Doctor of Philosophy

dissertationThe development of devices to electrically interact with the brain is a challenging task that could potentially restore motion to paralyzed patients and sight to those with profound blindness. Neural engineers have designed many types of microelectrode arrays (MEAs) with this challenge in mind. These MEAs can be implanted into brain tissue to both record neural signals and electrically stimulate neurons with high selectivity and spatial resolution. Implanted MEAs have allowed patients to control of a variety of prosthetic devices in clinical trials, but the longevity of such motor prostheses is limited to a few years. Performance decreases over time as MEAs lose the ability to record neuronal signals, preventing their widespread clinical use. Microstimulation via intracortical MEAs has also not achieved broad clinical implementation. While microstimulation for the restoration of vision is promising, human clinical trials are needed. Chronic in vivo functionality assays in model systems will provide key insight to facilitate such trials. There are three goals that may help address insufficient MEA longevity, as well as provide insight on microstimulation functionality. First, thorough characterizations of how performance decreases over time, both with and without stimulation, will be needed. Next, factors that affect the chronic performance of microstimulating MEAs must be further investigated. Finally, intervention strategies can be designed to mitigate these factors and improve long term MEA performance. This dissertation takes steps towards meeting these goals by means of three studies. First, the chronic performance of intracortically implanted recording and stimulating MEAs is examined. It is found that while performance of implanted MEAs in feline cortex is dynamic, catastrophic device failure does not occur with microstimulation. Next, a variety of factors that affect microstimulation studies are investigated. It is found that many factors, including device iv damage, anesthesia depth, the application of microstimulation, and the use of impedance as a reporter play a role in observations of performance variability. Finally, a promising intervention strategy, a carbon nanotube coating, is chronically tested in vivo, indicating that carbon nanotubes do not cause catastrophic device failure and may impart benefits to future generations of MEAs

Doctor of Philosophy

dissertationThis dissertation provides an in-depth evaluation of microstimulation of the primary visual cortex (V1) using chronically implanted Utah Electrode Arrays (UEAs) in macaque monkeys for use as a visual prosthesis. Within the scope of this dissertation are several significant contributions. First, a minimally invasive and robust device for head fixation was developed. In comparison to other available designs, this device improved long-term outcomes by providing a stronger, less invasive interface that reduced the risk of infection. This device made it possible to acquire chronic microstimulation data in macaque monkeys. It has been tested on three animals and has provided a stable interface for over two years. Second, this dissertation is the first to describe the factors influencing the performance and safety of microstimulation of V1 with the UEA. Two UEAs were implanted in V1 of two macaque monkeys, and experiments were performed several months following implantation. The electrical and recording properties of the electrodes and the high-resolution visuotopic organization of V1 were measured. In addition, threshold stimulation levels that evoked behavioural responses using single electrodes were determined. Periodic microstimulation at currents up to 96 pA did not impair the ability to record neural signals and did not affect the animal's vision where the UEAs were implanted. It was discovered, however, that microstimulation at these levels evoked behavioural responses on only 8 of 82 systematically stimulated electrodes. It was suggested that the ability to evoke behavioral responses may depend on the location of the electrode tips within the cortical layers of V1, the distance of the electrode tips to neuronal somata, and the inability of nonhuman primates to recognize and respond to a generalized set of evoked percepts. Finally, this dissertation is the first to describe the spatial and temporal characteristics of microstimulation of V1 with the UEA over chronic time periods. Two years after implantation, it was found that consistent behavioural responses could be evoked during simultaneous stimulation of multiple contiguous electrodes. Saccades to electrically-evoked targets using groups of nine electrodes showed that the animal could discriminate spatially distinct percepts with a resolution comparable to the current epiretinal prostheses. These results demonstrate chronic perceptual functionality and provide evidence for the feasibility of a UEA-based visual prosthesis for the blind

Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes

We investigated using poly(3,4-ethylenedioxythiophene) (PEDOT) to lower the impedance of small, gold recording electrodes with initial impedances outside of the effective recording range. Smaller electrode sites enable more densely packed arrays, increasing the number of input and output channels to and from the brain. Moreover, smaller electrode sizes promote smaller probe designs; decreasing the dimensions of the implanted probe has been demonstrated to decrease the inherent immune response, a known contributor to the failure of long-term implants. As expected, chronically implanted control electrodes were unable to record well-isolated unit activity, primarily as a result of a dramatically increased noise floor. Conversely, electrodes coated with PEDOT consistently recorded high-quality neural activity, and exhibited a much lower noise floor than controls. These results demonstrate that PEDOT coatings enable electrode designs 15 µm in diameter.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90823/1/1741-2552_8_1_014001.pd

