Doctor of Philosophy, Case Western Reserve University, 2018, Biomedical Engineering

Peripheral nerve cuff electrodes (NCEs) have been deployed in neuroprostheses restoring or modulating motor, sensory, and autonomic functions. They address myriad pathologies including stroke, spinal cord injury, amputation, seizure, chronic pain. As these applications encompass more indications, NCEs may be deployed in more anatomically-challenging locations while still delivering selective and stable stimulation and preserving the health of the implanted nerves. A novel class of reshaping electrodes with patterned regions of stiffness enable implantation in a widening range of anatomical locations. Patterning stiff regions and flexible regions of the electrode enables nerve reshaping while accommodating anatomical constraints of various implant locations ranging from peripheral nerves to spinal and autonomic plexi. We introduce the composite flat interface nerve electrode (C-FINE), flexible and small enough to be suitable for implantation near joints or other constrained locations. Benchtop testing verified the C-FINE does not exert ischemia-inducing pressure on nerves, even in the face of potential nerve swelling. Animal testing verified safety of C-FINE shells implanted on peripheral nerves for 3 months through a combination of nerve conduction studies and quantitative histology. Classically, this benchtop and animal testing followed by chronic observation of neuroprosthesis function have served as a proxy for directly measuring nerve health. We implanted the first-in-man C-FINEs on the proximal femoral nerves near the inguinal ligament of a man with cervical spinal cord injury. Over the first year of implantation we established the safety of C-FINEs in this anatomically constrained location directly via clinical electrodiagnostics. Future NCE designs can use these clinical results as a baseline for expected changes in a well-functioning neuroprosthesis. Previous NCEs have not been able to selectively activate hip flexors and knee extensors when i (open full item for complete abstract)

Committee: Ronald Triolo PhD (Advisor); Dustin Tyler PhD (Advisor); Dominique Durand PhD (Committee Chair); Stephen Selkirk MD/PhD (Committee Member) Subjects: Biomedical Engineering; Neurology

Doctor of Philosophy, Case Western Reserve University, 2015, Biomedical Engineering

The overall goal of this work is to optimize nerve cuff stimulation for selective activation of upper extremity nerves. The characterization of upper extremity nerve dimensions is important for electrode design development. Quantitative measures such as nerve diameter, number of fascicles, and fascicle diameters were used to guide neural electrode dimensions. The quantitative upper extremity measurements were used as a template to create upper extremity simulation models. We constructed physiologically based Finite Element Method (FEM) models of nerve cuff electrodes at low, moderate, and high contact densities at 16 nerve locations in median, ulnar, and radial nerves. We hypothesize that adding two flanking anodes to an active cathode is sufficient for optimal selectivity of fascicles in upper extremity nerves. We exhaustively tested one and two channel configurations, as well as, all three channel configuration within six contacts. Since the number of permutations of stimulation parameters increases exponentially by adding anodes, a genetic algorithm search routine was employed. Seventy-nine percent of all fascicles were selectively activated with high density electrodes and multiple channel stimulation. Only 2.5% of selective fascicles required more than 2 anodes in the stimulation configuration. The important implication of this work is that optimal system design requires high density nerve cuff electrodes, but no more than four simultaneously active stimulation channels routed through a multiplexor. We tested the capabilities of a high density electrode with multipolar stimulation in non-human primate upper extremity nerves. A high density Composite Flat Interface Nerve Electrode (CFINE) was implanted chronically in a non-human primate on the median, radial, and ulnar nerves. Electromyography (EMG) recordings were used to optimize nerve stimulation parameters to increase selective muscle activation of the hand and arm muscles using high density nerve cuf (open full item for complete abstract)

Committee: Dustin Tyler Ph.D. (Advisor); Robert Kirsch Ph.D. (Committee Member); Kevin Kilgore Ph.D. (Committee Member); Vira Chankong Ph.D. (Committee Member) Subjects: Biomedical Engineering

Master of Engineering, Case Western Reserve University, 2006, Biomedical Engineering

This project aims to show that a denervated muscle can be reanimated following spinal cord injury using upper motoneuron injured lower motoneurons regrowing through non-electrically excitable nerves. The newly reanimated muscle can then be stimulated with command signals from an electrical stimulation system. A rat model was created with a spinal cord injury and a transection of the tibial nerve to create the denervation. One week post injury, the upper motoneuron injured peroneal nerve was transferred to the sheath of the tibial nerve. About five weeks after that, force analysis showed significant regrowth. The same force analysis was performed on both the experimental side, which had undergone the surgical procedures outlined above, and the contralateral side, which previously had not undergone any peripheral surgical procedures. The maximum experimental side gastrocnemius force was approximately 50% that of contralateral side.

