[Truncated abstract] There is overwhelming evidence that PD leads to impairments in executing voluntary movements. However, it is less clear whether it also leads to impairment in the preparation of movement. The current investigation first aims to further our understanding of motor preparation in people with PD. Two techniques are commonly used to assess motor preparation. These are the manipulation of response complexity and cueing response-related information in advance of the imperative signal. They were both incorporated into a motor task in which participants performed two-movement sequences on a response board. In Experiment 1, people with PD (comprising two groups one on their anti-Parkinsonian medication, and the other following a delay in its normal administration) showed patterns in their motor performance that was similar to healthy age-matched adults. They showed lengthening in their reaction time (RT) with increased response complexity, indicating that the sequences were prepared before their initiation. In addition, both of the PD groups, as well as the healthy adult group, showed shorter RTs with valid cueing and longer RTs with invalid cueing relative to the neutral cue condition. In response to a part-invalid cue (with both valid and invalid information) all three groups had very similar RTs to that in the neutral cue condition. ... in the third experiment, participants were first presented with a sequence to perform, and then, while initiating and executing that sequence, they were presented with a second sequence, providing either valid or invalid visual information about the twomovement sequence. It was expected that if invalid visual information evokes a stronger obligatory response in people with PD, then these participants would experience greater difficulties ignoring such information. This was not found to be the case. Rather the PD group showed a similar pattern of performance to the healthy adults. This indicates that they were able to ignore visual information when it was invalid and unhelpful, and so suggests that people with PD use external information strategically. The results presented in this thesis suggest that motor preparation is largely intact in people with PD. Motor preparation may, however, be incomplete under reduced visual information. Furthermore, while visual information may be particularly important to people with PD, it does not seem to evoke a stronger obligatory response than in healthy adults. Rather, people with PD seem to use external information strategically.

Thesis (M. Sc.)--Carleton University, 2005. / Includes bibliographical references (p. 52-61). Also available in electronic format on the Internet.

Thesis (M.S.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 48-57). Also available on the World Wide Web.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (Ph. D.)--Rutgers University, 2010. / "Graduate Program in Chemistry and Chemical Biology." Includes bibliographical references (p. 153-165).

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (M.S.)--Oregon State University, 2006. / Printout. Includes bibliographical references (leaves 55-60). Also available on the World Wide Web.

