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

Cortical motor prosthetics: the development and use for paralysis

The emerging research field of Brain Computer Interfaces (BCIs) has created an invasive type of BCI, the Cortical Motor Prosthetic (CMP) or invasive BCI (iBCI). The goal is to restore lost motor function via prosthetic control signals to individuals who have long-term paralysis. The development of the CMP consists of two major entities: the implantable, chronic microelectrode array (MEA) and the data acquisition hardware (DAQ) specifically the decoder. The iBCI's function is to record primary motor cortex (M1) neural signals via chronic MEA and translate into a motor command via decoder extraction algorithms that can control a prosthetic to perform the intended movement. The ultimate goal is to use the iBCI as a clinical tool for individuals with long-term paralysis to regain lost motor functioning. Thus, the iBCI is a beacon of hope that could enable individuals to independently perform daily activities and interact once again with their environment. This review seeks to accomplish two major goals. First, elaborate upon the development of the iBCI and focus on the advancements and efforts to create a viable system. Second, illustrate the exciting improvements in the iBCI's use for reaching and grasping actions and in human clinical trials. The ultimate goal is to use the iBCI as a clinical tool for individuals with long-term paralysis to regain movement control. Despite the promise in the iBCI, many challenges, which are described in this review, persist and must be overcome before the iBCI can be a viable tool for individuals with long-term. iBCI future endeavors aim to overcome the challenges and develop an efficient system enhancing the lives of many living with paralysis. Standard terms: Intracortical Brain Computer Interface (iBCI), Intracortical Brain Machine Interface (iBMI), Cortical Motor Prosthetic (CMP), Neuromotor Prostheses (NMP), Intracortical Neural Prosthetics, Invasive Neural Prosthetic all terms used interchangeabl

Development of a Three Dimensional Neural Sensing Device by a Stacking Method

This study reports a new stacking method for assembling a 3-D microprobe array. To date, 3-D array structures have usually been assembled with vertical spacers, snap fasteners and a supporting platform. Such methods have achieved 3-D structures but suffer from complex assembly steps, vertical interconnection for 3-D signal transmission, low structure strength and large implantable opening. By applying the proposed stacking method, the previous techniques could be replaced by 2-D wire bonding. In this way, supporting platforms with slots and vertical spacers were no longer needed. Furthermore, ASIC chips can be substituted for the spacers in the stacked arrays to achieve system integration, design flexibility and volume usage efficiency. To avoid overflow of the adhesive fluid during assembly, an anti-overflow design which made use of capillary action force was applied in the stacking method as well. Moreover, presented stacking procedure consumes only 35 minutes in average for a 4 × 4 3-D microprobe array without requiring other specially made assembly tools. To summarize, the advantages of the proposed stacking method for 3-D array assembly include simplified assembly process, high structure strength, smaller opening area and integration ability with active circuits. This stacking assembly technique allows an alternative method to create 3-D structures from planar components

Doctor of Philosophy

dissertationIntracortical microelectrode arrays create a direct interface between the brain and external devices. This “brain-machine interface” has found clinical application by allowing patients with tetraplegia to control computer cursors and robotic limbs. Unfortunately, use of intracortical microelectrode array technology is currently limited by its inconsistent ability to record neural signals over time. It is widely believed that the foreign body response (FBR) contributes to recording inconsistency. Most characterizations of the FBR to intracortical microelectrodes have been in the rat using devices with simple architecture, while the only device currently used in humans, the Utah Electrode Array (UEA), is much larger and more complex. In this work, we characterized the FBR to the UEA and found that, unlike with simpler devices, implantation of a UEA results in extensive vascular injury and loss of cortical tissue. We also sought to determine which features of the FBR correlated with recording inconsistency and found that biomarkers of astrogliosis, blood-brain barrier leakage, and tissue loss were associated with decreased recording performance. Next, since a significant portion of potential brain-machine interface recipients are aged, we applied similar methods in an aged cohort of rats in order to understand the effect of aging on the FBR and recording performance. We found that, surprisingly, recording performance was superior in the aged cohort. Astrogliosis was again associated with decreased recording performance in the aged cohort. Finally, we continued our development and validation of a finite element model of cytokine diffusion to assist in designing next-generation devices with a reduced FBR. Taken as a whole, this work provides meaningful insights into the mechanisms of inconsistent recording performance and discusses several promising avenues for overcoming them

Physiologically responsive mechanically adaptive polymeric materials for biomedical applications

