Digital twin brain: a bridge between biological intelligence and artificial intelligence

In recent years, advances in neuroscience and artificial intelligence have paved the way for unprecedented opportunities for understanding the complexity of the brain and its emulation by computational systems. Cutting-edge advancements in neuroscience research have revealed the intricate relationship between brain structure and function, while the success of artificial neural networks highlights the importance of network architecture. Now is the time to bring them together to better unravel how intelligence emerges from the brain's multiscale repositories. In this review, we propose the Digital Twin Brain (DTB) as a transformative platform that bridges the gap between biological and artificial intelligence. It consists of three core elements: the brain structure that is fundamental to the twinning process, bottom-layer models to generate brain functions, and its wide spectrum of applications. Crucially, brain atlases provide a vital constraint, preserving the brain's network organization within the DTB. Furthermore, we highlight open questions that invite joint efforts from interdisciplinary fields and emphasize the far-reaching implications of the DTB. The DTB can offer unprecedented insights into the emergence of intelligence and neurological disorders, which holds tremendous promise for advancing our understanding of both biological and artificial intelligence, and ultimately propelling the development of artificial general intelligence and facilitating precision mental healthcare

What Can Computational Models Contribute to Neuroimaging Data Analytics?

Over the past years, nonlinear dynamical models have significantly contributed to the general understanding of brain activity as well as brain disorders. Appropriately validated and optimized mathematical models can be used to mechanistically explain properties of brain structure and neuronal dynamics observed from neuroimaging data. A thorough exploration of the model parameter space and hypothesis testing with the methods of nonlinear dynamical systems and statistical physics can assist in classification and prediction of brain states. On the one hand, such a detailed investigation and systematic parameter variation are hardly feasible in experiments and data analysis. On the other hand, the model-based approach can establish a link between empirically discovered phenomena and more abstract concepts of attractors, multistability, bifurcations, synchronization, noise-induced dynamics, etc. Such a mathematical description allows to compare and differentiate brain structure and dynamics in health and disease, such that model parameters and dynamical regimes may serve as additional biomarkers of brain states and behavioral modes. In this perspective paper we first provide very brief overview of the recent progress and some open problems in neuroimaging data analytics with emphasis on the resting state brain activity. We then focus on a few recent contributions of mathematical modeling to our understanding of the brain dynamics and model-based approaches in medicine. Finally, we discuss the question stated in the title. We conclude that incorporating computational models in neuroimaging data analytics as well as in translational medicine could significantly contribute to the progress in these fields

