This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.
Date of Award
Doctor of Philosophy (PhD)
Parkinson disease (PD) is a neurodegenerative disease with multiple motor and non-motor symptoms, including postural instability, gait impairments, and cognitive deficits. More than 50% of individuals with PD experience a symptom called freezing of gait (FOG), described as a transient inability to take another step forward. Individuals with PD who experience FOG (freezers) have further postural, gait, and cognitive impairments compared to individuals with PD without FOG (non-freezers). While degeneration of the dopaminergic neurons in the substantia nigra is accepted as the primary etiology of the disease, research shows that the disease has a global impact on the brain, accounting for the multiple symptoms displayed by people with PD.
People who experience freezing, in particular, show altered function of multiple neural networks. One theory on the mechanisms underlying FOG suggests that freezers have decreased attentional resources, and competing demands from motor and non-motor functions can exceed these limited attentional resources, leading to a freezing episode. Specifically, the theory, in conjunction with other research, proposes that the pedunculopontine nucleus (PPN) may be involved in the mechanisms underlying FOG. Changes in PPN connections with the cerebellum and cortical regions in freezers suggest that the cerebellum may play an integral role in the pathogenesis of FOG. Not only does the cerebellum impact movement, but growing research shows its involvement with cognitive function. Therefore, this dissertation examines FOG through multiple lenses to better understand the potential role of the cerebellum in FOG pathogenesis. Based on prior research, we expected to find novel evidence of cerebellar structural and functional differences in freezers compared to non-freezers. Additionally, we hypothesized freezers would exhibit similar cognitive and motor characteristics as individuals with cerebellar damage (i.e., cerebellar patients), further supporting the theory of the cerebellum’s involvement in the manifestation of FOG.
Three studies were conducted to investigate the mechanisms, mechanics, and management of FOG in PD, providing a broader understanding of the symptom and its impact. Study one (chapter 2) sought to compare cerebellar volumes in freezers and non-freezers, hypothesizing that freezers would have decreased volumes. We applied a spatially unbiased cerebellar atlas to anatomical MRI images of the cerebellum to get a reliable estimate of the individual volumes of the cerebellar lobules. Surprisingly, there were no volumetric differences between freezers and non-freezers. Study one also looked at relationships between cerebellar volumes and cognitive task performance, as cerebellar patients have associated cognitive deficits. We hypothesized volumes of the cerebellum would positively correlate with cognitive task performance. While freezers had decreased cognitive performance compared to non-freezers, volume and cognitive performance were negatively correlated in the non-freezers only.
Study two (chapter 3) examined the joint mechanics of freezers and non-freezers during multiple walking conditions. Freezers show greater spatiotemporal gait deficits (e.g., velocity and stride length) during forward, backward, and dual-task walking, suggesting that the way freezers move their joints during gait may be altered. To determine whether and how joint movements are altered in freezers, we used three-dimensional motion capture techniques to track the movements of the hip, knee, and ankle in various walking conditions, and conditions were compared between freezers and non-freezers. We hypothesized freezers would have greater amounts of single-joint, rather than multi-joint, movements during the gait cycle compared to non-freezers. We assessed single-joint movement by calculating a decomposition index between any two joints, giving a metric for how much one joint was held steady while the other joint moved. This analysis showed that freezers decompose their movement during gait more than non-freezers, particularly between the hip and both the knee and ankle. This increased movement decomposition echoes symptoms seen in cerebellar patients. We also hypothesized a principal component analysis on gait cycle variability would be able to differentiate freezers and non-freezers. While neither group significantly differed in variability from the other, backward gait had different sources of variability than forward or dual-task gait.
The third and final study (chapter 4) examined exercise as a means of managing symptoms in PD. Additionally, this study probed underlying neural changes associated with improvements in gait due to exercise. We collected functional MRI data before and after a 12-week exercise intervention from both freezers and non-freezers. During the MRI session, participants were asked to imagine themselves walking forward and backward. We used a region of interest analysis to examine activity in the parts of the somatomotor network while participants performed the task. As backward gait is a more challenging and less familiar movement, we hypothesized that imagining backward gait would result in increased activity in regions of the somatomotor network. We also hypothesized freezers would have reduced activity in the cerebellum overall, providing evidence for cerebellar dysfunction in freezing of gait. Though there were no significant changes in either gait performance or functional MRI signal in any of the regions of interest, freezers consistently had decreased signal when imagining backward gait, particularly in the cerebellar region of the somatomotor network.
Together, these studies examined FOG from multiple angles. The results support potential cerebellar involvement in FOG, suggesting decreased recruitment of the somatomotor network and symptomatology that resembles that of cerebellar patients. The results may also inform rehabilitation for freezers and non-freezers. While response to exercise did not differ between the groups, the similarity of freezer symptoms with cerebellar patient symptoms may be important to consider when developing new interventions.
Chair and Committee
Gammon M. Earhart
Meghan C. Campbell, Gretchen A. Meyer, Dan W. Moran, Michael J. Mueller,
Myers, Peter S., "Freezing of Gait: Mechanisms, Mechanics, and Management" (2018). Arts & Sciences Electronic Theses and Dissertations. 1721.
Available for download on Saturday, December 05, 2020