ObjectiveTo investigate the spatiotemporal evolution and predictive properties of intramedullary damage and midsagittal tissue bridges at the epicenter of a thoracic spinal cord injury (SCI) using MRI.MethodsWe retrospectively assessed midsagittal T2-weighted scans from 25 patients with thoracic SCI (14 traumatic, 11 ischemic) at 1 month post-SCI. In 12 patients with SCI, linear mixed-effects models on serial MRI explored temporal trajectories of quantifiable lesion markers (area, length, and width) and tissue bridges. Using partial correlation analysis, we assessed associations between structural lesion characteristics at 1 month post-SCI and recovery at 1 year postinjury, adjusting for baseline clinical status, age, and sex.ResultsLesion area decreased by 5.68 mm2 (p = 0.005), lesion length by 2.14 mm (p = 0.004), and lesion width by 0.13 mm (p = 0.004) per month. Width of tissue bridges increased by 0.06 mm (p = 0.019) per month, being similar in traumatic and ischemic SCI (p = 0.576). Smaller lesion area, length, width, and wider tissue bridges at 1 month post-SCI predicted better recovery at 1-year follow-up.ConclusionsOver time, the immediate area of cord damage shrunk while the cystic cavity became demarcated. Adjacent to the cyst, midsagittal tissue bridges became visible. The width of tissue bridges at 1 month post-SCI predicted recovery at 1 year follow-up. Measures of lesion area and tissue bridges early after traumatic and ischemic thoracic SCI therefore allow characterizing the evolution of focal cord damage and are predictive of recovery in thoracic SCI. Thus, lesion extent and tissue bridges hold potential to improve diagnosis and patient stratification in interventional trials.

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 an (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 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.

ObjectivesTraumatic and non-traumatic spinal cord injury produce neurodegeneration across the entire neuraxis. However, the spatiotemporal dynamics of spinal cord grey and white matter neurodegeneration above and below the injury is understudied.MethodsWe acquired longitudinal data from 13 traumatic and 3 non-traumatic spinal cord injury patients (8–8 cervical and thoracic cord injuries) within 1.5 years after injury and 10 healthy controls over the same period. The protocol encompassed structural and diffusion-weighted MRI rostral (C2/C3) and caudal (lumbar enlargement) to the injury level to track tissue-specific neurodegeneration. Regression models assessed group differences in the temporal evolution of tissue-specific changes and associations with clinical outcomes.ResultsAt 2 months post-injury, white matter area was decreased by 8.5% and grey matter by 15.9% in the lumbar enlargement, while at C2/C3 only white matter was decreased (−9.7%). Patients had decreased cervical fractional anisotropy (FA: −11.3%) and increased radial diffusivity (+20.5%) in the dorsal column, while FA was lower in the lateral (−10.3%) and ventral columns (−9.7%) of the lumbar enlargement. White matter decreased by 0.34% and 0.35% per month at C2/C3 and lumbar enlargement, respectively, and grey matter decreased at C2/C3 by 0.70% per month.ConclusionsThis study describes the spatiotemporal dynamics of tissue-specific spinal cord neurodegeneration above and below a spinal cord injury. While above the injury, grey matter atrophy lagged initially behind white matter neurodegeneration, in the lumbar enlargement these processes progressed in parallel. Tracking trajectories of tissue-specific neurodegeneration provides valuable assessment tools for monitoring recovery and treatment effects.

