New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivo

Significance Characterizing the microstructure of an organ noninvasively using molecular diffusion measurements represents a major challenge in medical imaging and life science. In this work, we propose concepts in diffusion magnetic resonance to noninvasively extract morphological properties of brain cells that are out of reach of existing neuroimaging techniques, such as diffusion-weighted MRI. We show how long-range morphology of neurons and astrocytes can affect the diffusion of cell-specific metabolites at ultra-long diffusion times and that adequate modeling strategy seems to allow extracting morphological parameters such as astrocytic and neuronal process length and complexity, opening the way to noninvasive histology of the brain. We believe that the concepts and methods introduced here may represent a significant breakthrough in neuroimaging and neurosciences. The brain is one of the most complex organs, and tools are lacking to assess its cellular morphology in vivo. Here we combine original diffusion-weighted magnetic resonance (MR) spectroscopy acquisition and novel modeling strategies to explore the possibility of quantifying brain cell morphology noninvasively. First, the diffusion of cell-specific metabolites is measured at ultra-long diffusion times in the rodent and primate brain in vivo to observe how cell long-range morphology constrains metabolite diffusion. Massive simulations of particles diffusing in synthetic cells parameterized by morphometric statistics are then iterated to fit experimental data. This method yields synthetic cells (tentatively neurons and astrocytes) that exhibit striking qualitative and quantitative similarities with histology (e.g., using Sholl analysis). With our approach, we measure major interspecies difference regarding astrocytes, whereas dendritic organization appears better conserved throughout species. This work suggests that the time dependence of metabolite diffusion coefficient allows distinguishing and quantitatively characterizing brain cell morphologies noninvasively.