John Kramer
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Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
According to international human rights, it is necessary for countries to provide pain management strategies¹. Today the average wait time for treatment at publicly funded pain clinics in Canada is 1-3 years. The lack of diagnostic methods to test treatment efficacy are major factors contributing to this delay in care. The role of the brain in processing pain has been extensively investigated using various functional imaging techniques coupled with well controlled noxious stimuli. Studies applying experimental pain have also used proton magnetic resonance spectroscopy (¹H-MRS). The advantage of MRS compared to other techniques is the capacity to non-invasively examine metabolites involved in the neurotransmission of pain, including glutamate, the primary excitatory neurotransmitter. The aim of this work is to characterize the neurochemical patterns of the brain in relation to experimental pain while incorporating additional neurophysiological techniques (i.e., perfusion and electrical activity measurements). Experiments in this thesis range from examining brain responses during an in-scanner pain model, after multiple days of painful stimulation, to spatially mapping the cingulate cortex at rest in relation to pain sensitivity outcomes. These studies were performed all while implementing the recent consensus recommendations of MRS data acquisition and analysis. Subsequent analysis examined sex-differences to gain a more thorough understanding of how these affect the neurotransmitter systems, contribute to pain, and could provide novel avenues for sex-specific treatments. By investigating the pattern and specificity of neurotransmitter changes in relation to pain, these findings shed new insights into MRS application in pain in improving our understanding of pain physiology. More broadly, this work provides insight into the biochemical processes in the healthy brain, which can serve as a foundation for understanding neurological diseases.
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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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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Purpose: Pain is a multifaceted experience shaped by various factors including context of pain, previous life events, and ongoing ethnocultural circumstances. Moreover, pain’s definition is inconsistent across cultures. Western medicine views physical pain (e.g., fractured bone) and non-physical pain (e.g., depression) as two distinct conditions. Indigenous perspectives are often more wholistic, encompassing mental, spiritual, emotional, and physical hurt. The subjective nature of pain invites ample opportunity for discrimination in both its assessment and management. As such, it is important to consider Indigenous perspectives of pain in research and clinical practice. To investigate what aspects of Indigenous pain knowledge is currently considered by Western research, we conducted a scoping review on pain among Indigenous Peoples of Canada. Methods: In June 2021, 9 databases were searched with 8,220 papers downloaded after duplicates removed. Abstract and full-text screening was conducted by two independent reviewers. Principle Findings: 77 papers were included for analysis. Using grounded theory, five themes emerged: pain measures/scales (n=7), interventions (n=13), pharmaceuticals (n=17), pain expression/experiences (n=45), and pain conditions (n=70). The lack of research in pain measurement and scales (n=7) is discouraging, considering the emerging perspective that Indigenous peoples perceive their pain as ignored, minimized, or disbelieved. Conclusions drawn from the pain expression and experiences theme also highlight a divide between pain expression in Indigenous peoples and pain assessment in medical professionals. Conclusion: The limited research on pain measurement is discouraging in light of numerous studies reporting Indigenous Peoples experience their pain is ignored, minimized, or disbelieved. Furthermore, a clear disconnect emerged between pain expression in Indigenous Peoples and assessment in medical professionals. Overall, this review intends to translate current knowledge to other non-Indigenous academics and to initiate meaningful collaboration with Indigenous partners. Future research led by Indigenous academics and community partners is critically needed to better address pain needs in Canada.
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Background: The pelvic floor muscles (PFM) play a critical role in maintaining urogenital function. Pelvic floor muscle training (PFMT) is a commonly prescribed, non-invasive, exercise intervention to manage urinary incontinence. It involves the practice of voluntary contractions of the muscles to different intensities and durations, as well as in combination with different functional tasks. As a non-invasive intervention with few to no side effects, PFMT is an attractive intervention for the management of urinary incontinence in different clinical populations. Despite its known clinical benefits, we still do not have a full understanding of the underlying neurophysiological effects of the intervention.Objective: The objective of this study was to investigate the acute neurophysiological changes in sensorimotor pathways following a single session of PFMT, compared to a control intervention (biceps brachii contractions).Methods: We randomly assigned participants to either the experimental (PFMT) or control (biceps training) group. Participants completed a training program consisting of 55 contractions to different intensities and durations of either their PFM or biceps brachii. To examine changes in somatosensory excitability associated with the PFM, we used electroencephalography to record somatosensory evoked potentials in response to pudendal nerve stimulation. To examine changes in corticospinal excitability, we used surface electromyography to record motor evoked potentials from the PFM elicited by transcranial magnetic stimulation over the primary motor cortex. All measures were recorded before and after a single session of training and compared between groups.Results: Our data show no significant modulation in P40 amplitude of pudendal somatosensory evoked potential and PFM motor evoked potential amplitude. However, exploratory analysis suggests a possible relationship between intervention responder type (whether there was improvement in PFM contraction) and participant age, as well as somatosensory and corticospinal excitability.Conclusion: We found no acute modulation of somatosensory and corticospinal excitability of the PFM following a single session of PFMT. However, further exploration of the data revealed possible effect of age on the response to PFMT, as well as between responder type and changes in somatosensory and corticospinal excitability, which needs to be investigated further.
