Medical Bionics - Theses
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ItemDeep brain stimulation evoked resonant neural activity( 2023-02)Deep brain stimulation (DBS) involves surgically implanting electrodes within targeted subcortical structures and applying chronic electrical stimulation to produce therapeutic effects. DBS has utility for a range of movement and psychiatric disorders, with DBS of the subthalamic nucleus (STN) for the treatment of Parkinson’s disease a common application. Although DBS can be remarkably effective, several challenges can limit its application and efficacy, including 1) the target neural structures are very small and challenging to accurately implant with electrodes; 2) DBS implantation surgery commonly requires the patient to be awake; 3) selection of beneficial stimulation parameters for chronic therapy is a laborious manual process prone to suboptimal outcomes; 4) chronic therapy is applied constantly regardless of the patient’s present therapeutic needs; and 5) the mechanisms of action of DBS are yet to be fully elucidated. Electrophysiological feedback signals may provide the means for addressing these challenges. A signal localised to the target neural structure could be used like a homing beacon to guide electrode implantation and configuration for chronic therapy. Furthermore, if the signal was measurable under general anaesthesia, it could be used to guide implantation in unconscious patients. A signal that varies with patient symptomatic state and the application of DBS could also guide selection of stimulation parameters, inform on mechanisms of action, and act as a feedback signal for monitoring patient state in real-time and automatically adapting stimulation settings to optimise therapy. This thesis identifies a novel evoked potential – termed evoked resonant neural activity (ERNA) – elicited by DBS pulses applied in the vicinity of the STN and investigates its potential for improving DBS therapy. ERNA is confirmed to be of neural origin and is shown to have largest amplitude in the dorsal subregion of the STN, where DBS for Parkinson’s disease is typically most effective. ERNA and its localisation are also shown to be present and readily measurable under general anaesthesia. Additionally, both the frequency and amplitude of ERNA are shown to vary with the application of therapeutically-effective DBS. The characteristics of ERNA make it an electrophysiological signal with considerable potential for addressing the challenges associated with applying DBS therapy, particularly STN-DBS. ERNA’s localisation to dorsal STN and presence under anaesthesia indicate utility in guiding electrode implantation and configuration in both awake and unconscious patients. Variation in ERNA with therapeutically-effective DBS also indicates potential utility in guiding the selection of chronic stimulation parameters, investigating mechanisms of action, and automatically adapting therapy according to the patient’s real-time needs.
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ItemIdentifying and addressing limitations in deep brain stimulation for Parkinson's disease using novel neuronal biomarkers( 2020)Deep brain stimulation (DBS) is an effective treatment in Parkinson’s disease (PD). DBS is postulated to modulate and restore ‘functionality’ to the pathological brain networks implicated in PD. DBS therapy improves motor symptoms and quality of life and allows for substantial medication reduction. However, there is little information on the long-term outcomes after DBS implantation including programming rates, battery changes, hardware complication surgeries or the duration of the therapy. This knowledge is crucial to inform on clinical decision making, distribution of healthcare resources and guide research direction for device development. The first part of this thesis presents a cross-sectional, population-based study of 1849 patients with PD implanted with DBS in Australia over a 15-year period (2002-2016). Individual-level patient data was derived from three linked national government databases and the requirements for DBS care and servicing was evaluated, referenced from the time of surgery. The mean annual programming rate was 6.9 in the first year, and 2.8 annually thereafter. Over 50% of patients required repeat hardware surgery after DBS implantation. 11.3% of patients had repeat intracranial electrode surgery (including 1.1% of patients who were completely explanted). 47.6% of patients had repeat implantable pulse generator/extension-cable surgery including for presumed battery depletion. 6.2% of patients had surgery of the implantable pulse generator /extension-cable surgery within one year of any previous such surgery. 30-day post-operative mortality was 0.3% after initial DBS implantation and 0.6% after any repeat hardware surgery. The median time from DBS surgery to residential care admission was 10.2 years and, to death was 11.4 years. These findings support development of technologies to reduce therapy burden such as enhanced surgical navigation, hardware miniaturisation and improved battery efficiency. The second part of the thesis focuses on two key contributors to DBS therapy burden, device programming and electrode redo surgery. DBS efficacy relies on the delivery of stimulation to the ideal location to achieve optimal motor benefit. This site is determined by the electrode location and the contact selected to apply DBS by the clinician. DBS programming is an arduous, time-consuming process, and highly dependent on clinician expertise. Neuronal signals have been proposed as biomarkers to assist in DBS programming and guide electrode implantation. The most widely studied signals are local field potentials (LFPs) such as beta oscillations and high frequency oscillations (HFO). However, LFPs hold recording challenges due to their small size and low signal to noise ratio. More recently, our group has described an evoked potential, elicited by DBS, termed ‘evoked resonant neural activity’ (ERNA). ERNA is a large amplitude signal, with a characteristic decaying oscillation morphology, that is reliably recordable in patients with PD implanted with subthalamic nucleus (STN) DBS. It localises to the postulated ideal anatomical location to apply DBS, in the dorsal STN. However, the clinical relevance of ERNA and its utility compared to LFPs or electrode anatomical location is unknown. Thus, in 50 (100 hemispheres) consecutive patients with PD implanted with STN DBS, ERNA power, beta power and HFO power was measured from each of the four contacts on the DBS lead during surgery. Neuroimaging was obtained peri-operatively to visualise each contact and determine its proximity to a nominated ideal anatomical location. The four contacts in each hemisphere were ranked from one to four according to neuronal signal power and anatomical location. In 14 patients (28 hemispheres), therapeutic stimulation was applied to each of the four contacts on the DBS lead and the degree of motor benefit measured. ERNA, beta oscillations and the anatomical location of contacts similarly predicted how motor benefit varied across contacts with STN DBS therapy. Combining ERNA, beta and HFO ranking data yielded the strongest predictive model. However, only first-ranked contacts according to ERNA delivered a motor benefit that was significantly better than at the other three contacts on the lead. Furthermore, only first-ranked ERNA contacts delivered a motor benefit that was not significantly less than the maximal available in each hemisphere. When monopolar configuration was chosen at 6 months after DBS surgery, the clinician-chosen contact corresponded most frequently with the first-ranked ERNA contact in 81% of hemispheres compared to 71% for anatomy and 52% for beta. ERNA performed significantly better than anatomy and beta oscillations and combining data using machine learning algorithms did not improve model performance compared to using ERNA data alone. These results support the role of ERNA in guiding contact selection and assisting intra-operative electrode navigation to ultimately, reduce the treatment burden of DBS therapy.
