Neural Dynamics During the Generation and Evaluation of Creative and Non-Creative Ideas.

What are the neural dynamics that drive creative thinking? Recent studies have provided much insight into the neural mechanisms of creative thought. Specifically, the interaction between the executive control, default mode, and salience brain networks has been shown to be an important marker of individual differences in creative ability. However, how these different brain systems might be recruited dynamically during the two key components of the creative process- generation and evaluation of ideas-remains far from understood. In the current study we applied state-of-the-art network neuroscience methodologies to examine the neural dynamics related to the generation and evaluation of creative and non-creative ideas using a novel within-subjects design. Participants completed two functional magnetic resonance imaging sessions, taking place a week apart. In the first imaging session, participants generated either creative (alternative uses) or non-creative (common characteristics) responses to common objects. In the second imaging session, participants evaluated their own creative and non-creative responses to the same objects. Network neuroscience methods were applied to examine and directly compare reconfiguration, integration, and recruitment of brain networks during these four conditions. We found that generating creative ideas led to significantly higher network reconfiguration than generating non-creative ideas, whereas evaluating creative and non-creative ideas led to similar levels of network integration. Furthermore, we found that these differences were attributable to different dynamic patterns of neural activity across the executive control, default mode, and salience networks. This study is the first to show within-subject differences in neural dynamics related to generating and evaluating creative and non-creative ideas.

A socioemotional network perspective on momentary experiences of family conflict in young adults.

Family conflict is an established predictor of psychopathology in youth. Traditional approaches focus on between-family differences in conflict. Daily fluctuations in conflict within families might also impact psychopathology, but more research is needed to understand how and why. Using 21 days of daily diary data and 6-times a day experience-sampling data (N = 77 participants; mean age = 21.18, SD = 1.75; 63 women, 14 men), we captured day-to-day and within-day fluctuations in family conflict, anger, anxiety, and sadness. Using multilevel models, we find that days of higher-than-usual anger are also days of higher-than-usual family conflict. Examining associations between family conflict and emotions within days, we find that moments of higher-than-usual anger predict higher-than-usual family conflict later in the day. We observe substantial between-family differences in these patterns with implications for psychopathology; youth showing the substantial interplay between family conflict and emotions across time had a more perseverative family conflict and greater trait anxiety. Overall, findings indicate the importance of increases in youth anger for experiences of family conflict during young adulthood and demonstrate how intensive repeated measures coupled with network analytic approaches can capture long-theorized notions of reciprocal processes in daily family life.

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression.

BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. METHODS: Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3-6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression. RESULTS: Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers. CONCLUSIONS: This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

Generalizable Links Between Borderline Personality Traits and Functional Connectivity.

BACKGROUND: Symptoms of borderline personality disorder (BPD) often manifest during adolescence, but the underlying relationship between these debilitating symptoms and the development of functional brain networks is not well understood. Here, we aimed to investigate how multivariate patterns of functional connectivity are associated with borderline personality traits in large samples of young adults and adolescents. METHODS: We used functional magnetic resonance imaging data from young adults and adolescents from the HCP-YA (Human Connectome Project Young Adult) (n = 870, ages 22-37 years, 457 female) and the HCP-D (Human Connectome Project Development) (n = 223, ages 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five-Factor Inventory. A ridge regression model with cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity. The trained model was further tested on data from HCP-D without further tuning. Finally, we tested how the connectivity patterns associated with BPD aligned with age-related changes in connectivity. RESULTS: Multivariate functional connectivity patterns significantly predicted out-of-sample BPD scores in unseen data in young adults (HCP-YA ppermuted = .001) and older adolescents (HCP-D ppermuted = .001). Regional predictive capacity was heterogeneous; the most predictive regions were found in functional systems relevant for emotion regulation and executive function, including the ventral attention network. Finally, regional functional connectivity patterns that predicted BPD scores aligned with those associated with development in youth. CONCLUSIONS: Individual differences in functional connectivity in developmentally sensitive regions are associated with borderline personality traits.

