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Traumatic spinal cord injury occurs when an external physical impact damages the spinal cord and leads to permanent neurological dysfunction and disability, and it is associated with a high socioeconomic burden. Conventional MRI plays a crucial role in the diagnostic workup as it reveals extrinsic compression of the spinal cord and disruption of the discoligamentous complex. Additionally, it can reveal macrostructural evidence of primary intramedullary damage such as haemorrhage, oedema, post-traumatic cystic cavities, and tissue bridges. Quantitative MRI, such as magnetisation transfer, magnetic resonance relaxation mapping, and diffusion imaging, enables the tracking of secondary changes across the neuraxis at the microstructural level. Both conventional MRI and quantitative MRI metrics, obtained early after spinal cord injury, are predictive of clinical outcome. Thus, neuroimaging biomarkers could serve as surrogate endpoints for more efficient future trials targeting acute and chronic spinal cord injury. The adoption of neuroimaging biomarkers in centres for spinal cord injury might lead to personalised patient care.

Pathophysiological changes in the spinal cord white and grey matter resulting from injury can be observed with MRI techniques. These techniques provide sensitive markers of macrostructural and microstructural tissue integrity, which correlate with histological findings. Spinal cord MRI findings in traumatic spinal cord injury (tSCI) and nontraumatic spinal cord injury — the most common form of which is degenerative cervical myelopathy (DCM) — have provided important insights into the pathophysiological processes taking place not just at the focal injury site but also rostral and caudal to the spinal injury. Although tSCI and DCM have different aetiologies, they show similar degrees of spinal cord pathology remote from the injury site, suggesting the involvement of similar secondary degenerative mechanisms. Advanced quantitative MRI protocols that are sensitive to spinal cord pathology have the potential to improve diagnosis and, more importantly, predict outcomes in patients with tSCI or nontraumatic spinal cord injury. This Review describes the insights into tSCI and DCM that have been revealed by neuroimaging and outlines current activities and future directions for the field.

In patients with chronic spinal cord injury, imaging of the spinal cord and brain above the level of the lesion provides evidence of neural degeneration; however, the spatial and temporal patterns of progression and their relation to clinical outcomes are uncertain. New interventions targeting acute spinal cord injury have entered clinical trials but neuroimaging outcomes as responsive markers of treatment have yet to be established. We aimed to use MRI to assess neuronal degeneration above the level of the lesion after acute spinal cord injury. In our prospective longitudinal study, we enrolled patients with acute traumatic spinal cord injury and healthy controls. We assessed patients clinically and by MRI at baseline, 2 months, 6 months, and 12 months, and controls by MRI at the same timepoints. We assessed atrophy in white matter in the cranial corticospinal tracts and grey matter in sensorimotor cortices by tensor-based analyses of T1-weighted MRI data. We used cross-sectional spinal cord area measurements to assess atrophy at cervical level C2/C3. We used myelin-sensitive magnetisation transfer (MT) and longitudinal relaxation rate (R1) maps to assess microstructural changes associated with myelin. We also assessed associations between MRI parameters and clinical improvement. All analyses of brain scans done with statistical parametric mapping were corrected for family-wise error. Between Sept 17, 2010, and Dec 31, 2012, we recruited 13 patients and 18 controls. In the 12 months from baseline, patients recovered by a mean of 5·27 points per log month (95% CI 1·91–8·63) on the international standards for the neurological classification of spinal cord injury (ISNCSCI) motor score (p=0·002) and by 10·93 points per log month (6·20–15·66) on the spinal cord independence measure (SCIM) score (p<0·0001). Compared with controls, patients showed a rapid decline in cross-sectional spinal cord area (patients declined by 0·46 mm per month compared with a stable cord area in controls; p<0·0001). Patients had faster rates than controls of volume decline of white matter in the cranial corticospinal tracts at the level of the internal capsule (right Z score 5·21, p=0·0081; left Z score 4·12, p=0·0004) and right cerebral peduncle (Z score 3·89, p=0·0302) and of grey matter in the left primary motor cortex (Z score 4·23, p=0·041). Volume changes were paralleled by significant reductions of MT and R1 in the same areas and beyond. Improvements in SCIM scores at 12 months were associated with a reduced loss in cross-sectional spinal cord area over 12 months (Pearson's correlation 0·77, p=0·004) and reduced white matter volume of the corticospinal tracts at the level of the right internal capsule (Z score 4·30, p=0·0021), the left internal capsule (Z score 4·27, p=0·0278), and left cerebral peduncle (Z score 4·05, p=0·0316). Improvements in ISNCSCI motor scores were associated with less white matter volume change encompassing the corticospinal tract at the level of the right internal capsule (Z score 4·01, p<0·0001). Extensive upstream atrophic and microstructural changes of corticospinal axons and sensorimotor cortical areas occur in the first months after spinal cord injury, with faster degenerative changes relating to poorer recovery. Structural volumetric and microstructural MRI protocols remote from the site of spinal cord injury could serve as neuroimaging biomarkers in acute spinal cord injury. SRH Holding, Swiss National Science Foundation, Clinical Research Priority Program “NeuroRehab” University of Zurich, Wellcome Trust.

