Network dynamics investigation of omics-data-driven circadian-hypoxia crosstalk logical model in gallbladder cancer reveals key therapeutic target combinations.

Recent findings in cancer research have pointed towards the bidirectional interaction between circadian and hypoxia pathways. However, little is known about their crosstalk mechanism. In this work, we aimed to investigate this crosstalk at a network level utilizing the omics information of gallbladder cancer. Differential gene expression and pathway enrichment analysis were used for selecting the crucial genes from both the pathways, followed by the construction of a logical crosstalk model using GINsim. Functional circuit identification and node perturbations were then performed. Significant node combinations were used to investigate the temporal behavior of the network through MaBoSS. Lastly, the model was validated using published in vitro experimentations. Four new positive circuits and a new axis viz. BMAL1/ HIF1αß/ NANOG, responsible for stemness were identified. Through triple node perturbations viz.a. BMAL:CLOCK (KO or E1) + P53 (E1) + HIF1α (KO); b. P53 (E1) + HIF1α (KO) + MYC (E1); and c. HIF1α (KO) + MYC (E1) + EGFR (KO), the model was able to inhibit cancer growth and maintain a homeostatic condition. This work provides an architecture for drug simulation analysis to entrainment circadian rhythm and in vitro experiments for chronotherapy-related studies. Insight Box. Circadian rhythm and hypoxia are the key dysregulated processes which fuels-up the cancer growth. In the present work we have developed a gallbladder cancer (GBC) specific Boolean model, utilizing the RNASeq data from GBC dataset and tissue specific interactions. This work adequately models the bidirectional nature of interactions previously illustrated in experimental papers showing the effect of hypoxia on dysregulation of circadian rhythm and the influence of this disruption on progression towards metastasis. Through the dynamical study of the model and its response to different perturbations, we report novel triple node combinations that can be targeted to efficiently reduce GBC growth. This network can be used as a generalized framework to investigate different crosstalk pathways linked with cancer progression.

Deciphering the topological landscape of glioma using a network theory framework.

Glioma stem cells have been recognized as key players in glioma recurrence and therapeutic resistance, presenting a promising target for novel treatments. However, the limited understanding of the role glioma stem cells play in the glioma hierarchy has drawn controversy and hindered research translation into therapies. Despite significant advances in our understanding of gene regulatory networks, the dynamics of these networks and their implications for glioma remain elusive. This study employs a systemic theoretical perspective to integrate experimental knowledge into a core endogenous network model for glioma, thereby elucidating its energy landscape through network dynamics computation. The model identifies two stable states corresponding to astrocytic-like and oligodendrocytic-like tumor cells, connected by a transition state with the feature of high stemness, which serves as one of the energy barriers between astrocytic-like and oligodendrocytic-like states, indicating the instability of glioma stem cells in vivo. We also obtained various stable states further supporting glioma's multicellular origins and uncovered a group of transition states that could potentially induce tumor heterogeneity and therapeutic resistance. This research proposes that the transition states linking both glioma stable states are central to glioma heterogeneity and therapy resistance. Our approach may contribute to the advancement of glioma therapy by offering a novel perspective on the complex landscape of glioma biology.

Social interactions among ants are impacted by food availability and group size.

Social interactions are important for how societies function, conferring robustness and resilience to environmental changes. The structure of social interactions can shape the dynamics of information and goods transmission. In addition, the availability and types of resources that are transferred might impact the structure of interaction networks. For example, storable resources might reduce the required speed of distribution and altering interaction structure can facilitate such change. Here, we use Camponotus fragilis ants as a model system to examine how social interactions are impacted by group size, food availability, and food type. We compare global- and individual-level network measures across experiments in which groups of different sizes received limited or unlimited food that is either favorable and cannot be stored (carbohydrates), or unfavorable but with a potential of being stored (protein). We found that in larger groups, individuals interacted with more social partners and connected more individuals, and interaction networks became more compartmentalized. Furthermore, the number of individuals that ants interacted with and the distance they traveled both increased when food was limited compared to when it was unlimited. Our findings highlight how biological systems can adjust their interaction networks in ways that relate to their function. The study of such biological flexibility can inspire novel and important solutions to the design of robust and resilient supply chains.

