Optimizing Filter-Probe Diffusion Weighting in the Rat Spinal Cord for Human Translation

Abstract

Diffusion tensor imaging (DTI) is a promising biomarker of spinal cord injury (SCI). In the acute aftermath, DTI in SCI animal models consistently demonstrates high sensitivity and prognostic performance, yet translation of DTI to acute human SCI has been limited. In addition to technical challenges, interpretation of the resulting metrics is ambiguous, with contributions in the acute setting from both axonal injury and edema. Novel diffusion MRI acquisition strategies such as double diffusion encoding (DDE) have recently enabled detection of features not available with DTI or similar methods. In this work, we perform a systematic optimization of DDE using simulations and an in vivo rat model of SCI and subsequently implement the protocol to the healthy human spinal cord. First, two complementary DDE approaches were evaluated using an orientationally invariant or a filter-probe diffusion encoding approach. While the two methods were similar in their ability to detect acute SCI, the filter-probe DDE approach had greater predictive power for functional outcomes. Next, the filter-probe DDE was compared to an analogous single diffusion encoding (SDE) approach, with the results indicating that in the spinal cord, SDE provides similar contrast with improved signal to noise. In the SCI rat model, the filter-probe SDE scheme was coupled with a reduced field of view (rFOV) excitation, and the results demonstrate high quality maps of the spinal cord without contamination from edema and cerebrospinal fluid, thereby providing high sensitivity to injury severity. The optimized protocol was demonstrated in the healthy human spinal cord using the commercially-available diffusion MRI sequence with modifications only to the diffusion encoding directions. Maps of axial diffusivity devoid of CSF partial volume effects were obtained in a clinically feasible imaging time with a straightforward analysis and variability comparable to axial diffusivity derived from DTI. Overall, the results and optimizations describe a protocol that mitigates several difficulties with DTI of the spinal cord. Detection of acute axonal damage in the injured or diseased spinal cord will benefit the optimized filter-probe diffusion MRI protocol outlined here.

Probabilistic Assessment of Nerve Regeneration with Diffusion MRI in Rat Models of Peripheral Nerve Trauma

“…2). In addition, diffusion models that account for the effects of edema 12 or filter out signal contributions from the extra-cellular space 36 may improve predictions of nerve recovery within the first few weeks.…”

Diffusion‐prepared fast spin echo for artifact‐free spinal cord imaging

“…fADC || maps in the 1D-fDWI scheme had a clear decrease of fADC || in an area of intact cord (uninjured C3) as rotation angle increased. The underestimation of fADC || followed the expected cos 2 ( ) dependence, 10 assuming straight and coherent fibers in the white matter (Supporting Information Figure S3). Therefore, the 2D-fDWI maintained lesion-to-healthy contrast and was generally unaffected by in-plane deviations of the cord axis from the diffusion-encoding directions.…”

“…The derived fADC || had an expected cos 2 dependence on the angle between the underlying axonal fibers and the diffusion-weighted direction (as in 1D-fDWI). 10 As a compromise, this study evaluated a 2D "in-plane" orientationally invariant diffusion encoding scheme that was more tolerant of orientation than the 1D scheme. Out-of-plane rotations, although not explicitly evaluated here, are likely to result in similar orientational dependent behavior.…”

“…Initial experiments used a single 2D slice and 2 images with b = 0 s/mm 2 image and 2000 s/mm 2 perpendicular to the spinal cord axis (left-right in animal coordinates) because the cord has the least curvature in this direction, and the white matter retains high signal with a perpendicular diffusion gradient. 10 For each condition, TEs of the diffusion preparation (TE prep ) module were minimized. TE prep times with a b value of 2000 s/mm 2 were 15.6, 24.4, and 27.6 ms for m0, m1, and m2, respectively.…”

“…2 To minimize the confounding effects of edema, filtered DWI (fDWI) was used for the spinal cord to attenuate signals from extra-axonal components using a high-strength diffusion filter perpendicular to the cord. 4,10 This approach reduced the signal contribution from edema and CSF, while diffusion encoding parallel to the cord probed filtered axial diffusivity (fADC || ), which predominantly reflects intra-axonal diffusivity. Despite improved detection of injury in preclinical SCI, several prominent barriers remain.…”