Principles and Operation of Virtual Brain Twins

Current clinical methods often overlook individual variability by relying on population-wide trials, while mechanism-based trials remain underutilized in neuroscience due to the brain's complexity. A Virtual Brain Twin (VBT) is a personalized digital replica of an individual's brain, integrating structural and functional brain data into advanced computational models and inference algorithms. By bridging the gap between molecular mechanisms, whole-brain dynamics, and imaging data, VBTs enhance the understanding of (patho)physiological mechanisms, advancing insights into both healthy and disordered brain function. Central to VBT is the network modeling that couples mesoscopic representation of neuronal activity through white matter connectivity, enabling the simulation of brain dynamics at a network level. This transformative approach provides interpretable predictive capabilities, supporting clinicians in personalizing treatments and optimizing interventions. This manuscript outlines the key components of VBT development, covering the conceptual, mathematical, technical, and clinical aspects. We describe the stages of VBT construction--from anatomical coupling and modeling to simulation and Bayesian inference--and demonstrate their applications in resting-state, healthy aging, epilepsy, and multiple sclerosis. Finally, we discuss potential extensions to other neurological disorders, such as Parkinson's disease, and explore future applications in consciousness research and brain-computer interfaces, paving the way for advancements in personalized medicine and brain-machine integration.