Künstliche neurale Schnittstellen können verwendet werden, um das zentrale Nervensystem mit der äusseren Welt zu verbinden. Sie bieten deshalb grosses Potential für die Rehabilitierung von Patienten, die unter Lähmung, anderen Formen von motorischer Dysfunktion oder Amputationen leiden. Es wurden verschiedene Arten neuraler Gehirnschnittstellen entwickelt, mit unterschiedlichen Invasivitätsgraden sowie der Fähigkeit, neurale Signale aufzunehmen. Beispielsweise können nicht-eindringende aufzeichnende Elektroden, welche extern auf der Kopfhaut oder subdural auf der Hirnoberfläche angebracht werden, funktionale Informationen gewinnen. Allerdings ist unter Forschern die Annahme verbreitet, dass Aufzeichnungs- und Stimulationsgeräte, die in spezifische Regionen des Gehirns eindringen (z. B. intrakortikale Mikroelektroden), wahrscheinlich die nützlichsten Signale einer neuralen Schnittstelle liefern werden. Trotz des Potentials, welches intrakortikale Mikroelektroden gezeigt haben, ist die breite klinische Implementation durch die Tatsache behindert, dass es schwierig ist, beständig qualitativ hochwertige neurale Signale über einen klinisch relevanten Zeitrahmen aufzuzeichnen. Dies wird hauptsächlich durch Neuroinflammation verursacht, was sowohl Neuronendegeneration als auch Fremdkörperverkapselung beinhaltet. Viele Faktoren werden in Zusammenhang gebracht, einen Beitrag zur Entzündung der Gehirnareale in Folge von Geräteimplantationen zu leisten, darunter die mechanische Diskrepanz zwischen dem häufig sehr steifen Implantat und dem deutlich weicheren Hirngewebe, sowie dem oxidativen Stresszustand, der um das Implantat als Resultat der Entzündung entsteht. Um langzeit-beständige neurale Aufzeichnungen zu ermöglichen, werden neue Materialien für die nächste Generation intrakortikaler Mikroelektroden benötigt, mit grösserer Betonung auf einer Reduktion der neuroinflammatorischen Antwort benötigt. Die vorliegende Dissertation verfolgt die Entwicklung physiologisch responsiver, mechanisch adaptiver Polymere für neurale Schnittstellenapplikationen sowie eine Studie zur Struktur-Eigenschaftsbeziehung dieser Materialien. Ausgehend von einem zuvor etablierten Designprinzip für chemisch-responsive mechanisch adaptive Materialien, inspiriert durch die Architektur der Dermis von Seegurken, wurden verschiedene Familien von Nanokompositen entworfen, präpariert und untersucht. Diese Materialien beinhalten ein Matrixpolymer, welches durch steife Cellulose Nanokristalle (cellulose nanocrystalls, CNCs) und die Wechselwirkungen zwischen den CNCs verstärkt wird, so dass auch die gesamten mechanischen Eigenschaften durch Kontakt mit Wasser beeinflusst werden können. Die adaptive Natur dieses Materials lässt es nützlich erscheinen als Basis für eindringende kortikale Mikroelektroden, die ausreichend steif sind, um einfach in den Kortex implantiert werden zu können, aber unter physiologischen Bedingungen erweichen und besser zur Steifigkeit des Gehirns passen. Mehrere neue, rational entworfene Materialien wurden untersucht. Nanokomposite basierend auf Polyvinylalkohol (PVA) und CNCs, gewonnen aus Manteltieren und Baumwolle, wurden hinsichtlich des Einflusses von Aspektverhältnis, Oberflächenladungsdichte und Füllstoffkonzentration auf die mechanischen Eigenschaften untersucht. Die neuen Materialien bieten eine anfängliche Steifigkeit, welche signifikant höher ist als bei vorangegangenen Generationen solcher responsiver Materialien, vermutlich wegen der Wechselwirkungen zwischen Polymer und CNCs. Ferner wurde gezeigt, dass die Quellcharakteristika der Nanokomposite im wässrigen Medium durch die Verarbeitungsbedingungen kontrolliert werden konnten. Unter Verwendung dieses Instruments konnte der „Schaltkontrast“ der Nanokomposite durch Kontakt mit (emulierten) physiologischen Bedingungen variiert werden. Physiologisch responsive mechanisch adaptive Materialien basierend auf Polyvinylalkohol oder Polyvinylacetat und CNCs, die aus Manteltieren oder Baumwolle gewonnen wurden, wurden so konzipiert, auch lokal die antioxidativen Wirkstoffe Curcumin, Resveratrol oder Superoxiddismutase mimetisch mit plötzlichen („burst“) oder nachhaltigen Freisetzungsprofilen zu regulieren. Diese Materialien repräsentieren die ersten Beispiele für interkortikale Implantate, welche zwei voneinander unabhängig effektive Mechanismen kombinieren – mechanische Verformbarkeit und lokale Freisetzung von Antioxidantien. Sie erlauben erstmals Untersuchungen darüber, wie die Freisetzungskinetik bei Antioxidanstherapie an der intrakortikalen Implantat-Gewebe Grenzfläche die neurale Integration beeinflusst. Eine erste in-vivo Studie mit PVA/CNC/Curcumin Nanokompositen an Ratten zeigte, dass über die ersten vier Wochen der Implantation Curcumin-freisetzende, mechanisch adaptive Implantate mit einer höheren Neuronenüberlebensrate und einer stabileren Blut-Hirn-Schranke an der Grenzfläche zwischen Implantat und Gewebe assoziiert wurden als die reinen Polyvinylalkohol Kontrollproben. Abschliessend wurde die Fähigkeit der mechanischen Verformung durch Einfluss physiologischer Bedingungen für optische Fasern für die Optogenetik verwendet. Diese kürzlich entwickelte Plattform für neurale Schnittstellen beruht auf der Aktivierung oder Stummschaltung von Neuronen, die Licht verwenden. Es wird erwartet, dass die mechanische Diskrepanz zwischen konventionellen optischen Fasern und kortikalem Gewebe auch zur chronischen neuroinflammatorischen Antwort beiträgt. Daher wurden mechanisch adaptive optische Fasern aus PVA entwickelt, welche dieses Problem lindern könnten. Die Fasern wurden in einem einstufigen „dry-jet“ Nassspinnprozess produziert und sie zeigen eine anfängliche Steifigkeit, die geringfügig höher ist als die kommerziell erhältlicher optischer Fasern, und die müheloses Einführen von Implantaten mit geringem Durchmesser in den Kortex ermöglicht. Unter (emulierten) physiologischen Bedingungen quellen die Fasern mit Wasser geringfügig auf und ihre Steifigkeit wird signifikant reduziert, während die begleitenden Veränderungen der optischen Eigenschaften der Faser gering sind. Die optischen Fasern aus PVA erlauben es, Licht in einem Wellenlängenbereich zu transportieren, der hinreichend intensiv ist, Neuronen im Gehirn zu stimulieren und optischen Anforderungen für optogenetische Anwendungen gerecht zu werden. Die vorliegende Dissertation leitet fundamentale Einblicke in Struktur- Eigenschaftsbeziehungen her, indem sie die adaptive Natur dieser Materialien durch Zusammensetzung (z.B. unterschiedliche Polymermatrices, Art und Menge der Nanofüller und therapeutischer Substanzen) sowie die Verarbeitungsbedingungen vertieft. Während in-vivo Studien zum hier vorliegenden neuen Material gerade erst begonnen haben, ist es schon heute ersichtlich, dass die im Rahmen dieser Dissertation hergestellten und untersuchten Materialien zum Fortschritt des Verständnisses nützlich sind, wie stimuli-responsive Polymere helfen können, neuroinflammatorische Effekte in Zusammenhang mit Intrakortikalimplantaten zu verringern

