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The nervous system, especially the human brain, is characterized by its highly complex network topology. The neurodevelopment of some of its features has been described in terms of dynamic optimization rules. We discuss the principle of adaptive rewiring, i.e., the dynamic reorganization of a network according to the intensity of internal signal communication as measured by synchronization or diffusion, and its recent generalization for applications in directed networks. These have extended the principle of adaptive rewiring from highly oversimplified networks to more neurally plausible ones. Adaptive rewiring captures all the key features of the complex brain topology: it transforms initially random or regular networks into networks with a modular small-world structure and a rich-club core. This effect is specific in the sense that it can be tailored to computational needs, robust in the sense that it does not depend on a critical regime, and flexible in the sense that parametric variation generates a range of variant network configurations. Extreme variant networks can be associated at macroscopic level with disorders such as schizophrenia, autism, and dyslexia, and suggest a relationship between dyslexia and creativity. Adaptive rewiring cooperates with network growth and interacts constructively with spatial organization principles in the formation of topographically distinct modules and structures such as ganglia and chains. At the mesoscopic level, adaptive rewiring enables the development of functional architectures, such as convergent-divergent units, and sheds light on the early development of divergence and convergence in, for example, the visual system. Finally, we discuss future prospects for the principle of adaptive rewiring. [ABSTRACT FROM AUTHOR]

Digital twins enable simulation, comprehensive analysis and predictions, as virtual representations of physical systems. They are also finding increasing interest and application in the healthcare sector, with a particular focus on digital twins of the brain. We discuss how digital twins in neuroscience enable the modeling of brain functions and pathology as they offer an in-silico approach to studying the brain and illustrating the complex relationships between brain network dynamics and related functions. To showcase the capabilities of digital twinning in neuroscience we demonstrate how the impact of brain tumors on the brain's physical structures and functioning can be modeled in relation to the philosophical concept of plasticity. Against this technically derived backdrop, which assumes that the brain's nonlinear behavior toward improvement and repair can be modeled and predicted based on MRI data, we further explore the philosophical insights of Catherine Malabou. Malabou emphasizes the brain's dual capacity for adaptive and destructive plasticity. We will discuss in how far Malabou's ideas provide a more holistic theoretical framework for understanding how digital twins can model the brain's response to injury and pathology, embracing Malabou's concept of both adaptive and destructive plasticity which provides a framework to address such yet incomputable aspects of neuroscience and the sometimes seemingly unfavorable dynamics of neuroplasticity helping to bridge the gap between theoretical research and clinical practice. [ABSTRACT FROM AUTHOR]

One of the longstanding aims of network neuroscience is to link a connectome's topological properties--i.e., features defined from connectivity alone-with an organism's neurobiology. One approach for doing so is to compare connectome properties with annotational maps. This type of analysis is popular at the meso-/macroscale, but is less common at the nano-scale, owing to a paucity of neuron-level connectome data. However, recent methodological advances have made possible the reconstruction of whole-brain connectomes at single-neuron resolution for a select set of organisms. These include the fruit fly, Drosophila melanogaster, and its developing larvae. In addition to fine-scale descriptions of connectivity, these datasets are accompanied by rich annotations. Here, we use a variant of the stochastic blockmodel to detect multilevel communities in the larval Drosophila connectome. We find that communities partition neurons based on function and cell type and that most interact assortatively, reflecting the principle of functional segregation. However, a small number of communities interact nonassortatively, forming form a "rich-club" of interneurons that receive sensory/ascending inputs and deliver outputs along descending pathways. Next, we investigate the role of community structure in shaping communication patterns. We find that polysynaptic signaling follows specific trajectories across modular hierarchies, with interneurons playing a key role in mediating communication routes between modules and hierarchical scales. Our work suggests a relationship between systemlevel architecture and the biological function and classification of individual neurons. We envision our study as an important step toward bridging the gap between complex systems and neurobiological lines of investigation in brain sciences. [ABSTRACT FROM AUTHOR]

Introduction: Historically, Parkinson's Disease (PD) research has focused on the dysfunction of dopamine-producing cells in the substantia nigra pars compacta, which is linked to motor regulation in the basal ganglia. Therapies have mainly aimed at restoring dopamine (DA) levels, showing effectiveness but variable outcomes and side effects. Recent evidence indicates that PD complexity implicates disruptions in DA, noradrenaline (NA), and serotonin (5-HT) systems, which may underlie the variations in therapy effects. Methods: We present a system-level bio-constrained computational model that comprehensively investigates the dynamic interactions between these neurotransmitter systems. The model was designed to replicate experimental data demonstrating the impact of NA and 5-HT depletion in a PD animal model, providing insights into the causal relationships between basal ganglia regions and neuromodulator release areas. Results: The model successfully replicates experimental data and generates predictions regarding changes in unexplored brain regions, suggesting avenues for further investigation. It highlights the potential efficacy of alternative treatments targeting the locus coeruleus and dorsal raphe nucleus, though these preliminary findings require further validation. Sensitivity analysis identifies critical model parameters, offering insights into key factors influencing brain area activity. A stability analysis underscores the robustness of our mathematical formulation, bolstering the model validity. Discussion: Our holistic approach emphasizes that PD is amultifactorial disorder and opens promising avenues for early diagnostic tools that harness the intricate interactions amongmonoaminergic systems. Investigating NA and 5-HT systems alongside the DA system may yield more effective, subtype-specific therapies. The exploration of multisystem dysregulation in PD is poised to revolutionize our understanding and management of this complex neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Altruism is an enigmatic form of prosocial behavior, characterized by diverse motivations and significant interindividual differences. Studying neural mechanisms of altruism is crucial to identify objective markers of pro- and antisocial tendencies in behavior. This study was designed to delve into the mechanisms of altruism by analyzing EEG-based functional connectivity patterns within the framework of the network approach. To experimentally induce a situation of altruistic decision-making, we employed the Pain versus Gain (PvsG) task, which implies making choices concerning financial self-benefit and pain of the other. Our results reveal that the behavioral measure of altruism in the experiment correlated with emotional empathy, which is in line with the "empathy-altruism" hypothesis. Applying the network approach to EEG functional connectivity analysis, we discovered that the very process of decision-making in the PvsG is characterized by the synchronous activity of structures in the right hemisphere, which are involved in empathy for pain. The prosociality of decisions was reflected in functional connectivity between the rostral ACC and orbital IFG in the left hemisphere and the overall network centrality of the caudal ACC. This finding additionally points to the distinct functional roles of the ACC subregions in altruistic decision-making. The proposed neural mechanisms of altruism can further be used to identify neurophysiological markers of prosociality in behavior. [ABSTRACT FROM AUTHOR]