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ItemThe utility of an instrumented pull test to evaluate postural instability in Parkinson’s disease( 2019)Postural instability is one of the cardinal symptoms of Parkinson’s disease (PD). Postural instability can present on diagnosis, and commonly becomes more prominent with disease progression, resulting in subsequent falls and diminished quality of life. The treatment of postural instability is challenging, as it is often refractory to management with levodopa and deep brain stimulation of conventional targets such as the subthalamic nucleus. To assess postural instability, the most commonly used measure in the clinical setting is the pull test according to item 30 of the Unified Parkinson’s disease rating scale (UPDRS), where an examiner performs a brisk backward tug at the patient’s shoulder level and grades the corrective response. While easy to administer, outcomes can vary due to variability in test administration and interpretation. A comprehensive literature review revealed laboratory based assessments provided a more objective method to measure postural responses compared to clinical assessments in people with PD. These techniques were conventionally employed in people with PD in later disease stages who already demonstrate postural instability. Laboratory based assessments presented a method to identify abnormalities before postural instability is clinically evident and effects of therapies. The recent development of instrumentation of clinical balance tests offered an alternative technique to precisely quantify postural responses. Here, we developed an instrumented version of the pull test and investigate its utility to quantify postural instability in people with PD ranging from mild to moderate disease severity. In Study 1, the sensitivity of the instrumented pull test was investigated in healthy young participants. Postural responses were modified by presenting a startling auditory stimulus concurrent with the backwards pull. Such stimuli evoke StartReact effects and are known to speed reaction times. The instrumented pull test could detect small 10 ms decreases in postural reaction time evoked by the startling stimulus. The ability to detect such changes in healthy individuals highlights the utility of instrumented techniques and justifies further investigation in people where changes to balance is of interest. Subsequently, the instrumented pull test was used to characterise postural responses in eighteen people with mild PD (Hoehn and Yahr less than 2) in Study 2. Subclinical abnormalities in trunk and step responses were detected in participants with mild PD compared to healthy controls. Furthermore, levodopa did not restore postural responses in participants with PD to that of healthy controls (Study 3). These findings demonstrate changes to postural stability can occur in mild disease. Abnormalities of postural responses which remain refractory to levodopa also suggest non-dopaminergic pathways may be implicated in the pathophysiology of postural instability in mild PD. Pedunculopontine deep brain stimulation (PPN DBS) is a therapy developed specifically to alleviate axial symptoms of gait and postural abnormalities unresponsive to conventional therapies such as levodopa. In Study 4, the instrumented pull test was used to quantify postural responses in five people with PD and moderate to severe postural instability receiving PPN DBS. Off and on stimulation, the instrumented pull test was able to detect postural responses with greater resolution compared to clinical assessments (axial items 27 to 30 of the motor subsection of the Unified Parkinson’s disease rating scale (UPDRS) and the Mini-BESTest. However, the use of the instrumented pull test, and interpretation of findings was limited by the small sample size and highly variable postural responses in participants with moderate to severe postural instability. On stimulation, improvement in overall balance scores was demonstrated across all participants with the Mini-BESTest but not axial items of the UPDRS. This thesis demonstrated the utility of the instrumented pull test as a potential assessment tool to evaluate postural instability in PD. Identification of postural abnormalities provides valuable insights in the assessment and management of postural instability in people with PD. Clinicians should consider that subclinical postural abnormalities can be present in people with mild PD, even when patients are on levodopa. Findings from this thesis strongly support the need for further studies to explore variables of postural responses that may be useful to detect people with PD at risk of falls and for clinicians to deliver targeted interventions earlier in disease course.