Periodic Reporting for period 3 - Neurotwin (Digital twins for model-driven non-invasive electrical brain stimulation)
Berichtszeitraum: 2023-07-01 bis 2025-06-30
Alzheimer’s disease (AD) and other neuropsychiatric disorders impose a major global burden, yet current treatments remain limited. Beyond amyloid and tau pathology, AD is increasingly understood as a disorder of large-scale brain networks, marked by impaired gamma oscillations and excitation–inhibition imbalance. These circuit-level alterations affect cognition and represent promising therapeutic targets.
Transcranial alternating current stimulation (tACS), especially at 40 Hz, can modulate these networks, but current approaches do not account for individual variability in anatomy or physiology. Neurotwin addresses this gap by developing personalized hybrid brain models (“neurotwins”) integrating electric-field modelling, neural-mass physiology, and multimodal neuroimaging to predict and optimize stimulation effects.
The project delivered a multiscale modelling framework capable of (i) mapping electric fields with high anatomical precision, (ii) linking stimulation to laminar, mesoscale, and whole-brain dynamics, (iii) assimilating multimodal human and animal data, and (iv) defining quantitative targets representing healthy neural dynamics. This enables individualized, mechanism-informed, home-deployable neuromodulation strategies.
Overall objectives
1. Develop a validated multiscale modelling framework.
2. Build personalization/data-assimilation pipelines.
3. Define objective functions for healthy dynamics.
4. Conduct in-vivo and in-human experiments.
5. Run a clinical pilot of personalized tES at home.
6. Deliver an operational engineering pipeline.
Conclusions of the Action
NEUROTWIN delivered the first full platform for digital-twin–based personalized brain stimulation, combining modelling, experimentation, engineering, and clinical validation.
1. Modelling framework: A complete architecture—laminar NMMs, whole-brain models, and personalization pipelines—was achieved, reproducing AD biomarkers (e.g. oscillatory changes during the course of disease) and generating actionable stimulation targets.
2. Experimental validation: Rodent optogenetics, Neuropixel recordings, and 40 Hz tACS studies established mechanistic grounding. Human EEG, TMS-EEG, and multimodal MRI validated effects across scales and informed personalization.
3. Clinical pilot in AD: The home-based personalized 40 Hz tACS trial (n=30) showed high feasibility, excellent safety, and strong adherence. While clinical endpoints did not differ between conditions, neurophysiological markers (gamma power, cortical reactivity, connectivity) showed stimulation-specific effects consistent with model predictions.
4. Engineering pipeline: A regulatory-ready software suite (NADL and Neurotwin Library) was delivered, enabling construction, personalization, optimization, and export of neurotwins. The Xpress pipeline supported the clinical pilot; the full HBM pipeline is released for research.
5. Neurotwin Database: multimodal datasets were curated, anonymized, BIDS-aligned, and deposited with DOIs for long-term reuse.
6. Ethics, dissemination, exploitation: Ethical guidance was completed; dissemination exceeded targets.
Overall conclusion
NEUROTWIN demonstrated the safety, feasibility, and mechanistic validity of personalized, model-driven brain stimulation in AD. The project leaves a mature scientific and engineering foundation, a rich multimodal database, and a clear translational pathway, positioning Europe at the forefront of precision neuromodulation.
Transcranial alternating current stimulation (tACS), especially at 40 Hz, can modulate these networks, but current approaches do not account for individual variability in anatomy or physiology. Neurotwin addresses this gap by developing personalized hybrid brain models (“neurotwins”) integrating electric-field modelling, neural-mass physiology, and multimodal neuroimaging to predict and optimize stimulation effects.
The project delivered a multiscale modelling framework capable of (i) mapping electric fields with high anatomical precision, (ii) linking stimulation to laminar, mesoscale, and whole-brain dynamics, (iii) assimilating multimodal human and animal data, and (iv) defining quantitative targets representing healthy neural dynamics. This enables individualized, mechanism-informed, home-deployable neuromodulation strategies.
Overall objectives
1. Develop a validated multiscale modelling framework.
2. Build personalization/data-assimilation pipelines.
3. Define objective functions for healthy dynamics.
4. Conduct in-vivo and in-human experiments.
5. Run a clinical pilot of personalized tES at home.
6. Deliver an operational engineering pipeline.
Conclusions of the Action
NEUROTWIN delivered the first full platform for digital-twin–based personalized brain stimulation, combining modelling, experimentation, engineering, and clinical validation.
1. Modelling framework: A complete architecture—laminar NMMs, whole-brain models, and personalization pipelines—was achieved, reproducing AD biomarkers (e.g. oscillatory changes during the course of disease) and generating actionable stimulation targets.
2. Experimental validation: Rodent optogenetics, Neuropixel recordings, and 40 Hz tACS studies established mechanistic grounding. Human EEG, TMS-EEG, and multimodal MRI validated effects across scales and informed personalization.
3. Clinical pilot in AD: The home-based personalized 40 Hz tACS trial (n=30) showed high feasibility, excellent safety, and strong adherence. While clinical endpoints did not differ between conditions, neurophysiological markers (gamma power, cortical reactivity, connectivity) showed stimulation-specific effects consistent with model predictions.
4. Engineering pipeline: A regulatory-ready software suite (NADL and Neurotwin Library) was delivered, enabling construction, personalization, optimization, and export of neurotwins. The Xpress pipeline supported the clinical pilot; the full HBM pipeline is released for research.
