Geo-Net4Net allows us to establish a more reasonable understanding of resting-state FCs by capturing the geometric patterns (aka. spectral/shape signature) associated with resting states on the Riemannian manifold. We have conducted extensive experiments on both simulated data and task-based functional resonance magnetic imaging (fMRI) data from the Human Connectome Project (HCP) database, where our Geo-Net4Net not only achieves more accurate change detection results than other state-of-the-art counterpart methods but also yields ubiquitous geometric patterns that manifest putative insights into brain function.

Contrasting topologies of synchronous and asynchronous functional brain networks.

We generated asynchronous functional networks (aFNs) using a novel method called optimal causation entropy (oCSE) and compared aFN topology to the correlation-based synchronous functional networks (sFNs) which are commonly used in network neuroscience studies. Functional magnetic resonance imaging (fMRI) time series from 212 participants of the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study were used to generate aFNs and sFNs. As a demonstration of how aFNs and sFNs can be used in tandem, we used multivariate mixed effects models to determine whether age interacted with node efficiency to influence connection probabilities in the two networks. After adjusting for differences in network density, aFNs had higher global efficiency but lower local efficiency than the sFNs. In the aFNs, nodes with the highest outgoing global efficiency tended to be in the brainstem and orbitofrontal cortex. aFN nodes with the highest incoming global efficiency tended to be members of the Default Mode Network (DMN) in sFNs. Age interacted with node global efficiency in aFNs and node local efficiency in sFNs to influence connection probability. We conclude that the sFN and aFN both offer information about functional brain connectivity which the other type of network does not.

Association of physical function with connectivity in the sensorimotor and dorsal attention networks: why examining specific components of physical function matters.

Declining physical function with aging is associated with structural and functional brain network organization. Gaining a greater understanding of network associations may be useful for targeting interventions that are designed to slow or prevent such decline. Our previous work demonstrated that the Short Physical Performance Battery (eSPPB) score and body mass index (BMI) exhibited a statistical interaction in their associations with connectivity in the sensorimotor cortex (SMN) and the dorsal attention network (DAN). The current study examined if components of the eSPPB have unique associations with these brain networks. Functional magnetic resonance imaging was performed on 192 participants in the BNET study, a longitudinal and observational trial of community-dwelling adults aged 70 or older. Functional brain networks were generated for resting state and during a motor imagery task. Regression analyses were performed between eSPPB component scores (gait speed, complex gait speed, static balance, and lower extremity strength) and BMI with SMN and DAN connectivity. Gait speed, complex gait speed, and lower extremity strength significantly interacted with BMI in their association with SMN at rest. Gait speed and complex gait speed were interacted with BMI in the DAN at rest while complex gait speed, static balance, and lower extremity strength interacted with BMI in the DAN during motor imagery. Results demonstrate that different components of physical function, such as balance or gait speed and BMI, are associated with unique aspects of brain network organization. Gaining a greater mechanistic understanding of the associations between low physical function, body mass, and brain physiology may lead to the development of treatments that not only target specific physical function limitations but also specific brain networks.

3M_BANTOR: A regression framework for multitask and multisession brain network distance metrics.

Brain network analyses have exploded in recent years and hold great potential in helping us understand normal and abnormal brain function. Network science approaches have facilitated these analyses and our understanding of how the brain is structurally and functionally organized. However, the development of statistical methods that allow relating this organization to phenotypic traits has lagged behind. Our previous work developed a novel analytic framework to assess the relationship between brain network architecture and phenotypic differences while controlling for confounding variables. More specifically, this innovative regression framework related distances (or similarities) between brain network features from a single task to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. Here we extend that work to the multitask and multisession context to allow for multiple brain networks per individual. We explore several similarity metrics for comparing distances between connection matrices and adapt several standard methods for estimation and inference within our framework: standard F test, F test with scan-level effects (SLE), and our proposed mixed model for multitask (and multisession) BrAin NeTwOrk Regression (3M_BANTOR). A novel strategy is implemented to simulate symmetric positive-definite (SPD) connection matrices, allowing for the testing of metrics on the Riemannian manifold. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing multivariate distance matrix regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.

