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Mathematical framework for large-scale brain network modeling in The Virtual Brain
Open accessAbstract
In this article, we describe the mathematical framework of the computational model at the core of the tool The Virtual Brain (TVB), designed to simulate collective whole brain dynamics by virtualizing brain structure and function, allowing simultaneous outputs of a number of experimental modalities such as electro- and magnetoencephalography (EEG, MEG) and functional Magnetic Resonance Imaging (fMRI). The implementation allows for a systematic exploration and manipulation of every underlying component of a large-scale brain network model (BNM), such as the neural mass model governing the local dynamics or the structural connectivity constraining the space time structure of the network couplings. Here, a consistent notation for the generalized BNM is given, so that in this form the equations represent a direct link between the mathematical description of BNMs and the components of the numerical implementation in TVB. Finally, we made a summary of the forward models implemented for mapping simulated neural activity (EEG, MEG, sterotactic electroencephalogram (sEEG), fMRI), identifying their advantages and limitations.
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![Fig. 3 a) A generic neural mass model with 2 neural masses and two state variables per neural mass. b) To avoid the need for multiple subscripts, the following notation is sometimes used Φ i ={ φ n =1} i , where the subindex i only refers to the mass or population; and Ψ ≡ [ Φ 1 , Φ 2 ] represents the activity of the neural mass model. This denotes the fact that the neural masses at a node are in general interconnected through their fi rst state variable, or have two masses with one state variable as in the Wilson and Cowan model. c) A reader friendly diagram network diagram. This representation emphasizes the functional character of each population represented in the NMM. The notation [ Φ e , Φ i ] is often found in the models descriptions.](/paper-figures/2f3a0675f277465d86eb2591dec960f4/mathematical-framework-for-large-scale-brain-network-modeling-in-the-virtual-figure-3.png)










![Fig. 14 Network stability maps for a) the 74 ROIs matrix (global coupling strength: a Γ ϵ [0.012, 0.042], conduction speed: c 2 ∈ [1, 14]; and b) averaged dataset from DTI ( a Γ ∈ [0.2, 0.9], c 2 ∈ [1, 14]). The metric displayed is the variance computed over all the datapoints after discarding the fi rst 500 ms (e.g., each element of the map represents one simulation). Only the traces of the fi rst state variable, V , were used. The y-axis of the temporal traces is between [ -4, 4].](/paper-figures/efc5fc524df246369d693dec1866cfbe/mathematical-framework-for-large-scale-brain-network-modeling-in-the-virtual-figure-14.png)












![Fig. 27 Larter -Breakspear. Metastability plane. The colormap range is [0, 8.8]. High values of metastability re fl ect fi xed point attractor dynamics. Looking at the bottom row of the parameter plane, for C =0.19, we can see that when δ V N 0.54 the system exhibits chaotic attractor dynamics.](/paper-figures/0ee4413d3d2a45fa8034222f343f3464/mathematical-framework-for-large-scale-brain-network-modeling-in-the-virtual-figure-27.png)










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“Models can involve highly parameterized simulations of regional activity (Hansen et al., 2015; Messe et al., 2014; Sanz-Leon et al., 2015), or sparser analytic predictions of FC using graph metrics of mutual communication (Goni et al., 2014; Grayson et al., 2016) (although, both approaches appear to be comparably effective; see Figure 1D).”
From Development of large-scale functional networks from birth to adulthood: A guide to the neuroimaging literature (2017) · cites this paper as Sanz-Leon et al., 2015
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“Given that macroscale FC is modulated by both interregional connectivity strength as well as local population dynamics (Sanz-Leon et al., 2015), alterations in SC-FC coupling could potentially point to important shifts in the underlying drivers of various network phenomena.”
BackgroundThe Virtual Epileptic Patient: Individualized whole-brain models of epilepsy spread
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“A BNM (Sanz-Leon et al., 2015) was constructed by placing at each node of the parcellation a neural mass model able to reproduce the temporal seizure dynamics and to switch autonomously between interictal and ictal states, the so-called Epileptor model (Jirsa et al., 2014).”