DEVELOPMENT OF A CEREBELLAR MEAN FIELD MODEL: THE THEORETICAL FRAMEWORK, THE IMPLEMENTATION AND THE FIRST APPLICATION

Brain modeling constantly evolves to improve the accuracy of the simulated brain dynamics with the ambitious aim to build a digital twin of the brain. Specific models tuned on brain regions specific features empower the brain simulations introducing bottom-up physiology properties into data-driven simulators. Despite the cerebellum contains 80 % of the neurons and is deeply involved in a wide range of functions, from sensorimotor to cognitive ones, a specific cerebellar model is still missing. Furthermore, its quasi-crystalline multi-layer circuitry deeply differs from the cerebral cortical one, therefore is hard to imagine a unique general model suitable for the realistic simulation of both cerebellar and cerebral cortex. The present thesis tackles the challenge of developing a specific model for the cerebellum. Specifically, multi-neuron multi-layer mean field (MF) model of the cerebellar network, including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells, was implemented, and validated against experimental data and the corresponding spiking neural network microcircuit model. The cerebellar MF model was built using a system of interdependent equations, where the single neuronal populations and topological parameters were captured by neuron-specific inter- dependent Transfer Functions. The model time resolution was optimized using Local Field Potentials recorded experimentally with high-density multielectrode array from acute mouse cerebellar slices. The present MF model satisfactorily captured the average discharge of different microcircuit neuronal populations in response to various input patterns and was able to predict the changes in Purkinje Cells firing patterns occurring in specific behavioral conditions: cortical plasticity mapping, which drives learning in associative tasks, and Molecular Layer Interneurons feed-forward inhibition, which controls Purkinje Cells activity patterns. The cerebellar multi-layer MF model thus provides a computationally efficient tool that will allow to investigate the causal relationship between microscopic neuronal properties and ensemble brain activity in health and pathological conditions. Furthermore, preliminary attempts to simulate a pathological cerebellum were done in the perspective of introducing our multi-layer cerebellar MF model in whole-brain simulators to realize patient-specific treatments, moving ahead towards personalized medicine. Two preliminary works assessed the relevant impact of the cerebellum on whole-brain dynamics and its role in modulating complex responses in causal connected cerebral regions, confirming that a specific model is required to further investigate the cerebellum-on- cerebrum influence. The framework presented in this thesis allows to develop a multi-layer MF model depicting the features of a specific brain region (e.g., cerebellum, basal ganglia), in order to define a general strategy to build up a pool of biology grounded MF models for computationally feasible simulations. Interconnected bottom-up MF models integrated in large-scale simulators would capture specific features of different brain regions, while the applications of a virtual brain would have a substantial impact on the reality ranging from the characterization of neurobiological processes, subject-specific preoperative plans, and development of neuro-prosthetic devices

Resting state networks in empirical and simulated dynamic functional connectivity

It is well-established that patterns of functional connectivity (FC) - measures of correlated activity between pairs of voxels or regions observed in the human brain using neuroimaging - are robustly expressed in spontaneous activity during rest. These patterns are not static, but exhibit complex spatio-temporal dynamics. Over the last years, a multitude of methods have been proposed to reveal these dynamics on the level of the whole brain. One finding is that the brain transitions through different FC configurations over time, and substantial effort has been put into characterizing these configurations. However, the dynamics governing these transitions are more elusive, specifically, the contribution of stationary vs. non-stationary dynamics is an active field of inquiry. In this study, we use a whole-brain approach, considering FC dynamics between 66 ROIs covering the entire cortex. We combine an innovative dimensionality reduction technique, tensor decomposition, with a mean field model which possesses stationary dynamics. It has been shown to explain resting state FC averaged over time and multiple subjects, however, this average FC summarizes the spatial distribution of correlations while hiding their temporal dynamics. First, we apply tensor decomposition to resting state scans from 24 healthy controls in order to characterize spatio-temporal dynamics present in the data. We simultaneously utilize temporal and spatial information by creating tensors that are subsequently decomposed into sets of brain regions (“communities”) that share similar temporal dynamics, and their associated time courses. The tensors contain pairwise FC computed inside of overlapping sliding windows. Communities are discovered by clustering features pooled from all subjects, thereby ensuring that they generalize. We find that, on the group level, the data give rise to four distinct communities that resemble known resting state networks (RSNs): default mode network, visual network, control networks, and somatomotor network. Second, we simulate data with our stationary mean field model whose nodes are connected according to results from DTI and fiber tracking. In this model, all spatio-temporal structure is due to noisy fluctuations around the average FC. We analyze the simulated data in the same way as the empirical data in order to determine whether stationary dynamics can explain the emergence of distinct FC patterns (RSNs) which have their own time courses. We find that this is the case for all four networks using the spatio-temporal information revealed by tensor decomposition if nodes in the simulation are connected according to model-based effective connectivity. Furthermore, we find that these results require only a small part of the FC values, namely the highest values that occur across time and ROI pair. Our findings show that stationary dynamics can account for the emergence of RSNs. We provide an innovative method that does not make strong assumptions about the underlying data and is generally applicable to resting state or task data from different subject populations.This work was supported by the European Union, FP7 Marie Curie ITN “INDIREA” (Grant N. 606901; KG), FP7 FET ICT Flagship Human Brain Project (Grant N. 604102; MG), ERC Advanced Human Brain Project (Grant N. 604102; GD), European Union Horizon2020 (ERC Consolidator grant BrainModes 683049; PR); the Spanish Ministry for Economy, Industry and Competitiveness (MINECO) project “PIRE-PICCS” (Grant N. PCIN-2015-079; KG), SEMAINE ERA-Net NEURON Project (Grant N. PCIN2013-026; APA), and ICoBAM (Grant N. PSI2013-42091-P; GD); the James S. McDonnell Foundation (Brain Network Recovery Group, Grant N. JSMF22002082; PR); the German Ministry of Education and Research (Grant N. 01GQ1504A and 01GQ0971-5; PR); the Max-Planck Society (Minerva Program; PR)

