Magnetic resonance spectroscopy investigation in the right human hippocampus following spinal cord injury.

OBJECTIVE Preclinical studies have shown that cognitive impairments following spinal cord injury (SCI), such as impaired spatial memory, are linked to inflammation, neurodegeneration, and reduced neurogenesis in the right hippocampus. This cross-sectional study aims to characterize metabolic and macrostructural changes in the right hippocampus and their association to cognitive function in traumatic SCI patients. METHODS Within this cross-sectional study, cognitive function was assessed in 28 chronic traumatic SCI patients and 18 age-, sex-, and education-matched healthy controls by a visuospatial and verbal memory test. A magnetic resonance spectroscopy (MRS) and structural MRI protocol was performed in the right hippocampus of both groups to quantify metabolic concentrations and hippocampal volume, respectively. Group comparisons investigated changes between SCI patients and healthy controls and correlation analyses investigated their relationship to memory performance. RESULTS Memory performance was similar in SCI patients and healthy controls. The quality of the recorded MR spectra was excellent in comparison to the best-practice reports for the hippocampus. Metabolite concentrations and volume of the hippocampus measured based on MRS and MRI were not different between two groups. Memory performance in SCI patients and healthy controls was not correlated with metabolic or structural measures. CONCLUSION This study suggests that the hippocampus may not be pathologically affected at a functional, metabolic, and macrostructural level in chronic SCI. This points toward the absence of significant and clinically relevant trauma-induced neurodegeneration in the hippocampus

Magnetic resonance spectroscopy investigation in the right human hippocampus following spinal cord injury

OBJECTIVE Preclinical studies have shown that cognitive impairments following spinal cord injury (SCI), such as impaired spatial memory, are linked to inflammation, neurodegeneration, and reduced neurogenesis in the right hippocampus. This cross-sectional study aims to characterize metabolic and macrostructural changes in the right hippocampus and their association to cognitive function in traumatic SCI patients. METHODS Within this cross-sectional study, cognitive function was assessed in 28 chronic traumatic SCI patients and 18 age-, sex-, and education-matched healthy controls by a visuospatial and verbal memory test. A magnetic resonance spectroscopy (MRS) and structural MRI protocol was performed in the right hippocampus of both groups to quantify metabolic concentrations and hippocampal volume, respectively. Group comparisons investigated changes between SCI patients and healthy controls and correlation analyses investigated their relationship to memory performance. RESULTS Memory performance was similar in SCI patients and healthy controls. The quality of the recorded MR spectra was excellent in comparison to the best-practice reports for the hippocampus. Metabolite concentrations and volume of the hippocampus measured based on MRS and MRI were not different between two groups. Memory performance in SCI patients and healthy controls was not correlated with metabolic or structural measures. CONCLUSION This study suggests that the hippocampus may not be pathologically affected at a functional, metabolic, and macrostructural level in chronic SCI. This points toward the absence of significant and clinically relevant trauma-induced neurodegeneration in the hippocampus

Longitudinal motor system changes from acute to chronic spinal cord injury

BACKGROUND AND PURPOSE In acute spinal cord injury (SCI), magnetic resonance imaging (MRI) reveals tissue bridges and neurodegeneration for 2 years. This 5-year study aims to track initial lesion changes, subsequent neurodegeneration, and their impact on recovery. METHODS This prospective longitudinal study enrolled acute SCI patients and healthy controls who were assessed clinically-and by MRI-regularly from 3 days postinjury up to 60 months. We employed histologically cross-validated quantitative MRI sequences sensitive to volume, myelin, and iron changes, thereby reflecting indirectly processes of neurodegeneration and neuroinflammation. General linear models tracked lesion and remote changes in volume, myelin- and iron-sensitive magnetic resonance indices over 5 years. Associations between lesion, degeneration, and recovery (using the Spinal Cord Independence Measure [SCIM] questionnaire and the International Standards for Neurological Classification of Spinal Cord Injury total motor score) were assessed. RESULTS Patients' motor scores improved by an average of 12.86 (95% confidence interval [CI] = 6.70-19.00) points, and SCIM by 26.08 (95% CI = 17.00-35.20) points. Within 3-28 days post-SCI, lesion size decreased by more than two-thirds (3 days: 302.52 ± 185.80 mm$^{2}$ , 28 days: 76.77 ± 88.62 mm$^{2}$ ), revealing tissue bridges. Cervical cord and corticospinal tract volumes transiently increased in SCI patients by 5% and 3%, respectively, accompanied by cervical myelin decreases and iron increases. Over time, progressive atrophy was observed in both regions, which was linked to early lesion dynamics. Tissue bridges, reduced swelling, and myelin content decreases were predictive of long-term motor score recovery and improved SCIM score. CONCLUSIONS Studying acute changes and their impact on longer follow-up provides insights into SCI trajectory, highlighting the importance of acute intervention while indicating the potential to influence outcomes in the later stages

