Virtual brain twins: from basic neuroscience to clinical use.

Virtual brain twins are personalized, generative and adaptive brain models based on data from an individual's brain for scientific and clinical use. After a description of the key elements of virtual brain twins, we present the standard model for personalized whole-brain network models. The personalization is accomplished using a subject's brain imaging data by three means: (1) assemble cortical and subcortical areas in the subject-specific brain space; (2) directly map connectivity into the brain models, which can be generalized to other parameters; and (3) estimate relevant parameters through model inversion, typically using probabilistic machine learning. We present the use of personalized whole-brain network models in healthy ageing and five clinical diseases: epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and psychiatric disorders. Specifically, we introduce spatial masks for relevant parameters and demonstrate their use based on the physiological and pathophysiological hypotheses. Finally, we pinpoint the key challenges and future directions.

Personalised virtual brain models in epilepsy.

Individuals with drug-resistant focal epilepsy are candidates for surgical treatment as a curative option. Before surgery can take place, the patient must have a presurgical evaluation to establish whether and how surgical treatment might stop their seizures without causing neurological deficits. Virtual brains are a new digital modelling technology that map the brain network of a person with epilepsy, using data derived from MRI. This technique produces a computer simulation of seizures and brain imaging signals, such as those that would be recorded with intracranial EEG. When combined with machine learning, virtual brains can be used to estimate the extent and organisation of the epileptogenic zone (ie, the brain regions related to seizure generation and the spatiotemporal dynamics during seizure onset). Virtual brains could, in the future, be used for clinical decision making, to improve precision in localisation of seizure activity, and for surgical planning, but at the moment these models have some limitations, such as low spatial resolution. As evidence accumulates in support of the predictive power of personalised virtual brain models, and as methods are tested in clinical trials, virtual brains might inform clinical practice in the near future.

Delineating epileptogenic networks using brain imaging data and personalized modeling in drug-resistant epilepsy.

Precise estimates of epileptogenic zone networks (EZNs) are crucial for planning intervention strategies to treat drug-resistant focal epilepsy. Here, we present the virtual epileptic patient (VEP), a workflow that uses personalized brain models and machine learning methods to estimate EZNs and to aid surgical strategies. The structural scaffold of the patient-specific whole-brain network model is constructed from anatomical T1 and diffusion-weighted magnetic resonance imaging. Each network node is equipped with a mathematical dynamical model to simulate seizure activity. Bayesian inference methods sample and optimize key parameters of the personalized model using functional stereoelectroencephalography recordings of patients' seizures. These key parameters together with their personalized model determine a given patient's EZN. Personalized models were further used to predict the outcome of surgical intervention using virtual surgeries. We evaluated the VEP workflow retrospectively using 53 patients with drug-resistant focal epilepsy. VEPs reproduced the clinically defined EZNs with a precision of 0.6, where the physical distance between epileptogenic regions identified by VEP and the clinically defined EZNs was small. Compared with the resected brain regions of 25 patients who underwent surgery, VEP showed lower false discovery rates in seizure-free patients (mean, 0.028) than in non-seizure-free patients (mean, 0.407). VEP is now being evaluated in an ongoing clinical trial (EPINOV) with an expected 356 prospective patients with epilepsy.

Full-scale scaffold model of the human hippocampus CA1 area.

The increasing availability of quantitative data on the human brain is opening new avenues to study neural function and dysfunction, thus bringing us closer and closer to the implementation of digital twin applications for personalized medicine. Here we provide a resource to the neuroscience community: a computational method to generate full-scale scaffold model of human brain regions starting from microscopy images. We have benchmarked the method to reconstruct the CA1 region of a right human hippocampus, which accounts for about half of the entire right hippocampal formation. Together with 3D soma positioning we provide a connectivity matrix generated using a morpho-anatomical connection strategy based on axonal and dendritic probability density functions accounting for morphological properties of hippocampal neurons. The data and algorithms are supplied in a ready-to-use format, suited to implement computational models at different scales and detail.

Brain simulation augments machine-learning-based classification of dementia.

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 (Aß) 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 Aß can improve the ML-driven classification of AD and demonstrates TVB's ability to decode information in empirical data using connectivity-based brain simulation.

Unimanual sensorimotor learning-A simultaneous EEG-fMRI aging study.