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

Non-Penetrating Microelectrode Interfaces for Cortical Neuroprosthetic Applications with a Focus on Sensory Encoding: Feasibility and Chronic Performance in Striate Cortex

abstract: Growing understanding of the neural code and how to speak it has allowed for notable advancements in neural prosthetics. With commercially-available implantable systems with bi- directional neural communication on the horizon, there is an increasing imperative to develop high resolution interfaces that can survive the environment and be well tolerated by the nervous system under chronic use. The sensory encoding aspect optimally interfaces at a scale sufficient to evoke perception but focal in nature to maximize resolution and evoke more complex and nuanced sensations. Microelectrode arrays can maintain high spatial density, operating on the scale of cortical columns, and can be either penetrating or non-penetrating. The non-penetrating subset sits on the tissue surface without puncturing the parenchyma and is known to engender minimal tissue response and less damage than the penetrating counterpart, improving long term viability in vivo. Provided non-penetrating microelectrodes can consistently evoke perception and maintain a localized region of activation, non-penetrating micro-electrodes may provide an ideal platform for a high performing neural prosthesis; this dissertation explores their functional capacity. The scale at which non-penetrating electrode arrays can interface with cortex is evaluated in the context of extracting useful information. Articulate movements were decoded from surface microelectrode electrodes, and additional spatial analysis revealed unique signal content despite dense electrode spacing. With a basis for data extraction established, the focus shifts towards the information encoding half of neural interfaces. Finite element modeling was used to compare tissue recruitment under surface stimulation across electrode scales. Results indicated charge density-based metrics provide a reasonable approximation for current levels required to evoke a visual sensation and showed tissue recruitment increases exponentially with electrode diameter. Micro-scale electrodes (0.1 – 0.3 mm diameter) could sufficiently activate layers II/III in a model tuned to striate cortex while maintaining focal radii of activated tissue. In vivo testing proceeded in a nonhuman primate model. Stimulation consistently evoked visual percepts at safe current thresholds. Tracking perception thresholds across one year reflected stable values within minimal fluctuation. Modulating waveform parameters was found useful in reducing charge requirements to evoke perception. Pulse frequency and phase asymmetry were each used to reduce thresholds, improve charge efficiency, lower charge per phase – charge density metrics associated with tissue damage. No impairments to photic perception were observed during the course of the study, suggesting limited tissue damage from array implantation or electrically induced neurotoxicity. The subject consistently identified stimulation on closely spaced electrodes (2 mm center-to-center) as separate percepts, indicating sub-visual degree discrete resolution may be feasible with this platform. Although continued testing is necessary, preliminary results supports epicortical microelectrode arrays as a stable platform for interfacing with neural tissue and a viable option for bi-directional BCI applications.Dissertation/ThesisDoctoral Dissertation Biomedical Engineering 201