Investigation of structural, functional, and metabolic magnetic resonance biomarkers in the spinal cord and brain after spinal cord injury

Spinal cord injury (SCI) is a devastating and life-changing incident that leads to immediate and usually persisting motor, sensory, and autonomic dysfunctions, such as impairments in bladder and bowel function. These are often accompanied by the development of chronic pain and psychological concomitants, for instance depression or cognitive decline, which are negatively associated with rehabilitation and quality of life after SCI. Trauma-induced mechanical disruption and dislocation of the spinal vertebral column lead to an immediate damage of the spinal cord which is characterized by neuronal and glial cell death and disruption of axons and the spinal vasculature. This primary injury initiates a multifaceted cascade of secondary injury processes which is hallmarked by the recruitment of reactive astrocytes forming a glial scar to encapsulate the toxic environment of the lesion core that represents an inhibitory barrier to axonal regrowth. Injury-induced neurodegenerative and neuroinflammatory processes can last for years, spreading to supralesional levels and exacerbating the initial damage. Early post-injury treatment includes neuroprotective and neuroregenerative medication, aiming at preventing secondary damage and increasing the intramedullary regenerative potential, beyond endogenous plasticity and attempts of repair. Evaluation of the efficacy of distinct treatment approaches in interventional trials calls for assessments that can sensitively detect changes of clinically relevant markers. Clinical examinations usually lack the necessary sensitivity as they use ordinal scales for the classification of patients, and are also unspecific to structural correlates underlying the clinical deficits. Magnetic resonance imaging (MRI) is a non-invasive and objective method which enables the qualitative and quantitative assessment of macroscopic and microscopic changes within the neural tissue after SCI. It can thus improve our understanding of pathological primary and secondary injury processes along the whole neuraxis post-SCI and how these change during the course of recovery and relate to clinical outcomes. Previous studies found MRI-derived cervical spinal cord atrophy above the lesion level of up to 30% at 5 years post-injury. Volumetric changes in clinically relevant motor and sensory regions in the brain were also detected, which were paralleled by decreased tract integrity, pathological reductions in myelin-sensitive markers, and increases in neuroinflammatory metabolites in chronic SCI. The overall goal of this thesis was to improve our understanding of conventional and advanced MRI-derived structural, molecular, and functional changes at the lesion site and above the lesion following SCI and to explore their value as biomarkers for characterization of lesion severity and neurological disability, prediction of clinical outcome, and potential implementation as surrogate markers in interventional trials. In the first study, we investigated the longitudinal spatiotemporal dynamics of the lesion extent and the width of injury-spared tissue bridges in paraplegic SCI patients by means of conventional MRI and how baseline lesion characteristics relate to clinical outcome. At 1 month following SCI, after widespread edema and hemorrhage have resolved, midsagittal lesion segmentation was reliably and accurately performable. Over the course of 2 years, the lesion extent slightly decreased while tissue bridges' width increased, possibly due to the cystic cavity getting fully demarcated at around three to four weeks post-SCI. Crucially, patients of traumatic or ischemic etiology showed similar lesion evolutions and courses of neurological recovery, its magnitude being associated with the size of the lesion and spared tissue bridges in both patient groups. The second study aimed at exploring the value of conventional MRI-derived spared tissue bridges for prediction of neurological recovery at 1 year post-SCI, focusing not only on the width, as in most previous studies, but also on the localization of tissue bridges. Larger 1-month ventral and dorsal tissue bridges demonstrated a predictive relationship with higher American Spinal Injury Association Impairment Scale (AIS) grade conversion rates at 1 year follow-up. Using unbiased recursive partitioning conditional inference tree (URP-CTREE) analysis, ventral tissue bridges were identified as predictors of pin prick and motor scores and dorsal tissue bridges as predictors of functional independence scores, adding value to baseline clinical scores for improved stratification of patients into more homogenous and recovery-specific sub-groups. In the third study, we explored the role of spared tissue bridges for the development of neuropathic pain (NP), which represents one of the main burdens following SCI and is often refractory to treatment. We found that 1-month ventral tissue bridges were larger in patients with NP when compared to pain-free SCI patients. Representing a proxy for spinothalamic tract function, ventral tissue bridges were furthermore predictive of 1-year pin prick score and pain intensity. Crucially, the URP-CTREE algorithm identified a critical cut-off in ventral tissue bridges’ width (≤2.1mm or >2.1mm), dividing patients into sub-groups of higher and lower scores of pin prick sensation and pain intensity. These two studies highlight the potential of spared tissue bridges to improve prediction of outcome and optimize stratification of SCI patients in interventional trials. The fourth study aimed at identifying neurochemical biomarkers of chronic NP after SCI above the lesion level by means of advanced and quantitative proton magnetic resonance spectroscopy (MRS). At the remote cervical spinal cord at level C2/3, we revealed a pain-specific molecular fingerprint of increased neuroinflammatory but similar neurodegenerative metabolite concentrations in patients with NP when compared to pain-free SCI patients. Increased neuroinflammatory metabolite levels were furthermore associated with less cord atrophy and higher pin prick scores, which might represent molecular surrogate markers of NP and potentially provide new NP treatment targets. In the fifth study, we investigated whether the right hippocampus is pathologically affected in chronic SCI patients, using a multimodal approach including structural MRI, quantitative MRS, and memory performance. Previous studies reported that SCI patients suffer from cognitive impairments including deficits in learning and memory, possibly caused by brain inflammation. In this study, no secondary supralesional changes were detected in terms of an altered metabolic profile indicative of potential neurodegeneration or neuroinflammation, hippocampal atrophy, or memory impairments. SCI thus does not seem to directly affect the hippocampal integrity and post-SCI cognitive deficits might be attributable to secondary concomitants of SCI or methodological study differences. In conclusion, the studies in this thesis made use of conventional and advanced MRI for characterization of the primary injury at the focal lesion site and investigation of far-reaching structural, molecular, and functional biomarkers above the lesion level which are indicative of remote secondary injury processes following SCI, such as neurodegeneration, neuroinflammation, or reorganization. We were able to identify preserved tissue bridges adjacent to the lesion as predictive neuroimaging biomarkers of tract-specific neurological recovery and pathological somatosensory function in terms of NP. This thesis expands previous knowledge of secondary neurodegenerative and demyelinating processes at the remote cervical spinal cord and reveals a NP-related neuroinflammatory metabolic profile in the upper cervical cord in chronic SCI patients by means of advanced quantitative MRS. At the same time, the hippocampus was not found to be pathologically affected on a structural or molecular level after SCI. Conventional and advanced MRI-derived quantitative biomarkers have the potential to detect subclinical changes post-SCI and to be used as surrogate markers in interventional trials for monitoring of recovery processes and treatment effects with the ultimate goal of improving personalized patient care and achieving clinically meaningful recovery following SCI. Adding complementary value to neurological and electrophysiological assessments, clinically applicable conventional and advanced MRI might be especially powerful when used synergistically and acquired longitudinally across different centers. This could help us to improve our understanding of neuropathological and reorganizational processes along the neuraxis post-injury and to identify the most reliable and sensitive neuroimaging biomarkers to evaluate the efficacy of interventions aiming at reducing neurodegeneration and enhancing recovery following SCI