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“A notable example of the rapid development of large-scale BNMs for neuroimaging data is the ‘‘Virtual Brain’’ project (Jirsa et al., 2010; Sanz-Leon et al., 2015).”
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“Mixed connectivities in network architectures are common in large-scale brain models 39,40 .”
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“Mean-field models at the whole-brain scale roughly fall into two categories: coupled neural masses (Gollo and Breakspear, 2014; Sanz-Leon et al., 2015; Schmidt et al., 2015) and neural fields (Atasoy et al., 2016; Jirsa and Haken, 1996; Robinson et al., 2001; Robinson et al., 2016).”
BackgroundStefanovski, L., Triebkorn, P., Spiegler, A., Díaz-Cortés, M.-A., Solodkin, A., Jirsa, V., McIntosh, A. R., Ritter, P., & Initiative, A. D. N. (2019) · Frontiers in Computational Neuroscience · doi:10.3389/fncom.2019.00054 · Cited by 145
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“…to take action locally and spread through anatomical connections (Cabral et al., 2012; Friston et al., 2014; Iturria-Medina et al., 2014; Mišić et al., 2015; Raj et al., 2012; Sanz Leon et al., 2013; Sanz-Leon et al., 2015; Sotero et al., 2007; Stam et al., 2016; Valdes-sosa et al., 2011a).”
Transmission time delays organize the brain network synchronization
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CoreNEURON : An Optimized Compute Engine for the NEURON Simulator
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“Moreover, Wilson–Cowan style neural mass models are a key component of the Virtual Brain project that aims to deliver the first simulation of the human brain based on personalised large-scale connectivity [105].”
BackgroundSpiegler, A., Hansen, E. C. A., Bernard, C., McIntosh, A. R., & Jirsa, V. (2016) · eNeuro · doi:10.1523/eneuro.0068-16.2016 · Cited by 96
Self-citationIndividual structural features constrain the mouse functional connectome
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“36 We use The Virtual Brain (TVB), a neuroinformatics and simulation platform, which allows 37 connectome-based whole brain modeling of multiple species including human [28] and mice [29].”
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“, The Virtual Brain (Sanz-Leon et al., 2015), the Blue Brain Project (Markram et al.”
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“…(BNMs) are networks of neural masses that can provide a first order approximation to explain such brain signals (Bojak and Oostendorp, 2011; Deco et al., 2009; Deco and Jirsa, 2012; Ghosh et al., 2008; Jirsa et al., 2010; Ritter et al., 2013; Sanz-Leon et al., 2015; Spiegler and Jirsa, 2013).”
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“…of the system was performed using stochastic Heun’s method (Mannella 2002), with an integration step size of 0.0122 ms. (5) The BOLD signals were derived from the field potentials using a hemodynamic response function implemented with a gamma kernel (Boynton et al., 1996; Sanz-Leon et al., 2015).”
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“The Virtual Brain (Ritter et al., 2013; Sanz-Leon et al., 2015; Schirner et al., 2021) is an excellent example of a toolbox that affords access to this approach, and has been used to demonstrate important links between structure and function across many spatiotemporal scales.”
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Self-citationHeterogeneity of time delays determines synchronization of coupled oscillators
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Self-citationModel-based whole-brain effective connectivity to study distributed cognition in health and disease
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Multiscale modeling of brain dynamics: from single neurons and networks to mathematical tools
Siettos, C. I., & Starke, J. (2016) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1348 · Cited by 58
Becker, R., Knock, S. A., Ritter, P., & Jirsa, V. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004352 · Cited by 53
Self-citationKuramoto Model for Excitation-Inhibition-Based Oscillations
Montbrió, E., & Pazó, D. (2018) · Physical Review Letters · doi:10.1103/physrevlett.120.244101 · Cited by 57
Papadopoulos, L., Lynn, C. W., Battaglia, D. A., & Bassett, D. S. (2020) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008144 · Cited by 54
NFTsim: Theory and Simulation of Multiscale Neural Field Dynamics
Sanz‐Leon, P., Robinson, P. A., Knock, S. A., Drysdale, P. M., Abeysuriya, R., Fung, F., RENNIE, C. J., & Zhao, X. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006387 · Cited by 57
“125 A few software packages are available to model neural masses and neural fields: [7] 126 developed a neuroinformatics platform for large-scale brain modeling in terms of a 127 network of linked neural masses with anatomically specified cortical geometry [55], 128 long-range connectivity, and local short-range conne…”
BackgroundMethodSelf-citationThe Virtual Brain: Modeling Biological Correlates of Recovery after Chronic Stroke
Falcon, M. I., Riley, J. D., Jirsa, V., McIntosh, A. R., Shereen, A. D., Chen, E. E., & Solodkin, A. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00228 · Cited by 54
Self-citationHashemi, M., Vattikonda, A. N., Jha, J., Ší́p, V., Woodman, M., Bartoloméi, F., & Jirsa, V. (2023) · Neural Networks · doi:10.1016/j.neunet.2023.03.040 · Cited by 52
Self-citationPartial synchronization patterns in brain networks
Schöll, E. (2021) · Europhysics Letters (EPL) · doi:10.1209/0295-5075/ac3b97 · Cited by 50
Tesler, F., Linne, M., & Alain Destexhe, A. (2023) · Scientific Reports · doi:10.1038/s41598-023-32618-0 · Cited by 47
“Furthermore, our framework can be combined with different neuronal models and has the potential of being incorporated in whole brain simulators such as The Virtual Brain 44,69 .”