This study aimed to compare macrostructural and microstructural neurodegenerative changes remote from a cervical spinal cord injury in traumatic spinal cord injury (tSCI) and degenerative cervical myelopathy (DCM) patients using quantitative magnetic resonance imaging (MRI). Twenty-nine tSCI patients, 20 mild/moderate DCM patients, and 22 healthy controls underwent a high-resolution MRI protocol at the cervical cord (C2/C3). High-resolution T2*-weighted and diffusion-weighted scans provided data to calculate tissue-specific cross-sectional areas of the spinal cord and tract-specific diffusion indices of cord white matter, respectively. Regression analysis determined associations between neurodegeneration and clinical impairment. tSCI patients showed more impairment in upper limb strength and manual dexterity when compared with DCM patients. While macrostructural MRI measures revealed a similar extent of remote cord atrophy at cervical level, microstructural measures (diffusion indices) were able to distinguish more pronounced tract-specific neurodegeneration in tSCI patients when compared with DCM patients. Tract-specific neurodegeneration was associated with upper limb impairment. Despite clinical differences between severely impaired tSCI compared with mildly affected DCM patient, extensive cord atrophy is present remotely from the focal spinal cord injury. Diffusion indices revealed greater tract-specific alterations in tSCI patients. Therefore, diffusion indices are more sensitive than macrostructural MRI measures as these are able to distinguish between traumatic and non-traumatic spinal cord injury. Neuroimaging biomarkers of cervical cord integrity hold potential as predictors of recovery and might be suitable biomarkers for interventional trials both in traumatic and non-traumatic SCI.

•Spinal cord morphology estimated based on synthetic T1-weighted MRI shows high repeatability.•Spinal cord atrophy following spinal cord injury can reliably be measured on synthetic MR images.•Synthetic MRI allows to reduce acquisition time in long imaging protocols and application in clinical studies. Short MRI acquisition time, high signal-to-noise ratio, and high reliability are crucial for image quality when scanning healthy volunteers and patients. Cross-sectional cervical cord area (CSA) has been suggested as a marker of neurodegeneration and potential outcome measure in clinical trials and is conventionally measured on T1-weigthed 3D Magnetization Prepared Rapid Acquisition Gradient-Echo (MPRAGE) images. This study aims to reduce the acquisition time for the comprehensive assessment of the spinal cord, which is typically based on MPRAGE for morphometry and multi-parameter mapping (MPM) for microstructure. The MPRAGE is replaced by a synthetic T1-w MRI (synT1-w) estimated from the MPM, in order to measure CSA. SynT1-w images were reconstructed using the MPRAGE signal equation based on quantitative maps of proton density (PD), longitudinal (R1) and effective transverse (R2*) relaxation rates. The reliability of CSA measurements from synT1-w images was determined within a multi-center test-retest study format and validated against acquired MPRAGE scans by assessing the agreement between both methods. The response to pathological changes was tested by longitudinally measuring spinal cord atrophy following spinal cord injury (SCI) for synT1-w and MPRAGE using linear mixed effect models. CSA measurements based on the synT1-w MRI showed high intra-site (Coefficient of variation [CoV]: 1.43% to 2.71%) and inter-site repeatability (CoV: 2.90% to 5.76%), and only a minor deviation of -1.65 mm2 compared to MPRAGE. Crucially, by assessing atrophy rates and by comparing SCI patients with healthy controls longitudinally, differences between synT1-w and MPRAGE were negligible. These results demonstrate that reliable estimates of CSA can be obtained from synT1-w images, thereby reducing scan time significantly.

•We present a novel pneumatic vibrotactile stimulation device that can be used in the MR head coil.•This MR-compatible device works through soft pneumatic actuator technology.•To validate the device for studying somatotopy, we mapped the S1 finger layout.•We then use the device and representational similarity analysis to map the face.•In representational space, the chin is in-between the lip and forehead in S1. The exact somatotopy of the human facial representation in the primary somatosensory cortex (S1) remains debated. One reason that progress has been hampered is due to the methodological challenge of how to apply automated vibrotactile stimuli to face areas in a manner that is: (1) reliable despite differences in the curvatures of face locations; and (2) MR-compatible and free of MR-interference artefacts when applied in the MR head-coil. Here we overcome this challenge by using soft pneumatic actuator (SPA) technology. SPAs are made of a soft silicon material and can be in- or deflated by means of airflow, have a small diameter, and are flexible in structure, enabling good skin contact even on curved body surfaces (as on the face). To validate our approach, we first mapped the well-characterised S1 finger layout using this novel device and confirmed that tactile stimulation of the fingers elicited characteristic somatotopic finger activations in S1. We then used the device to automatically and systematically deliver somatosensory stimulation to different face locations. We found that the forehead representation was least distant from the representation of the hand. Within the face representation, we found that the lip representation is most distant from the forehead representation, with the chin represented in between. Together, our results demonstrate that this novel MR compatible device produces robust and clear somatotopic representational patterns using vibrotactile stimulation through SPA-technology.

