Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Jog, Mandar

Abstract

Dopaminergic replacement therapies (e.g. levodopa) provide limited to no response for axial motor symptoms including gait dysfunction and freezing of gait (FOG) in Parkinson’s disease (PD) and Richardson’s syndrome progressive supranuclear palsy (PSP-RS) patients. Dopaminergic-resistant FOG may be a sensorimotor processing issue that does not involve basal ganglia (nigrostriatal) impairment. Recent studies suggest that spinal cord stimulation (SCS) has positive yet variable effects for dopaminergic-resistant gait and FOG in parkinsonian patients. Further studies investigating the mechanism of SCS, optimal stimulation parameters, and longevity of effects for alleviating FOG are warranted. The hypothesis of the research described in this thesis is that mid-thoracic, dorsal SCS effectively reduces FOG by modulating the sensory processing system in gait and may have a dopaminergic effect in individuals with FOG. The primary objective was to understand the relationship between FOG reduction, improvements in upper limb visual-motor performance, modulation of cortical activity and striatal dopaminergic innervation in 7 PD participants. FOG reduction was associated with changes in upper limb reaction time, speed and accuracy measured using robotic target reaching choice tasks. Modulation of resting-state, sensorimotor cortical activity, recorded using electroencephalography, was significantly associated with FOG reduction while participants were OFF-levodopa. Thus, SCS may alleviate FOG by modulating cortical activity associated with motor planning and sensory perception. Changes to striatal dopaminergic innervation, measured using a dopamine transporter marker, were associated with visual-motor performance improvements. Axial and appendicular motor features may be mediated by non-dopaminergic and dopaminergic pathways, respectively. The secondary objective was to demonstrate the short- and long-term effects of SCS for alleviating dopaminergic-resistant FOG and gait dysfunction in 5 PD and 3 PSP-RS participants without back/leg pain. SCS programming was individualized based on which setting best improved gait and/or FOG responses per participant using objective gait analysis. Significant improvements in stride velocity, step length and reduced FOG frequency were observed in all PD participants with up to 3-years of SCS. Similar gait and FOG improvements were observed in all PSP-RS participants up to 6-months. SCS is a promising therapeutic option for parkinsonian patients with FOG by possibly influencing cortical and subcortical structures involved in locomotion physiology.

Summary for Lay Audience

Shuffling, freezing in place and slowness can force people living with Parkinson’s disease (PD) and Richardson’s syndrome progressive supranuclear palsy (PSP-RS) to lose independence and become housebound. Treating these walking problems is very challenging as available treatment options, such as dopamine replacement therapies (the gold standard is levodopa) or deep brain stimulation (which is surgical), do not improve these symptoms and have left a large patient population untreated. A new approach to regain mobility and reduce freezing is spinal cord stimulation (SCS), an implantable battery that delivers electrical pulses to a patient’s spinal cord and stimulates nerve fibers within the spinal cord. In this thesis, dramatic improvements in walking speed, longer strides and significant reduction in freezing were seen in 5 PD patients with up to 3-years of therapy and in 3 PSP-RS patients with up to 6-months of therapy. However, it is not fully understood how SCS works to relieve freezing in PD. The theory is that SCS improves the way the brain perceives the environment thereby altering movement. This sensory-motor processing is dysfunctional in PD freezers. Both freezing and hand-eye coordination, measured by targeting shapes on a screen using their hands to move a robotic device, were improved over 6-months with SCS therapy in PD patients. The reduction in freezing was related to changes in brain activity of areas associated with sensory processing and movement control, which was independent of levodopa use (without dopamine replacement therapy). Thus, SCS may reduce freezing episodes by improving how the brain perceives and processes sensory information and ultimately refines movement (e.g. walking). Additionally, improvements in hand-eye coordination skills were related to changes in the deep brain structure (striatum), which is otherwise altered in PD due to the loss of dopamine producing cells. This current thesis suggests that freezing may be associated to the activity of brain areas for motor planning and locomotion and that hand-eye coordination skills may be related to changes in the presence of dopamine producing cells. SCS is a promising therapeutic option for PD and PSP-RS patients with primarily freezing in place who are unresponsive to currently available therapies.

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