MethodYu, Y., Fan, Y., Han, F., Luan, G., & Wang, Q. (2023) · Science China Technological Sciences · doi:10.1007/s11431-022-2341-x · Cited by 49
Stefanovski, L., Meier, J. M., Pai, R. K., Triebkorn, P., Lett, T. A. P., Martin, L., Bülau, K., Hofmann‐Apitius, M., Solodkin, A., McIntosh, A. R., et al. (2021) · Frontiers in Neuroinformatics · doi:10.3389/fninf.2021.630172 · Cited by 47
Synchronization patterns: from network motifs to hierarchical networks
Krishnagopal, S., Lehnert, J., Poel, W., Zakharova, A., & Schöll, E. (2017) · Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Sciences · doi:10.1098/rsta.2016.0216 · Cited by 45
Dubois, J., Adibpour, P., Poupon, C., Hertz-Pannier, L., & Dehaene-Lambertz, G. (2016) · Brain Plasticity · doi:10.3233/bpl-160031 · Cited by 40
“Thus accurate anatomo-functional models of networks would require to integer all these properties and account for spatial and temporal constraints [150].”
BackgroundArbabyazd, L., Shen, K., Wang, Z., Hofmann‐Apitius, M., Ritter, P., McIntosh, A. R., Battaglia, D. A., & Jirsa, V. (2021) · eNeuro · doi:10.1523/eneuro.0475-20.2021 · Cited by 44
Self-citationDoes the brain behave like a (complex) network? I. Dynamics
Papo, D., & Buldú, J. M. (2023) · Physics of Life Reviews · doi:10.1016/j.plrev.2023.12.006 · Cited by 44
Data-driven brain network models differentiate variability across language tasks
Bansal, K., Medaglia, J. D., Bassett, D. S., Vettel, J. M., & Muldoon, S. F. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006487 · Cited by 42
“Using experimentally obtained structural brain network data combined with biologically motivated computational models of brain dynamics [36], one can build personalized brain network models of human brain activity [37, 38, 39].”
MethodHashemi, M., Vattikonda, A. N., Ší́p, V., Diaz-Pier, S., Peyser, A., Wang, H., Guye, M., Bartoloméi, F., Woodman, M., & Jirsa, V. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1009129 · Cited by 39
“The Virtual Brain (TVB) is a computational framework to simulate large-scale brain network models based on individual subject data [59, 60].”
BackgroundSelf-citationStructural and functional, empirical and modeled connectivity in the cerebral cortex of the rat
Díaz‐Parra, A., Osborn, Z. G., Canals, S., Moratal, D., & Sporns, O. (2017) · NeuroImage · doi:10.1016/j.neuroimage.2017.07.046 · Cited by 41
“TVB simulations take structural data about a brain - structural connectivity, spatial coordinates of ROIs, and tract length distances between ROIs - and output simulated neural activity time series for each ROI, using a given model type and set of simulation parameter values (Sanz-Leon et al., 2015).”