Decreased neuronal specificity of the brain in response to cognitive demands (i.e., neural dedifferentiation) has been implicated in age-related cognitive decline. Investigations into functional connectivity analogs of these processes have focused primarily on measuring segregation of nonoverlapping networks at rest. Here, we used an edge-centric network approach to derive entropy, a measure of specialization, from spatially overlapping communities during cognitive task fMRI. Using Human Connectome Project Lifespan data (713 participants, 36-100 years old, 55.7% female), we characterized a pattern of nodal despecialization differentially affecting the medial temporal lobe and limbic, visual, and subcortical systems. At the whole-brain level, global entropy moderated declines in fluid cognition across the lifespan and uniquely covaried with age when controlling for the network segregation metric modularity. Importantly, relationships between both metrics (entropy and modularity) and fluid cognition were age dependent, although entropy's relationship with cognition was specific to older adults. These results suggest entropy is a potentially important metric for examining how neurological processes in aging affect functional specialization at the nodal, network, and whole-brain level. [ABSTRACT FROM AUTHOR]

The nervous system, especially the human brain, is characterized by its highly complex network topology. The neurodevelopment of some of its features has been described in terms of dynamic optimization rules. We discuss the principle of adaptive rewiring, i.e., the dynamic reorganization of a network according to the intensity of internal signal communication as measured by synchronization or diffusion, and its recent generalization for applications in directed networks. These have extended the principle of adaptive rewiring from highly oversimplified networks to more neurally plausible ones. Adaptive rewiring captures all the key features of the complex brain topology: it transforms initially random or regular networks into networks with a modular small-world structure and a rich-club core. This effect is specific in the sense that it can be tailored to computational needs, robust in the sense that it does not depend on a critical regime, and flexible in the sense that parametric variation generates a range of variant network configurations. Extreme variant networks can be associated at macroscopic level with disorders such as schizophrenia, autism, and dyslexia, and suggest a relationship between dyslexia and creativity. Adaptive rewiring cooperates with network growth and interacts constructively with spatial organization principles in the formation of topographically distinct modules and structures such as ganglia and chains. At the mesoscopic level, adaptive rewiring enables the development of functional architectures, such as convergent-divergent units, and sheds light on the early development of divergence and convergence in, for example, the visual system. Finally, we discuss future prospects for the principle of adaptive rewiring.

Digital twins enable simulation, comprehensive analysis and predictions, as virtual representations of physical systems. They are also finding increasing interest and application in the healthcare sector, with a particular focus on digital twins of the brain. We discuss how digital twins in neuroscience enable the modeling of brain functions and pathology as they offer an in-silico approach to studying the brain and illustrating the complex relationships between brain network dynamics and related functions. To showcase the capabilities of digital twinning in neuroscience we demonstrate how the impact of brain tumors on the brain’s physical structures and functioning can be modeled in relation to the philosophical concept of plasticity. Against this technically derived backdrop, which assumes that the brain’s nonlinear behavior toward improvement and repair can be modeled and predicted based on MRI data, we further explore the philosophical insights of Catherine Malabou. Malabou emphasizes the brain’s dual capacity for adaptive and destructive plasticity. We will discuss in how far Malabou’s ideas provide a more holistic theoretical framework for understanding how digital twins can model the brain’s response to injury and pathology, embracing Malabou’s concept of both adaptive and destructive plasticity which provides a framework to address such yet incomputable aspects of neuroscience and the sometimes seemingly unfavorable dynamics of neuroplasticity helping to bridge the gap between theoretical research and clinical practice.

We perform targeted attack, a systematic computational unlinking of the network, to analyze its effects on global communication across the brain network through its giant cluster. Across diffusion magnetic resonance images from individuals in the UK Biobank, Adolescent Brain Cognitive Development Study and Developing Human Connectome Project, we find that targeted attack procedures on increasing white matter tract lengths and densities are remarkably invariant to aging and disease. Time-reversing the attack computation suggests a mechanism for how brains develop, for which we derive an analytical equation using percolation theory. Based on a close match between theory and experiment, our results demonstrate that tracts are limited to emanate from regions already in the giant cluster and tracts that appear earliest in neurodevelopment are those that become the longest and densest.

Brain network definitions typically assume nonoverlap or minimal overlap, ignoring regions' connections to multiple networks. However, new methods are emerging that emphasize network overlap. Here, we investigated the reliability and validity of one assignment method, the mixed membership algorithm, and explored its potential utility for identifying gaps in existing network models of cognition. We first assessed between-sample reliability of overlapping assignments with a split-half design; a bootstrapped Dice similarity analysis demonstrated good agreement between the networks from the two subgroups. Next, we assessed whether overlapping networks captured expected nonoverlapping topographies; overlapping networks captured portions of one to three nonoverlapping topographies, which aligned with canonical network definitions. Following this, a relative entropy analysis showed that a majority of regions participated in more than one network, as is seen biologically, and many regions did not show preferential connection to any one network. Finally, we explored overlapping network membership in regions of the dual-networks model of cognitive control, showing that almost every region was a member of multiple networks. Thus, the mixed membership algorithm produces consistent and biologically plausible networks, which presumably will allow for the development of more complete network models of cognition.

Precision neuromodulation of central brain circuits is a promising emerging therapeutic modality for a variety of neuropsychiatric disorders. Reliably identifying in whom, where, and in what context to provide brain stimulation for optimal pain relief are fundamental challenges limiting the widespread implementation of central neuromodulation treatments for chronic pain. Current approaches to brain stimulation target empirically derived regions of interest to the disorder or targets with strong connections to these regions. However, complex, multidimensional experiences like chronic pain are more closely linked to patterns of coordinated activity across distributed large-scale functional networks. Recent advances in precision network neuroscience indicate that these networks are highly variable in their neuroanatomical organization across individuals. Here we review accumulating evidence that variable central representations of pain will likely pose a major barrier to implementation of population-derived analgesic brain stimulation targets. We propose network-level estimates as a more valid, robust, and reliable way to stratify personalized candidate regions. Finally, we review key background, methods, and implications for developing network topology-informed brain stimulation targets for chronic pain.