5. Neurotwin Database: multimodal datasets were curated, anonymized, BIDS-aligned, and deposited with DOIs for long-term reuse.
6. Ethics, dissemination, exploitation: Ethical guidance was completed; dissemination exceeded targets.
Overall conclusion
NEUROTWIN demonstrated the safety, feasibility, and mechanistic validity of personalized, model-driven brain stimulation in AD. The project leaves a mature scientific and engineering foundation, a rich multimodal database, and a clear translational pathway, positioning Europe at the forefront of precision neuromodulation.
From the start of the project to the end of the final reporting period, NEUROTWIN advanced through coordinated phases of modelling, experimentation, engineering, and clinical validation. Early periods established the scientific plans, initial datasets, preliminary hybrid brain models, and the core software architecture.
In the final period, all components were completed and integrated. WP1 delivered the full multiscale modelling framework—laminar neural-mass models, whole-brain models, and data-assimilation pipelines—now capable of reproducing Alzheimer’s disease (AD) biomarkers and generating personalized stimulation targets.
WP2 completed the full experimental programme: rodent optogenetics and Neuropixels studies validating mechanistic assumptions; healthy-human EEG, TMS-EEG, and multimodal MRI; and the randomized clinical pilot of home-based 40 Hz tACS in 30 AD patients. The pilot confirmed excellent safety, high adherence, and stimulation-specific neurophysiological effects.
WP3 operationalized the scientific results into a regulator-ready engineering ecosystem, including the Neurotwin Library, the NADL model standard, personalized stimulation pipelines, and the Neurotwin Database containing curated human, rodent, and model-derived datasets.
WP4 ensured ethical compliance and delivered extensive dissemination: 66 publications, 68 conferences, and multiple outreach events. The exploitation roadmap was finalized, and project continuity is planned through future trials, building directly on Neurotwin’s tools and findings. Patents were submitted to protect future actions.
Overall, NEUROTWIN has produced a complete, validated, and publicly accessible digital-twin platform for personalized brain stimulation, with clear pathways for future clinical and technological exploitation.
In the final period, all components were completed and integrated. WP1 delivered the full multiscale modelling framework—laminar neural-mass models, whole-brain models, and data-assimilation pipelines—now capable of reproducing Alzheimer’s disease (AD) biomarkers and generating personalized stimulation targets.
WP2 completed the full experimental programme: rodent optogenetics and Neuropixels studies validating mechanistic assumptions; healthy-human EEG, TMS-EEG, and multimodal MRI; and the randomized clinical pilot of home-based 40 Hz tACS in 30 AD patients. The pilot confirmed excellent safety, high adherence, and stimulation-specific neurophysiological effects.
WP3 operationalized the scientific results into a regulator-ready engineering ecosystem, including the Neurotwin Library, the NADL model standard, personalized stimulation pipelines, and the Neurotwin Database containing curated human, rodent, and model-derived datasets.
WP4 ensured ethical compliance and delivered extensive dissemination: 66 publications, 68 conferences, and multiple outreach events. The exploitation roadmap was finalized, and project continuity is planned through future trials, building directly on Neurotwin’s tools and findings. Patents were submitted to protect future actions.
Overall, NEUROTWIN has produced a complete, validated, and publicly accessible digital-twin platform for personalized brain stimulation, with clear pathways for future clinical and technological exploitation.
NEUROTWIN has advanced the state of the art by creating the first fully integrated digital-twin platform for personalized non-invasive brain stimulation. The project combined biophysical electric-field modelling, neural-mass physiology, and multimodal neuroimaging into a validated multiscale framework capable of predicting and optimizing stimulation effects at the individual level—an innovation not available in current neuromodulation practice.
Through comprehensive rodent, human, and clinical studies, the project provided mechanistic evidence for gamma-frequency stimulation in Alzheimer’s disease and demonstrated the feasibility and safety of home-based, model-informed 40 Hz tACS. The accompanying software ecosystem (NADL + Neurotwin Library) and the Neurotwin Database represent major technical outputs.
By project end, NEUROTWIN delivers a mature modelling and engineering pipeline, personalized stimulation tools, and high-value datasets that will support future clinical trials.
Potential Impact: The project lays the foundation for precision neuromodulation, enabling individualized, scalable, and low-cost interventions for AD and other brain disorders. Expected socio-economic benefits include reduced treatment variability, improved patient quality of life, and strengthened European leadership in digital-health innovation, supported by strong dissemination and an ethical framework for responsible adoption.
Through comprehensive rodent, human, and clinical studies, the project provided mechanistic evidence for gamma-frequency stimulation in Alzheimer’s disease and demonstrated the feasibility and safety of home-based, model-informed 40 Hz tACS. The accompanying software ecosystem (NADL + Neurotwin Library) and the Neurotwin Database represent major technical outputs.
By project end, NEUROTWIN delivers a mature modelling and engineering pipeline, personalized stimulation tools, and high-value datasets that will support future clinical trials.
Potential Impact: The project lays the foundation for precision neuromodulation, enabling individualized, scalable, and low-cost interventions for AD and other brain disorders. Expected socio-economic benefits include reduced treatment variability, improved patient quality of life, and strengthened European leadership in digital-health innovation, supported by strong dissemination and an ethical framework for responsible adoption.