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

Abstract

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.

Keywords: cell morphology; diffusion-weighted NMR spectroscopy; metabolites; noninvasive histology; numerical simulations.

Fig. 1.

Scheme of the simulation-fitting pipeline proposed. (A) The set of parameters describing cellular morphometric statistics is initialized. (B) Many synthetic cells are generated according to the morphometric statistics in A and the intracellular diffusion of many particles, corresponding diffusion-weighted signal, and relative ADC are simulated. (C) If the difference between simulated and measured ADC satisfies the selected convergence criteria, the pipeline provides the best fitting morphometric statistics, otherwise steps A, B, and C are iteratively repeated, adjusting the morphometric statistics to fit experimental data.

Fig. 2.

DW-MRS results and modeling in the mouse and macaque brain. The investigated volume of interest within the brain (green box) and a typical DW-MRS spectrum at t_d = 2 s (here without diffusion weighting), as used to measure ADC time dependence for each metabolite (Inset plots), are shown for each species. Points and error bars stand for ADC means and SEMs, respectively, estimated among the cohorts. Best fit of ADC (averaged over the cohorts) is also displayed as a continuous curve. A subset of the extracted synthetic cells for each metabolite is also reported. (Scale bar, 100 µm.)

Fig. 3.

Conventional vs. noninvasive histology. Comparison between conventional histological images of astrocytes and the corresponding synthetic tissue in the mouse and macaque brain. Confocal microscopy images by GFAP staining of astrocytes in the hippocampus of the mouse brain (A) and of the macaque brain (C). Collection of synthetic astrocytes extracted from Ins and tCho compartments in the mouse brain (B) and in the macaque brain (D). (Scale bars, 50 μm.) Corner Insets are a 1.5× magnification of a portion of the main image.