Introduction: Subcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer's disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core. Methods: Chronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling. Results: Pharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling. Discussion: This study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design. [ABSTRACT FROM AUTHOR]

This Preface overviews a four-part opinion series on the role of tradtional neuropsychological tests in evaluating mild traumatic brain injury (mTBI), juxtaposed to all of the progress that has occurred with advanced neuroimaging and allied technologies. The four areas of review and critique are: I. Neuropathology; II: Limitations in Test Development, Statistical and Psychometric Issues; III. Implications of Advanced Neuroimaging Findings inn the Neuropsychological Assessment of the mTBI Patient, and IV: Clinical Applications and Future Directions. The example is made that since their inception in the early to mid-20th Century, traditional neuropsychological measures mostly have remained invariant, have been used as omnibus measures for assessing all types of neurological and neuropsychiatric conditions, and were never specifically designed to asses the effects of mTBI. Extensive discussion is provided across all four parts concerning the limits of traditional neuropsychological methods, especially in the absences of any integration with advanced neuroimaging and biomarker findings. Part IV provides an outline for future research and clinical application in the development of novel neuropsychological assessment mesasures specific to mTBI. [ABSTRACT FROM AUTHOR]

IntroductionHistorically, Parkinson's Disease (PD) research has focused on the dysfunction of dopamine-producing cells in the substantia nigra pars compacta, which is linked to motor regulation in the basal ganglia. Therapies have mainly aimed at restoring dopamine (DA) levels, showing effectiveness but variable outcomes and side effects. Recent evidence indicates that PD complexity implicates disruptions in DA, noradrenaline (NA), and serotonin (5-HT) systems, which may underlie the variations in therapy effects.MethodsWe present a system-level bio-constrained computational model that comprehensively investigates the dynamic interactions between these neurotransmitter systems. The model was designed to replicate experimental data demonstrating the impact of NA and 5-HT depletion in a PD animal model, providing insights into the causal relationships between basal ganglia regions and neuromodulator release areas.ResultsThe model successfully replicates experimental data and generates predictions regarding changes in unexplored brain regions, suggesting avenues for further investigation. It highlights the potential efficacy of alternative treatments targeting the locus coeruleus and dorsal raphe nucleus, though these preliminary findings require further validation. Sensitivity analysis identifies critical model parameters, offering insights into key factors influencing brain area activity. A stability analysis underscores the robustness of our mathematical formulation, bolstering the model validity.DiscussionOur holistic approach emphasizes that PD is a multifactorial disorder and opens promising avenues for early diagnostic tools that harness the intricate interactions among monoaminergic systems. Investigating NA and 5-HT systems alongside the DA system may yield more effective, subtype-specific therapies. The exploration of multisystem dysregulation in PD is poised to revolutionize our understanding and management of this complex neurodegenerative disorder.

Communication protocols in the brain connectome describe how to transfer information from one region to another. Typically, these protocols hinge on either the spatial distances between brain regions or the intensity of their connections. Yet, none of them combine both factors to achieve optimal efficiency. Here, we introduce a continuous spectrum of decentralized routing strategies that integrates link weights and the spatial embedding of connectomes to route signal transmission. We implemented the protocols on connectomes from individuals in two cohorts and on group-representative connectomes designed to capture weighted connectivity properties. We identified an intermediate domain of routing strategies, a sweet spot, where navigation achieves maximum communication efficiency at low transmission cost. This phenomenon is robust and independent of the particular configuration of weights. Our findings suggest an interplay between the intensity of neural connections and their topology and geometry that amplifies communicability, where weights play the role of noise in a stochastic resonance phenomenon. Such enhancement may support more effective responses to external and internal stimuli, underscoring the intricate diversity of brain functions.

Synchronous neural oscillations within the beta frequency range are observed across the parkinsonian basal ganglia network, including within the subthalamic nucleus (STN) - globus pallidus (GPe) subcircuit. The emergence of pathological synchrony in Parkinson’s disease is often attributed to changes in neural properties or connection strength, and less often to the network topology, i.e. the structural arrangement of connections between neurons. This study investigates the relationship between network structure and neural synchrony in a model of the STN-GPe circuit comprised of conductance-based spiking neurons. Changes in net synaptic input were controlled for through a synaptic scaling rule, which facilitated separation of the effects of network structure from net synaptic input. Five topologies were examined as structures for the STN-GPe circuit: Watts-Strogatz, preferential attachment, spatial, stochastic block, k-regular random. Beta band synchrony generally increased as the number of connections increased, however the exact relationship was topology specific. Varying the wiring pattern while maintaining a constant number of connections caused network synchrony to be enhanced or suppressed, demonstrating the ability of purely structural changes to alter synchrony. This relationship was well-captured by the algebraic connectivity of the network, the second smallest eigenvalue of the network’s Laplacian matrix. The structure-synchrony relationship was further investigated in a network model designed to emulate the action selection role of the STN-GPe circuit. It was found that increasing the number of connections and/or the overlap of action selection channels could lead to a rapid transition to synchrony, which was also predicted by the algebraic connectivity.

