Periodic Reporting for period 1 - Neurotwin (Digital twins for model-driven non-invasive electrical brain stimulation)
Berichtszeitraum: 2021-01-01 bis 2021-12-31
Neuropsychiatric disorders are a leading cause of global disability-adjusted life years, and solutions are lacking. Can digital twins be useful? At least in some cases, we hold they will be central to progress. Recent findings suggest that non-invasive brain stimulation may be a valuable option in conditions such as epilepsy or Alzheimer's (AD). Still, a better understanding of mechanisms and patient-specific factors is needed. Personalized hybrid brain models uniting the physics of electromagnetism with physiology – neurotwins or NeTs – are poised to play a fundamental role in understanding and optimizing the effects of stimulation at the individual level. We ambition to deliver disruptive solutions through model-driven, individualized therapy. We will build a computational framework – weaved a validated across scales and levels of detail– to represent the mechanisms of interaction of electric fields with brain networks and assimilate neuroimaging data. This will allow us to characterize the dynamical landscape of the individual brain and define strategies to restore healthy dynamics. Benefitting from existing databases of healthy and AD individuals, we will deliver the first human and rodent NeTs predicting the effects of stimulation on dynamics.
We will then collect detailed multimodal measurements in mice and humans to improve the predictive power of local and whole-brain models under the effects of electrical stimulation, and translate these findings into a technology pipeline for the design of new personalized neuromodulation protocols which we will test in a cohort of AD patients and healthy controls in randomized double-blinded studies. With research at the intersecting frontier of nonlinear dynamics, network theory, biophysics, engineering, neuroscience, clinical research, and ethics, Neurotwin will deliver model-driven breakthroughs in basic and clinical neuroscience, with patients ultimately benefiting from safe, individualized therapy solutions.
1. Create a validated multiscale scientific framework for the creation of hybrid brain models (HBMs) representing the effects of electrical stimulation appropriate in the context of large-scale connectivity alterations and oscillatory deficits – characteristics of diseases such as AD.
2. Develop practical and effective data assimilation/personalization techniques from neuroimaging and neurophysiology data representing key physical and physiological individual characteristics.
3. Determine target objective functions at the mesoscale and whole-brain scales for designing stimulation by defining “healthy” dynamics in quantitative terms at different brain scales that can be used to drive stimulation therapeutic interventions.
4. Define and carry out an in-vivo and in-human experimental plan to validate and refine theory elements and develop techniques for probing and stimulation.
5. Carry out a clinical pilot in AD and healthy controls (HCs) with Neurotwin-optimized tES protocols.
6. Translate our scientific findings into an engineering framework for the creation of personalized hybrid brain models (neurotwins) and optimization of brain stimulation protocols.
7. Create NeT human and mice databases for future simulation and research.
We will then collect detailed multimodal measurements in mice and humans to improve the predictive power of local and whole-brain models under the effects of electrical stimulation, and translate these findings into a technology pipeline for the design of new personalized neuromodulation protocols which we will test in a cohort of AD patients and healthy controls in randomized double-blinded studies. With research at the intersecting frontier of nonlinear dynamics, network theory, biophysics, engineering, neuroscience, clinical research, and ethics, Neurotwin will deliver model-driven breakthroughs in basic and clinical neuroscience, with patients ultimately benefiting from safe, individualized therapy solutions.
1. Create a validated multiscale scientific framework for the creation of hybrid brain models (HBMs) representing the effects of electrical stimulation appropriate in the context of large-scale connectivity alterations and oscillatory deficits – characteristics of diseases such as AD.
2. Develop practical and effective data assimilation/personalization techniques from neuroimaging and neurophysiology data representing key physical and physiological individual characteristics.
3. Determine target objective functions at the mesoscale and whole-brain scales for designing stimulation by defining “healthy” dynamics in quantitative terms at different brain scales that can be used to drive stimulation therapeutic interventions.
4. Define and carry out an in-vivo and in-human experimental plan to validate and refine theory elements and develop techniques for probing and stimulation.
5. Carry out a clinical pilot in AD and healthy controls (HCs) with Neurotwin-optimized tES protocols.
6. Translate our scientific findings into an engineering framework for the creation of personalized hybrid brain models (neurotwins) and optimization of brain stimulation protocols.
7. Create NeT human and mice databases for future simulation and research.
The Neurotwin project is structured to proceed in two biennial iterations, each with intermediate targets to allow for the flexible development of new ideas and research directions. At this stage, we are reporting progress for the first half of the first biennial iteration.