Committee: Robert Kirsch (Advisor) Subjects:

Doctor of Philosophy, Case Western Reserve University, 2025, Biomedical Engineering

This dissertation focuses on non-perceptual effects of artificial sensation measured by effects in the motor system. Tactile feedback is used throughout the brain, from the “highest” cortical level to the “lower” spinal or brain stem level. Touch is first used before perception, or pre-perceptually, by the brain stem in simple, automatic modulation of the motor system. For example, carrying an object from place to place or even shifting it in one's hand involves many changing tactile signals. Even a single ridge of a fingertip supplies a unique signal for use in object manipulation. If one had to actively perceive and act upon all this information, merely picking up an object would become overwhelming. Fortunately, the lower levels of our brain automatically make minor adjustments to grip based on tactile information. What is not known is how relevant perceptual qualities are to these automatic corrections to grip. The cortex, not the brainstem, is the location of tactile perception, so it stands to reason that the brainstem does not require “natural” qualities of tactile feedback. Our lab has a group of participants with peripheral nerve cuff electrodes we can stimulation through. We tested how well artificial tactile feedback would integrate with the sensorimotor system in tasks of increasing complexity. We found that peripheral nerve stimulation is processed similarly to naturally generated touch with and without perception and may engage with the motor system as seen by the intent to modulate grip force.

Committee: Dustin Tyler (Advisor); A Bolu Ajiboye (Committee Chair); Hillel Chiel (Committee Member); M. Cenk Çavuşoğlu (Committee Member) Subjects: Biomedical Engineering; Engineering; Neurosciences

Master of Sciences, Case Western Reserve University, 2021, EECS - Electrical Engineering

We elicit tactile sensation through peripheral nerve stimulation (PNS) for rehabilitation of people with limb loss. We use the Composite Flat Interface Nerve Electrode that has 15 contacts that can be used for stimulation individually or simultaneously. Current PNS paradigms designed for single-percept sensory restoration stimulate through a single contact. Existing biomimetic paradigms that reproduce aspects of natural afferent activity do not consider all four critical neural coding properties: firing rate, population size, type, and location. We present a new biomimetic PNS paradigm that approximates all four critical neural coding properties. Our paradigm provides multi-contact stimulation, where two contacts can be active simultaneously and contacts can be switched on a pulse-by-pulse basis throughout each stimulus. We show that switching between contacts outperforms using a single contact, as does using two-contact stimulation compared to single-contact stimulation. We hypothesize that our new paradigm can improve sensory feedback for those with limb loss.

Committee: Kenneth Loparo (Committee Chair); Emily Graczyk (Advisor); Dustin Tyler (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Electrical Engineering; Neurosciences; Rehabilitation

Doctor of Philosophy, Case Western Reserve University, 2020, Biomedical Engineering

Over one million individuals in the United States have a lower-limb amputation. Though locomotion is a sensorimotor process, no commercially available prostheses offer somatosensory feedback, and amputees continue to face locomotor challenges. Recent studies have demonstrated that electrically stimulating the residual nerves of amputees can elicit somatosensory percepts referred to the missing limb. Though peripheral nerve stimulation (PNS) takes advantage of the existing neural pathways that carry sensory information from the amputated limb to the brain, neural stimulation does not activate these afferent fibers in the same manner as physically-applied tactile stimuli. We hypothesized that these differences in neural activation may cause PNS-evoked sensation to be perceived differently than natural touch with respect to temporal synchrony and multisensory integration. In Aim 1, we found that the processing time and temporal sensitivity were not different between PNS-evoked and natural somatosensation. The similarity in visuotactile synchrony provided further evidence that PNS-evoked sensations are processed in broadly the same way as natural touch. In Aim 2, we established that much like natural somatosensation, vision and postural manipulations could reinforce PNS-evoked somatosensation. This multisensory integration had not been previously demonstrated and it is important for sensory neuroprostheses, which will be used in diverse environments with various sensory resources. The findings from Aims 1-2 demonstrated that PNS-evoked and natural somatosensation have similar properties, but did not guarantee that the body would utilize the sensory information accordingly. In Aim 3, we showed that amputees utilized PNS-evoked plantar sensation while performing a challenging locomotor task, revealing a significant and immediate benefit of somatosensory feedback to amputees. The use of a sensory-enabled prosthesis did not change the amputees' locomotor strategies, (open full item for complete abstract)