Spinal cord pathology revealed by MRI in traumatic spinal cord injury

PURPOSE OF REVIEW This review covers recent advances in identifying conventional and quantitative neuroimaging spinal cord biomarkers of lesion severity and remote spinal cord pathology following traumatic spinal cord injury (SCI). It discusses the potential of the most sensitive neuroimaging spinal cord biomarkers to complement clinical workup and improve prediction of recovery. RECENT FINDINGS At the injury site, preserved midsagittal tissue bridges - based on conventional sagittal T2-weighted scans - can be identified in the majority of SCI patients; its width being predictive of recovery. Remote from the injury, diffusion indices, and myelin/iron-sensitive neuroimaging-based changes are sensitive to secondary disease processes; its magnitude of change being associated with neurological outcome. SUMMARY Neuroimaging biomarkers reveal focal and remote cord pathology. These biomarkers show sensitivity to the underlying disease processes and are clinically eloquent. Thus, they improve injury characterization, enable spatiotemporal tracking of cord pathology, and predict recovery of function following traumatic SCI. Neuroimaging biomarkers, therefore, hold potential to complement the clinical diagnostic workup, improve patient stratification, and can serve as potential endpoints in clinical trials

Tissue bridges predict neuropathic pain emergence after spinal cord injury

OBJECTIVE: To 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. METHODS: This 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. RESULTS: Pin-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). INTERPRETATION: Larger 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

Finger somatotopy is preserved after tetraplegia but deteriorates over time

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

Tissue bridges predict recovery after traumatic and ischemic thoracic spinal cord injury

OBJECTIVE To 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. METHODS We 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. RESULTS Lesion area decreased by 5.68 mm ( = 0.005), lesion length by 2.14 mm ( = 0.004), and lesion width by 0.13 mm ( = 0.004) per month. Width of tissue bridges increased by 0.06 mm ( = 0.019) per month, being similar in traumatic and ischemic SCI ( = 0.576). Smaller lesion area, length, width, and wider tissue bridges at 1 month post-SCI predicted better recovery at 1-year follow-up. CONCLUSIONS Over 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

Metabolites of neuroinflammation relate to neuropathic pain after spinal cord injury

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

Predictive Value of Midsagittal Tissue Bridges on Functional Recovery After Spinal Cord Injury

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