Network dynamics-based subtyping of Alzheimer's disease with microglial genetic risk factors.

BACKGROUND: The potential of microglia as a target for Alzheimer's disease (AD) treatment is promising, yet the clinical and pathological diversity within microglia, driven by genetic factors, poses a significant challenge. Subtyping AD is imperative to enable precise and effective treatment strategies. However, existing subtyping methods fail to comprehensively address the intricate complexities of AD pathogenesis, particularly concerning genetic risk factors. To address this gap, we have employed systems biology approaches for AD subtyping and identified potential therapeutic targets. METHODS: We constructed patient-specific microglial molecular regulatory network models by utilizing existing literature and single-cell RNA sequencing data. The combination of large-scale computer simulations and dynamic network analysis enabled us to subtype AD patients according to their distinct molecular regulatory mechanisms. For each identified subtype, we suggested optimal targets for effective AD treatment. RESULTS: To investigate heterogeneity in AD and identify potential therapeutic targets, we constructed a microglia molecular regulatory network model. The network model incorporated 20 known risk factors and crucial signaling pathways associated with microglial functionality, such as inflammation, anti-inflammation, phagocytosis, and autophagy. Probabilistic simulations with patient-specific genomic data and subsequent dynamics analysis revealed nine distinct AD subtypes characterized by core feedback mechanisms involving SPI1, CASS4, and MEF2C. Moreover, we identified PICALM, MEF2C, and LAT2 as common therapeutic targets among several subtypes. Furthermore, we clarified the reasons for the previous contradictory experimental results that suggested both the activation and inhibition of AKT or INPP5D could activate AD through dynamic analysis. This highlights the multifaceted nature of microglial network regulation. CONCLUSIONS: These results offer a means to classify AD patients by their genetic risk factors, clarify inconsistent experimental findings, and advance the development of treatments tailored to individual genotypes for AD.

Prefrontal multistimulus integration within a dedicated disambiguation circuit guides interleaving contingency judgment learning.

Understanding how cortical network dynamics support learning is a challenge. This study investigates the role of local neural mechanisms in the prefrontal cortex during contingency judgment learning (CJL). To better understand brain network mechanisms underlying CJL, we introduce ambiguity into associative learning after fear acquisition, inducing a generalized fear response to an ambiguous stimulus sharing nontrivial similarities with the conditioned stimulus. Real-time recordings at single-neuron resolution from the prelimbic (PL) cortex show distinct PL network dynamics across CJL phases. Fear acquisition triggers PL network reorganization, led by a disambiguation circuit managing spurious and predictive relationships during cue-danger, cue-safety, and cue-neutrality contingencies. Mice with PL-targeted memory deficiency show malfunctioning disambiguation circuit function, while naive mice lacking unconditioned stimulus exposure lack the disambiguation circuit. This study shows that fear conditioning induces prefrontal cortex cognitive map reorganization and that subsequent CJL relies on the disambiguation circuit's ability to learn predictive relationships.

Tai Chi Practice Buffers Aging Effects in Functional Brain Connectivity.