Committee: Ronald Triolo (Advisor); Dustin Tyler (Committee Chair); Bolu Ajiboye (Committee Member); Cenk Cavusoglu (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2020, Biomedical Engineering

In upper limb amputation, sensory feedback from the hand is lost, significantly reducing users' ability to interact with the environment, even with a prosthesis. Sensation location, one of four basic dimensions of somatosensation, provides valuable information about how the hand interacts with objects or the environment. Location is encoded by the receptive fields of individual axons and then cortically processed to create the perception of touch in the intact system. We hypothesized that artificial somatosensory locations are encoded, processed, and utilized similarly to intact somatosensory locations. We quantified the effects of various electrical and functional conditions on the location and functional use of evoked sensory percepts. Patient-specific computational and statistical models probed the underlying mechanisms driving experimental outputs. We found that peripheral nerves of the upper arm retain a somatotopic organization proximal to the elbow. Consequently, cuff electrodes, which recruit spatially grouped axon populations, encode focal percepts across targeted regions of the hand independent of placement along the peripheral nerve. However, functional use of the arm can induce some variability to the cuff-nerve interface. This changes the size of the active axon population and, correspondingly, the size of the perceived sensation location, as a prosthesis is actively used. We also found that perception of artificial sensation is not solely dependent on the active axon population. Instead, like intact perception, top-down modulators influence tactile perception. Perceived sensory locations are more stable and more aligned with expected sensory locations when tested in a functional context. Further, this alignment becomes permanent with prolonged exposure to functionally-relevant artificial somatosensation over months of take-home usage. Such changes are dependent on the transduction of meaningful information through the percept; sensory locations (open full item for complete abstract)

Committee: Dustin Tyler PhD (Advisor); Kenneth Gustafson PhD (Committee Chair); Robert Kirsch PhD (Committee Member); Vira Chankong PhD (Committee Member) Subjects: Biomedical Engineering; Neurosciences; Rehabilitation

Doctor of Philosophy, Case Western Reserve University, 2018, Biomedical Engineering

Following an upper limb amputation, both the functional and sensory capabilities of the hand are lost. Prior studies demonstrated the ability of neural stimulation to evoke sensations on the missing hand of persons with upper limb loss. However, the sensations have only been cursorily assessed in terms of their perceptual characteristics and psychosocial impacts. Further, we do not know to what extent mimicking natural firing patterns can improve the stimulation-evoked sensations. Using classical psychophysical techniques, we characterized the perception of intensity of sensations evoked by electrical stimulation through Flat Interface Nerve Electrodes (FINEs) implanted in three humans with upper limb loss, and compared these characteristics to natural intensity perception. We found that intensity perception is equivalent for natural and artificial touch, including intensity sensitivity, dynamic range, and the time course and extent of adaptation resulting from prolonged stimulation. We demonstrated that population spike rate is the neural basis of perceived intensity. To determine the impact of sensation on the holistic experience of having a hand, two persons with upper limb loss utilized a sensory restoration system in their homes and communities. We found that sensation improved the psychosocial experience of using the prosthesis, including confidence in abilities, prosthesis incorporation, perception of social interactions, and body image. Sensation improved prosthesis function and increased prosthesis usage. This study indicated that extraneural stimulation is a feasible method of long-term sensory restoration in community use. Participant perspectives revealed that sensation was critical for outcome acceptance. We developed a theoretical model of the impacts of sensation based on a qualitative analysis of participant experiences, which may provide a unified framework to study outcome acceptance following amputation. To determine whether mimicking na (open full item for complete abstract)

Committee: Dustin Tyler PhD (Advisor); Robert Kirsch PhD (Committee Chair); Ronald Triolo PhD (Committee Member); Grover Gilmore PhD (Committee Member) Subjects: Biomedical Engineering; Neurosciences; Rehabilitation

