Evolution of Magnetic Resonance Imaging as Predictors and Correlates of Functional Outcome after Spinal Cord Contusion Injury in the Rat

Clinical methods for assessing spinal cord injury (SCI) severity and predicting outcomes are limited due to injury heterogeneity and progression.
This study evaluates advanced magnetic resonance imaging (MRI) in relation to neurological recovery in a rat contusion model.
Rats received graded contusion at T10, followed by MRI using T2-weighted imaging, quantitative T2 imaging, and diffusion-weighted imaging (DWI) at 1, 30, and 90 days post-injury (dpi).
MRI metrics correlated with neurological function measured by weekly Basso, Beattie, and Bresnahan (BBB) locomotor scoring and reflexive micturition function.
Results indicated varied sensitivity of MRI metrics over time: DWI correlated best with BBB at 1 dpi, while atrophy metrics were more predictive at 90 dpi.

Spinal Cord Injury (SCI): Affects approximately 17,000 individuals annually in the USA, impacting mobility, bladder control, and sexual function throughout life.
Challenges: Effective diagnostic methods like the International Standards for Neurological Classification of SCI have limited prognostic ability, affecting patient management and clinical trial efficiency.
MRI Utilization: Less than 40% of practitioners use MRI due to limits in prognostic value regarding long-term outcomes.
- T2-weighted imaging: Primarily used for visualizing spinal cord compression and associated edema but shows limited predictive utility for long-term outcomes.
- BASIC Score: Uses axial T2-weighted images to assess injury severity; its strongest grade indicates intramedullary hemorrhage, linked to more severe injuries.
- DWI: Explores water diffusion to assess spinal cord microstructure; shows correlation with functional outcomes via fractional anisotropy (FA) and other measures.
- Neuroimaging Techniques: Both DTI and advanced DWI modeling reveal axonal density and damage, including axonal water fraction (AWF) and double-diffusion encoding (DDE).

Evaluate sensitivity of diffusion and T2 MRI metrics to neurological function from acute to chronic SCI.
Hypotheses:
- DDE will outperform T2 imaging as a predictor in acute phases.
- Hemorrhage will impact long-term outcomes.
- AWF will correlate strongly with injury severity in subacute phases.
- T2 measures of atrophy will correlate well in chronic settings.
- Micturition and locomotor function will correlate closely, with similar sensitivities to MRI metrics.

Approval: Conducted under guidelines from Clemet J. Zablocki VA Medical Center and Medical College of Wisconsin.
Subjects: Forty 8-week old female Sprague–Dawley rats subjected to graded thoracic spinal cord contusion injuries using a weight-drop apparatus at T10.
Injury Severity: Contused using a 10-g rod dropped from varied heights (50 mm for severe, 25 mm for moderate, 12.5 mm for mild injuries).
Monitoring: Post-injury, fluid therapy and carprofen administered; bladder expression conducted for those without reflexive micturition.

System: 9.4 Tesla small animal MRI at 24 h, 30 d, and 90 d post-injury.
Technique: Rats were anesthetized, positioned supine, and T1-weighted images localized injury sites.
DWI Acquisition: Tailored diffusion-weighted protocols; voxel-sized targeting and respiratory gating employed.

T2 Mapping: Derived from log-transformed signal fittings via linear least squares optimization.
DWI Metrics: Analysis of diffusion parameters (parallel and perpendicular diffusivity), AWF, and CSA using region of interest (ROI) methods.
Histological Validation: Quantitative staining for axonal integrity at 90 dpi concurrent with MRI metrics assessments.

1 dpi: Diffusion metrics showed significant changes, correlating hyper/hypointensities to edema and hemorrhage in acute injury.
30 dpi: Evidence of spinal atrophy and abnormal DWI metrics as the injury matured.
90 dpi: Marked spinal cord atrophy; chronic changes reflected in T2 hyperintensities with outcomes supported by histological analysis.

Correlation analysis between MRI metrics and BBB scores revealed DDE-derived fADCj j as significant predictors at acute, subacute, and chronic time points.
Negative correlation observed between hemorrhagic area and BBB scores at acute phases; AWF and CSA were front-runners in predictive ability at 30 dpi.

Lack of strong correlation between recovery of micturition reflex and MRI metrics at acute and chronic time points; regional analysis indicated involvement of lateral white matter tracts.

MRI Metrics: Identified differential sensitivity of MRI metrics in reflecting injury severity and predictive capabilities over time.
- DWI metrics like fADCj j were most indicative in acute phases, while T2-derived measures showed stronger relationships with chronic outcome.
- Overall, DWI has high specificity as a prognostic tool when applied in acute SCI contexts.

BBB scoring noted subjectivity and various biases potential.
Focus solely on injury sites limits broader applicability across spinal regions.
Consideration of male rats could provide insight into sex-specific differences in functional recovery.

In rat models of SCI, acute DWI metrics significantly outperform quantitative T2 MRI measurements for predicting long-term outcomes, emphasizing their utility in clinical diagnostics.