Brain Metabolite Diffusion from Ultra-Short to Ultra-Long Time Scales: What Do We Learn, Where Should We Go?

Abstract

In vivo diffusion-weighted MR spectroscopy (DW-MRS) allows measuring diffusion properties of brain metabolites. Unlike water, most metabolites are confined within cells. Hence, their diffusion is expected to purely reflect intracellular properties, opening unique possibilities to use metabolites as specific probes to explore cellular organization and structure. However, interpretation and modeling of DW-MRS, and more generally of intracellular diffusion, remains difficult. In this perspective paper, we will focus on the study of the time-dependency of brain metabolite apparent diffusion coefficient (ADC). We will see how measuring ADC over several orders of magnitude of diffusion times, from less than 1 ms to more than 1 s, allows clarifying our understanding of brain metabolite diffusion, by firmly establishing that metabolites are neither massively transported by active mechanisms nor massively confined in subcellular compartments or cell bodies. Metabolites appear to be instead diffusing in long fibers typical of neurons and glial cells such as astrocytes. Furthermore, we will evoke modeling of ADC time-dependency to evaluate the effect of, and possibly quantify, some structural parameters at various spatial scales, departing from a simple model of hollow cylinders and introducing additional complexity, either short-ranged (such as dendritic spines) or long-ranged (such as cellular fibers ramification). Finally, we will discuss the experimental feasibility and expected benefits of extending the range of diffusion times toward even shorter and longer values.

Magnetic resonance spectroscopy extended by oscillating diffusion gradients: Cell-specific anomalous diffusion as a probe for tissue microstructure in human brain

“…2). Taking all b-values into account for ADC estimation then yielded a more than 4-fold averaged ADC value for NAA, tCr and tCho (for the cohort data) when moving from long TD (PGSE) to short TD (OGSE), which is clearly much larger than expected from theory and animal data (Najac et al, 2016) (Valette et al, 2018). However, scrutinizing the signal decay for OGSE, one will realize that the area decay is not truly Fig.…”

“…Diffusion-weighted magnetic resonance spectroscopy (DW-MRS 1 Depending on diffusion time (TD), apparent diffusion coefficients (ADCs) are affected by different dimensions and mechanisms of cellular barriers (Valette et al, 2018). Pulsed gradient spin-echo (PGSE) sequences, commonly used, measure at long TD (>50 ms) where ADCs represent diffusion mostly along tissue fibers (Kroenke et al, 2004) (Najac et al, 2016).…”

“…This (together with the faster diffusion constants at short TD) limits explorations at high b values. However, the anomalous diffusion behavior, where the ADC depends on TD, directly encodes tissue specific structural information (Palombo et al, 2016) (Palombo et al, 2018) (Valette et al, 2018). The detailed dependence of ADCs over several orders of TDs is influenced by a multitude of effects (e.g.…”

Inflammation‐driven glial alterations in the cuprizone mouse model probed with diffusion‐weighted magnetic resonance spectroscopy at 11.7 T

“…Despite the complexity of metabolic dynamics in the intra-cellular environment, previous studies have shown evidence that the metabolites under investigation mainly diffuse in the cellular cytoplasm, with a negligible fraction confined in sub-cellular compartments. 26,[34][35][36][37] Thus, the metabolite displacement probed by DW-MRS mostly reflects the microstructure of the cells in which metabolites are compartmentalized. Under our experimental conditions (eg maximum b = 6 ms/μm 2 , t d = 64 ms), it was not possible to extract from the DW-MRS data quantitative morphological parameters such as soma radii, fiber diameters and length; however, variations in metabolite diffusion allowed us to capture qualitative alterations in cell size.…”

In vivo diffusion‐weighted MRS using semi‐LASER in the human brain at 3 T: Methodological aspects and clinical feasibility

“…From metabolite diffusion measures, it is possible to derive information on cell size and morphology, [5][6][7][8] as well as on the properties of the intracellular environment, such as viscosity and molecular crowding. 9 When combined with DW imaging techniques, DW-MRS provides a unique way to differentiate between axonal degeneration, glial activation, and demyelination. [10][11][12][13] Although very promising, the application of DW-MRS techniques in clinical studies is challenging due to the intrinsic low signal-to-noise ratio (SNR) of metabolites, especially when the spectra are acquired at high diffusion-weightings.…”