Tai Chi (TC) practice has been shown to improve both cognitive and physical function in older adults. However, the neural mechanisms underlying the benefits of TC remain unclear. Our primary aims are to explore whether distinct age-related and TC-practice-related relationships can be identified with respect to either temporal or spatial (within/between-network connectivity) differences. This cross-sectional study examined recurrent neural network dynamics, employing an adaptive, data-driven thresholding approach to source-localized resting-state EEG data in order to identify meaningful connections across time-varying graphs, using both temporal and spatial features derived from a hidden Markov model (HMM). Mann-Whitney U tests assessed between-group differences in temporal and spatial features by age and TC practice using either healthy younger adult controls (YACs, n = 15), healthy older adult controls (OACs, n = 15), or Tai Chi older adult practitioners (TCOAs, n = 15). Our results showed that aging is associated with decreased within-network and between-network functional connectivity (FC) across most brain networks. Conversely, TC practice appears to mitigate these age-related declines, showing increased FC within and between networks in older adults who practice TC compared to non-practicing older adults. These findings suggest that TC practice may abate age-related declines in neural network efficiency and stability, highlighting its potential as a non-pharmacological intervention for promoting healthy brain aging. This study furthers the triple-network model, showing that a balancing and reorientation of attention might be engaged not only through higher-order and top-down mechanisms (i.e., FPN/DAN) but also via the coupling of bottom-up, sensory-motor (i.e., SMN/VIN) networks.

Plant metabolites modulate social networks and lifespan in a sawfly.

Social interactions influence disease spread, information flow and resource allocation across species, yet heterogeneity in social interaction frequency and its fitness consequences are still poorly understood. Additionally, the role of exogenous chemicals, such as non-nutritive plant metabolites that are utilised by several animal species, in shaping social networks remains unclear. Here, we investigated how non-nutritive plant metabolites impact social interactions and the lifespan of the turnip sawfly, Athalia rosae. Adult sawflies acquire neo-clerodane diterpenoids ('clerodanoids') from non-food plants and this can serve as a defence against predation and increase mating success. We found intraspecific variation in clerodanoids in natural populations and laboratory-reared individuals. Clerodanoids could also be acquired from conspecifics that had prior access to the plant metabolites, which led to increased agonistic social interactions. Network analysis indicated increased social interactions in sawfly groups where some or all individuals had prior access to clerodanoids, while groups with no prior access had fewer interactions. The frequency of social interactions was influenced by the clerodanoid status of the focal individual and that of other conspecifics. Finally, we observed a shorter lifespan in adults with prior clerodanoid access when grouped with individuals without prior access, suggesting that social interactions to obtain clerodanoids have fitness costs. Our findings highlight the role of intraspecific variation in the acquisition of non-nutritional plant metabolites in shaping social networks. This variation influences individual fitness and social interactions, thereby shaping the individualised social niche.

Data-driven and equation-free methods for neurological disorders: analysis and control of the striatum network.

The striatum as part of the basal ganglia is central to both motor, and cognitive functions. Here, we propose a large-scale biophysical network for this part of the brain, using modified Hodgkin-Huxley dynamics to model neurons, and a connectivity informed by a detailed human atlas. The model shows different spatio-temporal activity patterns corresponding to lower (presumably normal) and increased cortico-striatal activation (as found in, e.g., obsessive-compulsive disorder), depending on the intensity of the cortical inputs. By applying equation-free methods, we are able to perform a macroscopic network analysis directly from microscale simulations. We identify the mean synaptic activity as the macroscopic variable of the system, which shows similarity with local field potentials. The equation-free approach results in a numerical bifurcation and stability analysis of the macroscopic dynamics of the striatal network. The different macroscopic states can be assigned to normal/healthy and pathological conditions, as known from neurological disorders. Finally, guided by the equation-free bifurcation analysis, we propose a therapeutic close loop control scheme for the striatal network.

Utilising activity patterns of a complex biophysical network model to optimise intra-striatal deep brain stimulation.

A large-scale biophysical network model for the isolated striatal body is developed to optimise potential intrastriatal deep brain stimulation applied to, e.g. obsessive-compulsive disorder. The model is based on modified Hodgkin-Huxley equations with small-world connectivity, while the spatial information about the positions of the neurons is taken from a detailed human atlas. The model produces neuronal spatiotemporal activity patterns segregating healthy from pathological conditions. Three biomarkers were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the frequency spectrum of the entire network (rhythmicity) and a combination of the above two. By minimising the deviation of the aforementioned biomarkers from the normal state, we compute the optimal deep brain stimulation parameters, regarding position, amplitude and frequency. Our results suggest that in the DBS optimisation process, there is a clear trade-off between frequency synchronisation and overall network activity, which has also been observed during in vivo studies.