Differences in Brain Network Topology Based on Alcohol Use History in Adolescents.

Approximately 6 million youth aged 12 to 20 consume alcohol monthly in the United States. The effect of alcohol consumption in adolescence on behavior and cognition is heavily researched; however, little is known about how alcohol consumption in adolescence may alter brain function, leading to long-term developmental detriments. In order to investigate differences in brain connectivity associated with alcohol use in adolescents, brain networks were constructed using resting-state functional magnetic resonance imaging data collected by the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) from 698 youth (12-21 years; 117 hazardous drinkers and 581 no/low drinkers). Analyses assessed differences in brain network topology based on alcohol consumption in eight predefined brain networks, as well as in whole-brain connectivity. Within the central executive network (CEN), basal ganglia network (BGN), and sensorimotor network (SMN), no/low drinkers demonstrated stronger and more frequent connections between highly globally efficient nodes, with fewer and weaker connections between highly clustered nodes. Inverse results were observed within the dorsal attention network (DAN), visual network (VN), and frontotemporal network (FTN), with no/low drinkers demonstrating weaker connections between nodes with high efficiency and increased frequency of clustered nodes compared to hazardous drinkers. Cross-sectional results from this study show clear organizational differences between adolescents with no/low or hazardous alcohol use, suggesting that aberrant connectivity in these brain networks is associated with risky drinking behaviors.

Associations of physical function and body mass index with functional brain networks in community-dwelling older adults.

Deficits in physical function that occur with aging contribute to declines in quality of life and increased mortality. There has been a growing interest in examining associations between physical function and neurobiology. Whereas high levels of white matter disease have been found in individuals with mobility impairments in structural brain studies, much less is known about the relationship between physical function and functional brain networks. Even less is known about the association between modifiable risk factors such as body mass index (BMI) and functional brain networks. The current study examined baseline functional brain networks in 192 individuals from the Brain Networks and mobility (B-NET) study, an ongoing longitudinal, observational study in community-dwelling adults aged 70 and older. Physical function and BMI were found to be associated with sensorimotor and dorsal attention network connectivity. There was a synergistic interaction such that high physical function and low BMI were associated with the highest network integrity. White matter disease did not modify these relationships. Future work is needed to understand the causal direction of these relationships.

A regression framework for brain network distance metrics.

Analyzing brain networks has long been a prominent research topic in neuroimaging. However, statistical methods to detect differences between these networks and relate them to phenotypic traits are still sorely needed. Our previous work developed a novel permutation testing framework to detect differences between two groups. Here we advance that work to allow both assessing differences by continuous phenotypes and controlling for confounding variables. To achieve this, we propose an innovative regression framework to relate distances (or similarities) between brain network features to functions of absolute differences in continuous covariates and indicators of difference for categorical variables. We explore several similarity metrics for comparing distances (or similarities) between connection matrices, and adapt several standard methods for estimation and inference within our framework: standard F test, F test with individual level effects (ILE), feasible generalized least squares (FGLS), and permutation. Via simulation studies, we assess all approaches for estimation and inference while comparing them with existing multivariate distance matrix regression (MDMR) methods. We then illustrate the utility of our framework by analyzing the relationship between fluid intelligence and brain network distances in Human Connectome Project (HCP) data.

Embedding Functional Brain Networks in Low Dimensional Spaces Using Manifold Learning Techniques.

