Browsing by Subject "Parkinson's disease"
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Item Development of Computational Models of Pedunculopontine Nucleus Stimulation for Clinical Trials and Mechanistic Studies(2016-03) Zitella Verbick, LauraDeep brain stimulation (DBS) in the pedunculopontine nucleus (PPN), a component of the mesencephalic locomotor region in the brainstem, has been proposed to alleviate gait and balance disturbances associated with Parkinson’s disease; however, clinical trials results have been highly inconsistent. Such variability may stem from inaccurate targeting in the PPN region, modulation of fiber pathways implicated in side effects, and lack of understanding of the modulatory effects of DBS in the brainstem. Here, we describe the development and refinement of computational models that can predict the neuromodulatory effects of PPN-DBS in both the non-human primate and human. These models included (1) brain atlas-based models that combined detailed biophysically realistic neuron and axon models with a finite element model simulating the voltage distribution in the brain during DBS, (2) high-field 7T MRI techniques to visualize and create volumetric morphologies of structures in the brainstem for use in the models, and (3) clinically relevant subject-specific computational models that incorporate the anisotropic conductivity of the brain tissue. Based on the validated results of these models, we can conclude that the neuronal pathways modulated by DBS in the brainstem are highly sensitive to both lead location and stimulation parameters. These computational models of DBS will be useful in future clinical trials, both prospectively to plan DBS lead trajectories and improve stimulation titration and retrospectively to investigate the underlying mechanisms of therapy and side effects of stimulation.Item Development of model-based and sensor-based programming techniques for optimizing directional deep brain stimulation therapy for movement disorders(2022-01) Brinda, AnneMarieDeep brain stimulation (DBS) therapy is a programmable neurosurgical intervention that can significantly improve quality of life for individuals with medication-refractory movement disorders, such as Essential Tremor and Parkinson’s Disease. However, clinical outcomes with DBS therapy still vary across patients, and the clinical time and effort necessary to program the stimulation settings to each patient’s symptoms presents practical challenges in the clinic. With the advent of directional lead technology and independent multi-channel current-controlled stimulation, the scope of possible DBS configurations is now substantially larger than it was even five years ago. This has greatly increased the time to determine the most effective electrode configuration, and in reality, much of the stimulation parameter space is left unexplored during a clinical visit. This thesis addressed the gap between the directional lead technology and its clinical implementation by developing three promising techniques to program directional DBS lead systems. The first programming technique involved developing subject-specific computational models of DBS based on individual MRI/CT scans. Comparing model predictions to clinical outcomes from patients with Essential Tremor revealed that lateral and medial parcellations of the motor-thalamic afferents of the cerebellothalamic tract were differentially associated with stimulation-induced therapy and side effects, respectively. Second, sensor-based evaluation of DBS in Essential Tremor patients revealed that directional contacts were superior to ring-mode contacts in providing optimized tremor reduction with reduced dysarthria. The third programming technique involved using neurophysiological feedback to guide the selection of which electrode(s) to use during DBS. In Parkinson’s disease, for example, stimulation through electrodes with higher resting-state beta-band oscillatory power in the subthalamic nucleus generally results in better clinical outcomes. Using a non-human primate model, we tracked how beta-band power changed spatially and temporally between intraoperative and chronic time points and showed that the strongest variability occurred within the first two weeks after lead implantation. This suggested that neurofeedback-based programming may be most consistent after the immune tissue response settles. Together, these results showed how model- and sensor-based programming techniques can limit the parameter space for programming directional DBS enabling more efficient and effective clinical outcomes in the future.Item The Dual Dependency of Varying Liposomes and Protein on Available αS Conformers(2016) Peterson, Kathrynα-Synuclein (αS) is a protein commonly found in protein aggregates associated with