Traditionally, the brainstem has been seen as hardwired and poorly capable of plastic adaptations following spinal cord injury (SCI). Data acquired over the past decades, however, suggest differently: following SCI in various animal models (lamprey, chick, rodents, nonhuman primates), different forms of spontaneous anatomic plasticity of reticulospinal projections, many of them originating from the gigantocellular reticular nucleus (NRG), have been observed. In line with these anatomic observations, animals and humans with incomplete SCI often show various degrees of spontaneous motor recovery of hindlimb/leg function. Here, we investigated the functional relevance of two different modes of reticulospinal fiber growth after cervical hemisection, local rewiring of axotomized projections at the lesion site versus compensatory outgrowth of spared axons, using projection-specific, adeno-associated virus-mediated chemogenetic neuronal silencing. Detailed assessment of joint movements and limb kinetics during overground locomotion in female adult rats showed that locally rewired as well as compensatory NRG fibers were responsible for different aspects of recovered forelimb and hindlimb functions (i.e., stability, strength, coordination, speed, or timing). During walking and swimming, both locally rewired as well as compensatory NRG plasticity were crucial for recovered function, while the contribution of locally rewired NRG plasticity to wading performance was limited. Our data demonstrate comprehensively that locally rewired as well as compensatory plasticity of reticulospinal axons functionally contribute to the observed spontaneous improvement of stepping performance after incomplete SCI and are at least partially causative to the observed recovery of function, which can also be observed in human patients with spinal hemisection lesions.

Objective:To determine whether cervical cord levels of metabolites are associated with pain sensation after spinal cord injury (SCI), we performed magnetic resonance spectroscopy in SCI patients with and without neuropathic pain (NP).Methods:Cervical cord single-voxel spectroscopic data of 24 SCI patients (14 with NP, 10 pain-free) and 21 healthy controls were acquired at C2/3 to investigate metabolite ratios associated with neuroinflammation (choline-containing compounds to myo-inositol (tCho/mI)) and neurodegeneration (total N-acetylaspartate to myo-inositol (tNAA/mI)). NP levels were measured and Spearman’s correlation tests assessed associations between metabolite levels, cord atrophy, and pin-prick score.Results:In patients with NP, tCho/mI levels were increased (p=0.024) compared to pain-free patients and negatively related to cord atrophy (p=0.006, r=0.714). Better pin-prick score was associated with higher tCho/mI levels (p=0.032, r=0.574). In pain-free patients, tCho/mI levels were not related to cord atrophy (p=0.881, r=0.055) or pin-prick score (p=0.676, r=0.152). tNAA/mI levels were similar in both patient groups (p=0.396) and were not associated with pin-prick score in patients with NP (p=0.405, r=0.242) and pain-free patients (p=0.117, r=0.527).Conclusions:Neuroinflammatory metabolite levels (i.e. tCho/mI) were elevated in patients with NP; its magnitude being associated with less cord atrophy and greater pain sensation (e.g. pin-prick score). This suggests that patients with NP have more residual spinal tissue and greater metabolite turnover than pain-free patients. Neurodegenerative metabolite levels (i.e. tNAA/mI) were associated with greater cord atrophy, but unrelated to NP. Identifying the metabolic NP signature provides new NP treatment targets and could improve patient stratification in interventional trials.Classification of Evidence:This study provides Class II evidence that levels of MR-spectroscopy-identified metabolites of neuroinflammation were elevated in SCI patients with NP compared to those without NP.

Background The majority of patients with spinal cord injury (SCI) have anatomically incomplete lesions and present with preserved tissue bridges, yet their outcomes vary. Objective To assess the predictive value of the anatomical location (ventral/dorsal) and width of preserved midsagittal tissue bridges for American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade conversion and SCI patient stratification into recovery-specific subgroups. Methods This retrospective longitudinal study includes 70 patients (56 men, age: 52.36 ± 18.58 years) with subacute (ie, 1 month) SCI (45 tetraplegics, 25 paraplegics), 1-month neuroimaging data, and 1-month and 12-month clinical data. One-month midsagittal T2-weighted scans were used to determine the location and width of tissue bridges. Their associations with functional outcomes were assessed using partial correlation and unbiased recursive partitioning conditional inference tree (URP-CTREE). Results Fifty-seven (81.4%) of 70 patients had tissue bridges (2.53 ± 2.04 mm) at 1-month post-SCI. Larger ventral ( P = .001, r = 0.511) and dorsal ( P < .001, r = 0.546) tissue bridges were associated with higher AIS conversion rates 12 months post-SCI (n = 39). URP-CTREE analysis identified 1-month ventral tissue bridges as predictors of 12-month total motor scores (0.4 mm cutoff, P = .008), recovery of upper extremity motor scores at 12 months (1.82 mm cutoff, P = .002), 12-month pin-prick scores (1.4 mm cutoff, P = .018), and dorsal tissue bridges at 1 month as predictors of 12-month Spinal Cord Independence Measure scores (0.5 mm cutoff, P = .003). Conclusions Midsagittal tissue bridges add predictive value to baseline clinical measures for post-SCI recovery. Based on tissue bridges’ width, patients can be classified into subgroups of clinical recovery profiles. Midsagittal tissue bridges provide means to optimize patient stratification in clinical trials.

