Implantable miniaturized probe for In-vivo Magnetic Resonance Spectroscopy: Application to murine models of Alzheimer's disease and gliomas – IvMRS

During the development of new therapeutics against brain diseases, the pre-clinical phase, i.e. the validation of treatment delivery, safety and efficacy in animal models of the disease, represents a crucial step. Magnetic Resonance Imaging (MRI) is a method of particular interest at this stage, as it provides non-invasive surrogate endpoints that can help selecting appropriate candidates during the process of drug development. Single Voxel Magnetic Resonance Spectroscopy (SVS) under MRI is particularly useful in this regard, as it provides non-invasive, in-vivo quantitative measurements of brain metabolites, which reflects functional changes at the cellular and subcellular levels, and can be repeated longitudinally. However its intrinsic low resolution limits the number of measurable metabolites. The use of higher magnetic fields improves signal-to-noise ratio and spectral resolution of MRS, allowing for the detection of a better panel of metabolites, typically between 5 and 10, over Voxels-of-Interest (VOI) of a few cubic centimeters. So, as high-field MRI has become the benchmark in preclinical research on animal models, it appears possible to investigate the cerebral metabolomics changes in animals, and to use it as a surrogate marker in preclinical therapeutic trials. However, the number of relevant metabolites is much higher than the low number of measurable metabolites with conventional in-vivo high-field SVS. This low number of measurable metabolites comes from the low volume of interest, i.e. a few cubic millimeters of tissue, and from the low concentrations of some metabolites in the brain. Finally, considering also the subtle changes of these metabolites at the early stage of the disease, the use of conventional high-field SVS in preclinical studies remains strongly limited. The high volume of the Voxel-of-Interest (VOI), ranging from 10 to 30mm3, which is required to have a usable signal in conventional SVS, and the inherent variability of longitudinal SVS measurement due to the variable position of the VOI in the successive experiments, remain the two major issues when looking during time for small changes in metabolic concentrations and metabolites ratios in a specific small region of the animal brain. The IvMRS project aims at filling this gap by developing the first chronic implantable MRS micro-probe (µ-probe), minimally invasive, exhibiting very high signal sensitivity, and sharp spectral peaks, from sub-millimetric VOI. Such a probe will allow detecting a much higher number of metabolites than conventional in-vivo SVS. The µ-probe will work at frequencies ranging from 300MHz to 500MHz in ultra-high field Magnetic Resonance Imaging scanners, 7T and 11.7T. It will embed a specific micro-coil antenna, a low-noise signal conditioning circuit designed in CMOS microelectronics technology, as well as an accurate on-chip positioning sensor. It will be dedicated to the study of changes in brain metabolite markers of two major diseases, Alzheimer's disease and cerebral gliomas, and to the assessment of effective therapeutic strategies.

This challenging objective will be addressed by gathering (i) the skills of ISA laboratory (Institut des Sciences Analytiques - Lyon) in the field of implantable micro-antennas for MRS, (ii) the skills of ICube laboratory (Laboratoire des sciences de l’Ingénieur, de l’Informatique et de l’Imagerie, Strasbourg) in the field of positioning sensors and low-noise CMOS integrated circuits compatible with MRI, and (iii) the end-users of the µ-probe from ICM laboratory (Institut du Cerveau et de la Moelle épinière, Paris) and New York University School of Medicine (New-York, USA).