Parkinson’s disease (PD). This intrinsically disordered protein is known to regulate synaptic vesicle (SV) trafficking in the pre-synaptic clefts of most neurons. Improper trafficking of SVs results in miscommunication between neurons, which could lead to symptoms of PD such as muscular tremors. Despite the prevalence of PD, much is still left unknown about the mechanism that causes protein aggregation due to αS binding to SVs. SVs are unique membranes as a result of their high cholesterol content (45%) and small diameter (0.03 microns). Both factors induce strain in the membrane leading to high fusion potential of the SV. For this research two SV mimics (simple and complex) were designed, utilizing a mass spectrometry study on SV membrane composition.1 The simple SV mimic measured the effects of interacting head groups and cholesterol on membrane annealing in the presence of αS using a Carboxyfluorescein (CF) release assay .To further probe the question of conformational changes of αS in the presence of membrane Circular Dichroism (CD) monitored the secondary structure character. Both membrane annealing and a change in secondary structure were observed making it necessary to further investigate the relationship between protein and membrane with other methods. Using Differential Scanning Calorimetry (DSC) to monitor a lipid transition I hypothesized that αS has specificity for high curvature and complex composition of membrane. We tested this by varying liposome sizes and cholesterol content. Oppositely, the membranes impact on αS conformers was studied utilizing a DSC protein transition to see its effects. A conformational shift was found in the presence of complex SV mimic, showing αS’s conformational specificity for this highly complex mimic. Due to this preference, a binding mechanism using the complex SV mimic needs to be studied. The mechanism of αS binding to membrane has the potential to shed light on the pathogenesis of αS in amyloid formation. Through Isothermal Titration Calorimetry (ITC) we will predict a simulated binding model for αS that will give more information about possible reasons for protein aggregation and benefit future studies on PD.Item Effects of subthalamic nucleus DBS on haptic perception and sensorimotor control in Parkinson's disease(2012-11) Aman, Joshua EmanuelParkinson’s disease (PD) is a neurodegenerative disease that affects the basal ganglia-thalamocortical pathway resulting in a progressive decline in motor function. An established treatment for the motor symptoms of PD is deep brain stimulation (DBS) of the subthalamic nucleus (STN). Mounting evidence suggests that PD is also associated with somatosensory deficits, specifically a loss of kinaesthetic and haptic precision, yet the effect of STN-DBS on sensory processing is largely unknown. Thus, this study investigated whether STN-DBS affects somatosensory processing by systematically examining the precision of haptic perception of object size. Without vision, 11 PD patients with implanted STN-DBS and 9 healthy controls haptically explored the heights of two successively presented three-dimensional blocks using a precision grip. In each trial, a 6cm reference block was judged against a comparison block (heights: 5.2-6.8 cm). Participants verbally indicated which block was taller (perceptual judgment). While still grasping the comparison block, they then matched its perceived size by opening the non-probing hand accordingly (motor judgment). Patients were tested during ON and OFF stimulation, following a 12-hour medication wash-out period. Based on their verbal responses haptic discrimination thresholds (DT) at the 75% correct response level and areas of uncertainty were derived. Based on the hand kinematic data collected by a motion capture system, a grip aperture error (difference between grip aperture and actual block height) was calculated. The main results were: First, with their stimulators OFF, PD patients showed deficits in both perceptual and motor judgments compared to controls as measured by increased DT and aperture errors. When PD patients used their more affected hand to probe the block, DT was elevated by 233% (PD: 0.37 cm; controls: 0.11 cm) and mean aperture error increased by 97% (PD: 1.48 cm; controls: 0.75 cm). Second, DBS improved the precision of both perceptual and motor judgments. In the ON state, DT of the more affected hand decreased by 30% with respect to OFF state, while aperture error decreased by 15%. Third, probing with the motorically more affected hand resulted in less precise perceptual and motor judgments than probing with the less affected hand. This study offers first evidence that STN-DBS improves haptic precision. Results of this study speak to the notion that deficits seen in PD are not simply motor based, but rather