MethodIturria‐Medina, Y., Carbonell, F., & Evans, A. C. (2018) · NeuroImage · doi:10.1016/j.neuroimage.2018.06.028 · Cited by 42
Mean-Field Models for EEG/MEG: From Oscillations to Waves
Byrne, Á., Ross, J., Nicks, R., & Coombes, S. (2021) · Brain Topography · doi:10.1007/s10548-021-00842-4 · Cited by 42
“2020), and are a key ingredient of the Virtual Brain project that aims to deliver the first open simulation of the human brain based on individual large-scale connectivity (Sanz-Leon et al. 2015).”
BackgroundPetkoski, S., Ritter, P., & Jirsa, V. (2022) · Cerebral Cortex · doi:10.1093/cercor/bhac500 · Cited by 43
“Time delays and the weights compose the space-time structure of the connectivity that is crucial in shaping its macroscopic activity (Deco et al. 2009; Ghosh et al. 2008; Sanz-Leon et al. 2015).”
BackgroundMethodInfluentialSelf-citationNormalizing the brain connectome for communication through synchronization
Petkoski, S., & Jirsa, V. (2022) · Network Neuroscience · doi:10.1162/netn_a_00231 · Cited by 44
“Models of brain networks based on human connectomes (10) have demonstrated individual predictive power in resting state paradigms (11), cognitive tasks (12) and brain disease such as epilepsy (13, 14).”
Self-citationA Stochastic Version of the Jansen and Rit Neural Mass Model: Analysis and Numerics
Ableidinger, M., Buckwar, E., & Hinterleitner, H. (2017) · The Journal of Mathematical Neuroscience · doi:10.1186/s13408-017-0046-4 · Cited by 41
“They have successfully been used to fit neuroimaging data, understanding EEG rhythms [8] or epileptic brain dynamics [9], and are now also a major building block in the Virtual Brain [10].”
MethodModeling seizures: From single neurons to networks
Depannemaecker, D., Alain Destexhe, A., Jirsa, V., et al. (2021) · Seizure · doi:10.1016/j.seizure.2021.06.015 · Cited by 41
Self-citationDynamic primitives of brain network interaction
Schirner, M., Kong, X., Yeo, B. T. T., Deco, G., & Ritter, P. (2022) · NeuroImage · doi:10.1016/j.neuroimage.2022.118928 · Cited by 42
Sorrentino, P., Petkoski, S., Sparaco, M., Lopez, E. T., Signoriello, E., Baselice, F., Bonavita, S., Pirozzi, M. A., Quarantelli, M., Sorrentino, G., et al. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0938-22.2022 · Cited by 40
“For this reason, estimating a comprehensive map of the delays poses great challenges, and most modeling studies assume homogeneous velocities of conduction (typically ranging from 2 to 10 m/s; Sanz-Leon et al., 2015; Breakspear, 2017).”
BackgroundSelf-citationGerster, M., Taher, H., Škoch, A., Hlinka, J., Guye, M., Bartoloméi, F., Jirsa, V., Zakharova, A., & Olmi, S. (2021) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2021.675272 · Cited by 39
Self-citationNetworks of piecewise linear neural mass models
Coombes, S., Lai, Y. M., Şaylı, M., & Thul, R. (2018) · European Journal of Applied Mathematics · doi:10.1017/s0956792518000050 · Cited by 37
Mills, B. D., Grayson, D. S., Shunmugavel, A., Miranda-Domínguez, Ó., Feczko, E., Earl, E., Neve, K. A., & Fair, D. A. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2910-17.2018 · Cited by 33
“Modeling approaches to predict FC networks based on macro- or meso-scale anatomical connectivity networks commonly simulate mass neuronal activity by optimizing parameters that describe local population dynamics as well as the contribution of inter-areal connectivity (Honey et al., 2009; Messé et al., 2014; Sanz-Leon…”
BackgroundDomhof, J. W. M., Jung, K., Eickhoff, S. B., & Popovych, O. V. (2021) · Network Neuroscience · doi:10.1162/netn_a_00202 · Cited by 37
“Previous studies suggested that dynamical whole-brain models are able to simulate the restingstate brain activity on a personalized level (Bansal et al., 2018; Deco et al., 2017; Ritter et al., 2013; Sanz-Leon et al., 2015; Zimmermann et al., 2018).”
