Ileana Ozana Jelescu1 and Dmitry S Novikov2
1Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 2Dept. of Radiology, New York University School of Medicine, New York, NY, United States
Synopsis
In
the absence of a myelin sheath, exchange generally is non-negligible over the typical
diffusion times of MRI experiments (10 – 100 ms) and should be accounted for in
gray matter modeling. Here we use time-dependent kurtosis and the Kärger model (KM)
of two slowly exchanging compartments to evaluate water exchange time between
intra-neurite and extra-cellular compartments in rat GM in vivo. We report
exchange times on the order of 10 – 30 ms. Future work will focus on exploring
a broader range of diffusion times to test the asymptotic decay of kurtosis
toward zero.
Introduction
If anything the many years of white matter
modeling taught us, it is that elucidating and validating model assumptions
should occur before bringing model fitting into the clinic. For gray matter
(GM), the very basic relevant “compartments” are not established yet: Should we
account for soma[1]? Is there a “stick” compartment[2,
3]? How
fast is the exchange? Here we attempt to make first steps into this by quantifying
water exchange.
In the absence of a myelin sheath, exchange
generally is non-negligible over the typical diffusion times of MRI experiments
(10 – 100 ms). The estimation of water exchange time between intra-neurite/axon
and extra-cellular spaces has so far yielded very diverse results, from 60 ms
in freshly excised bovine optic nerve[4] to over 500 ms in major human white matter tracts using FEXI[5] and 100 – 150 ms in astrocyte and neuron cultures, respectively[6].
Here we use time-dependent kurtosis and the
Kärger model (KM) of two slowly exchanging compartments[7] to evaluate water exchange time in rat GM in
vivo. One substantial advantage of rat brain vs. human is the large GM volume
which removes confounding effects of partial volume with white matter or CSF.Methods
All experiments were approved by the local
Service for Veterinary Affairs. Three Wistar rats (250 - 300g) were
scanned on a 14T Bruker system using a home-built surface quadrature
transceiver. Diffusion MRI data were acquired using a PGSE EPI sequence (TE/TR
= 50/2500 ms; matrix: 128x96; FOV=25.6x19.2 mm2; 16 0.5-mm thick
coronal slices; Partial Fourier = 0.55; b = 0 (4 rep); 7 b-shells, 24 dirs
each: b = 1:1.5:10 ms/μm2) at four diffusion times Δ = 12/20/30/40 ms, keeping δ = 4.5 ms constant.
Images were denoised and corrected for
Rician bias, Gibbs ringing and motion[8].
Diffusion and kurtosis tensors were estimated from b=0, 1 and 2.5 shells using
a weighted linear least-squares algorithm, from which mean diffusivity and kurtosis
were derived. Powder-average signal was also computed for each shell.
Regions of interest (ROI) covering the
corpus callosum (CC), hippocampus (HPC) and cortex (CTX) were manually drawn.
KM assumes time-independent diffusivity $$$D_{KM}
= f·Di + (1-f)De$$$ in which case the only source of kurtosis
is the inter-compartment heterogeneity which decays to zero as 1/t at long t[7, 9]:
$$K_{KM}(t)=K_{0}\frac{2t_{ex}}{t}\left[1-\frac{t_{ex}}{t}\left(1-\exp(-t/t_{ex})\right)\right]\quad (1)$$
where tex is the exchange time. Mean
kurtosis MK(t)
was fit to Equation (1) to estimate K0
and tex, both on the
average ROI signal and individually in each voxel.
The isotropic average of the full KM signal $$$S_\mathrm{anisoKM}$$$
for two anisotropic compartments[10] was also fit to the powder-averaged ROI signal over the whole
b-value range (0 – 10 ms/μm2):
$$\overline{S} =
\int\!{d{\bf\hat{q}}\over4\pi}\,S_\mathrm{anisoKM}({\bf q},t;\;t_{ex},f,D_i,D_e)\quad (2)$$
where
Di was fixed to 2.4 μm2/ms
and the extra-neurite compartment was modeled as Gaussian isotropic with De = 0.8 μm2/ms,
leaving tex and f to be estimated.Results
Over the range t =
12 – 40 ms explored
here, diffusivities displayed little to no time-dependence in GM (Figure 1), consistent
with previous literature[11-13],
which supported the applicability of Eq. (1) to estimate the exchange time from
MK(t).
Parametric maps of tex derived from Equation (1) were homogeneous across GM
regions and consistent between rats (Figure 2). Overall, exchange times averaged
around 15 – 30 ms in the cortex and around 10 – 15 ms in the hippocampus.
In CC, asymptotic signal decay followed the
expected power law $$$b^{-1/2}$$$ characteristic of a stick compartment[2,
3],
while in GM a deviation from this power law, attributable to exchange[10], was evident (Figure 3).
Estimates of exchange time and compartment
fractions from fitting the two-compartment anisotropic Kärger model to powder-average
data for each diffusion time were overall consistent with results from fitting
K(t) in the cortex (Figure 4). Estimates were less reliable in the hippocampus
(data not shown).Discussion and Conclusions
Time-dependent kurtosis from the KM yielded
rather short exchange times, similar to those found on human Connectome scanner[10], suggesting exchange cannot be neglected in gray matter modeling. The
validity of Equation (1) hinges on reaching the Gaussian diffusion limit in all
compartments if exchange is switched off. The near-absence of diffusivity
t-dependence supports this assumption.
Fitting the full KM was more prone to noise
and estimates were unphysical for certain datasets. Given the limited number of
data points (i.e. b-shells) available, diffusivities also had to be
fixed. More data points at high b-values will be acquired in the forthcoming
months.
The low-b part of the acquisition,
yielding K(t), is advantageous because it does not require high b-values
or special sequences and data can be acquired on any clinical scanner. Future
work will focus also on exploring a broader range of diffusion times to test
the asymptotic decay of kurtosis toward zero, and estimating the competing role
of intra-compartment kurtosis (structural disorder)[14].Acknowledgements
The authors thank Analina da Silva and Stefan Mitrea for assistance with animal setup and monitoring. This work was supported by Centre d'Imagerie Biomédicale (CIBM) of the EPFL, Unil, CHUV, UniGe and HUG.References
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