•Multi parametric mapping (MPM) of the cervical cord shows a high repeatability and reproducibility for quantifying micro- and macrostructural readouts within a clinically feasible acquisition time (∼20 min).•This optimized MPM protocol that covers the brain and cervical cord can be applied in multi-center studies interested in assessing changes in the brain and spinal cord, simultaneously.•By including diverse hardware and software, this study provides a realistic reference for the performance of MPM protocol in multicenter studies using widely available product sequences and processing methods. MRI based multicenter studies which target neurological pathologies affecting the spinal cord and brain – including spinal cord injury (SCI) – require standardized acquisition protocols and image processing methods. We have optimized and applied a multi-parameter mapping (MPM) protocol that simultaneously covers the brain and the cervical cord within a traveling heads study across six clinical centers (Leutritz et al., 2020). The MPM protocol includes quantitative maps (magnetization transfer saturation (MT), proton density (PD), longitudinal (R1), and effective transverse (R2*) relaxation rates) sensitive to myelination, water content, iron concentration, and morphometric measures, such as cross-sectional cord area. Previously, we assessed the repeatability and reproducibility of the brain MPM data acquired in the five healthy participants who underwent two scan-rescans (Leutritz et al., 2020). This study focuses on the cervical cord MPM data derived from the same acquisitions to determine its repeatability and reproducibility in the cervical cord. MPM matrices of the cervical cord were generated and processed using the hMRI and the spinal cord toolbox. To determine reliability of the cervical MPM data, the intra-site (i.e., scan-rescan) coefficient of variation (CoV), inter-site CoV, and bias within region of interests (C1, C2 and C3 levels) were determined. The range of the mean intra- and inter-site CoV of MT, R1 and PD was between 2.5% and 12%, and between 1.1% and 4.0% for the morphometric measures. In conclusion, the cervical MPM data showed a high repeatability and reproducibility for key imaging biomarkers and hence can be employed as a standardized tool in multi-center studies, including clinical trials.

Magnetic resonance imaging (MRI) enables the investigation of pathological changes in gray and white matter at the lumbosacral enlargement (LSE) and conus medullaris (CM). However, conducting group-level analyses of MRI metrics in the lumbosacral spinal cord is challenging due to variability in CM length, lack of established image-based landmarks, and unknown scan-rescan reliability. This study aimed to improve inter-subject alignment of the lumbosacral cord to facilitate group-level analyses of MRI metrics. Additionally, we evaluated the scan-rescan reliability of MRI-based cross-sectional area (CSA) measurements and diffusion tensor imaging (DTI) metrics. Fifteen participants (10 healthy volunteers and 5 patients with spinal cord injury) underwent axial T2*-weighted and diffusion MRI at 3T. We assessed the reliability of spinal cord and gray matter-based landmarks for inter-subject alignment of the lumbosacral cord, the inter-subject variability of MRI metrics before and after adjusting for the CM length, the intra- and inter-rater reliability of CSA measurements, and the scan-rescan reliability of CSA measurements and DTI metrics. The slice with the largest gray matter CSA as an LSE landmark exhibited the highest reliability, both within and across raters. Adjusting for the CM length greatly reduced the inter-subject variability of MRI metrics. The intra-rater, inter-rater, and scan-rescan reliability of MRI metrics were the highest at and around the LSE (scan-rescan coefficient of variation <3% for CSA measurements and <7% for DTI metrics within the white matter) and decreased considerably caudal to it. To facilitate group-level analyses, we recommend using the slice with the largest gray matter CSA as a reliable LSE landmark, along with an adjustment for the CM length. We also stress the significance of the anatomical location within the lumbosacral cord in relation to the reliability of MRI metrics. The scan-rescan reliability values serve as valuable guides for power and sample size calculations in future longitudinal studies.

Previous studies showed reorganised and/or altered activity in the primary sensorimotor cortex after a spinal cord injury (SCI), suggested to reflect abnormal processing. However, little is known about whether somatotopically specific representations can be activated despite reduced or absent afferent hand inputs. In this observational study, we used functional MRI and a (attempted) finger movement task in tetraplegic patients to characterise the somatotopic hand layout in primary somatosensory cortex. We further used structural MRI to assess spared spinal tissue bridges. We found that somatotopic hand representations can be activated through attempted finger movements in the absence of sensory and motor hand functioning, and no spared spinal tissue bridges. Such preserved hand somatotopy could be exploited by rehabilitation approaches that aim to establish new hand-brain functional connections after SCI (e.g. neuroprosthetics). However, over years since SCI the hand representation somatotopy deteriorated, suggesting that somatotopic hand representations are more easily targeted within the first years after SCI.

•Healthy participants trained for four weeks in a complex motor task while undergoing volumetric and myelin-sensitive MRI.•Training was associated with volume and myelin changes in grey and white matter of the motor and limbic systems.•Coherent (correlated but time-lagged) waves of plasticity across multiple brain areas were observed.•These dynamic, microstructural responses to task acquisition support hypotheses about motor learning.•Multimodal MRI may be employed in the study of task and skill learning and in the evolution of disease states. Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes—and their microstructural underpinnings—remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.