BackgroundMethodCombining hypothesis- and data-driven neuroscience modeling in FAIR workflows
Eriksson, O., Bhalla, U. S., Blackwell, K. T., Crook, S. M., Keller, D. X., Kramer, A., Linne, M., Saudargienė, A., Wade, R. C., & Kotaleski, J. H. (2022) · eLife · doi:10.7554/elife.69013 · Cited by 36
Synchronization in Functional Networks of the Human Brain
Hövel, P., Viol, A., Loske, P., Merfort, L., & Vuksanović, V. (2018) · Journal of Nonlinear Science · doi:10.1007/s00332-018-9505-7 · Cited by 37
Vagus nerve stimulation for epilepsy: A narrative review of factors predictive of response
Clifford, H. J., Paranathala, M. P., Wang, Y., Thomas, R. H., Costa, T. D. S., Duncan, J. S., & Taylor, P. N. (2024) · Epilepsia · doi:10.1111/epi.18153 · Cited by 34
Yu, Y., Wang, H., Liu, X., & Wang, Q. (2024) · Nonlinear Dynamics · doi:10.1007/s11071-024-10132-w · Cited by 34
“The propagation matrix is obtained by solving the boundary element method and is available in the TVB dataset [34,35].”
What Can Computational Models Contribute to Neuroimaging Data Analytics?
Popovych, O. V., Manos, T., Hoffstaedter, F., & Eickhoff, S. B. (2019) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2018.00068 · Cited by 33
“, (dynamic) FC of RSNs, can be reached by an appropriate parameter calibration (Ritter et al., 2013; Sanz Leon et al., 2013; Sanz-Leon et al., 2015; Falcon et al., 2016).”
BackgroundBrain simulation augments machine‐learning–based classification of dementia
Triebkorn, P., Stefanovski, L., Dhindsa, K., Díaz-Cortés, M.-A., Bey, P., Bülau, K., Pai, R. K., Spiegler, A., Solodkin, A., Jirsa, V., et al. (2022) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12303 · Cited by 31
Self-citationFully Bayesian estimation of virtual brain parameters with self-tuning Hamiltonian Monte Carlo
Jha, J., Hashemi, M., Vattikonda, A. N., Wang, H., & Jirsa, V. (2022) · Machine Learning Science and Technology · doi:10.1088/2632-2153/ac9037 · Cited by 29
Self-citationSheheitli, H., & Jirsa, V. (2020) · Network Neuroscience · doi:10.1162/netn_a_00134 · Cited by 31
Self-citationMascaro, A. L. A., Falotico, E., Petkoski, S., Pasquini, M., Vannucci, L., Tort‐Colet, N., Conti, E., Resta, F., Spalletti, C., Ramalingasetty, S. T., et al. (2020) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2020.00031 · Cited by 32
“Neural masses formalisms have been used over many years to develop macroscopic models that capture the collective dynamics of large neural assemblies (Deco et al., 2008; Sanz-Leon et al., 2015).”
BackgroundMethodSelf-citation
Metadata
- Authors
- Sanz-Leon, P., Knock, S. A., Spiegler, A., & Jirsa, V. K.
- Affiliations
- QIMR Berghofer Medical Research Institute (AU)
- Inserm (FR)
- Corresponding author
- Jirsa, Viktor K.
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 111
- Pages
- 385-430
- ISSN
- 1053-8119 (ISSN-L)
- OpenAlex
- W2074725578
- Semantic Scholar
- 23be65f2b2fee15432e3086c0d98a6610709848f
- Cited by
- 356
- References
- 240
- Citations by year
- 2026: 27 · 2025: 53 · 2024: 41 · 2023: 34 · 2022: 37 · 2021: 36 · 2020: 29 · 2019: 23 · 2018: 25 · 2017: 21 · 2016: 15 · 2015: 13
- FWCI
- 14.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- NeuroImage (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- James S. McDonnell Foundation (FP7-ICT BrainScales - 2009-6)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- The Virtual Brain, whole-brain dynamics, neural mass model, structural connectivity, forward model, EEG, MEG, functional MRI, stereoelectroencephalography, mathematical notation, computational neuroscience simulation
- MeSH terms
- Brain, Humans, Models, Neurological, Nerve Net, Functional Neuroimaging
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