Historical EU-funding for NRU post docs

Abstract: Sufficient sleep is a key determinant of health, and sleep loss is associated with severe health risks. Nevertheless, the reason for why we sleep is not yet understood. Recently, a molecular function of sleep was described in rodents. The ‘glymphatic system’ (GS) is a sleep dependent macroscopic pathway of the brain that facilitates the removal of metabolites, including amyloid-beta. This project will for the first time reveal a sleep-driven human GS and show whether glymphatic flow (GF) can be linked to cognitive impairments associated with sleep loss. Secondly, I will promote GF with the adrenergic antagonist Carvedilol. This manipulation of glymphatic clearance may define new approaches for treating sleep-disorders and Alzheimer’s disease, or reduce or delay our need for sleep. I will investigate the human GS by applying state of the art, 5-10 Hz, ultra-fast MR sequences across sleep and wakefulness. Preliminary data show that these sequences enable the detection of cardiac, respiration, and slow pulsations, previously considered noise in fMRI imaging and distorted by aliasing effects. These pulsations are now believed to drive GF. The project will be a major step forward for sleep and neuroscience research, but also provide a key step in my career, demonstrating independent work and allowing me to learn advanced data-analysis skills and develop a novel imaging method, which I can apply in future studies. The chosen host institution is perfectly situated for the project, as they have established expertise and an exceptional skill-set in analyzing novel neuroimaging data including ultra-fast MRI. Secondly, my host provides unique infrastructure that allows for completion of the study, with key personnel in neuropsychology and data-analysis, as well as the world leading experts in glymphatic mechanisms. The project forms a foundation for a more general approach to integrate imaging of sleep-regulation and glymphatic mechanisms with patient or trait specific data.

Abstract: Imaging of physiological functions in the living brain provides a unique possibility to study biological processes during disease or drug interventions. Functional magnetic resonance imaging (fMRI) and Positron Emission Tomography (PET) are important tools that enable brain imaging. Whereas PET enables determination of molecular target densities, fMRI provides information about brain hemodynamic responses to, e.g., a drug intervention. There are several research questions where the synergy between these modalities combined provides unique opportunities, including drug development and pharmacokinetic modeling. With the development of imaging systems that simultaneously acquire PET and fMRI signals, a need for analytical tools to interpret the recorded data has become paramount. My proposal focuses on the development of quantification schemes that use both signals.

I will investigate two areas where simultaneous PET-MR can make a significant difference: 1) assessment of drug effects by coupling drug binding to a receptor to its downstream effect in tissue, 2) using cerebral blood flow estimates to inform modeling of PET data. I will develop models that serve for quantification of simultaneous PET- and fMRI data, validate them via simulations, and evaluate them using experimental data. The project will serve to leverage usage of simultaneous PET-MR, and assist in future studies with task- or drug-induced interventions. The project seeks to establish quantification methods that serve not only the imaging society, but specifically address the pharmaceutical companies' need to test their compounds prior to clinical trials. By transitioning to hybrid imaging, I have the possibility to use my strong background in PET to impact a young field under development. The host institution is world leading in applied simultaneous PET-MR studies, thus the MSCA fellowship presents a unique possibility for me to gain invaluable knowledge of the next generation of medical imaging.