Central nervous system microstimulation: Towards selective micro-neuromodulation

Electrical stimulation technologies capable of modulating neural activity are well established for neuroscientific research and neurotherapeutics. Recent micro-neuromodulation experimental results continue to explain neural processing complexity and suggest the potential for assistive technologies capable of restoring or repairing of basic function. Nonetheless, performance is dependent upon the specificity of the stimulation. Increasingly specific stimulation is hypothesized to be achieved by progressively smaller interfaces. Miniaturization is a current focus of neural implants due to improvements in mitigation of the body's foreign body response. It is likely that these exciting technologies will offer the promise to provide large-scale micro-neuromodulation in the future. Here, we highlight recent successes of assistive technologies through bidirectional neuroprostheses currently being used to repair or restore basic brain functionality. Furthermore, we introduce recent neuromodulation technologies that might improve the effectiveness of these neuroprosthetic interfaces by increasing their chronic stability and microstimulation specificity. We suggest a vision where the natural progression of innovative technologies and scientific knowledge enables the ability to selectively micro-neuromodulate every neuron in the brain

Abiotic-biotic characterization of Pt/Ir microelectrode arrays in chronic implants

Pt/Ir electrodes have been extensively used in neurophysiology research in recent years as they provide a more inert recording surface as compared to tungsten or stainless steel. While floating microelectrode arrays (FMA) consisting of Pt/Ir electrodes are an option for neuroprosthetic applications, long-term in vivo functional performance characterization of these FMAs is lacking. In this study, we have performed comprehensive abiotic-biotic characterization of Pt/Ir arrays in 12 rats with implant periods ranging from 1 week up to 6 months. Each of the FMAs consisted of 16-channel, 1.5 mm long, and 75 μm diameter microwires with tapered tips that were implanted into the somatosensory cortex. Abiotic characterization included (1) pre-implant and post-explant scanning electron microscopy (SEM) to study recording site changes, insulation delamination and cracking, and (2) chronic in vivo electrode impedance spectroscopy. Biotic characterization included study of microglial responses using a panel of antibodies, such as Iba1, ED1, and anti-ferritin, the latter being indicative of blood-brain barrier (BBB) disruption. Significant structural variation was observed pre-implantation among the arrays in the form of irregular insulation, cracks in insulation/recording surface, and insulation delamination. We observed delamination and cracking of insulation in almost all electrodes post-implantation. These changes altered the electrochemical surface area of the electrodes and resulted in declining impedance over the long-term due to formation of electrical leakage pathways. In general, the decline in impedance corresponded with poor electrode functional performance, which was quantified via electrode yield. Our abiotic results suggest that manufacturing variability and insulation material as an important factor contributing to electrode failure. Biotic results show that electrode performance was not correlated with microglial activation (neuroinflammation) as we were able to observe poor performance in the absence of neuroinflammation, as well as good performance in the presence of neuroinflammation. One biotic change that correlated well with poor electrode performance was intraparenchymal bleeding, which was evident macroscopically in some rats and presented microscopically by intense ferritin immunoreactivity in microglia/macrophages. Thus, we currently consider intraparenchymal bleeding, suboptimal electrode fabrication, and insulation delamination as the major factors contributing toward electrode failure

Predicting neural recording performance of implantable electrodes

Recordings of neural activity can be used to aid communication, control prosthetic devices or alleviatedisease symptoms. Chronic recordings require a high signal-to-noise ratio that is stable for years. Currentcortical devices generally fail within months to years after implantation. Development of novel devices toincrease lifetime requires valid testing protocols and a knowledge of the critical parameters controllingelectrophysiological performance. Here we present electrochemical and electrophysiological protocolsfor assessing implantable electrodes. Biological noise from neural recording has significant impact on signal-to-noise ratio. A recently developed surgical approach was utilised to reduce biological noise. This allowed correlation of electrochemical and electrophysiological behaviour. The impedance versus frequency of modified electrodes was non-linear. It was found that impedance at low frequencies was astronger predictor of electrophysiological performance than the typically reported impedance at 1 kHz.Low frequency impedance is a function of electrode area, and a strong correlation of electrode area with electrophysiological response was also seen. Use of these standardised testing protocols will allow future devices to be compared before transfer to preclinical and clinical trials

Complex impedance spectroscopy for monitoring tissue responses to inserted neural implants

A series of animal experiments was conducted to characterize changes in the complex impedance of chronically implanted electrodes in neural tissue. Consistent trends in impedance changes were observed across all animals, characterized as a general increase in the measured impedance magnitude at 1 kHz. Impedance changes reach a peak approximately 7 days post-implant. Reactive responses around individual electrodes were described using immuno- and histo-chemistry and confocal microscopy. These observations were compared to measured impedance changes. Several features of impedance changes were able to differentiate between confined and extensive histological reactions. In general, impedance magnitude at 1 kHz was significantly increased in extensive reactions, starting about 4 days post-implant. Electrodes with extensive reactions also displayed impedance spectra with a characteristic change at high frequencies. This change was manifested in the formation of a semi-circular arc in the Nyquist space, suggestive of increased cellular density in close proximity to the electrode site. These results suggest that changes in impedance spectra are directly influenced by cellular distributions around implanted electrodes over time and that impedance measurements may provide an online assessment of cellular reactions to implanted devices.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58178/2/jne7_4_007.pd