Speech and music recruit frequency-specific distributed and overlapping cortical networks.

To what extent does speech and music processing rely on domain-specific and domain-general neural networks? Using whole-brain intracranial EEG recordings in 18 epilepsy patients listening to natural, continuous speech or music, we investigated the presence of frequency-specific and network-level brain activity. We combined it with a statistical approach in which a clear operational distinction is made between shared, preferred, and domain-selective neural responses. We show that the majority of focal and network-level neural activity is shared between speech and music processing. Our data also reveal an absence of anatomical regional selectivity. Instead, domain-selective neural responses are restricted to distributed and frequency-specific coherent oscillations, typical of spectral fingerprints. Our work highlights the importance of considering natural stimuli and brain dynamics in their full complexity to map cognitive and brain functions.

Design Principles for Perfect Adaptation in Biological Networks with Nonlinear Dynamics.

Establishing a mapping between the emergent biological properties and the repository of network structures has been of great relevance in systems and synthetic biology. Adaptation is one such biological property of paramount importance that promotes regulation in the presence of environmental disturbances. This paper presents a nonlinear systems theory-driven framework to identify the design principles for perfect adaptation with respect to external disturbances of arbitrary magnitude. Based on the prior information about the network, we frame precise mathematical conditions for adaptation using nonlinear systems theory. We first deduce the mathematical conditions for perfect adaptation for constant input disturbances. Subsequently, we translate these conditions to specific necessary structural requirements for adaptation in networks of small size and then extend to argue that there exist only two classes of architectures for a network of any size that can provide local adaptation in the entire state space, namely, incoherent feed-forward (IFF) structure and negative feedback loop with buffer node (NFB). The additional positiveness constraints further narrow the admissible set of network structures. This also aids in establishing the global asymptotic stability for the steady state given a constant input disturbance. The proposed method does not assume any explicit knowledge of the underlying rate kinetics, barring some minimal assumptions. Finally, we also discuss the infeasibility of certain IFF networks in providing adaptation in the presence of downstream connections. Moreover, we propose a generic and novel algorithm based on non-linear systems theory to unravel the design principles for global adaptation. Detailed and extensive simulation studies corroborate the theoretical findings.

4D dynamic spatial brain networks at rest linked to cognition show atypical variability and coupling in schizophrenia.

Despite increasing interest in the dynamics of functional brain networks, most studies focus on the changing relationships over time between spatially static networks or regions. Here we propose an approach to study dynamic spatial brain networks in human resting state functional magnetic resonance imaging (rsfMRI) data and evaluate the temporal changes in the volumes of these 4D networks. Our results show significant volumetric coupling (i.e., synchronized shrinkage and growth) between networks during the scan, that we refer to as dynamic spatial network connectivity (dSNC). We find that several features of such dynamic spatial brain networks are associated with cognition, with higher dynamic variability in these networks and higher volumetric coupling between network pairs positively associated with cognitive performance. We show that these networks are modulated differently in individuals with schizophrenia versus typical controls, resulting in network growth or shrinkage, as well as altered focus of activity within a network. Schizophrenia also shows lower spatial dynamical variability in several networks, and lower volumetric coupling between pairs of networks, thus upholding the role of dynamic spatial brain networks in cognitive impairment seen in schizophrenia. Our data show evidence for the importance of studying the typically overlooked voxel-wise changes within and between brain networks.

Lattice structures that parameterize regulatory network dynamics.