a function of deficits in proprioceptive processing. We conclude that DBS-related improvements in movement accuracy are not explained by improvements in motor function alone, but rather by improved somatosensory processing.Item Factors Contributing to Rigidity Expression and Response to Pallidal Deep Brain Stimulation in People with Parkinson’s Disease(2021-09) Linn-Evans, MariaParkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic cells in the substantia nigra, buildup of alpha-synuclein in specific regions of the brain, and the emergence of cardinal motor symptoms including rigidity, slowness of movement, tremor, and gait dysfunction. Despite these shared characteristics, there is a great deal of heterogeneity in symptom presentation and response to therapies within the population of individuals with PD. Understanding the driving factors behind this heterogeneity is crucial for developing targeted and effective therapies for the disease and improving outcomes for those living with Parkinson’s disease. In this dissertation, two studies are described: 1) an investigation into the effects of rapid eye movement (REM) sleep without atonia (RSWA) on the presentation of rigidity in a population of individuals with mild-to-moderate Parkinson’s disease and 2) the development and implementation of a computational model of pallidal deep brain stimulation (GP-DBS) to identify neural pathways associated with rigidity suppression in individuals with PD. Both studies utilize a quantitative measure of rigidity as a tool to assess symptom severity. In the first study, our findings demonstrate that people with mild to moderate PD and RSWA have dysfunctional regulation of muscle tone during both sleep and wakefulness. The results show that the presence of RSWA is associated with increased forearm rigidity magnitude and symmetry. In the second study, a patient-specific computational model of GP-DBS was developed and implemented. By combining pathway activation estimates from the model with quantitative measurements of rigidity, the analyses identified the internal capsule as an important pathway for reducing parkinsonian rigidity. In particular, profound decreases in rigidity were associated with activation of internal capsule fibers projecting from Brodmann’s area 6, which contains axons from premotor cortex and supplementary motor area. The results of these studies reveal the importance of understanding factors like RSWA that may drive heterogeneity in PD, while also identifying potential pipelines for developing symptom-specific targets for treatment.Item Investigating the effects of subthalamic nucleus stimulation on gait and pedunculopontine nucleus activity in a preclinical animal model of Parkinson’s disease(2022-02) Doyle, AlexandraDopamine-replacement therapy and deep brain stimulation therapy can reliably manage several cardinal motor signs of Parkinson’s disease including tremor, rigidity, and bradykinesia. The efficacy of these treatments on gait and postural dysfunction, however, are often variable and wane over time. This doctoral dissertation advanced our understanding of parkinsonian gait dysfunction by (1) defining spatiotemporal progression of gait changes with increasing parkinsonian severity in the MPTP non-human primate model of Parkinson’s disease, (2) characterizing changes in gait parameters with targeted subthalamic deep brain stimulation, and (3) defining how targeted subthalamic deep brain stimulation differentially affects neuronal spike rate and pattern changes in the pedunculopontine nucleus, which is a key structure in the mesencephalic locomotor region. The major findings were that the MPTP non-human primate model displays progressive bradykinetic gait that align with severity of other cardinal motor signs; however, asymmetric and disordered gait patterns only appeared in the more advanced parkinsonian state. Deep brain stimulation of the subthalamic nucleus showed a spatial map in of improving and worsening bradykinetic gait, and this map aligned with a differential effect on pedunculopontine nucleus modulation. These results suggest that deep brain stimulation can impart therapeutic effects on gait symptoms, but the effects depend on how one modulates pathways involved in locomotion. Such findings will be useful for future efforts to optimize deep brain stimulation for individuals with Parkinson’s disease.Item Investigating the mechanisms underlying synaptic and cognitive deficits in alpha-synucleinopathies(2019-06) Singh, BalvindarParkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically related -synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. While alpha-synuclein (aS) abnormalities are directly implicated in PDD and DLB pathogenesis, it is unknown how aS contributes to memory loss. Previously, we found that familial Parkinson’s disease (PD)-linked human mutant A53T aS causes aberrant mislocalization of tau to dendritic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the progressive postsynaptic and memory deficits observed in a mouse model of alpha-synucleinopathy (TgA53T) are mediated by tau. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau-/-) completely ameliorates cognitive dysfunction and concurrent synaptic deficits. Memory deficits in TgA53T mice were also associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau-/- mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results implicate tau as a mediator of human mutant A53T aS-mediated abnormalities and suggest a mechanism for memory impairment that occurs via synaptic dysfunction rather than synaptic or neuronal loss. Fibrillar species of aS have also recently been implicated as a pathogenic component of synucleinopathies, capable of transmission between neurons and brain regions including the hippocampus. However, how aS fibrils impact hippocampal function and contribute to memory deficits are not well understood. We hypothesized that aS fibril-induced synaptic changes could be mediated through interactions with other proteins, including tau. Primary hippocampal neurons acutely exposed to fibrillar aS species display tau missorting to dendritic spines and both pre and postsynaptic electrophysiological deficits. However, some of these findings may be a product of concentration-dependent fibril-induced spine collapse. Importantly, the pathways behind fibril-mediated tau missorting and synapse loss could be differentiated in vitro. Taken together, these studies suggest that pathological aS fibrils and aggregates may act through distinct intracellular and extracellular mechanisms to contribute to neuronal dysfunction and neuronal toxicity. These approaches and results collectively indicate that pathological mutant and aggregated species of aS can drive synaptic deficits and represent potential therapeutic targets for amelioration of memory deficits in alpha-synucleinopathies.Item Multi-joint rigidity-testing device for titrating medication and deep brain stimulation therapies(2014-08) Mohsenian, Kevin J.Disabling motor signs of Parkinson's Disease including akinesia, bradykinesia, tremor, and muscle rigidity are typically quantified by clinicians using the Unified Parkinson's Disease Rating Scale (UPDRS). These subjective assessments, while useful, often vary among clinicians, making it challenging to evaluate medication and deep brain stimulation (DBS) therapies in multi-center trials. In this study, two designs for a multi-joint rigidity-testing device were developed to enable objective, quantitative measures of rigidity. The investigator passively manipulated the subject's joints while stabilizing the appendage distal to the joint with two opposing force transducers, providing a measurement of differential force during the movement. These forces were synchronized to the joint angle, measured by a motion capture camera system. Here, we show feasibility data for detecting changes in muscle rigidity in a parkinsonian non-human primate treated with Sinemet, Globus Pallidus internal (GPi) DBS and/or subthalamic nucleus (STN) DBS. For design 1, the device was tested on six joints: elbow, wrist, shoulder, hip, knee and ankle, and in three states: MPTP, DBS stimulation, and drug therapy. Device 1 was effectively able to quantify rigidity and determine changes in rigidity states among all joints except elbow (p<0.05). For design 2, the device was tested on only the shoulder abduction/adduction and was tested in three states: MPTP, DBS stimulation, and post-DBS stimulation. Design 2 was effectively able to quantify changes in rigidity as well (p<0.05). Ergonomics and durability were considered in the evaluation of the devices. While each device showed promising results, future iterations will also need to address several limitations of the current devices. The eventual goal of this rigidity testing device would be to use it in the clinic to assist neurologists in titrating medication levels and DBS parameters.Item Orientation-Selective Programming Strategies for Targeted Deep Brain Stimulation(2019-12) Slopsema, JuliaDeep Brain Stimulation (DBS) is a neurosurgical intervention that can be highly effective for treating several movement disorders, including Parkinson’s disease and Essential Tremor. However, the degree to which this therapy works depends on precisely targeting stimulation to key neural pathways within the brain and avoiding activation of neural pathways that produce side effects when stimulated. This thesis developed the theoretical and experimental framework for a novel ‘orientation selective stimulation’ (OSS) approach to more selectively target