The motor symptoms of Parkinson's disease (PD) have been linked to the emergence of exaggerated oscillatory activity in the 13 - 35 Hz beta range in recordings of the basal ganglia (BG) thalamocortical circuit of PD patients and animal models. PD patients and animal models also express dopamine-dependent cognitive impairments, implying effects of dopamine loss on the function of the anterior cingulate cortex (ACC). This thesis examines the electrophysiological behavior of the BG thalamocortical circuit in PD and dopamine-normal states during cognitive and motor activity. In vivo recordings in the BG of PD and dystonic patients were used to study the influence of dopamine during a test of executive function. Normal executive function was also investigated in the dopamine-healthy ACC of chronic pain patients. Both the BG and ACC exhibited lateralized electrophysiological responses to feedback valence. The BG also exhibited dopamine-sensitive event-related behavior. In additional experiments, chronically implanted recording electrodes in awake, behaving hemiparkinsonian rats were used to examine the transmission of synchronized oscillatory activity from the BG, through the ventral medial (VM) thalamus, to the ACC. Modulation of subthalamic nucleus, VM thalamus, and ACC activity during a simple cognitive/movement task was also investigated in hemiparkinsonian rats. Findings in the rat model suggest that ACC-mediated executive function is dopamine-sensitive and is reflected in the region's electrophysiology. These results may provide further insight into the significance of excessive oscillatory activity in PD and its influence on cognitive systems.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α- syn) is the major component of Lewy bodies (LBs) in PD, and impairment of the autophagy-lysosomal pathway has been linked to its accumulation. In our previous study, we identified corynoxine B (Cory B), an oxindole alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), as a Beclin-1-dependent autophagy enhancer. In this work, we continued to screen autophagy enhancers from Gouteng alkaloids, and found corynoxine (Cory), an isomer of Cory B, also induces autophagy in different neuronal cell lines and primary neurons. Meanwhile, Cory promotes the formation of autophagosomes in the fat bodies of Drosophila. By inducing autophagy, Cory promotes the clearance of wild-type and A53T α-syn in inducible PC12 cells. Interestingly, different from its enantiomer Cory B, Cory induces autophagy through the Akt/mTOR pathway as evidenced by the reduced levels of phospho-TSC2, phospho-Akt, phospho-mTOR and phospho-p70 S6 Kinase. To identify the different pathway between Cory and Cory B, we performed phosphoproteomic study on N2a cells. With the help of iGPS (In vivo Group-based Prediction System), protein kinases which were significantly regulated by Cory or Cory B were predicted. Based on these kinases, we drew the detailed kinasesubstrates network regulated by Cory or Cory B. The structures of Cory and Cory B differ only in the stereochemistry at the spiro carbon; however, Cory has more effect on the CAMK, Trb and TSSK families, while CDK and CDKL families are more sensitive to Cory B. Furthermore, we established a rotenone rat model of PD via injecting rotenone into the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), and evaluated the neuroprotection of Cory and Cory B on this rat model. Motor dysfunction, decreased TH level, impairment of autophagy, aggregation of α-syn and activation of microglia were all found on this PD model, which were consistent with previous reports. After the treatment of Cory or Cory B, we found that both Cory and Cory B improve motor dysfunction, increase the TH level, and inhibit microglial activation. Both Cory and Cory B decrease the puncta number of aggregated α-syn, likely due to the induction of autophagy. All these results indicate the neuroprotection of Cory and Cory B against PD. Collectively, our findings (1) provide the original finding of Coy to be an autophagy enhancer with experimental evidences that Cory inhibited the pathway of Akt/mTOR; (2) provide cellular and animal experimental evidences for developing Cory or Cory B as anti-PD agent, by inducing autophagy in neurons; and (3) provide candidate pathways to identify the primary molecular target of Cory or Cory B, which may turn out to be potential therapeutic targets for treating PD. Keywords: Parkinson’s disease, Cory, Cory B, autophagy, phosphoproteomic, neuroprotection.

abstract: The efficacy of deep brain stimulation (DBS) in Parkinson's disease (PD) has been convincingly demonstrated in studies that compare motor performance with and without stimulation, but characterization of performance at intermediate stimulation amplitudes has been limited. This study investigated the effects of changing DBS amplitude in order to assess dose-response characteristics, inter-subject variability, consistency of effect across outcome measures, and day-to-day variability. Eight subjects with PD and bilateral DBS systems were evaluated at their clinically determined stimulation (CDS) and at three reduced amplitude conditions: approximately 70%, 30%, and 0% of the CDS (MOD, LOW, and OFF, respectively). Overall symptom severity and performance on a battery of motor tasks - gait, postural control, single-joint flexion-extension, postural tremor, and tapping - were assessed at each condition using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and quantitative measures. Data were analyzed to determine whether subjects demonstrated a threshold response (one decrement in stimulation resulted in ≥ 70% of the maximum change) or a graded response to reduced stimulation. Day-to-day variability was assessed using the CDS data from the three testing sessions. Although the cohort as a whole demonstrated a graded response on several measures, there was high variability across subjects, with subsets exhibiting graded, threshold, or minimal responses. Some subjects experienced greater variability in their CDS performance across the three days than the change induced by reducing stimulation. For several tasks, a subset of subjects exhibited improved performance at one or more of the reduced conditions. Reducing stimulation did not affect all subjects equally, nor did it uniformly affect each subject's performance across tasks. These results indicate that altered recruitment of neural structures can differentially affect motor capabilities and demonstrate the need for clinical consideration of the effects on multiple symptoms across several days when selecting DBS parameters. / Dissertation/Thesis / Ph.D. Bioengineering 2013