Targeting hypokinesia in Parkinson's disease with quantitative measures and a computational model to determine its severity, its improvement from therapy, and explore underlying pathophysiological mechanisms [electronic resource]

Hypokinesia is one of the most disabling movement abnormalities caused by Parkinson's disease (PD). It is a clinical term that refers to the general reduction of mobility experienced by people with Parkinson's disease (PWPD). Hypokinesia affects movements in three ways: 1) movements are slow 2) movements are performed with reduced amplitude compared to what is required for the task and 3) it takes longer for PWPD to initiate movements. All of these impairments affect the ability of PWPD to perform common daily activities and can cause feelings of frustration and anger that may lead to altered self esteem, depression, and a reduction in their quality of life. Although effective treatments do exist for well-selected patients, there are many avenues open for improving current treatments, identifying new treatments, and understanding mechanisms of hypokinesia that could potentially lead to more effective therapies and greatly impact the lives of PWPD. In this dissertation we sought to improve current treatments and provide opportunities for future treatments for hypokinesia by addressing three important clinical questions relating to hypokinesia. First, are there immediate improvements in hypokinesia from a surgical procedure called deep brain stimulation (DBS) that can be measured during surgery and used to help guide surgical decisions and optimize clinical outcomes? Second, can we determine what types of movements are affected by hypokinesia in early stage, untreated PD in order to provide an objective metric used to assess an emerging treatment for PD? Third, might perceptual deficits that are linked to sensory processing impairments play a role in the manifestation of hypokinesia? If so, targeting these deficits may provide new and better therapies. We addressed these questions by using the quantitative and computational techniques outlined in the next three paragraphs. A common treatment for advanced PD is a surgical procedure called DBS. The surgery is performed on awake patients, and it entails surgically implanting electrodes (leads) that provide chronic stimulation to the affected brain area that controls movement. Although the treatment is almost always effective, the degree of improvement in hypokinesia varies among patients. The accuracy of the placement of the DBS lead in the affected area is believed to have the most effect on the improvement of hypokinesia. We suggest that using quantitative measurements of hypokinesia to evaluate the efficacy of the location of the DBS lead in improving hypokinesia during the surgical procedure might therefore improve the overall clinical outcomes. The surgical team would then have objective, accurate measurements of the degree of improvement in hypokinesia during the surgery, when the lead's position in the brain could be modified to achieve optimal results. Therefore, we designed a prospective study to measure upper extremity hypokinesia using a quantitative measure of angular velocity. Analysis of 98 DBS procedures performed on 61 patients showed that on average there was an 81% improvement in quantitative measures of hypokinesia from implanting and activating the DBS lead (p< 0.03). This study demonstrated that objective, high-resolution, accurate measurements of improvements in hypokinesia from intra-operative DBS are possible in this highly constrained environment and could therefore be used to help guide surgical decisions and optimize clinical outcomes. PD has no cure, but treatments in the near future may include disease-slowing medications. Although few studies have characterized the motor control abnormalities of very early stage PD, when symptoms are mild and usually unilateral, this group is the most targeted for potential disease-modifying therapeutics. In this study, we asked if quantitative measures of finger, limb, and postural movement velocity could detect hypokinesia in 20 patients with very early stage, untreated PD. The results revealed evidence of significant finger and limb hypokinesia of the patient group's more affected side when compared to the non-dominant side of 19 age-matched healthy adults (HAs) (p=0.001 and p< 0.001, respectively). Furthermore, the patient group's limb movement velocity on the more affected side was significantly slower than their less affected side (p=0.005), highlighting the importance of using an outcome measure that is lateralized in studies of very early stage PD. In contrast to our previous study that revealed significant postural hypokinesia in patients with advanced PD, we did not detect postural hypokinesia in patients with very early stage, untreated PD. Based on these findings, we suggest that the use of quantitative lateralized measures of hypokinesia would be useful in neuroprotective clinical studies of very early stage, untreated PD and may improve the chances of detecting a disease-modifying effect of potential neuroprotective therapeutics. Detecting such a therapy would have a large impact by improving the lives of PWPD. Although hypokinesia is considered a movement abnormality, new research is suggesting that perceptual deficits may play a role in the manifestation of abnormal movements in PWPD. Motor control theory posits that a sensorimotor integration process (SIP) is used by the central nervous system to perceive and control movement by combining internally generated predictions of movement parameters with the processing of sensory feedback. A previous study examining the SIP demonstrated that HAs overestimated their limb position in the direction of movement, and that the error and its variance (VOE) depended on movement duration. Using quantitative measures of hypokinesia, we asked if PWPD showed errors in perceived limb position and if the dependence on movement duration was different from HAs. We used an established computational model of the SIP to explore mechanisms for the error and VOE as a function of movement duration. Twenty PWPD, off medication, and 20 age-matched HAs were asked to estimate the position of their hand after performing 50, slow, non-visually guided wrist flexion or extension movements for a random period of time (< 4.0 sec). Both groups overestimated the amount they moved; however, the PWPD's error and VOE were larger (p< 0.001). More specifically, HAs exhibited increasing error/VOE for small movement durations that reduced/stabilized for longer movement durations. PWPD, however, showed increasing error/VOE with increasing movement duration that did not significantly improve/stabilize. The results from the model revealed an 88% increase in the variance (noise) in the sensory feedback parameter in PWPD compared to HAs, which suggests the PWPD's SIP could no longer effectively access sensory feedback information to correct errors in other components of the SIP due to the large amount of noise in this signal. This study provides experimental evidence that perceptual deficits may play a role in hypokinesia and computational evidence that abnormal processing of sensory feedback in PWPD's SIP could contribute to increased perceptual error in limb position after non-visually guided movements. The work in this dissertation quantified the immediate improvements in hypokinesia from intra-operative DBS, the presences of hypokinesia in early stage, untreated PD, and the degree of perceptual deficits and their dependency on movement duration in PD. Furthermore, this research has provided evidence for possible mechanisms for hypokinesia. Taken together, this work has the possibly to provide immediate improvements for current treatments and provides several platforms for future therapies to treat hypokinesia and improve the lives of PWPD.

Keywords: Mechanical Engineering
Advisor: Delp Scott primary advisor. Thesis advisor
Bronte-Stewart Helen advisor. Thesis advisor
Shenoy Krishna V. (Krishna Vaughn) advisor. Thesis advisor