High Fidelity Bioelectric Modelling of the Implanted Cochlea

Cochlear implants are medical devices that can restore sound perception in individuals with sensorineural hearing loss (SHL). Since their inception, improvements in performance have largely been driven by advances in signal processing, but progress has plateaued for almost a decade. This suggests that there is a bottleneck at the electrode-tissue interface, which is responsible for enacting the biophysical changes that govern neuronal recruitment. Understanding this interface is difficult because the cochlea is small, intricate, and difficult to access. As such, researchers have turned to modelling techniques to provide new insights. The state-of-the-art involves calculating the electric field using a volume conduction model of the implanted cochlea and coupling it with a neural excitation model to predict the response. However, many models are unable to predict patient outcomes consistently. This thesis aims to improve the reliability of these models by creating high fidelity reconstructions of the inner ear and critically assessing the validity of the underlying and hitherto untested assumptions. Regarding boundary conditions, the evidence suggests that the unmodelled monopolar return path should be accounted for, perhaps by applying a voltage offset at a boundary surface. Regarding vasculature, the models show that large modiolar vessels like the vein of the scala tympani have a strong local effect near the stimulating electrode. Finally, it appears that the oft-cited quasi-static assumption is not valid due to the high permittivity of neural tissue. It is hoped that the study improves the trustworthiness of all bioelectric models of the cochlea, either by validating the claims of existing models, or by prompting improvements in future work. Developing our understanding of the underlying physics will pave the way for advancing future electrode array designs as well as patient-specific simulations, ultimately improving the quality of life for those with SHL

Doctor of Philosophy

dissertationMilitary personnel with amputations face unique challenges due to their short residual limbs and high incidences of multiple limb loss sustained after blast injuries. However, transcutaneous osseointegrated implant (TOI) technology may provide an alternative for individuals with poor socket tolerance by allowing a structural and functional connection between living bone and the surface of a load bearing implant. While TOI has improved activity levels in European patients with limb loss, a lengthy rehabilitation period has limited the expansion of this technology, and may be accelerated with electrical stimulation. The unique advantage of electrically induced TOI is that the exposed exoprosthetic attachment may function as a cathode for regulating electrical current while also serving as the means of prosthetic limb attachment to the host bone. Using this design principle, the goal of this dissertation was to investigate the potential of electrical stimulation for enhancing the rate and magnitude of skeletal fixation at the periprosthetic interface using the implant as a cathode. Although previous studies have examined electrical stimulation for healing atrophic nonunions, inconsistent results have required new predictive measures. Therefore, finite element analysis (FEA) was used as a prerequisite for estimating electric field and current density magnitudes prior to in vivo experimentation. Retrospective computed tomography scans from 11 service members (28.3 ± 5.0 years) demonstrated the feasibility of electrically induced TOI, but variability in residual limb anatomy and the presence of heterotopic ossification confirmed the necessity for patient-specific modeling. Electrically induced osseointegration was also evaluated in vivo in skeletally mature rabbits after establishing design principles based on in vitro cell culturing and FEA. Data from the animal experiment indicated that there were no statistical differences for the appositional bone index (ABI), mineral apposition rate and porosity between the electrically stimulated implants and the unstimulated control implants (UCI). Higher mechanical push-out forces were observed for the UCI group at 6 weeks (p=0.034). In some cases, qualitative backscattered electron images and ABI did indicate that direct current may hold promise for improving suboptimal implant "fit and fill," as bone ongrowth around the cathode was observed despite not having direct contact with the endosteum

Altered excitation-contraction coupling in human chronic atrial fibrillation

This review focuses on the (mal)adaptive processes in atrial excitation-contraction coupling occurring in patients with chronic atrial fibrillation. Cellular remodeling includes shortening of the atrial action potential duration and effective refractory period, depressed intracellular Ca<sup>2+</sup> transient, and reduced myocyte contractility. Here we summarize the current knowledge of the ionic bases underlying these changes. Understanding the molecular mechanisms of excitation-contraction-coupling remodeling in the fibrillating human atria is important to identify new potential targets for AF therapy