We consider two types of models of regulatory network dynamics: Boolean maps and systems of switching ordinary differential equations. Our goal is to construct all models in each category that are compatible with the directed signed graph that describe the network interactions. This leads to consideration of lattice of monotone Boolean functions (MBF), poset of non-degenerate MBFs, and a lattice of chains in these sets. We describe explicit inductive construction of these posets where the induction is on the number of inputs in MBF. Our results allow enumeration of potential dynamic behavior of the network for both model types, subject to practical limitation imposed by the size of the lattice of MBFs described by the Dedekind number.

Investigating Communication Dynamics in Neuronal Network using 3D Gold Microelectrode Arrays.

Although in vitro neuronal network models hold great potential for advancing neuroscience research, with the capacity to provide fundamental insights into mechanisms underlying neuronal functions, the dynamics of cell communication within such networks remain poorly understood. Here, we develop a customizable, polymer modified three-dimensional gold microelectrode array with sufficient stability for high signal-to-noise, long-term, neuronal recording of cultured networks. By using directed spatial and temporal patterns of electrical stimulation of cells to explore synaptic-based communication, we monitored cell network dynamics over 3 weeks, quantifying communication capability using correlation heatmaps and mutual information networks. Analysis of synaptic delay and signal speed between cells enabled us to establish a communication connectivity model. We anticipate that our discoveries of the dynamic changes in communication across the neuronal network will provide a valuable tool for future studies in understanding health and disease as well as in developing effective platforms for evaluating therapies.

Unveiling the Dynamics behind Glioblastoma Multiforme Single-Cell Data Heterogeneity.

Glioblastoma Multiforme is a brain tumor distinguished by its aggressiveness. We suggested that this aggressiveness leads single-cell RNA-sequence data (scRNA-seq) to span a representative portion of the cancer attractors domain. This conjecture allowed us to interpret the scRNA-seq heterogeneity as reflecting a representative trajectory within the attractor's domain. We considered factors such as genomic instability to characterize the cancer dynamics through stochastic fixed points. The fixed points were derived from centroids obtained through various clustering methods to verify our method sensitivity. This methodological foundation is based upon sample and time average equivalence, assigning an interpretative value to the data cluster centroids and supporting parameters estimation. We used stochastic simulations to reproduce the dynamics, and our results showed an alignment between experimental and simulated dataset centroids. We also computed the Waddington landscape, which provided a visual framework for validating the centroids and standard deviations as characterizations of cancer attractors. Additionally, we examined the stability and transitions between attractors and revealed a potential interplay between subtypes. These transitions might be related to cancer recurrence and progression, connecting the molecular mechanisms of cancer heterogeneity with statistical properties of gene expression dynamics. Our work advances the modeling of gene expression dynamics and paves the way for personalized therapeutic interventions.

The influence of accelerated brain aging on coactivation pattern dynamics in Parkinson's disease.

Aging is widely acknowledged as the primary risk factor for brain degeneration, with Parkinson's disease (PD) tending to follow accelerated aging trajectories. We aim to investigate the impact of structural brain aging on the temporal dynamics of a large-scale functional network in PD. We enrolled 62 PD patients and 32 healthy controls (HCs). The level of brain aging was determined by calculating global and local brain age gap estimates (G-brainAGE and L-brainAGE) from structural images. The neural network activity of the whole brain was captured by identifying coactivation patterns (CAPs) from resting-state functional images. Intergroup differences were assessed using the general linear model. Subsequently, a spatial correlation analysis between the L-brainAGE difference map and CAPs was conducted to uncover the anatomical underpinnings of functional alterations. Compared to HCs (-3.73 years), G-brainAGE was significantly higher in PD patients (+1.93 years), who also exhibited widespread elevation in L-brainAGE. G-brainAGE was correlated with disease severity and duration. PD patients spent less time in CAPs involving activated default mode and the fronto-parietal network (DMN-FPN), as well as the sensorimotor and salience network (SMN-SN), and had a reduced transition frequency from other CAPs to the DMN-FPN and SMN-SN CAPs. Furthermore, the pattern of localized brain age acceleration showed spatial similarities with the SMN-SN CAP. Accelerated structural brain aging in PD adversely affects brain function, manifesting as dysregulated brain network dynamics. These findings provide insights into the neuropathological mechanisms underlying neurodegenerative diseases and imply the possibility of interventions for modifying PD progression by slowing the brain aging process.