Attention network theory proposes three distinct types of attention—alerting, orienting, and control—that are supported by separate brain networks and modulated by different neurotransmitters, that is, norepinephrine, acetylcholine, and dopamine. Here, we explore the extent of cortical, genetic, and molecular dissociation of these three attention systems using multimodal neuroimaging. We evaluated the spatial overlap between fMRI activation maps from the attention network test (ANT) and cortex‐wide gene expression data from the Allen Human Brain Atlas. The goal was to identify genes associated with each of the attention networks in order to determine whether specific groups of genes were co‐expressed with the corresponding attention networks. Furthermore, we analyzed publicly available PET‐maps of neurotransmitter receptors and transporters to investigate their spatial overlap with the attention networks. Our analyses revealed a substantial number of genes (3871 for alerting, 6905 for orienting, 2556 for control) whose cortex‐wide expression co‐varied with the activation maps, prioritizing several molecular functions such as the regulation of protein biosynthesis, phosphorylation, and receptor binding. Contrary to the hypothesized associations, the ANT activation maps neither aligned with the distribution of norepinephrine, acetylcholine, and dopamine receptor and transporter molecules, nor with transcriptomic profiles that would suggest clearly separable networks. Independence of the attention networks appeared additionally constrained by a high level of spatial dependency between the network maps. Future work may need to reconceptualize the attention networks in terms of their segregation and reevaluate the presumed independence at the neural and neurochemical level. [ABSTRACT FROM AUTHOR]

Recently, multi-voxel pattern analysis has verified that information can be removed from working memory (WM) via three distinct operations replacement, suppression, or clearing compared to information being maintained (Kim et al., 2020). While univariate analyses and classifier importance maps in Kim et al. (2020) identified brain regions that contribute to these operations, they did not elucidate whether these regions represent the operations similarly or uniquely. Using Leiden-community-detection on a sample of 55 humans (17 male), we identified four brain networks, each of which has a unique configuration of multi-voxel activity patterns by which it represents these WM operations. The visual network (VN) shows similar multi-voxel patterns for maintain and replace, which are highly dissimilar from suppress and clear, suggesting this network differentiates whether an item is held in WM or not. The somatomotor network (SMN) shows a distinct multi-voxel pattern for clear relative to the other operations, indicating the uniqueness of this operation. The default mode network (DMN) has distinct patterns for suppress and clear, but these two operations are more similar to each other than to maintain and replace, a pattern intermediate to that of the VN and SMN. The frontoparietal control network (FPCN) displays distinct multi-voxel patterns for each of the four operations, suggesting that this network likely plays an important role in implementing theseWMoperations. These results indicate that the operations involved in removing information fromWMcan be performed in parallel by distinct brain networks, each of which has a particular configuration by which they represent these operations. [ABSTRACT FROM AUTHOR]

ObjectiveDespite the overall success of responsive neurostimulation (RNS) therapy for drug-resistant focal epilepsy, clinical outcomes in individuals vary significantly and are hard to predict. Biomarkers that indicate the clinical efficacy of RNS-ideally before device implantation-are critically needed, but challenges include the intrinsic heterogeneity of the RNS patient population and variability in clinical management across epilepsy centers. The aim of this study is to use a multicenter dataset to evaluate a candidate biomarker from intracranial electroencephalographic (iEEG) recordings that predicts clinical outcome with subsequent RNS therapy.MethodsWe assembled a federated dataset of iEEG recordings, collected prior to RNS implantation, from a retrospective cohort of 30 patients across three major epilepsy centers. Using ictal iEEG recordings, each center independently calculated network synchronizability, a candidate biomarker indicating the susceptibility of epileptic brain networks to RNS therapy.ResultsIctal measures of synchronizability in the high-γ band (95-105 Hz) significantly distinguish between good and poor RNS responders after at least 3 years of therapy under the current RNS therapy guidelines (area under the curve = .83). Additionally, ictal high-γ synchronizability is inversely associated with the degree of therapeutic response.SignificanceThis study provides a proof-of-concept roadmap for collaborative biomarker evaluation in federated data, where practical considerations impede full data sharing across centers. Our results suggest that network synchronizability can help predict therapeutic response to RNS therapy. With further validation, this biomarker could facilitate patient selection and help avert a costly, invasive intervention in patients who are unlikely to benefit.

Music-based interventions are a common feature in long-term care with clinical reports highlighting music’s ability to engage individuals with complex diagnoses. While these findings are promising, normative findings from healthy controls are needed to disambiguate treatment effects unique to pathology and those seen in healthy aging. The present study examines brain network dynamics during music listening in a sample of healthy older adults before and after a music-based intervention. We found intervention effects from hidden Markov model-estimated fMRI network data. Following the intervention, participants demonstrated greater occupancy (the amount of time a network was occupied) in a temporal-mesolimbic network. We conclude that network dynamics in healthy older adults are sensitive to music-based interventions. We discuss these findings’ implications for future studies with individuals with neurodegeneration.

IntroductionSubcritical epileptiform activity is associated with impaired cognitive function and is commonly seen in patients with Alzheimer’s disease (AD). The anti-convulsant, levetiracetam (LEV), is currently being evaluated in clinical trials for its ability to reduce epileptiform activity and improve cognitive function in AD. The purpose of the current study was to apply pharmacokinetics (PK), network analysis of medical imaging, gene transcriptomics, and PK/PD modeling to a cohort of amyloidogenic mice to establish how LEV restores or drives alterations in the brain networks of mice in a dose-dependent basis using the rigorous preclinical pipeline of the MODEL-AD Preclinical Testing Core.MethodsChronic LEV was administered to 5XFAD mice of both sexes for 3 months based on allometrically scaled clinical dose levels from PK models. Data collection and analysis consisted of a multi-modal approach utilizing 18F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling.ResultsPharmacokinetics of LEV showed a sex and dose dependence in Cmax, CL/F, and AUC0-∞, with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18F-FDG specific regional differences in brain uptake, and in whole brain covariance measures such as clustering coefficient, degree, network density, and connection strength (i.e., positive and negative). In addition, transcriptomic analysis via nanoString showed dose-dependent changes in gene expression in pathways consistent 18F-FDG uptake and network changes, and PK/PD modeling showed a concentration dependence for key genes, but not for network covariance modeling.DiscussionThis study represents the first report detailing the relationships of metabolic covariance and transcriptomic network changes resulting from LEV administration in 5XFAD mice. Overall, our results highlight non-linear kinetics based on dose and sex, where gene expression analysis demonstrated LEV dose- and concentration-dependent changes, along with cerebral metabolism, and/or cerebral homeostatic mechanisms relevant to human AD, which aligned closely with network covariance analysis of 18F-FDG images. Collectively, this study show cases the value of a multimodal connectomic, transcriptomic, and pharmacokinetic approach to further investigate dose dependent relationships in preclinical studies, with translational value toward informing clinical study design.