Information decomposition in complex systems via machine learning.

One of the fundamental steps toward understanding a complex system is identifying variation at the scale of the system's components that is most relevant to behavior on a macroscopic scale. Mutual information provides a natural means of linking variation across scales of a system due to its independence of functional relationship between observables. However, characterizing the manner in which information is distributed across a set of observables is computationally challenging and generally infeasible beyond a handful of measurements. Here, we propose a practical and general methodology that uses machine learning to decompose the information contained in a set of measurements by jointly optimizing a lossy compression of each measurement. Guided by the distributed information bottleneck as a learning objective, the information decomposition identifies the variation in the measurements of the system state most relevant to specified macroscale behavior. We focus our analysis on two paradigmatic complex systems: a Boolean circuit and an amorphous material undergoing plastic deformation. In both examples, the large amount of entropy of the system state is decomposed, bit by bit, in terms of what is most related to macroscale behavior. The identification of meaningful variation in data, with the full generality brought by information theory, is made practical for studying the connection between micro- and macroscale structure in complex systems.

Diffusion MRI head motion correction methods are highly accurate but impacted by denoising and sampling scheme.

Head motion correction is particularly challenging in diffusion-weighted MRI (dMRI) scans due to the dramatic changes in image contrast at different gradient strengths and directions. Head motion correction is typically performed using a Gaussian Process model implemented in FSL's Eddy. Recently, the 3dSHORE-based SHORELine method was introduced that does not require shell-based acquisitions, but it has not been previously benchmarked. Here we perform a comprehensive evaluation of both methods on realistic simulations of a software fiber phantom that provides known ground-truth head motion. We demonstrate that both methods perform remarkably well, but that performance can be impacted by sampling scheme and the extent of head motion and the denoising strategy applied before head motion correction. Furthermore, we find Eddy benefits from denoising the data first with MP-PCA. In sum, we provide the most extensive known benchmarking of dMRI head motion correction, together with extensive simulation data and a reproducible workflow. PRACTITIONER POINTS: Both Eddy and SHORELine head motion correction methods performed quite well on a large variety of simulated data. Denoising with MP-PCA can improve head motion correction performance when Eddy is used. SHORELine effectively corrects motion in non-shelled diffusion spectrum imaging data.

Breaking reflection symmetry: evolving long dynamical cycles in Boolean systems.

In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of dynamical cycles range from circadian rhythms regulating sleep to cell cycles regulating reproductive behavior. Despite the crucial role of cycles in nature, the properties of network structure that give rise to cycles still need to be better understood. Here, we use a Boolean interaction network model to study the relationships between network structure and cyclic dynamics. We identify particular structural motifs that support cycles, and other motifs that suppress them. More generally, we show that the presence of dynamical reflection symmetry in the interaction network enhances cyclic behavior. In simulating an artificial evolutionary process, we find that motifs that break reflection symmetry are discarded. We further show that dynamical reflection symmetries are over-represented in Boolean models of natural biological systems. Altogether, our results demonstrate a link between symmetry and functionality for interacting dynamical systems, and they provide evidence for symmetry's causal role in evolving dynamical functionality.

Correction: Gender imbalances in the editorial activities of a selective journal run by academic editors.

[This corrects the article DOI: 10.1371/journal.pone.0294805.].

Understanding divergence: Placing developmental neuroscience in its dynamic context.

Neurodevelopment is not merely a process of brain maturation, but an adaptation to constraints unique to each individual and to the environments we co-create. However, our theoretical and methodological toolkits often ignore this reality. There is growing awareness that a shift is needed that allows us to study divergence of brain and behaviour across conventional categorical boundaries. However, we argue that in future our study of divergence must also incorporate the developmental dynamics that capture the emergence of those neurodevelopmental differences. This crucial step will require adjustments in study design and methodology. If our ultimate aim is to incorporate the developmental dynamics that capture how, and ultimately when, divergence takes place then we will need an analytic toolkit equal to these ambitions. We argue that the over reliance on group averages has been a conceptual dead-end with regard to the neurodevelopmental differences. This is in part because any individual differences and developmental dynamics are inevitably lost within the group average. Instead, analytic approaches which are themselves new, or simply newly applied within this context, may allow us to shift our theoretical and methodological frameworks from groups to individuals. Likewise, methods capable of modelling complex dynamic systems may allow us to understand the emergent dynamics only possible at the level of an interacting neural system.

