Characterizing extracellular diffusion properties using diffusion‐weighted MRS of sucrose injected in mouse brain

Abstract

Brain water and some critically important energy metabolites, such as lactate or glucose, are present in both intracellular and extracellular spaces (ICS/ECS) at significant levels. This ubiquitous nature makes diffusion MRI/MRS data sometimes difficult to interpret and model. While it is possible to glean information on the diffusion properties in ICS by measuring the diffusion of purely intracellular endogenous metabolites (such as NAA), the absence of endogenous markers specific to ECS hampers similar analyses in this compartment. In past experiments, exogenous probes have therefore been injected into the brain to assess their apparent diffusion coefficient (ADC) and thus estimate tortuosity in ECS. Here, we use a similar approach in mice by injecting sucrose, a well‐known ECS marker, in either the lateral ventricles or directly in the prefrontal cortex. For the first time, we propose a thorough characterization of ECS diffusion properties encompassing (1) short‐range restriction by looking at signal attenuation at high b values, (2) tortuosity and long‐range restriction by measuring ADC time‐dependence at long diffusion times and (3) microscopic anisotropy by performing double diffusion encoding (DDE) measurements. Overall, sucrose diffusion behavior is strikingly different from that of intracellular metabolites. Acquisitions at high b values not only reveal faster sucrose diffusion but also some sensitivity to restriction, suggesting that the diffusion in ECS is not fully Gaussian at high b. The time evolution of the ADC at long diffusion times shows that the tortuosity regime is not reached yet in the case of sucrose, while DDE experiments suggest that it is not trapped in elongated structures. No major difference in sucrose diffusion properties is reported between the two investigated routes of injection and brain regions. These original experimental insights should be useful to better interpret and model the diffusion signal of molecules that are distributed between ICS and ECS compartments.

Assessing potential correlation between T2 relaxation and diffusion of lactate in the mouse brain

“…Despite difference in methodologies to estimate ADCs, our measurements (∼0.15 μm 2 /ms) are of the same order of magnitude as those previously reported in the literature (∼0.1 μm 2 /ms using a DW‐stimulated echo sequence + monoexponential fitting in a [0; 5] ms/μm 2 b ‐value range) 5 in the mouse brain for NAA, tCr, tCho, and Tau. Actually, considering the ∼2‐fold shorter diffusion time used here (t d = 20 ms versus t d = 63 ms), our estimate of intracellular ADC is consistent with the increase in ADC as t d decreases for relatively short t d. 13 Lactate ADC being ∼70% larger than intracellular metabolite ADC presumably mostly reflects some extracellular contribution, 7 although lactate is also a smaller molecule with ∼30% larger intrinsic diffusivity.…”

“…Right: K app is plotted as a function of TE. No significant variation is noted used here (t d = 20 ms versus t d = 63 ms), our estimate of intracellular ADC is consistent with the increase in ADC as t d decreases for relatively short t d. 13 Lactate ADC being ∼70% larger than intracellular metabolite ADC presumably mostly reflects some extracellular contribution, 7 although lactate is also a smaller molecule with ∼30% larger intrinsic diffusivity.…”

“…Things seems to be simpler for intracellular metabolites in the mouse brain (mostly gray matter), where it was shown by Ligneul et al 5 that signal attenuation is fundamentally unchanged when increasing TE from 33.4 ms to 73.4 ms (although N‐acetylaspartate attenuation seemed to exhibit slight TE‐dependency at the highest diffusion weighting [ b ‐values], i.e., for b = 20 and 30 ms/μm 2 ). Nevertheless, the situation might be different for lactate, which is present in both intracellular and extracellular space, 6 two compartments which appear to have quite distinct diffusion properties, 7 and where T 2 could also be different, like for water. This TE dependence could be an important point to investigate in the perspective of modeling DW‐MRS data to determine lactate fraction in the different compartments in gray matter 8 .…”

A neuro-metabolic account of why daylong cognitive work alters the control of economic decisions

“…of molecules is faster), presumably related to strong spiking activity. 31,32 Note however that although release in the extracellular space is a standard interpretation of the diffusion measure, it could in principle reflect other phenomena, such as release from vesicles to the intracellular space, or change in the glutamate/glutamine ratio (because the two molecules may diffuse in different compartments).…”

“…Diffusion measures are useful to detect this sort of phenomenon because they are differentially sensitive to compartments, as diffusion is more limited inside cells or vesicles than outside cells. 31,32 The same three-way interaction between group, region, and session was therefore tested on diffusion MRS data.…”