New higher-order models of brain networks can provide new insights into brain organization and function while helping to address outstanding questions in network neuroscience. Edge-centric models shift the focus away from neural elements (nodes) onto edges. Edge time-series are an exact decomposition of correlation-based functional networks and facilitate the detection of overlapping communities while offering estimates of time-varying connectivity at framewise temporal resolution. Network neuroscience has emphasized the connectional properties of neural elements – cells, populations, and regions. This has come at the expense of the anatomical and functional connections that link these elements to one another. A new perspective – namely one that emphasizes 'edges' – may prove fruitful in addressing outstanding questions in network neuroscience. We highlight one recently proposed 'edge-centric' method and review its current applications, merits, and limitations. We also seek to establish conceptual and mathematical links between this method and previously proposed approaches in the network science and neuroimaging literature. We conclude by presenting several avenues for future work to extend and refine existing edge-centric analysis. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) is characterized by both atypical functional brain connectivity and cognitive challenges across multiple cognitive domains. The relationship between task-dependent brain connectivity and cognitive abilities, however, remains poorly understood. In this study, children with ASD and their typically developing (TD) peers engaged in semantic and pragmatic language tasks while their task-dependent brain connectivity was mapped and compared. A multivariate statistical approach revealed associations between connectivity and psychometric assessments of relevant cognitive abilities. While both groups exhibited brain–behavior correlations, the nature of these associations diverged, particularly in the directionality of overall correlations across various psychometric categories. Specifically, greater disparities in functional connectivity between the groups were linked to larger differences in Autism Questionnaire, BRIEF, MSCS, and SRS-2 scores but smaller differences in WASI, pragmatic language, and Theory of Mind scores. Our findings suggest that children with ASD utilize distinct neural communication patterns for language processing. Although networks recruited by children with ASD may appear less efficient than those typically engaged, they could serve as compensatory mechanisms for potential disruptions in conventional brain networks. [ABSTRACT FROM AUTHOR]

The ability to regulate emotions is key to goal attainment and well-being. Although much has been discovered about neurodevelopment and the acquisition of emotion regulation, very little of this work has leveraged information encoded in whole-brain networks. Here we employed a network neuroscience framework to parse the neural underpinnings of emotion regulation skill acquisition, while accounting for age, in a sample of children and adolescents (N = 70, 34 female, aged 8-17 years). Focusing on three key network metrics-network differentiation, modularity, and community number differences between active regulation and a passive emotional baseline-we found that the control network, the default mode network, and limbic network were each related to emotion regulation ability while controlling for age. Greater network differentiation in the control and limbic networks was related to better emotion regulation ability. With regards to network community structure (modularity and community number), more communities and more crosstalk between modules (i.e., less modularity) in the control network were associated with better regulatory ability. By contrast, less crosstalk (i.e., greater modularity) between modules in the default mode network was associated with better regulatory ability. Together, these findings highlight whole-brain connectome features that support the acquisition of emotion regulation in youth.

A large focus of modern neuroscience has revolved around preselected brain regions of interest based on prior studies. While there are reasons to focus on brain regions implicated in prior work, the result has been a biased assessment of brain function. Thus, many brain regions that may prove crucial in a wide range of neurobiological problems, including neurodegenerative diseases and neuropsychiatric disorders, have been neglected. Advances in neuroimaging and computational neuroscience have made it possible to make unbiased assessments of whole-brain function and identify previously overlooked regions of the brain. This review will discuss the tools that have been developed to advance neuroscience and network-based computational approaches used to further analyze the interconnectivity of the brain. Furthermore, it will survey examples of neural network approaches that assess connectivity in clinical (i.e., human) and preclinical (i.e., animal model) studies and discuss how preclinical studies of neurodegenerative diseases and neuropsychiatric disorders can greatly benefit from the unbiased nature of whole-brain imaging and network neuroscience.

Genuinely new discovery transcends existing knowledge. Despite this, many analyses in systems neuroscience neglect to test new speculative hypotheses against benchmark empirical facts. Some of these analyses inadvertently use circular reasoning to present existing knowledge as new discovery. Here, I discuss that this problem can confound key results and estimate that it has affected more than three thousand studies in network neuroscience over the last decade. I suggest that future studies can reduce this problem by limiting the use of speculative evidence, integrating existing knowledge into benchmark models, and rigorously testing proposed discoveries against these models. I conclude with a summary of practical challenges and recommendations.

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

The brain is a complex system comprising a myriad of interacting neurons, posing significant challenges in understanding its structure, function, and dynamics. Network science has emerged as a powerful tool for studying such interconnected systems, offering a framework for integrating multiscale data and complexity. To date, network methods have significantly advanced functional imaging studies of the human brain and have facilitated the development of control theory-based applications for directing brain activity. Here, we discuss emerging frontiers for network neuroscience in the brain atlas era, addressing the challenges and opportunities in integrating multiple data streams for understanding the neural transitions from development to healthy function to disease. We underscore the importance of fostering interdisciplinary opportunities through workshops, conferences, and funding initiatives, such as supporting students and postdoctoral fellows with interests in both disciplines. By bringing together the network science and neuroscience communities, we can develop novel network-based methods tailored to neural circuits, paving the way toward a deeper understanding of the brain and its functions, as well as offering new challenges for network science. [ABSTRACT FROM AUTHOR]

Many patients with glioma, primary brain tumors, suffer from poorly understood executive functioning deficits before and/or after tumor resection. We aimed to test whether frontoparietal network centrality of multilayer networks, allowing for integration across multiple frequencies, relates to and predicts executive functioning in glioma. Patients with glioma (n = 37) underwent resting-state magnetoencephalography and neuropsychological tests assessing word fluency, inhibition, and set shifting before (T1) and one year after tumor resection (T2). We constructed binary multilayer networks comprising six layers, with each layer representing frequency-specific functional connectivity between source-localized time series of 78 cortical regions. Average frontoparietal network multilayer eigenvector centrality, a measure for network integration, was calculated at both time points. Regression analyses were used to investigate associations with executive functioning. At T1, lower multilayer integration (p = 0.017) and epilepsy (p = 0.006) associated with poorer set shifting (adj. R2 = 0.269). Decreasing multilayer integration (p = 0.022) and not undergoing chemotherapy at T2 (p = 0.004) related to deteriorating set shifting over time (adj. R2 = 0.283). No significant associations were found for word fluency or inhibition, nor did T1 multilayer integration predict changes in executive functioning. As expected, our results establish multilayer integration of the frontoparietal network as a cross-sectional and longitudinal correlate of executive functioning in glioma patients. However, multilayer integration did not predict postoperative changes in executive functioning, which together with the fact that this correlate is also found in health and other diseases, limits its specific clinical relevance in glioma. [ABSTRACT FROM AUTHOR]

