Longitudinal assessment of recovery after spinal cord injury with behavioral measures and diffusion, quantitative magnetization transfer and functional magnetic resonance imaging

Abstract

Spinal cord injuries (SCIs) are a leading cause of disability and can severely impact the quality of life. However, to date, the processes of spontaneous repair of damaged spinal cord remain incompletely understood, partly due to a lack of appropriate longitudinal tracking methods. Noninvasive, multiparametric magnetic resonance imaging (MRI) provides potential biomarkers for the comprehensive evaluation of spontaneous repair after SCI. In this study in rats, a clinically relevant contusion injury was introduced at the lumbar level that impairs both hindlimb motor and sensory functions. Quantitative MRI measurements were acquired at baseline and serially post‐SCI for up to 2 wk. The progressions of injury and spontaneous recovery in both white and gray matter were tracked longitudinally using pool‐size ratio (PSR) measurements derived from quantitative magnetization transfer (qMT) methods, measurements of water diffusion parameters using diffusion tensor imaging (DTI) and intrasegment functional connectivity derived from resting state functional MRI. Changes in these quantitative imaging measurements were correlated with behavioral readouts. We found (a) a progressive decrease in PSR values within 2 wk post‐SCI, indicating a progressive demyelination at the center of the injury that was validated with histological staining, (b) PSR correlated closely with fractional anisotropy and transverse relaxation of free water, but did not show significant correlations with behavioral recovery, and (c) preliminary evidence that SCI induced a decrease in functional connectivity between dorsal horns below the injury site at 24 h. Findings from this study not only confirm the value of qMT and DTI methods for assessing the myelination state of injured spinal cord but indicate that they may also have further implications on whether therapies targeted towards remyelination may be appropriate. Additionally, a better understanding of changes after SCI provides valuable information to guide and assess interventions.

Association Between Magnetic Resonance Imaging-Based Spinal Morphometry and Sensorimotor Behavior in a Hemicontusion Model of Incomplete Cervical Spinal Cord Injury in Rats

“…Our MRI results on lesional volumes were similar to a recent diffusion MRI study of contusion SCI at the lumbar level, where pool size ratio measurements derived from quantitative magnetization transfer, indicative of myelination, progressively decreased at the injury epicenter and adjoining areas within 2 weeks after SCI (Wu et al 2020). However, the pool size ratio changes had no association with sensory and motor behavioral outcomes (Wu et al, 2020). These results indicate that the nonlesional spinal cord may harbor the bulk of the reorganization related to motor circuits during the subacute and chronic phases after SCI.…”

“…compared with spinal volumetric changes after SCI. Our MRI results on lesional volumes were similar to a recent diffusion MRI study of contusion SCI at the lumbar level, where pool size ratio measurements derived from quantitative magnetization transfer, indicative of myelination, progressively decreased at the injury epicenter and adjoining areas within 2 weeks after SCI (Wu et al 2020). However, the pool size ratio changes had no association with sensory and motor behavioral outcomes (Wu et al, 2020).…”

Test-retest reproducibility of in vivo magnetization transfer ratio and saturation index in mice at 9.4 Tesla

“…Recent preclinical investigations have included a combination of MT imaging and diffusion MRI. 20,25,49 Moreover, the findings in this study will complement a recent test-retest reproducibility study in advanced diffusion MRI techniques in mice at 9.4 T. 35…”

“…There is strong interest in applying MT to preclinical rodent neuroimaging studies at ultra-high field strengths, demonstrated by MTR 19–22 and qMT studies. 13,23–25 The feasibility of MTsat in mice at 9.4 T has been shown previously 26 and MTsat has been explored in a feline model of demyelination at 3 T. 27 Although most MTsat studies have been performed at 3 T, recently, Olsson et al reported an optimized whole-brain MTsat protocol at 7 T, 28 which highlights the increasing interest in this method. In vivo studies of MTsat in humans at 3 T have shown high reproducibility.…”

Sensitivity and specificity of CEST and NOE MRI in injured spinal cord in monkeys

“…These interactive and dynamic processes are not well understood, partially due to the lack of suitable monitoring tools. Non-invasive, multi-parametric, magnetic resonance imaging (mpMRI) methods allow detection and monitoring of the injury itself as well as injury-associated structural, functional and molecular changes over time ( Stroman et al, 2014 , Wheeler-Kingshott et al, 2014 , Chen et al, 2015 , Wang et al, 2015 , Wang et al, 2016b , Wang et al, 2018b , Wang et al, 2019 , Yang et al, 2015 , Wu et al, 2020 ). In previous studies, we have studied injured spinal cords of non-human primates (NHPs) using a mpMRI protocol, including chemical exchange saturation transfer (CEST) ( Wang et al, 2015 , Wang et al, 2018b ), relayed nuclear Overhauser enhancement (NOE) ( Wang et al, 2015 , Wang et al, 2018b ), diffusion tensor imaging (DTI) ( Wang et al, 2015 , Mishra et al, 2020 ), quantitative magnetization transfer (qMT) ( Wang et al, 2016b , Wang et al, 2019 ), and functional MRI (fMRI) ( Chen et al, 2015 , Yang et al, 2015 ).…”