CRCNS: US-France-Israel Research Proposal: A personalized approach to brain stimulation

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Deep brain stimulation is approved for a number of neurological disorders. However, the where, when and how to stimulate the brain are still empirically solved. The goal of this proposal is to develop a systematic framework that will enable a better understanding of the effects of deep brain stimulation. We will expand The Virtual Brain (TVB), a computational model we developed, with a data-driven approach taking into account cell-type specific control. The project relies on a tight interaction between experimentation and computational modelling. First, using enhancer-based genetics, we will activate/silence specific cell types with opto- /chemo-genetics while acquiring resting state and stimulus driven fMRI in individual mice. Each brain will be virtualized in TVB and undergo data fitting, validation and inference using Stan, a platform for statistical modeling. Model predictions will then be verified in the same individual mice. As a first step towards an application in pathologies, the cells and parameters that need to be controlled will be predicted in silico to stop seizures in experimental epilepsy, and to restore resting state dynamics and rescue motor behavior in an experimental model of Parkinson's disease. Predictions will then be tested experimentally. The proposed project will allow the generation and testing of hypotheses concerning the control of specific cell types with unparalleled biological relevance, precision, and speed. The main goal is to show that it is possible to drive brain activity with stimulation in a predictable way. Through cell type specific modeling of whole brain function in mice, we aim to achieve a major milestone in the development of a realistic, large- scale, anatomical, biophysical model of the human brain. Through unique expertise and technologies our international, interdisciplinary team has pioneered, we will address the problem of understanding how brain stimulation can be systematically designed for individual patients. RELEVANCE (See instructions): The success of deep brain stimulation in treating movement disorders led to its application to various psychiatric and neurological disorders, in an attempt to treat symptoms as well as to directly improve memory function. However, recent clinical trials failed to demonstrate significant effects in epilepsy, depression and dementia, calling for new scientific developments to better understand where, how, and when to stimulate the brain to obtain specific effects. Our experiments will provide fundamental mechanistic insight into how the stimulations impact the brain and how it can be designed for optimal therapeutic outcome in individual brains.