Spatial models of cell distribution in human lumbar dorsal root ganglia

Dorsal root ganglia (DRG), which contain the somata of primary sensory neurons, have increasingly been considered as novel targets for clinical neural interfaces, both for neuroprosthetic and pain applications. Effective use of either neural recording or stimulation technologies requires an appropriate spatial position relative to the target neural element, whether axon or cell body. However, the internal three- dimensional spatial organization of human DRG neural fibers and somata has not been quantitatively described. In this study, we analyzed 202 cross- sectional images across the length of 31 human L4 and L5 DRG from 10 donors. We used a custom semi- automated graphical user interface to identify the locations of neural elements in the images and normalize the output to a consistent spatial reference for direct comparison by spinal level. By applying a recursive partitioning algorithm, we found that the highest density of cell bodies at both spinal levels could be found in the inner 85% of DRG length, the outer- most 25- 30% radially, and the dorsal- most 69- 76%. While axonal density was fairly homogeneous across the DRG length, there was a distinct low density region in the outer 7- 11% radially. These findings are consistent with previous qualitative reports of neural distribution in DRG. The quantitative measurements we provide will enable improved targeting of future neural interface technologies and DRG- focused pharmaceutical therapies, and provide a rigorous anatomical description of the bridge between the central and peripheral nervous systems.Dorsal root ganglia (DRG) are novel targets for neural interface technologies that treat neurological disorders, such as chronic pain and spinal cord injury. The three- dimensional cellular anatomy of DRG are not well- mapped, particularly in humans, limiting the effectiveness of neurotechnology. We developed a semi- automated algorithm to quantify the three- dimensional distribution of neural elements in histologically- processed tissue. We applied this algorithm to sequential NF200- stained histology slices obtained from human lumbar DRG and demonstrated that cell bodies typically congregate around the dorsal edge of the ganglia. These results are crucial to the development of safe and effective clinical neural interface technologies.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155471/1/cne24848_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155471/2/cne24848.pd

Validation of Transcranial Electrical Stimulation (TES) Finite Element Modeling Against MREIT Current Density Imaging in Human Subjects

abstract: Transcranial electrical stimulation (tES) is a non-invasive brain stimulation therapy that has shown potential in improving motor, physiological and cognitive functions in healthy and diseased population. Typical tES procedures involve application of weak current (< 2 mA) to the brain via a pair of large electrodes placed on the scalp. While the therapeutic benefits of tES are promising, the efficacy of tES treatments is limited by the knowledge of how current travels in the brain. It has been assumed that the current density and electric fields are the largest, and thus have the most effect, in brain structures nearby the electrodes. Recent studies using finite element modeling (FEM) have suggested that current patterns in the brain are diffuse and not concentrated in any particular brain structure. Although current flow modeling is useful means of informing tES target optimization, few studies have validated tES FEM models against experimental measurements. MREIT-CDI can be used to recover magnetic flux density caused by current flow in a conducting object. This dissertation reports the first comparisons between experimental data from in-vivo human MREIT-CDI during tES and results from tES FEM using head models derived from the same subjects. First, tES FEM pipelines were verified by confirming FEM predictions agreed with analytic results at the mesh sizes used and that a sufficiently large head extent was modeled to approximate results on human subjects. Second, models were used to predict magnetic flux density, and predicted and MREIT-CDI results were compared to validate and refine modeling outcomes. Finally, models were used to investigate inter-subject variability and biological side effects reported by tES subjects. The study demonstrated good agreements in patterns between magnetic flux distributions from experimental and simulation data. However, the discrepancy in scales between simulation and experimental data suggested that tissue conductivities typically used in tES FEM might be incorrect, and thus performing in-vivo conductivity measurements in humans is desirable. Overall, in-vivo MREIT-CDI in human heads has been established as a validation tool for tES predictions and to study the underlying mechanisms of tES therapies.Dissertation/ThesisDoctoral Dissertation Biomedical Engineering 201

Simulating and optimizing electrical current flow and neuronal activation in retinal implants

© 2018 Dr Timothy Bede Esler[Abstract Withheld

Understanding the impact of carcass size, chilling rate, and electrical stimulation on beef quality

2019 Spring.Includes bibliographical references.Increasing carcass sizes and mass make it difficult for packers to appropriately chill beef carcasses, resulting in issues associated with tenderness and color. The wide variability in carcass size and weight and the lack of management practices to address it represent a challenge that the industry must address. To our knowledge, few studies have looked at the combined impact of chilling and electrical stimulation on postmortem biochemistry, tenderness, juiciness and color among the current consist of US beef carcasses, hence justifying this study. The study was conducted in two major parts: The first part focused on the effects of carcass size, chilling rate, and electrical stimulation on temperature and pH decline and postmortem biochemistry. Cattle (N =162, 0.05) that of heavy weight carcasses. Temperature decline was faster (P 0.05) by treatment factors. However, WBSF and SSF were affected (P < 0.05) by carcass size and chilling rate. Aging curves were developed using an exponential decay model to predict aging response and describe the tenderization process for the treatments groups. The models indicated significant differences in the rate and extent of tenderization between different treatment groups