Doctor of Philosophy in Experimental Medicine (PhD)
Investigating neurochemical patterns in relation to pain
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
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.
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.
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
The development of chronic pain is typically predicated by neuroplastic changes within the spinal cord in response to persistent noxious stimuli, termed central sensitization. Sensitization increases the sensitivity to stimuli of neurons directly in contact with the initial noxious stimulus, termed primary hyperalgesia, as well as those in the adjacent regions, termed secondary hyperalgesia. TRPV1 receptors, found throughout the spinal cord and periphery, are key contributors to the development t of sensitization. Capsaicin, the active ingredient in chili peppers, is a known agonist of TRPV1 receptors and, due to the unique ability of these receptors to become defunctionalized with intense or prolonged capsaicin exposure, is a common ingredient in pain relieving ointments. Defunctionalization, via capsaicin, eliminates the typical primary sensitization and has been demonstrated through the application of high dosage (>5%) capsaicin treatments. The purpose of this study was to analyze the effects of defunctionalizing capsaicin-sensitive nociceptors, using a prolonged low concentration (
Neurological recovery after acute spinal cord injury is highly variable and therefore difficult to predict. Besides initial injury characteristics, there remains a need for potential objective serum biomarkers that can predict neurological recovery. The main objective of this thesis was to identify such biomarkers. In chapter 2, I aimed to validate serum albumin as a valid biomarker for long-term neurological recovery after acute spinal cord injury. I performed unbiased recursive partitioning (URP) to examine the relationship between neurological outcomes and serum albumin concentration from the Spinal Cord Injury Rehabilitation study. Results showed that serum albumin could be used as a crude prognostic biomarker, particularly in cases where examination for injury characteristics is not complete. In chapter 3, I aimed to identify novel serum biomarkers that can predict long-term neurological recovery after acute spinal cord injury. I performed URP and Factor Analysis to investigate the relationship between neurological recovery and all baseline (i.e., up to 72 hours after injury) serum biomarkers from the Sygen clinical trial. I found that blood factor (including red blood cells, hematocrit, and hemoglobin) is significantly associated with neurological outcomes. However, similarly to results in chapter II, these blood factor markers can only serve as crude prognostic biomarkers, in cases where individuals have incomplete neurological examination. Taken together, these data demonstrate that serum biomarkers, including albumin, red blood cells, hematocrit, and hemoglobin, can predict neurological recovery after acute spinal cord injury. While further research is needed, these biomarkers can be useful for individuals who have incomplete injury characteristics examinations.
Objectively measuring pain has proven challenging, largely due to the subjective and multidimensional nature of pain. There is a pressing need to identify valid outcome measures to evaluate treatment modalities for individuals suffering from pain. Current treatment and diagnosis of pain conditions, are dependent on self-report measures. A critical limitation is the lack of mechanistic information from this measure. The objective of this thesis was to examine potential biochemical biomarkers that account for the variability of pain perception among healthy individuals. Specifically, to examine changes in excitatory neurotransmitter concentrations (glutamate and Glx: glutamate+glutamine) in the anterior cingulate cortex (ACC) using functional single voxel magnetic resonance spectroscopy during an in-scanner noxious intervention. Excitatory neurotransmitter values were quantified every 2 minutes, simultaneously, the rating of perceived pain intensity was recorded (using a 0-10 numeric rating scale) to examine the relationship of glutamate levels and pain perception. Results show individuals with higher baseline glutamate values report higher pain ratings, however when tracked dynamically no relationship is seen between glutamate (or Glx) levels and ratings of perceived pain intensity with the current methodology. While further research is needed, baseline glutamate values may prove useful in pre-treatment identification. For example, in clinical trials classifying high and low pain responders based on glutamate baseline values may provide insight into the variability of treatment responders.
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