Causation in neuroscience: keeping mechanism meaningful.

A fundamental goal of research in neuroscience is to uncover the causal structure of the brain. This focus on causation makes sense, because causal information can provide explanations of brain function and identify reliable targets with which to understand cognitive function and prevent or change neurological conditions and psychiatric disorders. In this research, one of the most frequently used causal concepts is 'mechanism' - this is seen in the literature and language of the field, in grant and funding inquiries that specify what research is supported, and in journal guidelines on which contributions are considered for publication. In these contexts, mechanisms are commonly tied to expressions of the main aims of the field and cited as the 'fundamental', 'foundational' and/or 'basic' unit for understanding the brain. Despite its common usage and perceived importance, mechanism is used in different ways that are rarely distinguished. Given that this concept is defined in different ways throughout the field - and that there is often no clarification of which definition is intended - there remains a marked ambiguity about the fundamental goals, orientation and principles of the field. Here we provide an overview of causation and mechanism from the perspectives of neuroscience and philosophy of science, in order to address these challenges.

Regression and Alignment for Functional Data and Network Topology.

In the brain, functional connections form a network whose topological organization can be described by graph-theoretic network diagnostics. These include characterizations of the community structure, such as modularity and participation coefficient, which have been shown to change over the course of childhood and adolescence. To investigate if such changes in the functional network are associated with changes in cognitive performance during development, network studies often rely on an arbitrary choice of pre-processing parameters, in particular the proportional threshold of network edges. Because the choice of parameter can impact the value of the network diagnostic, and therefore downstream conclusions, we propose to circumvent that choice by conceptualizing the network diagnostic as a function of the parameter. As opposed to a single value, a network diagnostic curve describes the connectome topology at multiple scales-from the sparsest group of the strongest edges to the entire edge set. To relate these curves to executive function and other covariates, we use scalar-on-function regression, which is more flexible than previous functional data-based models used in network neuroscience. We then consider how systematic differences between networks can manifest in misalignment of diagnostic curves, and consequently propose a supervised curve alignment method that incorporates auxiliary information from other variables. Our algorithm performs both functional regression and alignment via an iterative, penalized, and nonlinear likelihood optimization. The illustrated method has the potential to improve the interpretability and generalizability of neuroscience studies where the goal is to study heterogeneity among a mixture of function- and scalar-valued measures.

Macroscopic resting-state brain dynamics are best described by linear models.

It is typically assumed that large networks of neurons exhibit a large repertoire of nonlinear behaviours. Here we challenge this assumption by leveraging mathematical models derived from measurements of local field potentials via intracranial electroencephalography and of whole-brain blood-oxygen-level-dependent brain activity via functional magnetic resonance imaging. We used state-of-the-art linear and nonlinear families of models to describe spontaneous resting-state activity of 700 participants in the Human Connectome Project and 122 participants in the Restoring Active Memory project. We found that linear autoregressive models provide the best fit across both data types and three performance metrics: predictive power, computational complexity and the extent of the residual dynamics unexplained by the model. To explain this observation, we show that microscopic nonlinear dynamics can be counteracted or masked by four factors associated with macroscopic dynamics: averaging over space and over time, which are inherent to aggregated macroscopic brain activity, and observation noise and limited data samples, which stem from technological limitations. We therefore argue that easier-to-interpret linear models can faithfully describe macroscopic brain dynamics during resting-state conditions.

Gender imbalances in the editorial activities of a selective journal run by academic editors.