Background: fMRI data is inherently high-dimensional and difficult to visualize. A recent trend has been to find spaces of lower dimensionality where functional brain networks can be projected onto manifolds as individual data points, leading to new ways to analyze and interpret the data. Here, we investigate the potential of two powerful non-linear manifold learning techniques for functional brain networks representation: (1) T-stochastic neighbor embedding (t-SNE) and (2) Uniform Manifold Approximation Projection (UMAP) a recent breakthrough in manifold learning. Methods: fMRI data from the Human Connectome Project (HCP) and an independent study of aging were used to generate functional brain networks. We used fMRI data collected during resting state data and during a working memory task. The relative performance of t-SNE and UMAP were investigated by projecting the networks from each study onto 2D manifolds. The levels of discrimination between different tasks and the preservation of the topology were evaluated using different metrics. Results: Both methods effectively discriminated the resting state from the memory task in the embedding space. UMAP discriminated with a higher classification accuracy. However, t-SNE appeared to better preserve the topology of the high-dimensional space. When networks from the HCP and aging studies were combined, the resting state and memory networks in general aligned correctly. Discussion: Our results suggest that UMAP, a more recent development in manifold learning, is an excellent tool to visualize functional brain networks. Despite dramatic differences in data collection and protocols, networks from different studies aligned correctly in the embedding space.

Effects of a Motor Imagery Task on Functional Brain Network Community Structure in Older Adults: Data from the Brain Networks and Mobility Function (B-NET) Study.

Elucidating the neural correlates of mobility is critical given the increasing population of older adults and age-associated mobility disability. In the current study, we applied graph theory to cross-sectional data to characterize functional brain networks generated from functional magnetic resonance imaging data both at rest and during a motor imagery (MI) task. Our MI task is derived from the Mobility Assessment Tool-short form (MAT-sf), which predicts performance on a 400 m walk, and the Short Physical Performance Battery (SPPB). Participants (n = 157) were from the Brain Networks and Mobility (B-NET) Study (mean age = 76.1 ± 4.3; % female = 55.4; % African American = 8.3; mean years of education = 15.7 ± 2.5). We used community structure analyses to partition functional brain networks into communities, or subnetworks, of highly interconnected regions. Global brain network community structure decreased during the MI task when compared to the resting state. We also examined the community structure of the default mode network (DMN), sensorimotor network (SMN), and the dorsal attention network (DAN) across the study population. The DMN and SMN exhibited a task-driven decline in consistency across the group when comparing the MI task to the resting state. The DAN, however, displayed an increase in consistency during the MI task. To our knowledge, this is the first study to use graph theory and network community structure to characterize the effects of a MI task, such as the MAT-sf, on overall brain network organization in older adults.

Using Low-Dimensional Manifolds to Map Relationships Between Dynamic Brain Networks.

As the field of dynamic brain networks continues to expand, new methods are needed to allow for optimal handling and understanding of this explosion in data. We propose here a novel approach that embeds dynamic brain networks onto a two-dimensional (2D) manifold based on similarities and differences in network organization. Each brain network is represented as a single point on the low dimensional manifold with networks of similar topology being located in close proximity. The rich spatio-temporal information has great potential for visualization, analysis, and interpretation of dynamic brain networks. The fact that each network is represented by a single point makes it possible to switch between the low-dimensional space and the full connectivity of any given brain network. Thus, networks in a specific region of the low-dimensional space can be examined to identify network features, such as the location of brain network hubs or the interconnectivity between brain circuits. In this proof-of-concept manuscript, we show that these low dimensional manifolds contain meaningful information, as they were able to successfully discriminate between cognitive tasks and study populations. This work provides evidence that embedding dynamic brain networks onto low dimensional manifolds has the potential to help us better visualize and understand dynamic brain networks with the hope of gaining a deeper understanding of normal and abnormal brain dynamics.

Moderate-Heavy Alcohol Consumption Lifestyle in Older Adults Is Associated with Altered Central Executive Network Community Structure during Cognitive Task.

