Search

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fekonja, Schenk, Schröder, Tomasello, Tomšič and Picht.)

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 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., Competing Interests: SC was employed by Entersys s.r.l. SC and DC were employed by AI2Life s.r.l. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Carli, Brugnano and Caligiore.)

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 18 F-FDG PET/MRI imaging and analysis, transcriptomic analyses, and PK/PD modeling., Results: Pharmacokinetics of LEV showed a sex and dose dependence in C max , CL/F, and AUC 0-∞ , with simulations used to estimate dose regimens. Chronic dosing at 10, 30, and 56 mg/kg, showed 18 F-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 18 F-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 18 F-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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Burton, Chumin, Collins, Persohn, Onos, Pandey, Quinney and Territo.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rutkowski, Abe, Komendzinski, Sugimoto, Narebski and Otake-Matsuura.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chinichian, Kruschwitz, Reinhardt, Palm, Wellan, Erk, Heinz, Walter and Veer.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Faskowitz, Puxeddu, van den Heuvel, Mišić, Yovel, Assaf, Betzel and Sporns.)

Cascading activity is commonly observed in complex dynamical systems, including networks of biological neurons, and how these cascades spread through the system is reliant on how the elements of the system are connected and organized. In this work, we studied networks of neurons as they matured over 50 days in vitro and evaluated both their dynamics and their functional connectivity structures by observing their electrophysiological activity using microelectrode array recordings. Correlations were obtained between features of their activity propagation and functional connectivity characteristics to elucidate the interplay between dynamics and structure. The results indicate that in vitro networks maintain a slightly subcritical state by striking a balance between integration and segregation. Our work demonstrates the complementarity of these two approaches-functional connectivity and avalanche dynamics-in studying information propagation in neurons in vitro , which can in turn inform the design and optimization of engineered computational substrates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heiney, Huse Ramstad, Fiskum, Sandvig, Sandvig and Nichele.)

Traditionally, research on affordances and emotions follows two separate routes. For the first time, this article explicitly links the two phenomena by investigating whether, in a discrimination task (artifact vs. natural object), the motivational states induced by emotional images can modulate affordances-related motor response elicited by dangerous and neutral graspable objects. The results show faster RTs: (i) for both neutral and dangerous objects with neutral images; (ii) for dangerous objects with pleasant images; (iii) for neutral objects with unpleasant images. Overall, these data support a significant effect of emotions on affordances. The article also proposes a brain neural network underlying emotions and affordance interplay., Competing Interests: GB and DC are employed by the company AI2Life s.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Giocondo, Borghi, Baldassarre and Caligiore.)

Over the past 150 years of neuroscientific research, the field has undergone a tremendous evolution. Starting out with lesion-based inference of brain function, functional neuroimaging, introduced in the late 1980s, and increasingly fine-grained and sophisticated methods and analyses now allow us to study the live neural correlates of complex behaviors in individuals and multiple agents simultaneously. Classically, brain-behavior coupling has been studied as an association of a specific area in the brain and a certain behavioral outcome. This has been a crucial first step in understanding brain organization. Social cognitive processes, as well as their neural correlates, have typically been regarded and studied as isolated functions and blobs of neural activation. However, as our understanding of the social brain as an inherently dynamic organ grows, research in the field of social neuroscience is slowly undergoing the necessary evolution from studying individual elements to how these elements interact and their embedding within the overall brain architecture. In this article, we review recent studies that investigate the neural representation of social cognition as interacting, complex, and flexible networks. We discuss studies that identify individual brain networks associated with social affect and cognition, interaction of these networks, and their relevance for disorders of social affect and cognition. This perspective on social cognitive neuroscience can highlight how a more fine-grained understanding of complex network (re-)configurations could improve our understanding of social cognitive deficits in mental disorders such as autism spectrum disorder and schizophrenia, thereby providing new impulses for methods of interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maliske and Kanske.)

The human brain constitutes one of the most advanced networks produced by nature, consisting of billions of neurons communicating with each other. However, this communication is not in real-time, with different communication or time-delays occurring between neurons in different brain areas. Here, we investigate the impacts of these delays by modeling large interacting neural circuits as neural-field systems which model the bulk activity of populations of neurons. By using a Master Stability Function analysis combined with numerical simulations, we find that delays (1) may actually stabilize brain dynamics by temporarily preventing the onset to oscillatory and pathologically synchronized dynamics and (2) may enhance or diminish synchronization depending on the underlying eigenvalue spectrum of the connectivity matrix. Real eigenvalues with large magnitudes result in increased synchronizability while complex eigenvalues with large magnitudes and positive real parts yield a decrease in synchronizability in the delay vs. instantaneously coupled case. This result applies to networks with fixed, constant delays, and was robust to networks with heterogeneous delays. In the case of real brain networks, where the eigenvalues are predominantly real, owing to the nearly symmetric nature of these weight matrices, biologically plausible, small delays, are likely to increase synchronization, rather than decreasing it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Darabsah, Chen, Nicola and Campbell.)

