published_or_final_version / Anatomy / Master / Master of Philosophy

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

Functional magnetic resonance imaging (fMRI) has become a widely used technique for non-invasive brain mapping, and methods have now evolved to allow fMRI of the spinal cord (spinal fMRI) as well. With the goal of improving spinal fMRI, the studies presented herein have investigated potential sources of noise that might limit its sensitivity and reliability. For example, multiple studies had previously suggested that the majority of structured physiological noise, such as spinal cord motion and cerebrospinal fluid (CSF) flow, appeared to be synchronous with cardiac pulsations. Therefore, we measured cardiac-related spinal cord motion at various levels along the cord, finding that peak anterior-posterior spinal cord displacements often exceeded 0.5 mm throughout the cervical and upper-thoracic regions. On the other hand, we found that cord motion throughout the lower-thoracic, lumbar and sacral levels was consistently small. Based on these findings, we concluded that cord motion is likely to be a significant source of error in spinal fMRI throughout superior, but not inferior, cord regions. Since all motion measurements were acquired at 24 phases of the cardiac cycle, this also allowed us to determine, and subsequently model, the main components of cardiac-related spinal cord motion. By then including these terms in a general linear model (GLM) analysis and reanalyzing 100 previously acquired cervical spinal fMRI datasets, we showed that the sensitivity and specificity were improved by 15-20 % and 5-6 %, respectively, over previous spinal fMRI methods. To push the limits of these improvements, we then carried out the first event-related spinal fMRI study, consistently observing spinal cord responses to 1 s applications of 22 °C thermal stimulation. By measuring these responses at many different phases, we were also able, for the first time, to characterize the impulse response function of SEEP (signal enhancement by extravascular water protons) contrast in the human cervical spinal cord. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2010-08-23 13:35:36.534

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Serotonin (5-HT) is a well-known modulator of spinal cord excitability and motor output. In the spinal cord, the actions of 5-HT are primarily mediated by the 5-HT1AR, 5-HT2Rs and the 5-HT7R. Following a spinal cord transection, which results in a loss of supraspinal input, 5-HT agonists such as quipazine are used to provide excitation to the spinal cord to facilitate locomotor recovery. This is characterized by rhythmic alteration of left and right hindlimbs and ipsilateral flexor and extensor muscles. However, whether 5-HT has a global effect on spinal cord excitability or is confined to a specific motor group (i.e. flexors or extensors) is currently unknown. Furthermore, quipazine is used in conjunction with activity based interventions to enhance recovery following a spinal cord injury. However, the influence of limb activity on the responsiveness of the injured spinal cord to quipazine has not been examined. Lastly, the recovery of locomotion is at least in part thought to occur through an up-regulation of 5-HT receptors, although this has not been investigated in lumbar spinal cord. Chapter 2 examines whether quipazine had a differential effect on flexor and extensor motor output assessed by recording flexor and extensor reflexes, motoneurons and Ia extracellular field potentials pre- and post-quipazine. It was determined that following an acute spinal transection, quipazine induced a larger flexor monosynaptic reflex (MSR) compared to the extensor MSR due to pre-synaptic but not motoneuron modulation. Chapter 3 examines the influence of a chronic spinal transection with and without passive cycling on the hindlimb flexor and extensor MSR, both pre- and post-quipazine. It was found that three months post STx, the extensor but not flexor MSR demonstrated a hyperexcitable response, which was attenuated with passive cycling. Further, three months of passive cycling extensor MSR response to quipazine was similar to that seen in the control intact group. Chapter 4 examined 5-HT receptor expression in flexor and extensor motoneurons three months post spinalization with or without passive cycling. Following a chronic STx, the 5-HT1AR and 5-HT2CR are down regulated, whereas the 5-HT2AR is up-regulated. Passive cycling further enhanced the 5-HT2AR expression as well as up-regulated the 5-HT7R in extensor but not flexor motoneurons. Chapter 5 discusses the results and significance of these findings in detail.

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This study has investigated the role of neurokinin receptors, in particular the NK-1 receptor, in the regulation of excitability of SPN using selective agonists and antagonists. The whole-cell patch clamp technique was used to record from SPN in transverse slices of neonatal rat spinal cord <I>in vitro</I>. Neurones were positively identified as SPN due to their characteristic electrophysiological and morphological properties. Perfusion of the selective NK-1 receptor agonist GR73632 (25 nM-5μM; 2-120 s) induced concentration-dependent depolarising responses in SPN. The response to GR73632 (67% of SPN responsive) was maintained in the presence of TTX (250-500 nM), suggesting that NK-1 receptors are located directly upon SPN. The depolarising response to GR73632 was associated with an increase in neuronal input resistance, reduced with increasing membrane hyperpolarisation, and blocked by two selective NK-1 receptor antagonists, CP-99,994 (1-3 μM) and GR82334 (250 nM-1 μM). Excitatory postsynaptic potentials and strychnine-sensitive inhibitory postsynaptic potentials were also induced by GR73632 in approximately 10% of neurones. Application of GR73632 to a subpopulation of silent SPN induced rhythmical oscillations in membrane potential. The induction of oscillations following NK-1 receptor activation can lead to synchronised action potential firing within groups of SPN. This study has presented preliminary evidence to suggest that a presynaptic NK-1 receptor may exist upon the terminals of neurones which descend from supraspinal centres in synapse upon SPN. Activation of this subtype of NK-1 receptor was found to exert an inhibitory influence upon glutamatergic synaptic transmission to SPN. The results from this study suggest that activation of the NK-1 receptor may have a major excitatory effect upon the activity of SPN, probably by causing the closure of potassium channels open at rest.

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This dissertation presents the prediction of quality of life (QoL), composed of by life satisfaction and self-perceived health status, across 5 years post a spinal cord injury (SCI) hospital discharge. Predictor variables of functional independence, pain, and family satisfaction, as mediated by environmental accessibility are examined. Environmental accessibility is conceptualized as being composed of mobility and social integration. Data are a subset from a longitudinal study of adjustment following disability. Two models were examined in order to predict QoL, Model 1 (Life Satisfaction) and Model 2 (Self-Perceived Health Status). Results from this study were obtained by testing models using path modeling. Evaluation indices suggest good to adequate model fit, CFI, RMSEA, and SRMR for Model 1 and Model 2. In Model 1, results indicated that mobility and social integration, components of environmental accessibility, mediated the relationship between functional independence and life satisfaction (beta = 0.243, p = 0.009 and beta = 0.120, p = 0.038, respectively). In Model 2, the component of mobility of environmental accessibility mediated the relationship between functional independence and self-perceived health status (beta = 0.288, p = 0.002). Results indicate that access to the environment is an important predictor of life satisfaction and perceived health status five years after medical discharge for a traumatically-acquired SCI. These factors of environmental access ? mobility and social integration ? appear to be more important determinants of quality of life post-SCI than functional impairment or the presence of pain. Programs that enhance mobility and social integration following return to the community following SCI may be indicated. Furthermore, given that the construct of environmental accessibility is relatively new, studies that examine this construct are needed in order to better understand how it is best conceptualized.