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

Carbon Fiber Microelectrode Arrays for Neuroprosthetic and Neuroscience Applications.

The aim of this work is to develop, validate, and characterize the insertion mechanism, tissue response, and recording longevity of a new high-density carbon fiber microelectrode array. This technology was designed to significantly improve the field of penetrating microelectrodes while simultaneously accommodating the variable needs of both neuroscientists and neural engineers. The first study presents the fabrication and insertion dynamics of a high-density carbon fiber electrode array using a dual sided printed circuit board platform. The use of this platform has pushed electrode density to limits not seen in other works. This necessitated the use of an encapsulation method that served to temporarily stiffen the fibers during insertion, but did not enter the brain as many other shuttles do for other probe designs. The initial findings in this work informed the development of an even higher density array using a silicon support structure as a backbone. The second study reports on the tissue reaction of chronically implanted carbon fiber electrode arrays as compared to silicon electrodes. Due to their smaller footprint, the reactive response to carbon fibers should be greatly attenuated, if not non-existent. Results show a scarring response to the implanted silicon electrode with elevated astrocyte and microglia activity coupled to a local decrease in neuronal density. The area implanted with the carbon fiber electrodes showed a varied response, from no detectable increase in astrocytic or microglial activity to an elevated activation of both cell types, but with no detectable scars. Neuronal density in the carbon fiber implant region was unaffected. The data demonstrates that the small carbon fiber profile, even in an array configuration, shows an attenuated reactive response with no visible scaring. The final study reports on the viability of chronically implanted high-density carbon fiber arrays as compared to more traditional silicon planar arrays with comparable site sizes. While most new probe technologies or designs are able to demonstrate proof of concept functionality in acute preparations, very few show the ability to record chronic unit activity. This study aims to provide a comprehensive analysis of electrophysiology data collected over implant durations ranging from 3 – 5 months.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111557/1/parasp_1.pd

Intracortical Neural Probes with Post-Implant Self-Deployed Electrodes for Improved Chronic Stability.

This thesis presents a new class of implantable intracortical neural probe with small recording electrodes that deploy away from a larger main shank after insertion. This concept is hypothesized to enhance the performance of the electrodes in chronic applications. Today, electrodes that can be implanted into the brain for months or years, are an irreplaceable tool for brain machine interfaces and neuroscience studies. However, these chronically implanted neural probes suffer from continuous loss of signal quality, limiting their utility. Histological studies found a sheath of scar tissue with decreased neural density forming around probe shanks as part of an ongoing chronic inflammation. This was hypothesized to contribute to the deterioration of recorded signals. The neural probes developed in this thesis are designed to deploy electrodes outside this sheath such that they interface with healthier neurons. To achieve this, an actuation mechanism based on starch-hydrogel coated microsprings was integrated into the shank of neural probes. Recording electrodes were positioned at the tip of micrometer fine and flexible needles that were attached to the springs. Before insertion, the hydrogel dehydrates, retracting the springs. After insertion, the gel rehydrates, releasing the springs, which then deploy the electrodes. The actuation mechanism functions in a one-time release fashion, triggered by contact with biological fluids at body temperature. The deployment of the electrodes occurred over the course of two hours and can be divided into three stages: For the first 20 s, the electrodes did not deploy. Within the first three minutes they deployed by roughly 100 µm (0.5 µm/s). Tor the following two hours they deployed an additional 20 µm (0.17 µm/min). The employed design supported six deploying electrodes, each at the end of a 5 µm wide and thick, and 100 µm long needle. These were attached to a shank with 290 µm width, 12 µm thickness and 3 mm length. The shanks could be inserted into the cortex of rats through an opening in the pia without breaking. The acquired waveforms indicate that some of the deployed electrodes were able to record neural action potentials.PhDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113317/1/egertd_1.pd