Sensorimotor coordination requires orchestrated network activity in the brain, mediated by inter- and intra-hemispheric interactions that may be affected by aging-related changes. We adopted a theoretical model, according to which intra-hemispheric inhibition from premotor to primary motor cortex is mandatory to compensate for inter-hemispheric excitation through the corpus callosum. To test this as a function of age we acquired electroencephalography (EEG) simultaneously with functional magnetic resonance imaging (fMRI) in two groups of healthy adults (younger N = 13: 20-25 year and older N = 14: 59-70 year) while learning a unimanual motor task. On average, quality of performance of older participants stayed significantly below that of the younger ones. Accompanying decreases in motor-event-related EEG ß-activity were lateralized toward contralateral motor regions, albeit more so in younger participants. In this younger group, the mean ß-power during motor task execution was significantly higher in bilateral premotor areas compared to the older adults. In both groups, fMRI blood oxygen level dependent (BOLD) signals were positively correlated with source-reconstructed ß-amplitudes: positive in primary motor and negative in premotor cortex. This suggests that ß-amplitude modulation is associated with primary motor cortex "activation" (positive BOLD response) and premotor "deactivation" (negative BOLD response). Although the latter results did not discriminate between age groups, they underscore that enhanced modulation in primary motor cortex may be explained by a ß-associated excitatory crosstalk between hemispheres.

Brain simulation as a cloud service: The Virtual Brain on EBRAINS.

The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation.

Bridging Scales in Alzheimer's Disease: Biological Framework for Brain Simulation With The Virtual Brain.

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.

VEP atlas: An anatomic and functional human brain atlas dedicated to epilepsy patients.

BACKGROUND: Several automated parcellation atlases of the human brain have been developed over the past decades, based on various criteria, and have been applied in basic and clinical research. NEW METHOD: Here we present the Virtual Epileptic Patient (VEP) atlas that offers a new automated brain region parcellation and labeling, which has been developed for the specific use in the domains of epileptology and functional neurosurgery and is able to apply at individual patient's level. RESULTS: It comprises 162 brain regions, including 73 cortical and 8 subcortical regions per hemisphere. We demonstrate the successful application of the VEP atlas in a cohort of 50 retrospective patients. The structural organization is complemented by the functional variation of stereotactic intracerebral EEG (SEEG) signal data features establishing brain region-specific 3d-maps. COMPARISON WITH EXISTING METHODS: The VEP atlas integrates both anatomical and functional definitions in the same atlas, adapted to applications for epilepsy patients and individualizable. CONCLUSION: The covariation of structural and functional organization is the basis for current efforts of patient-specific large-scale brain network modeling exploiting virtual brain technologies for the identification of the epileptogenic regions in an ongoing prospective clinical trial EPINOV.

Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease.

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.

TVB-EduPack-An Interactive Learning and Scripting Platform for The Virtual Brain.

The Virtual Brain (TVB; thevirtualbrain.org) is a neuroinformatics platform for full brain network simulation based on individual anatomical connectivity data. The framework addresses clinical and neuroscientific questions by simulating multi-scale neural dynamics that range from local population activity to large-scale brain function and related macroscopic signals like electroencephalography and functional magnetic resonance imaging. TVB is equipped with a graphical and a command-line interface to create models that capture the characteristic biological variability to predict the brain activity of individual subjects. To enable researchers from various backgrounds a quick start into TVB and brain network modeling in general, we developed an educational module: TVB-EduPack. EduPack offers two educational functionalities that seamlessly integrate into TVB's graphical user interface (GUI): (i) interactive tutorials introduce GUI elements, guide through the basic mechanics of software usage and develop complex use-case scenarios; animations, videos and textual descriptions transport essential principles of computational neuroscience and brain modeling; (ii) an automatic script generator records model parameters and produces input files for TVB's Python programming interface; thereby, simulation configurations can be exported as scripts that allow flexible customization of the modeling process and self-defined batch- and post-processing applications while benefitting from the full power of the Python language and its toolboxes. This article covers the implementation of TVB-EduPack and its integration into TVB architecture. Like TVB, EduPack is an open source community project that lives from the participation and contribution of its users. TVB-EduPack can be obtained as part of TVB from thevirtualbrain.org.