Older adults today consume more alcohol than previous generations, the majority being social drinkers. The effects of heavy alcohol use on brain functioning closely resemble age-related changes, but it is not known if moderate-heavy alcohol consumption intensifies brain aging. Whether a lifestyle of moderate-heavy alcohol use in older adults increased age-related brain changes was examined. Forty-one older adults (65-80 years) that consumed light (< 2 drinks/week and ≥ 1 drink/month, n = 20) or moderate-heavy (7-21 drinks/week, non-bingers, n = 21) amounts of alcohol were enrolled. Twenty-two young adults (24-35 years) were also enrolled (light, n = 11 and moderate-heavy, n = 11). Functional brain networks based on magnetic resonance imaging data were generated for resting state and during a working memory task. Whole-brain, Central Executive Network (CEN), and Default Mode Network (DMN) connectivity were assessed in light and moderate-heavy alcohol consuming older adults with comparisons to young adults. The older adults had significantly lower whole brain connectivity (global efficiency) and lower regional connectivity (community structure) in the CEN during task and in the DMN at rest. Moderate-heavy older drinkers did not exhibit whole brain connectivity differences compared to the low drinkers. However, decreased CEN connectivity was observed during the task. There were no differences in the DMN connectivity between drinking groups. Taken together, a lifestyle including moderate-heavy alcohol consumption may be associated with further decreases in brain network connectivity within task-related networks in older adults. Further research is required to determine if this decrease is compensatory or an early sign of decline.

Brain Anatomy in Latino Farmworkers Exposed to Pesticides and Nicotine.

OBJECTIVE: Migrant tobacco farmworkers experience regular occupational exposure to pesticides and nicotine. The present study was designed to determine whether there are differences in brain anatomy between Latino farmworkers and non-farmworkers. METHODS: Magnetic resonance brain images were compared between farmworkers and non-farmworkers. In addition, blood cholinesterase activity and urinary cotinine levels were also used to identify associations with pesticide and nicotine exposure. RESULTS: Farmworkers had greater gray matter signal in putamen and cerebellum, and lower gray matter signal in frontal and temporal lobes. Urinary cotinine was associated with the observed differences in brain anatomy, but blood cholinesterase activity was not. CONCLUSIONS: Nicotine exposure was associated with neuroanatomical differences between Latino farmworkers and non-farmworkers. Future studies are needed to differentiate iron deposition from brain atrophy and to further assess the potential role of nicotine and pesticide exposure.

Global integration of the hot-state brain network of appetite predicts short term weight loss in older adult.

Obesity is a public health crisis in North America. While lifestyle interventions for weight loss (WL) remain popular, the rate of success is highly variable. Clearly, self-regulation of eating behavior is a challenge and patterns of activity across the brain may be an important determinant of success. The current study prospectively examined whether integration across the Hot-State Brain Network of Appetite (HBN-A) predicts WL after 6-months of treatment in older adults. Our metric for network integration was global efficiency (GE). The present work is a sub-study (n = 56) of an ongoing randomized clinical trial involving WL. Imaging involved a baseline food-cue visualization functional MRI (fMRI) scan following an overnight fast. Using graph theory to build functional brain networks, we demonstrated that regions of the HBN-A (insula, anterior cingulate cortex (ACC), superior temporal pole (STP), amygdala and the parahippocampal gyrus) were highly integrated as evidenced by the results of a principal component analysis (PCA). After accounting for known correlates of WL (baseline weight, age, sex, and self-regulatory efficacy) and treatment condition, which together contributed 36.9% of the variance in WL, greater GE in the HBN-A was associated with an additional 19% of the variance. The ACC of the HBN-A was the primary driver of this effect, accounting for 14.5% of the variance in WL when entered in a stepwise regression following the covariates, p = 0.0001. The HBN-A is comprised of limbic regions important in the processing of emotions and visceral sensations and the ACC is key for translating such processing into behavioral consequences. The improved integration of these regions may enhance awareness of body and emotional states leading to more successful self-regulation and to greater WL. This is the first study among older adults to prospectively demonstrate that, following an overnight fast, GE of the HBN-A during a food visualization task is predictive of WL.

Changes in brain network efficiency and working memory performance in aging.

