Characterization of evoked compound action potentials in targets of deep brain stimulation for Parkinson’s disease
2022-10
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Characterization of evoked compound action potentials in targets of deep brain stimulation for Parkinson’s disease
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2022-10
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Deep brain stimulation (DBS) for Parkinson’s disease relies on accurate targeting of stimulation to provide the best therapeutic outcomes for patients. Current clinical practices typically rely on a brute force approach to finding the ideal stimulation electrode, and despite improvements to lead geometries such as the inclusion of rows of directional electrodes for precise targeting of stimulation, time constraints often prevent clinicians from making good use of these advancements. Additionally, although research has uncovered specific stimulation targets in common implant areas that are ideal for the treatment of specific symptoms or the avoidance of certain side effects, the clinical capacity for localizing a lead after implantation is not sufficient for confident declarations of implant location, and even the best imaging techniques can only be confirmed with post-mortem histology. Evoked compound action potentials (ECAPs) have been shown to vary by brain region, and to be linked to therapeutic outcomes, but a detailed investigation of their spatiotemporal properties has not yet been conducted. Through a series of experiments, in parkinsonian non-human primates instrumented with scaled-down clinical DBS leads, ECAP responses to changes in stimulation amplitudes, pulse widths, and electrode configurations were systematically investigated. Additionally, a novel DBS lead with a liquid crystal polymer (LCP) substrate and a high-density array of electrodes with a rough platinum-iridium site coating was evaluated for improved spatial resolution in ECAP and local field potential recordings in DBS targets.
Project 1: One challenge with optimizing DBS therapy for a given patient is knowing where electrodes are located relative to the neural pathways around the DBS lead. We tested the hypothesis that ECAP features would differ between electrodes within gray matter (subthalamic nucleus, STN) and white matter (lenticular fasciculus, LF) for STN-DBS implants. ECAPs in these targets were characterized by short-latency ‘primary’ features (within 1.6 ms of stimulus pulse onset) and longer-latency ‘secondary’ features (>1.6 ms after stimulus pulse onset). We observed that ECAP primary feature responses were significantly larger in amplitude for LF/LF stimulation/record sites than for STN/STN stimulation/record sites. Furthermore, the number of secondary features detected in the STN (for STN or LF stimulation) was higher than that in LF (for LF stimulation). This supports the concept that ECAP primary features derive from direct axonal activation and secondary features result from post-synaptic axonal activation in the basal ganglia network. Primary feature amplitude was able to accurately predict electrode location at the border of the lenticular fasciculus and STN within and across all four subjects.
Project 2: Another challenge with optimizing DBS therapy for Parkinson’s disease has been finding biomarkers that align with the seconds to minutes wash-in effects of DBS therapy on parkinsonian motor signs. ECAP features were found to adapt over the duration of the applied high-frequency DBS pulse train. Primary features habituated over time, while secondary features increased in latency over the first 30 seconds of stimulation, and trended toward earlier latencies at higher stimulation amplitudes. The total increase in secondary feature latency over the 30 seconds following stimulation onset also increased with increasing stimulation amplitude. In comparison to the instantaneous changes in spectral local field potential (LFP) power observed during STN-DBS, the temporal wash-in dynamics of ECAP responses seem to better align with the temporal wash-in profiles of DBS therapy on parkinsonian motor signs, and future studies will need to further investigate correlations between ECAPs and motor signs.
Project 3: With the advent of microfabricated technology come opportunities to create bidirectional DBS lead technology to sense and modulate neural activity with higher spatial resolution. To further investigate the spatial features of ECAPs in the basal ganglia, we designed, developed, and evaluated a novel high-density LCP substrate DBS array. The arrays provided improvements in electrode longevity over previous high-density DBS arrays while also providing increased spatial resolution for both ECAP responses and LFP activity compared to state-of-the-art clinical electrodes.
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University of Minnesota Ph.D. dissertation. 2022. Major: Biomedical Engineering. Advisors: Matthew Johnson, Tay Netoff. 1 computer file (PDF); 86 pages.
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Rosing, Joshua. (2022). Characterization of evoked compound action potentials in targets of deep brain stimulation for Parkinson’s disease. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/250406.
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