neural pathways within the brain. The approach was investigated in the context of directional DBS leads with electrodes segmented both along and around the lead body. Computational models revealed that steering the primary direction of the electric field along the axonal pathways of interest in patient-specific models of Parkinson’s disease increased the therapeutic window between activation of a therapeutic hyperdirect pathway while limiting activation of the internal capsule, which is known to produce involuntary muscle contractions. The OSS approach was investigated in a swine model of DBS where OSS was applied through a 16-channel segmented DBS lead implanted in the ventral lateral (VL) thalamus while the swine were imaged with whole-brain fMRI. The results showed that BOLD activity in motor and premotor cortex were tuned to the orientation of the electric field adjacent to the lead with maximal activation occurring when the electric field was aligned to the cortico-thalamocortical pathway. Finally, patient-specific models of ventral intermediate nucleus (VIM) DBS for Essential Tremor were developed and revealed that portions of the superior cerebellar peduncle terminating in the external and internal regions of the VIM were differentially associated with therapy and side effects, respectively. OSS paradigms increased activation of the external VIM afferents and reduced activation of the internal VIM afferents. An OSS approach to programming has important clinical significance to enhance patient care by increasing therapeutic windows and could provide the ability to more selectively activate an individual pathway and evaluate its role in aspects of DBS therapy on individual symptoms.Item Programming and Sensing with Deep Brain Stimulation Arrays(2017-08) Zhang, SimengDeep brain stimulation (DBS) is a neurosurgical therapy for movement disorders that relies on both precise neurosurgical implantation of a DBS lead of electrodes and systematic optimization (or programming) of stimulation settings to achieve beneficial clinical outcomes. One recent advance to improve the targeting of stimulation is the development of DBS arrays with electrodes segmented both along and around the DBS lead. However, increasing the number of independent electrodes creates the logistical challenge of how to efficiently optimize stimulation parameters to target one or more pathways within the brain. This doctoral dissertation advanced the programming capabilities of DBS arrays by: (1) developing a multi-objective Particle Swarm Optimization (PSO) algorithm to program DBS arrays in the motor thalamus, and (2) investigating the PSO algorithm’s capacity to target DBS therapy within the globus pallidus (GP) and subthalamic nucleus (STN) for treating parkinsonian motor signs. With increased numbers of electrodes and decreased inter-electrode spacing, DBS arrays also open up opportunities to record local field potential (LFP) activity with improved spatial resolution, which could expand the feature set of neurophysiological feedback for closed-loop approaches to DBS therapy. This dissertation also (3) investigated the spatial resolution of local field potential (LFP) signals in the GP and STN in both resting state and during an active task in two non-human primates in both naïve and parkinsonian conditions. The primary findings of this dissertation suggest that the PSO algorithm produced solutions with accuracy, robustness, and consistency, and further that the PSO algorithm applied to targeting the STN in a parkinsonian non-human primate showed superior performance in reducing rigidity in comparison to conventional clinical monopolar review settings. Furthermore, it was demonstrated that segmented DBS arrays with higher density and smaller contacts were able to provide more spectral information within both GP and STN than could be sensed using grouped macroelectrode configurations consistent with commercial DBS leads. Together these results suggest that future translation of DBS array technology to the clinical setting will benefit both spatial and temporal optimization of DBS therapy on a patient-specific basis.Item Proneural transcription factor NeuroD1-mediated direct neuronal reprogramming - an AAV approach(2019-12) Radha, SwathiDirect cellular reprogramming to drive lineage switching from one differentiated cell type to another can be exploited to develop cell-based therapies for neurodegenerative diseases. In vivo reprogramming provides an attractive therapeutic strategy to circumvent the hurdles of immune rejection and ethical constraints associated with transplant-based therapy. Supporting glial cells of the CNS can be reprogrammed to neurons by targeted viral delivery of transcription factors and small molecules. Previous studies have demonstrated the