Master of Science, University of Akron, 2018, Biomedical Engineering

Electrical stimulation (ES) has previously demonstrated promising effects on peripheral nerve repair through enhanced neurite growth in vitro and shortened recovery time in vivo. In this study, we aimed to evaluate the effect of intraoperative short term ES on a clinically relevant isograft-repair model of a rodent peripheral nerve. In our model, an isograft was used to repair a 13 mm sciatic nerve gap-defect in adult male rats. Intraoperative ES was applied for 10 min at 24 V/m-DC to the experimental group and no stimulation was applied to the control group. We evaluated biweekly functional recovery over 12 weeks for motor function, using the sciatic functional index and external postural thrust. Sensory function was evaluated using a thermal stimulus. Motor nerves are more heavily myelinated and regenerate more quickly, while sensory nerves are less myelinated and have a slower recovery time. Structural repair outcomes were evaluated through histological examination of the sciatic nerves and gastrocnemius muscles at 6 and 12-week time points. The ES group had a significantly better motor recovery than the control group in weeks 4 and 6 after surgery. In addition, the ES group had 7% fewer paw contractures than the control group. Paw contractures form when the flexor muscles are innervated more quickly than extensor muscles, leaving the paw in a chronically curled over position that is representative of a clinical challenge in human nerve recovery. Furthermore, sensory functional testing and histology evaluation confirmed that ES was safe to use, as the ES- treated group had comparable recovery outcomes to the no-ES control group. Our previous study showed that 10 minutes of ES was effective in promoting functional recovery through a collagen scaffold bridging a 10-mm nerve defect. Here, we extend our findings by showing that ES can speed up motor recovery in an isograft-repair model, while slowing contracture formation. Demonstrating the benefits of applying short (open full item for complete abstract)

Committee: Rebecca Kuntz Willits (Advisor); Ge Zhang (Committee Member); Matthew Becker (Committee Member) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2007, Biomedical Engineering

Functional electrical stimulation (FES) is used to elicit contractions in paralyzed muscles and increase the independence of people with impaired neurological function. Most existing neuroprostheses consists of muscle-based electrodes. However, nerve electrodes are emerging as a tool to provide increased benefit for increasingly complicated systems. Many types of nerve electrodes have been developed and tested in animals but few have been transferred to clinical use and none have been used in motor neuroprostheses. This work has set up and followed a strategy to overcome the obstacles to clinical deployment for the spiral nerve cuff electrode. Initial intraoperative testing provided valuable information about the function of human nerves. Stimulation thresholds were determined to be similar to the animal studies and selective activation of a single muscle was possible from all nerves. This information was used to choose electrode locations and stimulation parameters for chronic testing. Chronically implanted spiral nerve cuff electrodes were found to be a stable platform for activation of paralyzed muscles. There were no adverse functional changes or sensation due to the implanted electrodes implanted for over 1.5 years. Nerve stimulation produced controllable activation of the distal muscles with joint moments sufficient for functional tasks. At least one muscle could be selectively activated from each proximal nerve trunk and the selectivity increased with the use of multi-contact stimulation. The spiral nerve cuff electrode is an effective tool for activating paralyzed muscles in the human extremities.

Committee: Dustin Tyler (Advisor) Subjects:

Doctor of Philosophy, Case Western Reserve University, 1995, Biomedical Engineering

The goal of this work was to develop electrodes and stimulation techniques that enable selective electrical excitation of discrete populations of peripheral nerve fibers within a peripheral nerve trunk. A nerve cuff electrode containing 12 individually addressable electrode contacts was tested in acute and chronic experiments on cat sciatic nerve. The forces developed in the ankle musculature were recorded either directly or by measurement of the ankle joint torque. Four distinct strategies to achieve selectivity were investigated: Electrode Geometry: spatially distributed electrode contacts generated localized patterns of excitation within the nerve trunk, Field Steering: sub-threshold currents applied from other electrode contacts coincident with the stimulus pulse modified the region of excitation, Stimulus Duration: different stimulus pulsewidths were tested for selectivity, and Manipulation of Membrane Excitability: the non-linear sodium conductance of the nerve membrane was controlled to invert the current-distance relationship. Using tripolar electrode geometries and field steering currents it was possible to achieve selective and graded activation of individual fascicles within the nerve trunk. Selectivity was dependent on the relative positions of the electrode contacts and nerve fascicles, and the spacing between neighboring fascicles. Selectivity between fascicles was increased when using short duration stimuli as compared to longer duration stimuli. Use of field steering current increased selectivity by restricting excitation to a more localized region of the nerve trunk in both acute and chronic implants. Measurements with chronically implanted electrode yielded recruitment properties that were independent of joint position. Recruitment properties were less variable between 8 weeks and 24 weeks after implant than between 1 week and 8 weeks after implant. These results indicated that the cuff enabled selective activation on a long-term basis, and that co (open full item for complete abstract)

Committee: J. Mortimer (Advisor) Subjects: Engineering, Biomedical

Doctor of Philosophy, Case Western Reserve University, 2013, Biomedical Engineering