Introduction: Modern neurotechnology research employing state-of-the-art machine learning algorithms within the so-called “AI for social good” domain contributes to improving the well-being of individuals with a disability. Using digital health technologies, home-based self-diagnostics, or cognitive decline managing approaches with neuro-biomarker feedback may be helpful for older adults to remain independent and improve their wellbeing. We report research results on early-onset dementia neuro-biomarkers to scrutinize cognitive-behavioral intervention management and digital non-pharmacological therapies. Methods: We present an empirical task in the EEG-based passive brain-computer interface application framework to assess working memory decline for forecasting a mild cognitive impairment. The EEG responses are analyzed in a framework of a network neuroscience technique applied to EEG time series for evaluation and to confirm the initial hypothesis of possible ML application modeling mild cognitive impairment prediction. Results: We report findings from a pilot study group in Poland for a cognitive decline prediction. We utilize two emotional working memory tasks by analyzing EEG responses to facial emotions reproduced in short videos. A reminiscent interior image oddball task is also employed to validate the proposed methodology further. Discussion: The proposed three experimental tasks in the current pilot study showcase the critical utilization of artificial intelligence for early-onset dementia prognosis in older adults. [ABSTRACT FROM AUTHOR]

Endel Tulving's proposal that episodic memory is distinct from other memory systems like semantic memory remains an extremely influential idea in cognitive neuroscience research. As originally suggested by Tulving, episodic memory involves three key components that differentiate it from all other memory systems: spatiotemporal binding, mental time travel, and autonoetic consciousness. Here, we focus on the idea of spatiotemporal binding in episodic memory and, in particular, how consideration of the precision of spatiotemporal context helps expand our understanding of episodic memory. Precision also helps shed light on another key issue in cognitive neuroscience, the role of the hippocampus outside of episodic memory in perception, attention, and working memory. By considering precision alongside item-context bindings, we attempt to shed new light on both the nature of how we represent context and what roles the hippocampus plays in episodic memory and beyond.

Patients with drug-resistant epilepsy often require surgery to become seizure-free. While laser ablation and implantable stimulation devices have lowered the morbidity of these procedures, seizure-free rates have not dramatically improved, particularly for patients without focal lesions. This is in part because it is often unclear where to intervene in these cases. To address this clinical need, several research groups have published methods to map epileptic networks but applying them to improve patient care remains a challenge. In this study we advance clinical translation of these methods by: (i) presenting and sharing a robust pipeline to rigorously quantify the boundaries of the resection zone and determining which intracranial EEG electrodes lie within it; (ii) validating a brain network model on a retrospective cohort of 28 patients with drug-resistant epilepsy implanted with intracranial electrodes prior to surgical resection; and (iii) sharing all neuroimaging, annotated electrophysiology, and clinical metadata to facilitate future collaboration. Our network methods accurately forecast whether patients are likely to benefit from surgical intervention based on synchronizability of intracranial EEG (area under the receiver operating characteristic curve of 0.89) and provide novel information that traditional electrographic features do not. We further report that removing synchronizing brain regions is associated with improved clinical outcome, and postulate that sparing desynchronizing regions may further be beneficial. Our findings suggest that data-driven network-based methods can identify patients likely to benefit from resective or ablative therapy, and perhaps prevent invasive interventions in those unlikely to do so.

Neurocysticercosis (NCC)—a parasitic CNS infection endemic to developing nations—has been called the leading global cause of acquired epilepsy yet remains understudied. It is currently unknown why a large proportion of patients develop recurrent seizures, often following the presentation of acute seizures. Furthermore, the presentation of NCC is heterogenous and the features that predispose to the development of an epileptogenic state remain uncertain. Perilesional factors (such as oedema and gliosis) have been implicated in NCC-related ictogenesis, but the effects of cystic factors, including lesion load and location, seem not to play a role in the development of habitual epilepsy. In addition, the cytotoxic consequences of the cyst's degenerative stages are varied and the majority of research, relying on retrospective data, lacks the necessary specificity to distinguish between acute symptomatic and unprovoked seizures. Previous research has established that epileptogenesis can be the consequence of abnormal network connectivity, and some imaging studies have suggested that a causative link may exist between NCC and aberrant network organisation. In wider epilepsy research, network approaches have been widely adopted; studies benefiting predominantly from the rich, multimodal data provided by advanced MRI methods are at the forefront of the field. Quantitative MRI approaches have the potential to elucidate the lesser-understood epileptogenic mechanisms of NCC. This review will summarise the current understanding of the relationship between NCC and epilepsy, with a focus on MRI methodologies. In addition, network neuroscience approaches with putative value will be highlighted, drawing from current imaging trends in epilepsy research. [Display omitted] [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) exhibits diverse symptomology and neuroimaging studies report widespread disruption of key brain areas. Numerous theories underpinning the network degeneration hypothesis (NDH) posit that neuropsychiatric diseases selectively target brain areas via meaningful network mechanisms rather than as indistinct disease effects. The present study tests the hypothesis that MDD is a network-based disorder, both structurally and functionally. Coordinate-based meta-analysis and Activation Likelihood Estimation (CBMA-ALE) were used to assess the convergence of findings from 92 previously published studies in depression. An extension of CBMA-ALE was then used to generate a node-and-edge network model representing the co-alteration of brain areas impacted by MDD. Standardized measures of graph theoretical network architecture were assessed. Co-alteration patterns among the meta-analytic MDD nodes were then tested in independent, clinical T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional (rs-fMRI) data. Differences in co-alteration profiles between MDD patients and healthy controls, as well as between controls and clinical subgroups of MDD patients, were assessed. A 65-node 144-edge co-alteration network model was derived for MDD. Testing of co-alteration profiles in replication data using the MDD nodes provided distinction between MDD and healthy controls in structural data. However, co-alteration profiles were not distinguished between patients and controls in rs-fMRI data. Improved distinction between patients and healthy controls was observed in clinically homogenous MDD subgroups in T1 data. MDD abnormalities demonstrated both structural and functional network architecture, though only structural networks exhibited between-groups differences. Our findings suggest improved utility of structural co-alteration networks for ongoing biomarker development. [ABSTRACT FROM AUTHOR]

