The proposed work is designed to prepare the applicant with the training necessary to establish an independent research program on advanced neuroimaging techniques in children with non-traumatic spinal cord injury and associated pain. The goal of this project is to examine more advanced imaging biomarkers and pain involvement in non-traumatic spinal cord injuries, specifically transverse myelitis. Although MRI is the modality of choice in the detection of neuroinflammation, studies have shown it to have poor correlation with clinical status of patients with myelitis (1-4). Because Diffusion Tensor Imaging (DTI) offers an understanding on structural anisotropy of axonal white matter, it is believed to be a sensitive measure in assessing damage to the spinal cord. Magnetization Transfer is thought to be more sensitive is detecting different levels of demyelination. Diffusion Tensor Tractography can be used to identify viable spinal cord fibers. Used in combination, these advanced imaging markers have the potential to provide a more sensitive approach to existing methods used to diagnose and classify non-traumatic spinal cord injury. The candidate will also examine the clinical correlations between these imaging biomarkers, pain and severity of spinal cord injury (complete vs. incomplete) as assessed by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). The hypothesis of this project is that children with transverse myelitis will show different DTI, Magnetization Transfer and Tractography parameter values compared to controls and that children with transverse myelitis will show strong correlation between imaging biomarkers and clinical exams (MRI, ISNCSCI, pain).
The specific aims are: (1) To determine alterations in spinal cord white matter tracts in patients with acute (<1month), persistent (>6months) and resolved transverse myelitis. In this study, we will measure alterations in white matter tracts at early and later stages of the onset of transverse myelitis patients (n=30). We will determine the dynamic nature of lesions that regress vs. those that persist and how specific imaging measures of changes in white matter tract can provide a metric of white matter alterations that may predict outcome. (2) To define the relationship between the location of the white matter alteration and the severity of pain in pediatric patients with transverse myelitis (n=30) compared with healthy controls (n=20). We will identify the location (e.g., dorsal, dorsolateral, or central spinal cord) of changes and correlate with clinical severity of pain (results from Quantitative Sensory Testing), motor (ventral spinal cord) and sensory (dorsal spinal cord) symptoms. In both aims we will use MRI, an approach that we have shown to work in children with traumatic cervical injury in children. Specifically, th approach will include magnetization transfer to detect demyelination, DTI metrics to measure structural changes, and tractography to examine spinal cord fiber density. We expect children with transverse myelitis to show different DTI, magnetization transfer and tractography values compared to controls.

Public Health Relevance

The focus of this work is to use magnetic resonance imaging to measure changes in a clinical model of spinal cord injury. Developing reliable imaging biomarkers which provide a definitive indication of the extent of spinal cord injury and an enhanced understanding of pain associated with spinal cord injury may help improve clinical care and prepare for potential human clinical trials for regeneration of spinal cord tissue following injury.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Quantitative Research Career Development Award (K25)
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Pediatrics Subcommittee (CHHD)
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Nitkin, Ralph M
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Children's Hospital Boston
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Barakat, Nadia; Gorman, Mark P; Benson, Leslie et al. (2015) Pain and spinal cord imaging measures in children with demyelinating disease. Neuroimage Clin 9:338-47