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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Decentralized Neural Circuits of Multisensory Information Integration in the Brain.

The brain combines multisensory inputs together to obtain a complete and reliable description of the world. Recent experiments suggest that several interconnected multisensory brain areas are simultaneously involved to integrate multisensory information. It was unknown how these mutually connected multisensory areas achieve multisensory integration. To answer this question, using biologically plausible neural circuit models we developed a decentralized system for information integration that comprises multiple interconnected multisensory brain areas. Through studying an example of integrating visual and vestibular cues to infer heading direction, we show that such a decentralized system is well consistent with experimental observations. In particular, we demonstrate that this decentralized system can optimally integrate information by implementing sampling-based Bayesian inference. The Poisson variability of spike generation provides appropriate variability to drive sampling, and the interconnections between multisensory areas store the correlation prior between multisensory stimuli. The decentralized system predicts that optimally integrated information emerges locally from the dynamics of the communication between brain areas and sheds new light on the interpretation of the connectivity between multisensory brain areas.

Disinhibition Is an Essential Network Motif Coordinated by GABA Levels and GABA B Receptors.

Network dynamics are crucial for action and sensation. Changes in synaptic physiology lead to the reorganization of local microcircuits. Consequently, the functional state of the network impacts the output signal depending on the firing patterns of its units. Networks exhibit steady states in which neurons show various activities, producing many networks with diverse properties. Transitions between network states determine the output signal generated and its functional results. The temporal dynamics of excitation/inhibition allow a shift between states in an operational network. Therefore, a process capable of modulating the dynamics of excitation/inhibition may be functionally important. This process is known as disinhibition. In this review, we describe the effect of GABA levels and GABAB receptors on tonic inhibition, which causes changes (due to disinhibition) in network dynamics, leading to synchronous functional oscillations.

Non-Negative Matrix Factorization for Analyzing State Dependent Neuronal Network Dynamics in Calcium Recordings.

Calcium imaging allows recording from hundreds of neurons in vivo with the ability to resolve single cell activity. Evaluating and analyzing neuronal responses, while also considering all dimensions of the data set to make specific conclusions, is extremely difficult. Often, descriptive statistics are used to analyze these forms of data. These analyses, however, remove variance by averaging the responses of single neurons across recording sessions, or across combinations of neurons, to create single quantitative metrics, losing the temporal dynamics of neuronal activity, and their responses relative to each other. Dimensionally Reduction (DR) methods serve as a good foundation for these analyses because they reduce the dimensions of the data into components, while still maintaining the variance. Non-negative Matrix Factorization (NMF) is an especially promising DR analysis method for analyzing activity recorded in calcium imaging because of its mathematical constraints, which include positivity and linearity. We adapt NMF for our analyses and compare its performance to alternative dimensionality reduction methods on both artificial and in vivo data. We find that NMF is well-suited for analyzing calcium imaging recordings, accurately capturing the underlying dynamics of the data, and outperforming alternative methods in common use.

SIRT1, a target of miR-708-3p, alleviates fluoride-induced neuronal damage via remodeling mitochondrial network dynamics.

INTRODUCTION: Neurological dysfunction induced by fluoride contamination is still one of major concern worldwide. Recently, neuroprotective roles of silent information regulator 1 (SIRT1) focusing on mitochondrial function have been highlighted. However, what roles SIRT1 exerts and the underlying regulative mechanisms, remain largely uncharacterized in such neurotoxic process of fluoride. OBJECTIVES: We aimed at evaluating the regulatory roles of SIRT1 in human neuroblastoma SH-SY5Y cells and Sprague-Dawley rats with fluoride treatment, and to further identify potential miRNA directly targeting SIRT1. METHODS: Pharmacological suppression of SIRT1 by nicotinamide (NIC) and promotion of SIRT1 by adenovirus (Ad-SIRT1) or resveratrol (RSV) were employed to assess the effects of SIRT1 in mitochondrial dysfunction induced by fluoride. Also, miRNAs profiling and bioinformatic prediction were used to screen the miRNAs which can regulate SIRT1 directly. Further, chemical mimic or inhibitor of chosen miRNA was applied to validate the modulation of chosen miRNA. RESULTS: NIC exacerbated defects in mitochondrial network dynamics and cytochrome c (Cyto C) release-driven apoptosis, contributing to fluoride-induced neuronal death. In contrast, the ameliorative effects were observed when overexpressing SIRT1 by Ad-SIRT1 in vitro or RSV in vivo. More importantly, miR-708-3p targeting SIRT1 directly was identified. And interestingly, moreover, treatment with chemically modified miR-708-3p mimic aggravated, while miR-708-3p inhibitor suppressed fluoride-caused neuronal death. Further confirmedly, overexpressing SIRT1 effectively neutralized miR-708-3p mimic-worsened fluoride neuronal death via correcting mitochondrial network dynamics. On contrary, inhibiting SIRT1 counteracted the promotive effects of miR-708-3p inhibitor against neurotoxic response by fluoride through aggravating abnormal mitochondrial network dynamics. CONCLUSION: These data underscore the functional importance of SIRT1 to mitochondrial network dynamics in neurotoxic process of fluoride and further screen a novel unreported neuronal function of miR-708-3p as an upstream regulator of targeting SIRT1, which has important theoretical implications for a potential therapeutic and preventative target for treatment of neurotoxic progression by fluoride.

Hyper-Null Models and Their Applications.

Null models are crucial tools for investigating network topological structures. However, research on null models for higher-order networks is still relatively scarce. In this study, we introduce an innovative method to construct null models for hypergraphs, namely the hyperedge swapping-based method. By preserving certain network properties while altering others, we generate six hyper-null models with various orders and analyze their interrelationships. To validate our approach, we first employ hypergraph entropy to assess the randomness of these null models across four datasets. Furthermore, we examine the differences in important statistical properties between the various null models and the original networks. Lastly, we investigate the impact of hypergraph randomness on network dynamics using the proposed hyper-null models, focusing on dismantling and epidemic contagion. The findings show that our proposed hyper-null models are applicable to various scenarios. By introducing a comprehensive framework for generating and analyzing hyper-null models, this research opens up avenues for further exploration of the intricacies of network structures and their real-world implications.