Introduction: While the prevalence of neurodegenerative diseases associated with dementia such as Alzheimer's disease (AD) increases, our knowledge on the underlying mechanisms, outcome predictors, or therapeutic targets is limited. In this work, we demonstrate how computational multi-scale brain modeling links phenomena of different scales and therefore identifies potential disease mechanisms leading the way to improved diagnostics and treatment. Methods: The Virtual Brain (TVB; thevirtualbrain.org ) neuroinformatics platform allows standardized large-scale structural connectivity-based simulations of whole brain dynamics. We provide proof of concept for a novel approach that quantitatively links the effects of altered molecular pathways onto neuronal population dynamics. As a novelty, we connect chemical compounds measured with positron emission tomography (PET) with neural function in TVB addressing the phenomenon of hyperexcitability in AD related to the protein amyloid beta (Abeta). We construct personalized virtual brains based on an averaged healthy connectome and individual PET derived distributions of Abeta in patients with mild cognitive impairment (MCI, N = 8) and Alzheimer's Disease (AD, N = 10) and in age-matched healthy controls (HC, N = 15) using data from ADNI-3 data base ( http://adni.loni.usc.edu ). In the personalized virtual brains, individual Abeta burden modulates regional Excitation-Inhibition balance, leading to local hyperexcitation with high Abeta loads. We analyze simulated regional neural activity and electroencephalograms (EEG). Results: Known empirical alterations of EEG in patients with AD compared to HCs were reproduced by simulations. The virtual AD group showed slower frequencies in simulated local field potentials and EEG compared to MCI and HC groups. The heterogeneity of the Abeta load is crucial for the virtual EEG slowing which is absent for control models with homogeneous Abeta distributions. Slowing phenomena primarily affect the network hubs, independent of the spatial distribution of Abeta. Modeling the N-methyl-D-aspartate (NMDA) receptor antagonism of memantine in local population models, reveals potential functional reversibility of the observed large-scale alterations (reflected by EEG slowing) in virtual AD brains. Discussion: We demonstrate how TVB enables the simulation of systems effects caused by pathogenetic molecular candidate mechanisms in human virtual brains.

Introduction. While the prevalence of neurodegenerative diseases associated with dementia such as Alzheimer's disease (AD) increases, our knowledge on the underlying mechanisms, outcome predictors, or therapeutic targets is limited. In this work, we demonstrate how computational multi--scale brain modelling links phenomena of different scales and therefore identifies potential disease mechanisms leading the way to improved diagnostics and treatment. Methods. The Virtual Brain (TVB; thevirtualbrain.org) neuroinformatics platform allows standardized large--scale structural connectivity--based simulations of whole brain dynamics. We provide proof of concept for a novel approach that quantitatively links the effects of altered molecular pathways onto neuronal population dynamics. As a novelty, we connect chemical compounds measured with positron emission tomography (PET) with neural function in TVB addressing the phenomenon of hyperexcitability in AD related to the protein amyloid beta (Abeta). We construct personalized virtual brains based on individual PET derived distributions of Abeta in patients with mild cognitive impairment (MCI, N=8) and Alzheimer's Disease (AD, N=10) and in age--matched healthy controls (HC, N=15) using data from ADNI--3 data base (http://adni.lni.usc.edu). In the personalized virtual brains, individual Abeta burden modulates regional inhibition, leading to disinhibition and hyperexcitation with high Abeta loads. We analyze simulated regional neural activity and electroencephalograms (EEG). Results. Known empirical alterations of EEG in patients with AD compared to HCs were reproduced by simulations. The virtual AD group showed slower frequencies in simulated local field potentials and EEG compared to MCI and HC groups. The heterogeneity of the Abeta load is crucial for the virtual EEG slowing which is absent for control models with homogeneous Abeta distributions. Slowing phenomena primarily affect the network hubs, independent of the spatial distribution of Abeta. Modeling the N--methyl--D--aspartate (NMDA) receptor antagonism of memantine in local population models, reveals potential functional reversibility of the observed large--scale alterations (reflected by EEG slowing) in virtual AD brains. Discussion. We demonstrate how TVB enables the simulation of systems effects caused by pathogenetic molecular candidate mechanisms in human virtual brains.