effectiveness of a single proneural transcription factor NeuroD1 to drive reprogramming in the reactive glial lesions of Alzheimer’s disease and stroke. However, the ability of NeuroD1 (ND1) to promote a similar benefit in models of Parkinson’s disease (PD) has yet to be demonstrated. The current study aims to test the hypothesis that NeuroD1 delivered via an Adeno-Associated Virus (AAV) can promote reprogramming in striatal astrocytes to neurons in an in vivo PD model. The FDA-approved, clinically employed AAV-9 gene delivery platform was used to transduce non-dividing cells with minimal off-target effects. A two-part AAV-9 viral system was designed to express ND1 in astrocytes, driven by the GFAP promoter. First, ND1-mediated direct neuronal reprogramming was tested using a simple and scalable in vitro culture system. Primary astrocytes in vitro transduced with the AAV9-ND1 dual virus system display characteristics of immature neuroglial precursor stage, suggesting successful reprogramming. Second, the potential of ND1 to drive reprogramming was assessed in vivo in mice. Intracranial and intravenously delivered AAV-9 dual virus system driven by the GFAP promoter targets astrocytes and surprisingly, mature resident neurons in vivo. Finally, ND1-mediated in vivo reprogramming was assessed in a well-established chemically-induced 6-hydroxydopamine (6-OHDA) Parkinson’s disease mouse model. The 6-OHDA injury model provides insight into the novel application of the AAV-9 dual virus system to target astrocyte-to-neuron reprogramming as well as to target resident neurons for potential neuronal repair in Parkinson’s disease.Item Proprioceptive Training And Motor Transfer In Patients With Parkinson’S Disease(2016-12) Elangovan, NaveenParkinson’s disease (PD) is a neurodegenerative disorder that affects the motor system, but is also associated with sensory impairments, such as anosmia or proprioceptive dysfunction. Recent research on healthy individuals shows that a sensorimotor training which challenges the proprioceptive system improves both proprioceptive and motor function. However, it is unknown whether proprioceptive function can be enhanced in PD. It is further unclear, if an improved proprioceptive-motor function after learning leads to general improvements in motor performance. That is, the extent of transfer to other motor tasks is unknown. To fill this knowledge gap, this study employed a robot-aided visuo-proprioceptive motor training to people with PD with the following objectives: First, to identify whether proprioceptive function in Parkinson’s disease (PD) can be enhanced by a visuo-proprioceptive training that emphasizes precise, small amplitude continuous wrist movements. Second, to determine if proprioceptive improvements after training are associated with improvements in an untrained discrete wrist movement task, i.e. demonstrating a sensorimotor transfer within the same joint degree of freedom. Third, to identify if the training transferred to improvements in a functional writing task that relied on multi-joint wrist-hand motion, i.e. showing a sensorimotor transfer for additional joint degrees of freedom. METHOD: 13 participants presenting with mild to moderate PD were tested in their ON medication state. Training involved tilting a virtual table projected on a screen with the aim to position a virtual ball on a target by making continuous and precise small amplitude wrist flexion/extension movements. Wrist position sense acuity, spatial errors for the untrained, goal-directed wrist pointing movement (local transfer) and the more functional hand writing task were assessed before and after training. RESULTS: First, proprioceptive function was improved after training. As a group, PD participants showed a statistically significant reduction in position sense acuity thresholds (mean: pre/post = 1.6° / 1.1°). Second, significant evidence for a localized sensorimotor transfer was found. In the untrained discrete wrist pointing movement, 10 out of 13 participants (77%) recorded improvements in spatial movement precision error (mean: pre/post = 2.4° / 1.8°). Third, spatial error measured in handwriting based tracing and tracking tasks did not show statistically significant training related improvements. CONCLUSION: Wrist proprioceptive function in PD patients can be enhanced with a brief specialized sensorimotor training that emphasizes proprioceptive acuity. Sensorimotor training involving continuous small-amplitude wrist movements improved movement accuracy in an untrained discrete non-visuomotor task. This transfer of spatial motor precision was evident for the same joint degree of freedom, but not in a multiple-joint-degrees-of-freedom handwriting task. These initial findings provide evidence that visuo-proprioceptive training can