Neurological disorders dramatically impact patients of any age population, their families, and societies. Pediatrics are among vulnerable age populations who differently experience the devastating consequences of neurological conditions, such as attention-deficit hyperactivity disorders (ADHD), autism spectrum disorders (ASD), cerebral palsy, concussion, and epilepsy. System-level understanding of these neurological disorders, particularly from the brain networks' dynamic perspective, has led to the significant trend of recent scientific investigations. While a dramatic maturation in the network science application domain is evident, leading to a better understanding of neurological disorders, such rapid utilization for studying pediatric neurological disorders falls behind that of the adult population. Aside from the specific technological needs and constraints in studying neurological disorders in children, the concept of development introduces uncertainty and further complexity topping the existing neurologically driven processes caused by disorders. To unravel these complexities, indebted to the availability of high-dimensional data and computing capabilities, approaches based on machine learning have rapidly emerged a new trend to understand pathways better, accurately diagnose, and better manage the disorders. Deep learning has recently gained an ever-increasing role in the era of health and medical investigations. Thanks to its relatively more minor dependency on feature exploration and engineering, deep learning may overcome the challenges mentioned earlier in studying neurological disorders in children. The current scoping review aims to explore challenges concerning pediatric brain development studies under the constraints of neurological disorders and offer an insight into the potential role of deep learning methodology on such a task with varying and uncertain nature. Along with pinpointing recent advancements, possible research directions are highlighted where deep learning approaches can assist in computationally targeting neurological disorder-related processes and translating them into windows of opportunities for interventions in diagnosis, treatment, and management of neurological disorders in children., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sargolzaei.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Simpson, Chen, Wellmeyer, Smith, Aragon Montes, George and Kimbrough.)

Modular organization is an emergent property of brain networks, responsible for shaping communication processes and underpinning brain functioning. Moreover, brain networks are intrinsically multilayer since their attributes can vary across time, subjects, frequency, or other domains. Identifying the modular structure in multilayer brain networks represents a gateway toward a deeper understanding of neural processes underlying cognition. Electroencephalographic (EEG) signals, thanks to their high temporal resolution, can give rise to multilayer networks able to follow the dynamics of brain activity. Despite this potential, the community organization has not yet been thoroughly investigated in brain networks estimated from EEG. Furthermore, at the state of the art, there is still no agreement about which algorithm is the most suitable to detect communities in multilayer brain networks, and a way to test and compare them all under a variety of conditions is lacking. In this work, we perform a comprehensive analysis of three algorithms at the state of the art for multilayer community detection (namely, genLouvain, DynMoga, and FacetNet) as compared with an approach based on the application of a single-layer clustering algorithm to each slice of the multilayer network. We test their ability to identify both steady and dynamic modular structures. We statistically evaluate their performances by means of ad hoc benchmark graphs characterized by properties covering a broad range of conditions in terms of graph density, number of clusters, noise level, and number of layers. The results of this simulation study aim to provide guidelines about the choice of the more appropriate algorithm according to the different properties of the brain network under examination. Finally, as a proof of concept, we show an application of the algorithms to real functional brain networks derived from EEG signals collected at rest with closed and open eyes. The test on real data provided results in agreement with the conclusions of the simulation study and confirmed the feasibility of multilayer analysis of EEG-based brain networks in both steady and dynamic conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Puxeddu, Petti and Astolfi.)