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

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

Electroconvulsive Therapy Regulates Brain Connectome Dynamics in Patients With Major Depressive Disorder.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for patients with major depressive disorder (MDD), but its underlying neural mechanisms remain largely unknown. The aim of this study was to identify changes in brain connectome dynamics after ECT in MDD and to explore their associations with treatment outcome. METHODS: We collected longitudinal resting-state functional magnetic resonance imaging data from 80 patients with MDD (50 with suicidal ideation [MDD-SI] and 30 without [MDD-NSI]) before and after ECT and 37 age- and sex-matched healthy control participants. A multilayer network model was used to assess modular switching over time in functional connectomes. Support vector regression was used to assess whether pre-ECT network dynamics could predict treatment response in terms of symptom severity. RESULTS: At baseline, patients with MDD had lower global modularity and higher modular variability in functional connectomes than control participants. Network modularity increased and network variability decreased after ECT in patients with MDD, predominantly in the default mode and somatomotor networks. Moreover, ECT was associated with decreased modular variability in the left dorsal anterior cingulate cortex of MDD-SI but not MDD-NSI patients, and pre-ECT modular variability significantly predicted symptom improvement in the MDD-SI group but not in the MDD-NSI group. CONCLUSIONS: We highlight ECT-induced changes in MDD brain network dynamics and their predictive value for treatment outcome, particularly in patients with SI. This study advances our understanding of the neural mechanisms of ECT from a dynamic brain network perspective and suggests potential prognostic biomarkers for predicting ECT efficacy in patients with MDD.

Structural constraints on the emergence of oscillations in multi-population neural networks.

Oscillations arise in many real-world systems and are associated with both functional and dysfunctional states. Whether a network can oscillate can be estimated if we know the strength of interaction between nodes. But in real-world networks (in particular in biological networks) it is usually not possible to know the exact connection weights. Therefore, it is important to determine the structural properties of a network necessary to generate oscillations. Here, we provide a proof that uses dynamical system theory to prove that an odd number of inhibitory nodes and strong enough connections are necessary to generate oscillations in a single cycle threshold-linear network. We illustrate these analytical results in a biologically plausible network with either firing-rate based or spiking neurons. Our work provides structural properties necessary to generate oscillations in a network. We use this knowledge to reconcile recent experimental findings about oscillations in basal ganglia with classical findings.

MEA-NAP compares microscale functional connectivity, topology, and network dynamics in organoid or monolayer neuronal cultures.

Microelectrode array (MEA) recordings are commonly used to compare firing and burst rates in neuronal cultures. MEA recordings can also reveal microscale functional connectivity, topology, and network dynamics-patterns seen in brain networks across spatial scales. Network topology is frequently characterized in neuroimaging with graph theoretical metrics. However, few computational tools exist for analyzing microscale functional brain networks from MEA recordings. Here, we present a MATLAB MEA network analysis pipeline (MEA-NAP) for raw voltage time-series acquired from single- or multi-well MEAs. Applications to 3D human cerebral organoids or 2D human-derived or murine cultures reveal differences in network development, including topology, node cartography, and dimensionality. MEA-NAP incorporates multi-unit template-based spike detection, probabilistic thresholding for determining significant functional connections, and normalization techniques for comparing networks. MEA-NAP can identify network-level effects of pharmacologic perturbation and/or disease-causing mutations and, thus, can provide a translational platform for revealing mechanistic insights and screening new therapeutic approaches.