The fairness of decisions made at various stages of the publication process is an important topic in meta-research. Here, based on an analysis of data on the gender of authors, editors and reviewers for 23,876 initial submissions and 7,192 full submissions to the journal eLife, we report on five stages of the publication process. We find that the board of reviewing editors (BRE) is men-dominant (69%) and that authors disproportionately suggest male editors when making an initial submission. We do not find evidence for gender bias when Senior Editors consult Reviewing Editors about initial submissions, but women Reviewing Editors are less engaged in discussions about these submissions than expected by their proportion. We find evidence of gender homophily when Senior Editors assign full submissions to Reviewing Editors (i.e., men are more likely to assign full submissions to other men (77% compared to the base assignment rate to men RE of 70%), and likewise for women (41% compared to women RE base assignment rate of 30%))). This tendency was stronger in more gender-balanced scientific disciplines. However, we do not find evidence for gender bias when authors appeal decisions made by editors to reject submissions. Together, our findings confirm that gender disparities exist along the editorial process and suggest that merely increasing the proportion of women might not be sufficient to eliminate this bias. Measures accounting for women's circumstances and needs (e.g., delaying discussions until all RE are engaged) and raising editorial awareness to women's needs may be essential to increasing gender equity and enhancing academic publication.

Functional brain networks are associated with both sex and gender in children.

Sex and gender are associated with human behavior throughout the lifespan and across health and disease, but whether they are associated with similar or distinct neural phenotypes is unknown. Here, we demonstrate that, in children, sex and gender are uniquely reflected in the intrinsic functional connectivity of the brain. Unimodal networks are more strongly associated with sex while heteromodal networks are more strongly associated with gender. These results suggest sex and gender are irreducible to one another not only in society but also in biology.

Frontoparietal functional connectivity moderates the link between time spent on social media and subsequent negative affect in daily life.

Evidence on the harms and benefits of social media use is mixed, in part because the effects of social media on well-being depend on a variety of individual difference moderators. Here, we explored potential neural moderators of the link between time spent on social media and subsequent negative affect. We specifically focused on the strength of correlation among brain regions within the frontoparietal system, previously associated with the top-down cognitive control of attention and emotion. Participants (N = 54) underwent a resting state functional magnetic resonance imaging scan. Participants then completed 28 days of ecological momentary assessment and answered questions about social media use and negative affect, twice a day. Participants who spent more than their typical amount of time on social media since the previous time point reported feeling more negative at the present moment. This within-person temporal association between social media use and negative affect was mainly driven by individuals with lower resting state functional connectivity within the frontoparietal system. By contrast, time spent on social media did not predict subsequent affect for individuals with higher frontoparietal functional connectivity. Our results highlight the moderating role of individual functional neural connectivity in the relationship between social media and affect.

Myelination and excitation-inhibition balance synergistically shape structure-function coupling across the human cortex.

Recent work has demonstrated that the relationship between structural and functional connectivity varies regionally across the human brain, with reduced coupling emerging along the sensory-association cortical hierarchy. The biological underpinnings driving this expression, however, remain largely unknown. Here, we postulate that intracortical myelination and excitation-inhibition (EI) balance mediate the heterogeneous expression of structure-function coupling (SFC) and its temporal variance across the cortical hierarchy. We employ atlas- and voxel-based connectivity approaches to analyze neuroimaging data acquired from two groups of healthy participants. Our findings are consistent across six complementary processing pipelines: 1) SFC and its temporal variance respectively decrease and increase across the unimodal-transmodal and granular-agranular gradients; 2) increased myelination and lower EI-ratio are associated with more rigid SFC and restricted moment-to-moment SFC fluctuations; 3) a gradual shift from EI-ratio to myelination as the principal predictor of SFC occurs when traversing from granular to agranular cortical regions. Collectively, our work delivers a framework to conceptualize structure-function relationships in the human brain, paving the way for an improved understanding of how demyelination and/or EI-imbalances induce reorganization in brain disorders.

Generalizable links between symptoms of borderline personality disorder and functional connectivity.

