CEST MRI to study BrAin MetaBolism and Function: insights from OptO fMRI and MR spectroscopy. – BAMBOO

Chemical exchange saturation transfer (CEST) and chemical exchange spin-lock (CESL) MRI are powerful tools for metabolic imaging. Indeed, detection of specific neurometabolites can be performed using CEST/CESL MRI with enhanced sensitivity, temporal or spatial resolutions compared to NMR Spectroscopy (MRS) by imaging the reduction in the bulk water signal after the application of dedicated presaturation or spin-locking modules. CEST protocols for imaging of a large number of different metabolites have been developed, and promising applications in different disciplines (e.g. oncology, musculoskeletal physiology or neurosciences) have been demonstrated. Recently, we employed CEST MRI to image glucose (glucoCEST) changes induced by sensory stimulation, and have shown that CEST functional MRI (CEST-fMRI) is a promising surrogate for detecting increased glycolytic activity during neural activation. One general limitation for CEST-fMRI is that signal changes cannot be unambiguously assigned to exclusively one metabolite. This is of particular concern for neuroimaging, since a number of transient changes in energy metabolites and neurotransmitter levels are involved.
In this project, we aim to elucidate the contributions of three major neurometabolites, glucose, lactate and glutamate, to the contrast detected during functional CEST/CESL experiments, and to develop and optimize these new CEST/CESL-fMRI techniques to study the coupling between energy metabolism and neurotransmission during neural activation. Our CEST/CESL-fMRI protocols will be implemented conjointly at high magnetic field strength on two small animal scanners, in France and Germany, and used to map concentration changes of these metabolites in the rat brain. To verify the specificity of CEST/CESL-fMRI and to separate the contributions of the individual metabolites, localized 1H and indirect 1H-{13C} MRS techniques will be employed by the French partners. To further assess cell type-specific contributions to the CEST/CESL signal, optogenetic methods will be used simultaneously with MRI by the German partners. Viral transduction will be used to express both opsins and fluorescence reporter proteins for calcium, lactate, or glutamate in defined cell types (neurons, astrocytes). Cell type-specific read out of fluorescence signal upon sensory or cell type-specific (optogenetic) stimulation will enable us to identify individual contributions to the observed functional CEST/CESL signal.
The outcome of this work will consist in robust and validated acquisition protocols with a strong potential for use in other organs. Application in humans may be facilitated by the upcoming high magnetic field clinical systems. At a more fundamental level, the use of CEST/CESL-fMRI methods could help exploring the metabolic coupling within the glial-neuronal-vascular functional unit during specifically designed activation paradigms in normal, pathological conditions or following pharmacological challenges.