Resolving Cellular Morphology in the Human Brain with Multiparametric Diffusion MR Spectroscopy
Diffusion-weighted magnetic resonance spectroscopy (dMRS) noninvasively probes the diffusion of mostly intracellular metabolites and can therefore report on brain microstructure with a cell-type specificity that water-based diffusion MRI cannot achieve. However, the morphological information accessible to conventional dMRS is limited: estimating both cell-body (soma) and neurite dimensions from a single diffusion-encoding scheme is an ill-posed problem, and neither ultra-high b-value nor diffusion-time-dependent measurements alone distinguish soma size from neurite radius. Here we introduce multiparametric dMRS in the human brain, combining diffusion-time- dependent encoding (apparent diffusion coefficient, ADC, and diffusion kurtosis, K, sampled over diffusion times of 6 ms to 250 ms and b-values up to 8 ms {micro}m-2) with double-diffusion-encoded spectroscopy (DDES). Using Monte-Carlo analysis, we show that fitting a two-compartment (soma + neurite) tissue model to diffusion-time data alone is degenerate, admitting two near-indistinguishable solutions. Adding the orthogonal angular information from DDES breaks this degeneracy: jointly fitting both experiments converges to a single, biophysically plausible solution irrespective of initialization, yielding cell-type- specific estimates of intrinsic diffusivity, soma radius, neurite radius, and neurite signal fraction for neuronal (NAA, glutamate) and glial (choline, myo-inositol) metabolites. Metabolite microscopic anisotropy approaches unity, consistent with predominantly intra-neurite diffusion, while simultaneously acquired water data reveal short-range structural disorder and intercompartmental exchange ({approx}15 ms). Multiparametric dMRS thus extends the standard model of metabolite diffusion by a soma compartment and offers a route toward in vivo, cell-type- specific morphometry of neurons and glia in humans--a foundation for biomarkers in conditions where soma and neurite morphology are altered.