Evolutionary psychology is the comprehensive study of cognition and behavior in the light of evolutionary theory, a unifying paradigm integrating a huge diversity of findings across different levels of analysis. Since natural selection shaped the brain into a functionally organized system of interconnected neural structures rather than an aggregate of separate neural organs, the network-based account of anatomo-functional architecture is bound to yield the best mechanistic explanation for how the brain mediates the onset of evolved cognition and adaptive behaviors. While this view of a flexible and highly distributed organization of the brain is more than a century old, it was largely ignored up until recently. Technological advances are only now allowing this approach to find its rightful place in the scientific landscape. Historically, early network theories mostly relied on lesion studies and investigations on white matter circuitry, subject areas that still provide great empirical findings to this day. Thanks to new neuroimaging techniques, the traditional localizationist framework, in which any given cognitive process is thought to be carried out by its dedicated brain structure, is slowly being abandoned in favor of a network-based approach. We argue that there is a special place for network neuroscience in the upcoming quest for the biological basis of information-processing systems identified by evolutionary psychologists. By reviewing history of network theories, and by addressing several theoretical and methodological implications of this view for evolutionary psychologists, we describe the current state of knowledge about human neuroanatomy for those who wish to be mindful of both evolutionary and network neuroscience paradigms., (Copyright © 2020 Elimari and Lafargue.)

Connections in nervous systems are disproportionately concentrated on a small subset of neural elements that act as network hubs. Hubs have been found across different species and scales ranging from C. elegans to mouse, rat, cat, macaque, and human, suggesting a role for genetic influences. The recent availability of brain-wide gene expression atlases provides new opportunities for mapping the transcriptional correlates of large-scale network-level phenotypes. Here we review studies that use these atlases to investigate gene expression patterns associated with hub connectivity in neural networks and present evidence that some of these patterns are conserved across species and scales.

The abnormality occurs at molecular, cellular as well as network levels in patients with Alzheimer's disease (AD) prior to diagnosis. Most previous connectivity studies were conducted at 1 out of 3 (local, meso and global) scales in subjects covering only part of the entire AD spectrum (subjective cognitive decline, SCD; amnestic mild cognitive impairment, aMCI; and then fully manifest AD). Data interpretation within the framework of disease progression is therefore difficult. The current study included 3 age- and sex-matched cohorts: SCD ( n = 32), aMCI ( n = 37) and fully-established AD ( n = 30). A group of healthy elderly subjects ( n = 40) were included as a normal control (NC). Network connectivity was examined at the local (degree centrality), meso [subgraph centrality (SC)], and global (eigenvector and page-rank centralities) levels. As compared to NC, SCD subjects had isolated decrease of SC in primary (somatomotor and visual) networks. aMCI subjects had decreased centralities at all three scales in associative (frontoparietal control, dorsal attention, limbic and default) networks. AD subjects had increased centrality at the global scale in all seven networks. There was a positive association between Montreal Cognitive Assessment (MoCA) scores and DC in the frontoparietal control network in SCD, a negative relationship between Mini-Mental State Examination (MMSE) scores and EC in the somatomotor network in AD. These findings suggest that the primary network is impaired as early as in SCD. Impairment in the associative network also starts at the local level at this stage and may contribute to the cognitive decline. As associative network impairment extends from local to meso and global scales in aMCI, compensatory mechanisms in the primary network are activated.

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.

Graph theory is a useful tool for deciphering structural and functional networks of the brain on various spatial and temporal scales. The clustering coefficient quantifies the abundance of connected triangles in a network and is a major descriptive statistics of networks. For example, it finds an application in the assessment of small-worldness of brain networks, which is affected by attentional and cognitive conditions, age, psychiatric disorders and so forth. However, it remains unclear how the clustering coefficient should be measured in a correlation-based network, which is among major representations of brain networks. In the present article, we propose clustering coefficients tailored to correlation matrices. The key idea is to use three-way partial correlation or partial mutual information to measure the strength of the association between the two neighboring nodes of a focal node relative to the amount of pseudo-correlation expected from indirect paths between the nodes. Our method avoids the difficulties of previous applications of clustering coefficient (and other) measures in defining correlational networks, i.e., thresholding on the correlation value, discarding of negative correlation values, the pseudo-correlation problem and full partial correlation matrices whose estimation is computationally difficult. For proof of concept, we apply the proposed clustering coefficient measures to functional magnetic resonance imaging data obtained from healthy participants of various ages and compare them with conventional clustering coefficients. We show that the clustering coefficients decline with the age. The proposed clustering coefficients are more strongly correlated with age than the conventional ones are. We also show that the local variants of the proposed clustering coefficients (i.e., abundance of triangles around a focal node) are useful in characterizing individual nodes. In contrast, the conventional local clustering coefficients were strongly correlated with and therefore may be confounded by the node's connectivity. The proposed methods are expected to help us to understand clustering and lack thereof in correlational brain networks, such as those derived from functional time series and across-participant correlation in neuroanatomical properties.