Resting state networks in empirical and simulated dynamic functional connectivity

It is well-established that patterns of functional connectivity (FC) - measures of correlated activity between pairs of voxels or regions observed in the human brain using neuroimaging - are robustly expressed in spontaneous activity during rest. These patterns are not static, but exhibit complex spatio-temporal dynamics. Over the last years, a multitude of methods have been proposed to reveal these dynamics on the level of the whole brain. One finding is that the brain transitions through different FC configurations over time, and substantial effort has been put into characterizing these configurations. However, the dynamics governing these transitions are more elusive, specifically, the contribution of stationary vs. non-stationary dynamics is an active field of inquiry. In this study, we use a whole-brain approach, considering FC dynamics between 66 ROIs covering the entire cortex. We combine an innovative dimensionality reduction technique, tensor decomposition, with a mean field model which possesses stationary dynamics. It has been shown to explain resting state FC averaged over time and multiple subjects, however, this average FC summarizes the spatial distribution of correlations while hiding their temporal dynamics. First, we apply tensor decomposition to resting state scans from 24 healthy controls in order to characterize spatio-temporal dynamics present in the data. We simultaneously utilize temporal and spatial information by creating tensors that are subsequently decomposed into sets of brain regions (“communities”) that share similar temporal dynamics, and their associated time courses. The tensors contain pairwise FC computed inside of overlapping sliding windows. Communities are discovered by clustering features pooled from all subjects, thereby ensuring that they generalize. We find that, on the group level, the data give rise to four distinct communities that resemble known resting state networks (RSNs): default mode network, visual network, control networks, and somatomotor network. Second, we simulate data with our stationary mean field model whose nodes are connected according to results from DTI and fiber tracking. In this model, all spatio-temporal structure is due to noisy fluctuations around the average FC. We analyze the simulated data in the same way as the empirical data in order to determine whether stationary dynamics can explain the emergence of distinct FC patterns (RSNs) which have their own time courses. We find that this is the case for all four networks using the spatio-temporal information revealed by tensor decomposition if nodes in the simulation are connected according to model-based effective connectivity. Furthermore, we find that these results require only a small part of the FC values, namely the highest values that occur across time and ROI pair. Our findings show that stationary dynamics can account for the emergence of RSNs. We provide an innovative method that does not make strong assumptions about the underlying data and is generally applicable to resting state or task data from different subject populations.This work was supported by the European Union, FP7 Marie Curie ITN “INDIREA” (Grant N. 606901; KG), FP7 FET ICT Flagship Human Brain Project (Grant N. 604102; MG), ERC Advanced Human Brain Project (Grant N. 604102; GD), European Union Horizon2020 (ERC Consolidator grant BrainModes 683049; PR); the Spanish Ministry for Economy, Industry and Competitiveness (MINECO) project “PIRE-PICCS” (Grant N. PCIN-2015-079; KG), SEMAINE ERA-Net NEURON Project (Grant N. PCIN2013-026; APA), and ICoBAM (Grant N. PSI2013-42091-P; GD); the James S. McDonnell Foundation (Brain Network Recovery Group, Grant N. JSMF22002082; PR); the German Ministry of Education and Research (Grant N. 01GQ1504A and 01GQ0971-5; PR); the Max-Planck Society (Minerva Program; PR)