John Kramer

Myelin water imaging (MWI) is a quantitative magnetic resonance (MR) method that specifically measures the myelin content in the central nervous system. MWI operates on the principle that the MR signal of water trapped between myelin bilayers can be extracted from the total MR signal based on a characteristic short T2 relaxation time. The ratio of myelin water signal relative to the total signal is termed myelin water fraction (MWF), used as a quantitative biomarker for myelin. This thesis explores three aspects of MWI: application, atlases, and algorithms. Firstly, the MWI was applied to study cervical spondylotic myelopathy (CSM), which is a common spinal cord neurodegenerative disease. The function of the spinal cord conduction was assessed by an electrophysiologic technique called somatosensory evoked potentials (SSEP). Significant MWF reduction was observed in those CSM patients with functional deficits (e.g. delayed SSEP latency). A linear correlation between the MWF and the SSEP latency was discovered in CSM. Secondly, the MWI atlases, which represent the MWI normative references of the normal myelin distribution in the brain and spinal cord, were created by coregistering and averaging the MWI images acquired from many healthy volunteers. These resulting atlases were utilized to demonstrate areas of demyelination in individuals with pathological conditions such as multiple sclerosis. The MWI atlases have been uploaded on the Internet and made publicly available. Thirdly, the current MWI data analysis, based on the non-negative least squares (NNLS) method, was accelerated by implementing the neural network (NN) algorithm. A NN model was trained by the ground truth labels produced by the commonly used NNLS method. The trained NN model achieved to yield a whole-brain MWF map in 33 seconds, which is 150 faster than the NNLS method. Finally, a novel T2 data analysis method, namely the spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS), was proposed. SAME-ECOS is a simulation-derived solver that tailored for different MR experimental conditions. When dealing with the MWI data, it is found that SAME-ECOS largely surpassed the NNLS method in terms of calculation accuracy and speed.

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Spinal cord injury is a devastating neurological condition that results in varying degrees of sensory and motor loss, along with other health complications. Neurological recovery after spinal cord injury is generally thought to be limited to the 6-9 month period after injury, and there are currently no approved pharmacological interventions to improve this recovery. Overlapping with a proposed “window of opportunity” for interventions, neuropathic pain can occur early after injury and necessitate pharmacological management. Among the management options, anticonvulsants are routinely administered.Utilizing longitudinal observational human spinal cord injury data, this thesis explored the effects of anticonvulsants on neurological recovery after spinal cord injury using mixed effects regression, and conduct a meta-analysis on the acute progression of neuropathic pain. The research studies within this thesis are bookended by an introduction and methodology section (Chapters 1 and 2) and the discussion (Chapter 7). In Chapter 3, I examined the effect of anticonvulsants and found a beneficial association with motor recovery contingent on administration at 4 weeks. A review of patient records revealed that the majority of anticonvulsants being administered were gabapentinoids (i.e. pregabalin and gabapentin). To further examine whether this effect was specific to gabapentinoids or obtained by all anticonvulsants, Chapter 4 examined a unique spinal cord injured population administered non-gabapentinoid anticonvulsants and found no statistically significant associations with neurological recovery. Chapter 5 included a chart review to examine the effect of gabapentinoid-specific administration, and found a continued beneficial association with motor score, as well as the sensory outcome of light touch. Further, this chapter identified that very early administration (e.g. within 5 days) was necessary to achieve the largest benefit. Finally, Chapter 6 produced a longitudinal framework of neuropathic pain progression in clinical trials.In short, this thesis presents novel findings regarding the administration of anticonvulsants after spinal cord injury, and the beneficial association of gabapentinoid-specific anticonvulsants on motor recovery. Further, it provides an advance in our understanding of neuropathic pain progression after injury and a framework to guide future clinical trials.

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