A brain scanner will track how dementia destroys the brain’s neural circuits, linking microscopic cell death to the loss of perception and behaviour. This matters because frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) strike young adults, devastate families, and have no effective treatments. The core problem is a missing link: scientists know that cells die and that patients change, but they do not understand how one causes the other. This project builds a mathematical bridge between the two, using magnetoencephalography to measure the brain’s electrical rhythms—specifically gamma oscillations—and fitting those signals to biophysical models of cortical microcircuits. If it succeeds, the work will create a platform for testing candidate therapies. Two existing drugs, Tiagabine and Memantine, will be used to validate the approach by targeting GABA and NMDA receptors respectively. The resulting models should help drug developers choose better endpoints, select the right compounds, and stratify patients for clinical trials. This forward translation into trials is matched by back-translation to improve preclinical models of disease. The research is fundamental neuroscience with a direct translational pathway—it aims to turn a mechanistic understanding of network degeneration into a practical tool for therapy development.
View original technical description
This program introduces a novel approach to dementia that is both scientifically important and clinically relevant. Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) are used as demonstrator conditions. Their importance lies partly in their young onset, high burden and devastating prognosis, but also because they epitomise degenerative network disorders. The first aim is to show how microscopic cellular changes lead to the neuropsychological changes we observe. Understa nding this connection through robust mesoscopic neural models will significantly advance translation to therapies. My hypothesis is that changes in cortical microcircuits, and their gamma oscillations, arise from cell loss in superficial cortical layers and imbalance between GABA, AMPA and NMDA. This is tested using multimodal imaging, biophysical models and pharmacology. Specifically, the impact of disease on brain networks for perception and behaviour will be analysed using hierarchical models , optimised at the level of cortical microcircuits by fitting to the spectral properties of magnetoencephalography. The second aim is to provide a platform to study candidate therapies, using magnetoencephalography to measure the generative networks and gamma-synchronisation that support cognition. The platform will be assessed initially with two test compounds, Tiagabine and Memantine, acting on GABA and NMDA respectively. The resulting theoretically enriched and principled mechanistic models will enable better selection of endpoints, compounds and stratification of novel therapies for complex neurodegenerative disorders such as FTD and PSP. This forward translation to clinical trials is matched by back-translation to improve pre-clinical models of disease and treatment.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know