Working memory is a complex psychological construct referring to the temporary storage and active processing of information. We used functional connectivity brain network metrics quantifying local and global efficiency of information transfer for predicting individual variability in working memory performance on an n-back task in both young (n = 14) and older (n = 15) adults. Individual differences in both local and global efficiency during the working memory task were significant predictors of working memory performance in addition to age (and an interaction between age and global efficiency). Decreases in local efficiency during the working memory task were associated with better working memory performance in both age cohorts. In contrast, increases in global efficiency were associated with much better working performance for young participants; however, increases in global efficiency were associated with a slight decrease in working memory performance for older participants. Individual differences in local and global efficiency during resting-state sessions were not significant predictors of working memory performance. Significant group whole-brain functional network decreases in local efficiency also were observed during the working memory task compared to rest, whereas no significant differences were observed in network global efficiency. These results are discussed in relation to recently developed models of age-related differences in working memory.

Changes in global and regional modularity associated with increasing working memory load.

Using graph theory measures common to complex network analyses of neuroimaging data, the objective of this study was to explore the effects of increasing working memory processing load on functional brain network topology in a cohort of young adults. Measures of modularity in complex brain networks quantify how well a network is organized into densely interconnected communities. We investigated changes in both the large-scale modular organization of the functional brain network as a whole and regional changes in modular organization as demands on working memory increased from n = 1 to n = 2 on the standard n-back task. We further investigated the relationship between modular properties across working memory load conditions and behavioral performance. Our results showed that regional modular organization within the default mode and working memory circuits significantly changed from 1-back to 2-back task conditions. However, the regional modular organization was not associated with behavioral performance. Global measures of modular organization did not change with working memory load but were associated with individual variability in behavioral performance. These findings indicate that regional and global network properties are modulated by different aspects of working memory under increasing load conditions. These findings highlight the importance of assessing multiple features of functional brain network topology at both global and regional scales rather than focusing on a single network property.

A permutation testing framework to compare groups of brain networks.

Brain network analyses have moved to the forefront of neuroimaging research over the last decade. However, methods for statistically comparing groups of networks have lagged behind. These comparisons have great appeal for researchers interested in gaining further insight into complex brain function and how it changes across different mental states and disease conditions. Current comparison approaches generally either rely on a summary metric or on mass-univariate nodal or edge-based comparisons that ignore the inherent topological properties of the network, yielding little power and failing to make network level comparisons. Gleaning deeper insights into normal and abnormal changes in complex brain function demands methods that take advantage of the wealth of data present in an entire brain network. Here we propose a permutation testing framework that allows comparing groups of networks while incorporating topological features inherent in each individual network. We validate our approach using simulated data with known group differences. We then apply the method to functional brain networks derived from fMRI data.

Defining nodes in complex brain networks.

Network science holds great promise for expanding our understanding of the human brain in health, disease, development, and aging. Network analyses are quickly becoming the method of choice for analyzing functional MRI data. However, many technical issues have yet to be confronted in order to optimize results. One particular issue that remains controversial in functional brain network analyses is the definition of a network node. In functional brain networks a node represents some predefined collection of brain tissue, and an edge measures the functional connectivity between pairs of nodes. The characteristics of a node, chosen by the researcher, vary considerably in the literature. This manuscript reviews the current state of the art based on published manuscripts and highlights the strengths and weaknesses of three main methods for defining nodes. Voxel-wise networks are constructed by assigning a node to each, equally sized brain area (voxel). The fMRI time-series recorded from each voxel is then used to create the functional network. Anatomical methods utilize atlases to define the nodes based on brain structure. The fMRI time-series from all voxels within the anatomical area are averaged and subsequently used to generate the network. Functional activation methods rely on data from traditional fMRI activation studies, often from databases, to identify network nodes. Such methods identify the peaks or centers of mass from activation maps to determine the location of the nodes. Small (~10-20 millimeter diameter) spheres located at the coordinates of the activation foci are then applied to the data being used in the network analysis. The fMRI time-series from all voxels in the sphere are then averaged, and the resultant time series is used to generate the network. We attempt to clarify the discussion and move the study of complex brain networks forward. While the "correct" method to be used remains an open, possibly unsolvable question that deserves extensive debate and research, we argue that the best method available at the current time is the voxel-wise method.