Multimodal Investigation of the Efficiency and Stability of Microstimulation using Electrodes Coated with PEDOT/CNT and Iridium Oxide

Electrical microstimulation is an invaluable tool in neuroscience research to dissect neural circuits, relate brain areas, and identify relationships between brain structure and behavior. In the clinic, electrical microstimulation has enabled partial restoration of vision, movement, sensation and autonomic functions. Recently, novel materials and new fabrication techniques of traditional metals have emerged such as iridium oxide and the conducting polymer PEDOT/CNT. These materials have demonstrated particular promise in the improvement in electrical efficiency. However, the in vivo stimulation efficiency and the in vivo stability of these materials have not been thoroughly characterized. In this dissertation, we use a multimodal approach to study the efficiency and stability of electrode-tissue interface using novel materials in microstimulation

Effects of Dip-coated films on the Properties of Implantable Intracortical Microelectrodes

The successful clinical use of implantable intracortical microelectrodes (ICMs) to treat certain types of deafness, blindness, and paralysis is limited by a reactive tissue response (RTR) of the brain. This RTR culminates in the formation of a tight glial scar and a loss of neuronal density around implanted ICMs, and is accompanied by a decrease in signal to noise ratio and an increase in impedance. While no comprehensive mechanistic understanding of the underlying biology is currently agreed upon in the field, a general consensus exists around a highly volatile acute RTR phase. During this acute phase, the electrical properties of ICMs do not always coincide with cellular responses, and the extent of initial injury appears to greatly influence the degree of the chronic RTR. While many electrode modifications and treatments are effective in the short term, the chronic RTR appears impervious to most interventions. To better understand the acute phase of the RTR, this dissertation aims to investigate the effects of various dip-coated biomolecules on the electrical properties of ICMs and cellular responses to microscale ICM-like foreign bodies. We first present an examination of silica sol-gel thin films as a potential biomolecule delivery platform which does not adversely affect the electrical properties of ICMs. The second study shows that adsorbed proteins, thought to play an important role in modulating the RTR, cause significant increases in electrode impedance. In contrast to prevalent electrical models of the electrode tissue interface which assume purely resistive impedance changes due to adsorbed proteins, our results show both resistive and capacitive changes. We also show that increases in impedance related to protein adsorption can be prevented by dip coating ICMs in an aqueous solution of high molecular weight polyethylene glycol (PEG). We then describe a method to clean electrode sites using direct current (DC) biasing, showing that DC biasing is capable of restoring electrode impedance following exposure to enzymatic cleaning solutions, proteins, phantom brains, and actual brain tissue. The final study in an in vitro mixed primary cortical cell culture model shows that lipopolysaccharide (LPS), a well-known ligand to toll-like 4 (TL4) receptors, dip-coated onto segments of metal microwire, can simulate localized inflammation around an implanted ICM. We observe elevated activation of glial cells in interface regions, and extending into more distant regions. This elevation in glial responses is not accompanied by a decrease in neuronal density. We additionally show that microwire dip-coated with a mixture of LPS and PEG exhibits significantly lower microglial and astrocyte responses. These findings highlight the importance of adsorbed proteins, some of which are implicated in aggravating the reactive tissue response, but which we show can result in significant increases in electrode impedance before the RTR even begins. These impedance changes can be prevented through the use of dip-coated PEG. Our cell culture data presents further evidence for the attractiveness of TL4 receptors as a target for intervention, and suggests that the loss of neuronal density observed in vivo is better explained by other mechanisms following device insertion than pure glial activation

Brain-Computer Interfaces using Electrocorticography and Surface Stimulation

The brain connects to, modulates, and receives information from every organ in the body. As such, brain-computer interfaces (BCIs) have vast potential for diagnostics, medical therapies, and even augmentation or enhancement of normal functions. BCIs provide a means to explore the furthest corners of what it means to think, to feel, and to act—to experience the world and to be who you are. This work focuses on the development of a chronic bi-directional BCI for sensorimotor restoration through the use of separable frequency bands for recording motor intent and providing sensory feedback via electrocortical stimulation. Epidural cortical surface electrodes are used to both record electrocorticographic (ECoG) signals and provide stimulation without adverse effects associated with penetration through the protective dural barrier of brain. Chronic changes in electrode properties and signal characteristics are discussed, which inform optimal electrode designs and co-adaptive algorithms for decoding high-dimensional information. Additionally, a multi-layered approach to artifact suppression is presented, which includes a systems-level design of electronics, signal processing, and stimulus waveforms. The results of this work are relevant to a wider range of applications beyond ECoG and BCIs that involve closed-loop recording and stimulation throughout the body. By enabling simultaneous recording and stimulation through the techniques described here, responsive therapies can be developed that are tuned to individual patients and provide precision therapies at exactly the right place and time. This has the potential to improve targeted therapeutic outcomes while reducing undesirable side effects