Human evolution has been marked by a striking increase in total brain volume relative to body size. While a prominent and characteristic feature of this volumetric shift has been the disproportionate expansion of association cortex across our evolutionary lineage, descent with modification is apparent throughout all neural systems in both human and nonhuman primates. However, despite evidence for the ubiquitous and complex influence of evolutionary forces on brain biology, within the psychological sciences the vast majority of the literature on human brain evolution is entirely corticocentric. This selective focus has contributed to a flawed theoretical framework in which the evolution of association cortex is viewed as an isolated process, removed from the rest of the brain. Here, we review our current understanding of how evolutionary pressures have acted across anatomically and functionally coupled networks, highlighting the diverse set of rules and principles that govern human brain development. In doing so we challenge the systemic mischaracterization of human cognition and behavior as a competition that pits phylogenetically recent cortical territories against evolutionarily ancient subcortical and cerebellar systems. Rather, we propose a comprehensive view of human brain evolution with critical importance for the use of animal models, theory development, and network-focused approaches in the study of behavior across health and disease. [ABSTRACT FROM AUTHOR]

Graph-theoretic metrics derived from neuroimaging data have been heralded as powerful tools for uncovering neural mechanisms of psychological traits, psychiatric disorders, and neurodegenerative diseases. In N = 8,185 human structural connectomes from UK Biobank, we examined the extent to which 11 commonly-used global graph-theoretic metrics index distinct versus overlapping information with respect to interindividual differences in brain organization. Using unthresholded, FA-weighted networks we found that all metrics other than Participation Coefficient were highly intercorrelated, both with each other (mean |r| = 0.788) and with a topologically-naïve summary index of brain structure (mean edge weight; mean |r| = 0.873). In a series of sensitivity analyses, we found that overlap between metrics is influenced by the sparseness of the network and the magnitude of variation in edge weights. Simulation analyses representing a range of population network structures indicated that individual differences in global graph metrics may be intrinsically difficult to separate from mean edge weight. In particular, Closeness, Characteristic Path Length, Global Efficiency, Clustering Coefficient, and Small Worldness were nearly perfectly collinear with one another (mean |r| = 0.939) and with mean edge weight (mean |r| = 0.952) across all observed and simulated conditions. Global graph-theoretic measures are valuable for their ability to distill a high-dimensional system of neural connections into summary indices of brain organization, but they may be of more limited utility when the goal is to index separable components of interindividual variation in specific properties of the human structural connectome.

Precision neuromodulation of central brain circuits is a promising emerging therapeutic modality for a variety of neuropsychiatric disorders. Reliably identifying in whom, where, and in what context to provide brain stimulation for optimal pain relief are fundamental challenges limiting the widespread implementation of central neuromodulation treatments for chronic pain. Current approaches to brain stimulation target empirically derived regions of interest to the disorder or targets with strong connections to these regions. However, complex, multidimensional experiences like chronic pain are more closely linked to patterns of coordinated activity across distributed large-scale functional networks. Recent advances in precision network neuroscience indicate that these networks are highly variable in their neuroanatomical organization across individuals. Here we review accumulating evidence that variable central representations of pain will likely pose a major barrier to implementation of population-derived analgesic brain stimulation targets. We propose network-level estimates as a more valid, robust, and reliable way to stratify personalized candidate regions. Finally, we review key background, methods, and implications for developing network topology-informed brain stimulation targets for chronic pain.

Generative models of the human connectome enable in silico generation of brain networks based on probabilistic wiring rules. These wiring rules are governed by a small number of parameters that are typically fitted to individual connectomes and quantify the extent to which geometry and topology shape the generative process. A significant shortcoming of generative modeling in large cohort studies is that parameter estimation is computationally burdensome, and the accuracy and reliability of current estimation methods remain untested. Here, we propose a fast, reliable, and accurate parameter estimation method for connectome generative models that is scalable to large sample sizes. Our method achieves improved estimation accuracy and reliability and reduces computational cost by orders of magnitude, compared to established methods. We demonstrate an inherent tradeoff between accuracy, reliability, and computational expense in parameter estimation and provide recommendations for leveraging this tradeoff. To enable power analyses in future studies, we empirically approximate the minimum sample size required to detect between-group differences in generative model parameters. While we focus on the classic two-parameter generative model based on connection length and the topological matching index, our method can be generalized to other growth-based generative models. Our work provides a statistical and practical guide to parameter estimation for connectome generative models.

Network models of anatomical connections allow for the extraction of quantitative features describing brain organization, and their comparison across brains from different species. Such comparisons can inform our understanding of between-species differences in brain architecture and can be compared to existing taxonomies and phylogenies. Here we performed a quantitative comparative analysis using the MaMI database (Tel Aviv University), a collection of brain networks reconstructed from ex vivo diffusion MRI spanning 125 species and 12 taxonomic orders or superorders. We used a broad range of metrics to measure between-mammal distances and compare these estimates to the separation of species as derived from taxonomy and phylogeny. We found that within-taxonomy order network distances are significantly closer than between-taxonomy network distances, and this relation holds for several measures of network distance. Furthermore, to estimate the evolutionary divergence between species, we obtained phylogenetic distances across 10,000 plausible phylogenetic trees. The anatomical network distances were rank-correlated with phylogenetic distances 10,000 times, creating a distribution of coefficients that demonstrate significantly positive correlations between network and phylogenetic distances. Collectively, these analyses demonstrate species-level organization across scales and informational sources: we relate brain networks distances, derived from MRI, with evolutionary distances, derived from genotyping data. [ABSTRACT FROM AUTHOR]

