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What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water?

ABSTRACT: Brownian motion of water molecules provides an essential length scale, the diffusion length, commensurate with cell dimensions in biological tissues. Measuring the diffusion coefficient as a function of diffusion time makes in vivo diffusion MRI uniquely sensitive to the cellular features about three orders of magnitude below imaging resolution. However, there is a longstanding debate, regarding which contribution - intra- or extra-cellular - is more relevant in the overall time-dependence of the MRI-derived diffusion metrics. Here we resolve this debate in the human brain white matter. By varying not just the diffusion time, but also the gradient pulse duration of a standard diffusion MRI sequence, we identify a functional form of the measured time-dependent diffusion coefficient transverse to white matter tracts in 10 healthy volunteers. This specific functional form is shown to originate from the extra-axonal space, and provides estimates of the fiber packing correlation length for axons in a bundle. Our results offer a metric for the outer axonal diameter, a promising candidate marker for demyelination in neurodegenerative diseases. From the methodological perspective, our analysis demonstrates how competing models, which describe different physics yet interpolate standard measurements equally well, can be distinguished based on their prediction for an independent "orthogonal" measurement.

SUBMITTER: Lee HH

PROVIDER: S-EPMC6004237 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water?

Lee Hong-Hsi HH Fieremans Els E Novikov Dmitry S DS

NeuroImage 20171216

Brownian motion of water molecules provides an essential length scale, the diffusion length, commensurate with cell dimensions in biological tissues. Measuring the diffusion coefficient as a function of diffusion time makes in vivo diffusion MRI uniquely sensitive to the cellular features about three orders of magnitude below imaging resolution. However, there is a longstanding debate, regarding which contribution - intra- or extra-cellular - is more relevant in the overall time-dependence of th ...[more]

PMID: 29253652

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Project description:Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De||), extra-axonal radial diffusivity (De?), axonal water fraction (AWF), and tortuosity (?) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy ((1)H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, ?, and fractional anisotropy; negative correlations between NAA and De,? and the overall radial diffusivity (D?). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De|| and Cho, and a positive trend between De|| and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De|| with mI and Cho, both predominantly present extra-axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra-axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De?, AWF, and ?).

Project description:ObjectiveThe goal of this work is to provide temperature and concentration calibration of water diffusivity in polyvinylpyrrolidone (PVP) solutions used in phantoms to assess system bias and linearity in apparent diffusion coefficient (ADC) measurements.MethodADC measurements were performed for 40 kDa (K40) PVP of six concentrations (0%, 10%, 20%, 30%, 40%, and 50% by weight) at three temperatures (19.5°C, 22.5°C, and 26.4°C), with internal phantom temperature monitored by optical thermometer (±0.2°C). To achieve ADC measurement and fit accuracy of better than 0.5%, three orthogonal diffusion gradients were calibrated using known water diffusivity at 0°C and system gradient nonlinearity maps. Noise-floor fit bias was also controlled by limiting the maximum b-value used for ADC calculation of each sample. The ADC temperature dependence was modeled by Arrhenius functions of each PVP concentration. The concentration dependence was modeled by quadratic function for ADC normalized by the theoretical water diffusion values. Calibration coefficients were obtained from linear regression model fits.ResultsMeasured phantom ADC values increased with temperature and decreasing PVP concentration, [PVP]. The derived Arrhenius model parameters for [PVP] between 0% and 50%, are reported and can be used for K40 ADC temperature calibration with absolute ADC error within ±0.016 μm2 /ms. Arrhenius model fit parameters normalized to water value scaled with [PVP] between 10% and 40%, and proportional change in activation energy increased faster than collision frequency. ADC normalization by water diffusivity, DW , from the Speedy-Angell relation accounted for the bulk of temperature dependence (±0.035 μm2 /ms) and yielded quadratic calibration for ADCPVP /DW = (12.5 ± 0.7) ·10-5 ·[PVP]2 - (23.2 ± 0.3)·10-3 ·[PVP]+1, nearly independent of PVP molecular weight and temperature.ConclusionThe study provides ground-truth ADC values for K40 PVP solutions commonly used in diffusion phantoms for scanning at ambient room temperature. The described procedures and the reported calibration can be used for quality control and standardization of measured ADC values of PVP at different concentrations and temperatures.

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What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water?

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What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water?

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