In vivo observation and biophysical interpretation of time-dependent diffusion in human cortical gray matter

Lee, Hong-Hsi; Papaioannou, Antonios; Novikov, Dmitry S.; Fieremans, Els

doi:10.1016/j.neuroimage.2020.117054

Cited by 75 publications

(126 citation statements)

References 75 publications

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“…Besides beading in WM, the ubiquitous 1= ffiffi t p time dependence along neurites in gray matter 15,39,53 suggests possible applications in other neurodegenerative diseases. For instance, reduced density of axonal varicosities was observed in the human superior frontal cortex of mild to moderate Alzheimer disease 54 ; decreased dendritic spine density was observed in the human prefrontal cortex of Schizophrenia 55 ; and an increased density of axonal varicosities was observed in injured dopaminergic neurons in the rat substantia nigra, an animal model of Parkinson's disease 56 .…”

Section: Discussionmentioning

confidence: 99%

A time-dependent diffusion MRI signature of axon caliber variations and beading

et al. 2020

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MRI provides a unique non-invasive window into the brain, yet is limited to millimeter resolution, orders of magnitude coarser than cell dimensions. Here, we show that diffusion MRI is sensitive to the micrometer-scale variations in axon caliber or pathological beading, by identifying a signature power-law diffusion time-dependence of the along-fiber diffusion coefficient. We observe this signature in human brain white matter and identify its origins by Monte Carlo simulations in realistic substrates from 3-dimensional electron microscopy of mouse corpus callosum. Simulations reveal that the time-dependence originates from axon caliber variation, rather than from mitochondria or axonal undulations. We report a decreased amplitude of time-dependence in multiple sclerosis lesions, illustrating the potential sensitivity of our method to axonal beading in a plethora of neurodegenerative disorders. This specificity to microstructure offers an exciting possibility of bridging across scales to image cellular-level pathology with a clinically feasible MRI technique.

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Section: Discussionmentioning

confidence: 99%

A time-dependent diffusion MRI signature of axon caliber variations and beading

et al. 2020

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“…and is time independent. The time dependence of all the cumulants in Equation ( 1), including D(t) and K(t), can be explored by varying the diffusion time t. 23,39,44,45 For short diffusion times, t t c , the kurtosis increases. 35,36 As shown by Fieremans et al (2010), 35 in the barrier-limited exchange case τ ex t c , K(t) peaks around t t c , beyond which point both intra-and extracellular spaces become effectively homogenized separately, while their mixing is not yet relevant (this is the physical meaning of exchange being barrier limited).…”

Section: Diffusional Kurtosis and Exchange Timementioning

confidence: 99%

“…Recently, time-dependent kurtosis was observed in normal human cortical gray matter, where the specific t −1/2 decrease of K(t) was ascribed to the structural disorder along the neurites. 39 However, the feasibility of measuring the water exchange time τ ex from K(t) has not yet been clearly demonstrated in vivo. Furthermore, K(t) in tumors has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Measurement of cellular‐interstitial water exchange time in tumors based on diffusion‐time‐dependent diffusional kurtosis imaging

et al. 2021

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Purpose: To assess the feasibility of using diffusion-time-dependent diffusional kurtosis imaging (tDKI) to measure cellular-interstitial water exchange time (τ ex ) in tumors, both in animals and in humans. Methods:Preclinical tDKI studies at 7 T were performed with the GL261 glioma model and the 4T1 mammary tumor model injected into the mouse brain. Clinical studies were performed at 3 T with women who had biopsy-proven invasive ductal carcinoma. tDKI measurement was conducted using a diffusion-weighted STEAM pulse sequence with multiple diffusion times (20-800 ms) at a fixed echo time, while keeping the b-values the same (0-3000 s/mm 2 ) by adjusting the diffusion gradient strength. The tDKI data at each diffusion time t were used for a weighted linear least-squares fit method to estimate the diffusion-time-dependent diffusivity, D(t), and diffusional kurtosis, K(t).Results: Both preclinical and clinical studies showed that, when diffusion time t ≥ 200 ms, D(t) did not have a noticeable change while K(t) decreased monotonically with increasing diffusion time in tumors and t ≥ 100 ms for the cortical ribbon of the mouse brain. The estimated τ ex averaged median and interquartile range (IQR) of GL261 and 4T1 tumors were 93 (IQR = 89) ms and 68 (78) ms, respectively. For the cortical ribbon, the estimated τ ex averaged median and IQR were 41 (34) ms for C57BL/6 and 30 (17) ms for BALB/c. For invasive ductal carcinoma, the estimated τ ex median and IQR of the two breast cancers were 70 (94) and 106 (92) ms. Conclusion:The results of this proof-of-concept study substantiate the feasibility of using tDKI to measure cellular-interstitial water exchange time without using an exogenous contrast agent.

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“…Another modelling assumption is the lack of exchange between compartments. According to some studies, the intra-cellular residence time of water is on the order of 500 ms [92], which would not play an important role at the diffusion time considered here (20 ms), although other recent studies show that water exchange across compartments can be faster in GM and can influence the dMRI signal at this diffusion time [93]. PGSE data acquired at a single diffusion time, as done in this study, is not appropriate to characterize the effects of intra-compartment kurtosis or exchange, which might produce some biases in the estimated parameters, that can be the focus of future work.…”

Section: Discussionmentioning

confidence: 98%

Soma and Neurite Density MRI (SANDI) of the in-vivo mouse brain

Ianuş

Carvalho

Fernandes

et al. 2021

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Diffusion MRI (dMRI) provides unique insights into the neural tissue milieu by probing interaction of diffusing molecules and tissue microstructure. Most dMRI techniques focus on white matter tissues (WM) due to the relatively simpler modelling of diffusion in the more organized tracts; however, interest is growing in gray matter characterisations. The Soma and Neurite Density MRI (SANDI) methodology harnesses a model incorporating water diffusion in spherical objects (assumed to be associated with cell bodies) and in impermeable 'sticks' (representing neurites), which potentially enables the characterisation of cellular and neurite densities. Recognising the importance of rodents in animal models of development, aging, plasticity, and disease, we here sought to develop SANDI for preclinical imaging and provide a validation of the methodology by comparing its metrics with the Allen mouse brain atlas. SANDI was implemented on a 9.4T scanner equipped with a cryogenic coil, and experiments were carried out on N=6 mice. Pixelwise, ROI-based, and atlas comparisons were performed, and results were also compared to more standard Diffusion Kurtosis MRI (DKI) metrics. We further investigated effects of different pre-processing pipelines, specifically the comparison of magnitude and real-valued data, as well as different acceleration factors. Our findings reveal excellent reproducibility of the SANDI parameters, including the sphere and stick fraction as well as sphere size. More strikingly, we find a very good rank correlation between SANDI-driven soma fraction and Allen brain atlas contrast (which represents the cellular density in the mouse brain). Although some DKI parameters (FA, MD) correlated with some SANDI parameters in some ROIs, they did not correlate nearly as well as SANDI parameters with the Allen atlas, suggesting a much more specific nature of the SANDI parameters. We conclude that SANDI is a viable preclinical MRI technique that can greatly contribute to research on brain tissue microstructure.

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In vivo observation and biophysical interpretation of time-dependent diffusion in human cortical gray matter

Cited by 75 publications

References 75 publications

A time-dependent diffusion MRI signature of axon caliber variations and beading

A time-dependent diffusion MRI signature of axon caliber variations and beading

Measurement of cellular‐interstitial water exchange time in tumors based on diffusion‐time‐dependent diffusional kurtosis imaging

Soma and Neurite Density MRI (SANDI) of the in-vivo mouse brain

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