Background. Given individuals with spinal cord injury (SCI) approaching 2 million, viable options for regenerative repair are desperately needed. Human central nervous system stem cells (HuCNS-SC) are self-renewing, multipotent adult stem cells that engraft, migrate, and differentiate in appropriate regions in multiple animal models of injured brain and spinal cord. Preclinical improved SCI locomotor function provided rationale for the first-in-human SCI clinical trial of HuCNS-SC cells. Evidence of feasibility and long-term safety of cell transplantation into damaged human cord is needed to foster translational progression of cellular therapies. Methods. A first-ever, multisite phase I/IIa trial involving surgical transplantation of 20 million HuCNS-SC cells into the thoracic cord in 12 AIS A or B subjects (traumatic, T2-T11 motor-complete, sensory-incomplete), aged 19 to 53 years, demonstrated safety and preliminary efficacy. Six-year follow-up data were collected (sensory thresholds and neuroimaging augmenting clinical assessments). Findings. The study revealed short- and long-term surgical and medical safety (well-tolerated immunosuppression in population susceptible to infections). Preliminary efficacy measures identified 5/12 with reliable sensory improvements. Unfortunately, without thoracic muscles available for manual muscle examination, thoracic motor changes could not be measured. Lower limb motor scores did not change during the study. Cervical cord imaging revealed, no tumor formation or malformation of the lesion area, and secondary supralesional structural changes similar to SCI control subjects. Interpretation. Short- and long-term safety and feasibility support the consideration of cell transplantation for patients with complete and incomplete SCI. This report is an important step to prepare, foster, and maintain the therapeutic development of cell transplantation for human SCI.

ObjectiveTo assess associations between preserved spinal cord tissue quantified by the width of ventral and dorsal tissue bridges and neuropathic pain development after spinal cord injury.MethodsThis retrospective longitudinal study includes 44 patients (35 men; mean (SD) age, 50.05 (18.88) years) with subacute (ie, 1 month) spinal cord injury (25 patients with neuropathic pain, 19 pain-free patients) and neuroimaging data who had a follow-up clinical assessment at 12 months. Widths of tissue bridges were calculated from midsagittal T2-weighted images and compared across groups. Regression analyses were used to identify relationships between these neuroimaging measures and previously assessed pain intensity and pin-prick score.ResultsPin-prick score of the 25 patients with neuropathic pain increased from 1 to 12 months (Δmean=10.08, 95% CI 2.66 to 17.50, p=0.010), while it stayed similar in pain-free patients (Δmean=2.74, 95% CI −7.36 to 12.84, p=0.576). They also had larger ventral tissue bridges (Δmedian=0.80, 95% CI 0.20 to 1.71, p=0.008) at 1 month when compared with pain-free patients. Conditional inference tree analysis revealed that ventral tissue bridges’ width (≤2.1 or >2.1 mm) at 1 month is the strongest predictor for 12 months neuropathic pain intensity (1.90±2.26 and 3.83±1.19, p=0.042) and 12 months pin-prick score (63.84±28.26 and 92.67±19.43, p=0.025).InterpretationLarger width of ventral tissue bridges—a proxy for spinothalamic tract function—at 1 month post-spinal cord injury is associated with the emergence and maintenance of neuropathic pain and increased pin-prick sensation. Spared ventral tissue bridges could serve as neuroimaging biomarkers of neuropathic pain and might be used for prediction and monitoring of pain outcomes and stratification of patients in interventional trials.