The work achieved during this period is the following:
- WP1: Data analysis plans for the first biennial iteration and preliminary results for the first year have been delivered. This includes the analysis of a multimodal dataset including AD patients pre and post tACS stimulation as well as rodent data for validation of microscale biophysics and mesoscale neural mass models. The first data analysis report describes a pipeline starting with L1 data (raw data), to L2 (preprocessed data), to L3 (features extracted), to L4 (model parameters estimated), and finally to L5 (with tES protocols defined). In Y1 we have been developing the methods to implement this pipeline, focusing on L2 processes for EEG, fMRI and dMRI, features extraction from fMRI, EEG and PET (L3) and modeling work relevant to personalization (L4).
- WP2: The experimental plans for the first period have been defined and experiments with human healthy subjects combining tACS and TMS and non-human animals assessing the effects of stimulation using dense cortical multiprobes and optogenetics are now underway.
- WP3: In parallel, modelers have begun work on the technical development of the Neurotwin software pipeline. This includes the definition of multimodal input data elements, processing stages and analysis of methods for personalization of the neurotwin model and optimization of tES.
- WP4: Impact. Dissemination channels have been set in place (web, twitter, etc), and documents for ethics' boards have been compile and submitted.
o Ethics: the ethics deliverables applicable to the Neurotwin project has been delivered as of June 2021.
o Dissemination: Website, slack, and twitter Neurotwin accounts are periodically updated.
- WP5 Management: Continuous monitoring of the Neurotwin project.
The work achieved during this period is the following:
- WP1: Data analysis plans for the first biennial iteration and preliminary results for the first year have been delivered. This includes the analysis of a multimodal dataset including AD patients pre and post tACS stimulation as well as rodent data for validation of microscale biophysics and mesoscale neural mass models. The first data analysis report describes a pipeline starting with L1 data (raw data), to L2 (preprocessed data), to L3 (features extracted), to L4 (model parameters estimated), and finally to L5 (with tES protocols defined). In Y1 we have been developing the methods to implement this pipeline, focusing on L2 processes for EEG, fMRI and dMRI, features extraction from fMRI, EEG and PET (L3) and modeling work relevant to personalization (L4).
- WP2: The experimental plans for the first period have been defined and experiments with human healthy subjects combining tACS and TMS and non-human animals assessing the effects of stimulation using dense cortical multiprobes and optogenetics are now underway.
- WP3: In parallel, modelers have begun work on the technical development of the Neurotwin software pipeline. This includes the definition of multimodal input data elements, processing stages and analysis of methods for personalization of the neurotwin model and optimization of tES.
- WP4: Impact. Dissemination channels have been set in place (web, twitter, etc), and documents for ethics' boards have been compile and submitted.
o Ethics: the ethics deliverables applicable to the Neurotwin project has been delivered as of June 2021.
o Dissemination: Website, slack, and twitter Neurotwin accounts are periodically updated.
- WP5 Management: Continuous monitoring of the Neurotwin project.
The brain is a complex, dynamic, plastic, electrical network operating at multiple scales. A growing body of evidence suggests that large-scale brain networks underlie both integration and differentiation processes that are fundamental for information processing. Neuropsychiatric disorders ultimately result from network dysfunctions that may arise from the abnormality in one or more isolated brain regions but produce alterations in larger brain networks. Because of this, dynamical networks are natural targets of therapeutic interventions. With electrical brain stimulation, technology, physics, and physiology interact in the context of a complex, individual brain network. Today, brain stimulation is optimized on the assumption that the effects can be directly estimated from the knowledge of the electric field (E-field) on nodes in the cortex, although we know that such “passive electrical” physical models – even if individualized – cannot fully describe the complex physiological phenomena that underlie brain function and stimulation effects. As neuroscience progresses with sophisticated new measurements, computational models of the brain function will play a key role in the development of novel mechanistic insights and derived brain stimulation solutions. And while digital carbon copies of detailed microcircuitry are most likely not required, brain models for brain stimulation should capture mechanisms at the appropriate scales and levels of detail to reproduce available physiological data such as EEG, improve predictions of local and global effects of stimulation, and enable the optimization of stimulation protocols at the individual level.
We contend that personalized hybrid models – neurotwins or NeTs – combining the physics of electric fields in biological systems with whole-brain models that represent our physiological mechanistic understanding of the dynamics at multiple scales will be key for describing brain networks and their interaction with external fields. NeTs will enable breakthroughs in fundamental and translational neuroscience with a major impact on neurotechnology – and patients.
We contend that personalized hybrid models – neurotwins or NeTs – combining the physics of electric fields in biological systems with whole-brain models that represent our physiological mechanistic understanding of the dynamics at multiple scales will be key for describing brain networks and their interaction with external fields. NeTs will enable breakthroughs in fundamental and translational neuroscience with a major impact on neurotechnology – and patients.