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Pain is a significant contributor to the development and potential persistence of motor dysfunction. A critical limitation to our understanding of motor related pain arises from measurements that overlook the contribution of movement in evoking pain. There is a pressing need to understand the influence of movement-evoked pain on motor system function during the stages of movement generation in pain inducing movements. The objectives of this thesis were two-fold. First, we aimed to examine how movement evoked pain influences cortical preparatory processes, muscle activity, and force/rate of force production (RFD) in healthy adults. Secondly, we aimed to explore whether cortical preparatory and peripheral changes persist in subsequent pain-free movement. Cortical preparatory activity was examined by the changes in event-related desynchronization (ERD) of beta (13-30 Hz) oscillatory activity and the movement-related cortical potential (MRCP) using electroencephalography (EEG) during a movement-evoked pain intervention. In addition, peripheral activity was assessed using electromyography (EMG), torque, and the rate of force development (RFD). These measures provide information about sensorimotor cortical activation and the cognitive factors that are involved in the preparation of movements that evoke pain. Peripheral measures provide complementary information on the pain induced adaptions to central motor pathways. The results showed a lack of change in beta ERD, an increase in the MRCP, and no changes in muscle activity and RFD with movements that evoked brief pain. Furthermore, there was no persistent change in any of these measures during subsequent pain-free movement. Transient movement-evoked pain changes aspects of preparatory corticomotor and peripheral activity; however, context dependent increases in the MRCP suggests that cognitive factors influence how the body adapts to the performance of movements that evoke pain.
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Laser evoked potentials (LEPs) provide an avenue to discern individual differences in nociception, to further understand pain perception. We aimed to investigate resting neurobiological differences that may contribute to the small and large responses to noxious laser stimulation in 50 participants (26 females). To do this, participants underwent a two-part protocol. First, LEPs and verbal pain ratings were collected at four different laser intensities, and the resultant signal amplitudes (N1, N2, and P2) were clustered, forming two respective groups for each LEP outcome of small vs. large signal amplitudes, as well as high vs. low pain ratings. Next, participants underwent a magnetic resonance spectroscopy (MRS) scan to measure excitatory glutamatergic activity within the cingulate cortex at rest in four regions: the anterior (ACC), anterior-mid (aMCC), posterior-mid (pMCC), and posterior (PCC) cingulate cortices. Glutamatergic activity (glutamate, glutamine, and combined (Glx)) was compared between each respective cluster across the four cingulate regions, with sex included as a covariate for glutamine specifically. We found three key findings: 1) Resting glutamatergic activity was significantly higher in anterior vs. posterior regions.2) Participants with higher verbal pain ratings had significantly higher glutamate concentrations in the ACC.3) Participants with larger P2 amplitudes had significantly higher glutamate concentrations in the PCC.These findings contribute to our knowledge and understanding of glutamatergic activity in the cingulate cortex at rest. Specifically, that pain ratings and P2 amplitudes (reflecting attention) are not equivocal, although they are both influenced by differences in regional cingulate activity, suggesting the involvement of the ‘hubs’ of the salience and default mode networks through the ACC and PCC, respectively. Further research expanding on our sample size, brain regions, metabolites investigated, and LEPs conditions will assist in further understanding the intrinsic neurobiological differences to provide further insight into different responses to nociception and pain.
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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
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Anticonvulsants like pregabalin (PGB) are the first-line treatment for neuropathic pain caused by traumatic injury and non-traumatic diseases of the central nervous system. Recent evidence from a human cohort study suggests that early use of pregabalin after spinal cord injury (SCI) may result in improved motor scores, however, it is unknown to what extent changes in spinal neural circuitry are involved. Backwards translation into a rat model is the first step towards understanding these possible changes. Using a rat model of unilateral cervical contusion, I examined the effect of pregabalin treatment on both motor and sensory function. For four weeks post-injury, rats were given daily pregabalin or filtered water via oral gavage. Motor function was scored using the Montoya staircase assessment (MSA) of fine motor skills. Additionally, pruritus and noxious mechanosensation were assessed through behavioural evidence of scratching and the Randall-Selitto analgesy-meter, respectively. I found no evidence of improved motor scores in the affected forelimb following MSA analysis with the early administration of pregabalin. There was an unexpected deterioration of motor function contralateral to injury, and this was mitigated by early PGB treatment. Additionally, I found that self-injurious scratching, often occurring in animals with this type of injury, was greatly reduced in those treated with PGB. Finally, results of the Randall-Selitto analgesy-meter indicate a protective effect of (PGB) even after its discontinuation. Our findings suggest that in rats with a unilateral SCI, pregabalin treatment has an at-time effect on pruritus and neuropathic pain, a possible protective effect on mechanosensory nociception, and contrary to a human cohort study, does not improve ipsilateral motor outcomes with early administration.
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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 (
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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.
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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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