Despite the acceleration of knowledge and data accumulation in neuroscience over the last years, the highly prevalent neurodegenerative disease of AD remains a growing problem. Alzheimer's Disease (AD) is the most common cause of dementia and represents the most prevalent neurodegenerative disease. For AD, disease-modifying treatments are presently lacking, and the understanding of disease mechanisms continues to be incomplete. In the present review, we discuss candidate contributing factors leading to AD, and evaluate novel computational brain simulation methods to further disentangle their potential roles. We first present an overview of existing computational models for AD that aim to provide a mechanistic understanding of the disease. Next, we outline the potential to link molecular aspects of neurodegeneration in AD with large-scale brain network modeling using The Virtual Brain (www.thevirtualbrain.org), an open-source, multiscale, whole-brain simulation neuroinformatics platform. Finally, we discuss how this methodological approach may contribute to the understanding, improved diagnostics, and treatment optimization of AD.

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Introduction Computational brain network modeling using The Virtual Brain (TVB) simulation platform acts synergistically with machine learning (ML) and multi‐modal neuroimaging to reveal mechanisms and improve diagnostics in Alzheimer's disease (AD). Methods We enhance large‐scale whole‐brain simulation in TVB with a cause‐and‐effect model linking local amyloid beta (Aβ) positron emission tomography (PET) with altered excitability. We use PET and magnetic resonance imaging (MRI) data from 33 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI3) combined with frequency compositions of TVB‐simulated local field potentials (LFP) for ML classification. Results The combination of empirical neuroimaging features and simulated LFPs significantly outperformed the classification accuracy of empirical data alone by about 10% (weighted F1‐score empirical 64.34% vs. combined 74.28%). Informative features showed high biological plausibility regarding the AD‐typical spatial distribution. Discussion The cause‐and‐effect implementation of local hyperexcitation caused by Aβ can improve the ML–driven classification of AD and demonstrates TVB's ability to decode information in empirical data using connectivity‐based brain simulation.

Using The Virtual Brain (TVB, thevirtualbrian.org) simulation platform, we explored for 50 individual adult human brains (ages 18-80), how personalized connectome based brain network modelling captures various empirical observations as measured by functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). We compare simulated activity based on individual structural connectomes (SC) inferred from diffusion weighted imaging with fMRI and EEG in the resting state. We systematically explore the role of the following model parameters:conduction velocity, global coupling and graph theoretical features of individual SC. First, a subspace of the parameter space is identified for each subject that results in realistic brain activity, i.e. reproducing the following prominent features of empirical EEG-fMRI activity: topology of resting-state fMRI functional connectivity (FC), functional connectivity dynamics (FCD), electrophysiological oscillations in the delta (3-4 Hz) and alpha (8-12 Hz) frequency range and their bimodality, i.e. low and high energy modes. Interestingly, FCD fit, bimodality and static FC fit are highly correlated. They all show their optimum in the same range of global coupling. In other words, only when our local model is in a bistable regime we are able to generate switching of modes in our global network. Second, our simulations reveal the explicit network mechanisms that lead to electrophysiological oscillations, their bimodal behaviour and inter-regional differences. Third, we discuss biological interpretability of the Stefanescu-Jirsa-Hindmarsh-Rose-3D model when embedded inside the large-scale brain network and mechanisms underlying the emergence of bimodality of the neural signal.With the present study, we set the cornerstone for a systematic catalogue of spatiotemporal brain activity regimes generated with the connectome-based brain simulation platform The Virtual Brain. Author SummaryIn order to understand brain dynamics we use numerical simulations of brain network models. Combining the structural backbone of the brain, that is the white matter fibres connecting distinct regions in the grey matter, with dynamical systems describing the activity of neural populations we are able to simulate brain function on a large scale. In order to make accurate prediction with this network, it is crucial to determine optimal model parameters. We here use an explorative approach to adjust model parameters to individual brain activity, showing that subjects have their own optimal point in the parameter space, depending on their brain structure and function. At the same time, we investigate the relation between bistable phenomena on the scale of neural populations and the changed in functional connectivity on the brain network scale. Our results are important for future modelling approaches trying to make accurate predictions of brain function.Brain network models allow us to investigate how realistic neural behaviour arises as a function of variations in specific neural parameters. Large-sc...

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