Background |: Symptoms of borderline personality disorder (BPD) often manifest in adolescence, yet the underlying relationship between these debilitating symptoms and the development of functional brain networks is not well understood. Here we aimed to investigate how multivariate patterns of functional connectivity are associated with symptoms of BPD in a large sample of young adults and adolescents. Methods |: We used high-quality functional Magnetic Resonance Imaging (fMRI) data from young adults from the Human Connectome Project: Young Adults (HCP-YA; N = 870, ages 22-37 years, 457 female) and youth from the Human Connectome Project: Development (HCP-D; N = 223, age range 16-21 years, 121 female). A previously validated BPD proxy score was derived from the NEO Five Factor Inventory (NEO-FFI). A ridge regression model with 10-fold cross-validation and nested hyperparameter tuning was trained and tested in HCP-YA to predict BPD scores in unseen data from regional functional connectivity, while controlling for in-scanner motion, age, and sex. The trained model was further tested on data from HCP-D without further tuning. Finally, we tested how the connectivity patterns associated with BPD aligned with age-related changes in connectivity. Results |: Multivariate functional connectivity patterns significantly predicted out-of-sample BPD proxy scores in unseen data in both young adults (HCP-YA; pperm = 0.001) and older adolescents (HCP-D; pperm = 0.001). Predictive capacity of regions was heterogeneous; the most predictive regions were found in functional systems relevant for emotion regulation and executive function, including the ventral attention network. Finally, regional functional connectivity patterns that predicted BPD proxy scores aligned with those associated with development in youth. Conclusion |: Individual differences in functional connectivity in developmentally-sensitive regions are associated with the symptoms of BPD.

Using network control theory to study the dynamics of the structural connectome.

Network control theory (NCT) is a simple and powerful tool for studying how network topology informs and constrains dynamics. Compared to other structure-function coupling approaches, the strength of NCT lies in its capacity to predict the patterns of external control signals that may alter dynamics in a desired way. We have extensively developed and validated the application of NCT to the human structural connectome. Through these efforts, we have studied (i) how different aspects of connectome topology affect neural dynamics, (ii) whether NCT outputs cohere with empirical data on brain function and stimulation, and (iii) how NCT outputs vary across development and correlate with behavior and mental health symptoms. In this protocol, we introduce a framework for applying NCT to structural connectomes following two main pathways. Our primary pathway focuses on computing the control energy associated with transitioning between specific neural activity states. Our second pathway focuses on computing average controllability, which indexes nodes' general capacity to control dynamics. We also provide recommendations for comparing NCT outputs against null network models. Finally, we support this protocol with a Python-based software package called network control theory for python (nctpy).

Accumbens connectivity during deep-brain stimulation differentiates loss of control from physiologic behavioral states.

BACKGROUND: Loss of control (LOC) eating, the subjective sense that one cannot control what or how much one eats, characterizes binge-eating behaviors pervasive in obesity and related eating disorders. Closed-loop deep-brain stimulation (DBS) for binge eating should predict LOC and trigger an appropriately timed intervention. OBJECTIVE/HYPOTHESIS: This study aimed to identify a sensitive and specific biomarker to detect LOC onset for DBS. We hypothesized that changes in phase-locking value (PLV) predict the onset of LOC-associated cravings and distinguish them from potential confounding states. METHODS: Using DBS data recorded from the nucleus accumbens (NAc) of two patients with binge eating disorder (BED) and severe obesity, we compared PLV between inter- and intra-hemispheric NAc subregions for three behavioral conditions: craving (associated with LOC eating), hunger (not associated with LOC), and sleep. RESULTS: In both patients, PLV in the high gamma frequency band was significantly higher for craving compared to sleep and significantly higher for hunger compared to craving. Maximum likelihood classifiers achieved accuracies above 88% when differentiating between the three conditions. CONCLUSIONS: High-frequency inter- and intra-hemispheric PLV in the NAc is a promising biomarker for closed-loop DBS that differentiates LOC-associated cravings from physiologic states such as hunger and sleep. Future trials should assess PLV as a LOC biomarker across a larger cohort and a wider patient population transdiagnostically.