enhance proprioceptive function in PD. Moreover, they reveal that somatosensory-based training may generalize to other motor tasks using the same trained joint degrees of freedom.Item Speech-Related Sensory Impairment in Parkinson’s Disease(2015-12) Chen, Yu-WenBackground. Persons with Parkinson’s disease (PD) show speech impairments that are not solely accounted for by motor impairment. In the literature on motor control of trunk and limbs in PD, somatosensory deficits were found and suggested to be associated with movement abnormalities. Less is known about speech-related sensory systems in PD, and little has been done to investigate the link between specific speech sounds and relevant sensory impairments in PD. Purpose. The primary goal of this dissertation is to determine whether there is a relationship between the speech of persons with PD and their auditory and tactile acuity. Using production of sibilants /s/ and /ʃ/ as the speech target, the study seeks to answer four questions: 1) Do persons with PD produce a smaller acoustic difference between sibilant fricatives relative to healthy controls? 2) Do persons with PD show decreased auditory acuity in discriminating spectral shapes? 3) Do persons with PD show decreased acuity to tactile stimuli on the tongue tip? And 4) Are there relationships of sibilant contrast to auditory and lingual-tactile acuity? Method. Ten participants with PD and ten age- and gender-matched healthy participants were studied. Participants performed three tasks. In the production task, they read a passage and eight sentences with /s/- and /ʃ/-initial words; acoustic contrast between the two sibilants was measured using difference between the average first spectral moments of /s/ and /ʃ/. For the auditory task, in each trial they listened to three aperiodic sounds, acoustically modified from /s/ and /ʃ/ and differing in spectral shapes, and judged which sound was different than the other two; auditory acuity measures were calculated from the psychoacoustic functions of their responses. For the tactile task, they judged the orientation of a dome-shaped grating probe gently touching their tongue tip; tactile acuity measures were extracted from the psychophysical functions of their responses. Group comparisons were made for every measure and correlation analyses were done between the speech-production measures and sensory acuity measures. Results. Results found that participants with PD had a smaller sibilant contrast than healthy controls for productions in sentences, but not for ones in the continuous speech passage. The PD participants had significantly reduced auditory acuity in discriminating spectral shapes relative to healthy controls, and significantly reduced tactile acuity of the tongue tip. Correlation analyses showed significant correlation between the tactile acuity and sibilant contrast for the PD group. Conclusions. Results from the study suggest associations of sensory impairment to speech production in persons with PD, calling for more research into the sensory underpinnings of the speech problems of this clinical population.Item Using Quantified Motor Behavior Outcomes to Improve Deep Brain Stimulation in Parkinson’s Disease(2020-06) Louie, KennethDeep brain stimulation (DBS) is a highly effective therapeutic option for Parkinson’s disease (PD). However, it can take 50 or more hours to obtain stimulation settings that optimally treat a patient’s symptoms. Additionally, axial symptoms, such as gait, are not adequately treated in the long term. In my work I explore the use of quantified motor behavior outcomes to reduce the time needed to obtain optimal stimulation parameters, and to develop a novel stimulation delivery approaches to better treat gait. First, I tested a Bayesian optimization approach to quickly and accurately model the input/output response of rigidity to stimulation frequency. I found, for PD patients that have a high degree of rigidity, Bayesian optimization models their response needing fewer samples than a traditional trial-and-error approach. Next, I tested a novel closed-loop stimulation delivery approach that delivered short duration pulse trains at specific phases of gait. I found that the patients that respond strongly to this type of stimulation delivery have a worse gait with their clinical settings. Overall, many patients saw small changes to their gait with this approach. Lastly, I analyzed the effects of turning stimulation on and off on gait. I found that a repeated measures of gait with short duration, 1 minute, wash-in and -out can detect significant changes. This is in contrast to previous reports that significant changes are only seen between 30-60 minutes. Through these studies I demonstrate the use of quantified motor behavior outcomes to improve DBS for PD.