The large number of different analytical choices used by researchers is partly responsible for the challenge of replication in neuroimaging studies. For an exhaustive robustness analysis, knowledge of the full space of analytical options is essential. We conducted a systematic literature review to identify the analytical decisions in functional neuroimaging data preprocessing and analysis in the emerging field of cognitive network neuroscience. We found 61 different steps, with 17 of them having debatable parameter choices. Scrubbing, global signal regression, and spatial smoothing are among the controversial steps. There is no standardized order in which different steps are applied, and the parameter settings within several steps vary widely across studies. By aggregating the pipelines across studies, we propose three taxonomic levels to categorize analytical choices: 1) inclusion or exclusion of specific steps, 2) parameter tuning within steps, and 3) distinct sequencing of steps. We have developed a decision support application with high educational value called METEOR to facilitate access to the data in order to design well-informed robustness (multiverse) analysis. • Data analysis variability in neuroimaging hinders replicability. • Analyses across multiple defensible options examine the robustness of the results. • We conducted a systematic literature review to identify analytical options. • We identified 61 steps and 102 parameter settings in performing graph-fMRI analysis. • Interactive visualization of these analytical choices is made available as a Shiny app. [ABSTRACT FROM AUTHOR]

Dynamic interactions between brain regions, either during rest or performance of cognitive tasks, have been studied extensively using a wide variance of methods. Although some of these methods allow elegant mathematical interpretations of the data, they can easily become computationally expensive or difficult to interpret and compare between subjects or groups. Here, we propose an intuitive and computationally efficient method to measure dynamic reconfiguration of brain regions, also termed flexibility. Our flexibility measure is defined in relation to an a-priori set of biologically plausible brain modules (or networks) and does not rely on a stochastic data-driven module estimation, which, in turn, minimizes computational burden. The change of affiliation of brain regions over time with respect to these a-priori template modules is used as an indicator of brain network flexibility. We demonstrate that our proposed method yields highly similar patterns of whole-brain network reconfiguration (i.e., flexibility) during a working memory task as compared to a previous study that uses a data-driven, but computationally more expensive method. This result illustrates that the use of a fixed modular framework allows for valid, yet more efficient estimation of whole-brain flexibility, while the method additionally supports more fine-grained (e.g. node and group of nodes scale) flexibility analyses restricted to biologically plausible brain networks.

Network models of anatomical connections allow for the extraction of quantitative features describing brain organization, and their comparison across brains from different species. Such comparisons can inform our understanding of between-species differences in brain architecture and can be compared to existing taxonomies and phylogenies. Here we performed a quantitative comparative analysis using the MaMI database (Tel Aviv University), a collection of brain networks reconstructed from ex vivo diffusion MRI spanning 125 species and 12 taxonomic orders or superorders. We used a broad range of metrics to measure between-mammal distances and compare these estimates to the separation of species as derived from taxonomy and phylogeny. We found that within-taxonomy order network distances are significantly closer than between-taxonomy network distances, and this relation holds for several measures of network distance. Furthermore, to estimate the evolutionary divergence between species, we obtained phylogenetic distances across 10,000 plausible phylogenetic trees. The anatomical network distances were rank-correlated with phylogenetic distances 10,000 times, creating a distribution of coefficients that demonstrate significantly positive correlations between network and phylogenetic distances. Collectively, these analyses demonstrate species-level organization across scales and informational sources: we relate brain networks distances, derived from MRI, with evolutionary distances, derived from genotyping data.

Network analysis can provide insight into key organizational principles of brain structure and help identify structural changes associated with brain disease. Though static differences between diseased and healthy networks are well characterized, the study of network dynamics, or how brain networks change over time, is increasingly central to understanding ongoing brain changes throughout disease. Accordingly, we present a short review of network models of spread, network dynamics, and network degeneration. Borrowing from recent suggestions, we divide this review into two processes by which brain networks can change: dynamics on networks, which are functional and pathological consequences taking place atop a static structural brain network; and dynamics of networks, which constitutes a changing structural brain network. We focus on diffusion magnetic resonance imaging-based structural or anatomic connectivity graphs. We address psychiatric disorders like schizophrenia; developmental disorders like epilepsy; stroke; and Alzheimer's disease and other neurodegenerative diseases.

This study investigates the dynamics of attention during continuous, naturalistic interactions in a video game. Specifically, the effect of repeated distraction on a continuous primary task is related to a functional model of network connectivity. We introduce the Non-linear Attentional Saturation Hypothesis (NASH), which predicts that effective connectivity within attentional networks increases non-linearly with decreasing distraction over time, and exhibits dampening at critical parameter values. Functional magnetic resonance imaging (fMRI) data collected using a naturalistic behavioral paradigm coupled with an interactive video game is used to test the hypothesis. As predicted, connectivity in pre-defined regions corresponding to attentional networks increases as distraction decreases. Moreover, the functional relationship between connectivity and distraction is convex, that is, network connectivity somewhat increases as distraction decreases during the continuous primary task, however, connectivity increases considerably as distraction falls below critical levels. This result characterizes the non-linear pattern of connectivity within attentional networks, particularly with respect to their dynamics during behavior. These results are also summarized in the form of a network structure analysis, which underscores the role of various nodes in regulating the global network state. In conclusion, we situate the implications of this research in the context of cognitive complexity and an emerging theory of flow during media exposure.

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE‐UP trial, comparing 127 imaging‐selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio‐topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network‐informed imaging biomarkers and improved prognostication in ischemic stroke. [ABSTRACT FROM AUTHOR]

Many organizational principles of structural brain networks are established before birth and undergo considerable developmental changes afterwards. These include the topologically central hub regions and a densely connected rich club. While several studies have mapped developmental trajectories of brain connectivity and brain network organization across childhood and adolescence, comparatively little is known about subsequent development over the course of the lifespan. Here, we present a cross‐sectional analysis of structural brain network development in N = 8066 participants aged 5–80 years. Across all brain regions, structural connectivity strength followed an "inverted‐U"‐shaped trajectory with vertex in the early 30s. Connectivity strength of hub regions showed a similar trajectory and the identity of hub regions remained stable across all age groups. While connectivity strength declined with advancing age, the organization of hub regions into a rich club did not only remain intact but became more pronounced, presumingly through a selected sparing of relevant connections from age‐related connectivity loss. The stability of rich club organization in the face of overall age‐related decline is consistent with a "first come, last served" model of neurodevelopment, where the first principles to develop are the last to decline with age. Rich club organization has been shown to be highly beneficial for communicability and higher cognition. A resilient rich club might thus be protective of a functional loss in late adulthood and represent a neural reserve to sustain cognitive functioning in the aging brain. [ABSTRACT FROM AUTHOR]