An interface implanted on or within the peripheral nerve provides the opportunity to stimulate a desired group of axons to control a single muscle or a group of muscles without requiring large current magnitudes. Intraneural electrodes can provide close access to the axons, but those that disrupt the perineurium can cause chronic damage to the nerve. Computational models have shown that directional electrical contacts placed within the epineurium, between the fascicles, and not penetrating the perineurium can achieve selectivity levels similar to point source contacts placed within the fascicle. This work examines the selectivity of an interface implanted within the epineurium, outside the fascicles without penetrating the perineurium. Further, the biomechanical characteristics and insertion into the membranes of the nerve are studied to identify the margins between the epineurium and the perineurium. This data is expected to aid insertion techniques and interface development for devices implanted within and outside the perineurium. The Young's moduli and ultimate strains of the perineurium and the epineurium and the forces necessary to penetrate them for electrode implant were quantified. Data suggested that the Young's modulus and the insertion forces were both an order of magnitude lower for the epineurium than the perineurium. These data provide design parameters that can be used to engineer materials that mechanically match the individual tissue membranes and facilitate implant mechanics suitable for each tissue. Further, this work tests the hypothesis that directional interfascicular contacts distributed in the epineurial space are selective. Examination of the recruitment data demonstrated selective axon population recruitment by these interfaces. Interfascicular interfaces with a directed contact were able to provide selective recruitment of axons without penetrating the perineurium.

Committee: Dustin Tyler (Advisor) Subjects: Biomedical Engineering

Doctor of Philosophy, Case Western Reserve University, 2013, Biomedical Engineering

Peripheral nerve interfaces have been used to restore motor function to paralyzed limbs. To restore the most natural function to paralyzed muscles requires a very selective interface. Arguably, ideal selectivity would entail independent control over each neuron. Neural interfaces based on electrical stimulation of neurons have made the most progress in restoring movement in paralyzed limbs, but increasing selectivity without increasing invasiveness remains a primary goal in developing stable and chronic nerve interfaces. Interfaces that use infrared light to stimulate may provide selective activation without penetrating the nerve. The work presented in this dissertation explores this concept, measuring sensitivity and motor response in peripheral nerves, and using computational models to investigate mechanisms of activation. The in vivo experimental work presented quantifies motor response to extraneural infrared stimulation in the rabbit sciatic nerve. It was hypothesized that infrared light would selectively stimulate motor response in at least three different regions of the nerve, and do so to a functionally significant level. Combined infrared and electrical stimulation was hypothesized to significantly change full-muscle recruitment over electrical recruitment alone. In this study, only 81% of nerves responded to infrared stimulus, with 1.7±0.5 sensitive regions detected per nerve. Single-muscle selectivity was measured in 79±12% of sensitive regions. Infrared stimulus activated significantly less than 10% of the muscle capability, though. Combined electrical and optical stimulation only yielded significant differences from electrical recruitment in 7% of cases. These results highlight challenges to address before translating infrared stimulation larger nerves. Mechanisms of infrared stimulation were studied using computational models. Intracellular currents generated by changes in membrane capacitance or intracellular calcium release were hypothesized (open full item for complete abstract)

Committee: Dustin Tyler Ph.D. (Advisor); Hillel Chiel Ph.D. (Committee Member); Dominique Durand Ph.D. (Committee Member); Andrew Rollins Ph.D. (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Optics

Master of Sciences, Case Western Reserve University, 2013, Biomedical Engineering

Stimulation electrodes with higher levels of selectivity than currently available are required to restore limb function, especially in the upper extremity. One strategy to increase the selectivity of an electrode is to move it closer to the target axons. A balance between selectivity and invasiveness can be made with interfascicular electrodes. We hypothesized that through Finite Element Method (FEM) models we could show that directed interfascicular electrodes placed within the nerve can achieve levels of selectivity equal to that of intrafasciclular contact without penetrating the perineurium. A simplified FEM model of a nerve was created of two cylindrical fascicles placed within a cube of epineurium. Using this model we showed that the contact-fascicle distance had a larger impact on the selectivity of a directed interfascicular contact than the relative diameter of the fascicles when the contact is less than 50 ¿¿m from the surface of the perineurium. When the contact is greater than 50 ¿¿m from the surface of the perineurium, the relative sizes of the fascicles have a more significant impact on the selectivity of the electrode. As the contact is placed closer to the surface of the perineurium, specifically within 50 ¿¿m, the surrounding fascicles have a reduced impact on the overall selectivity. Additionally, we have shown that interfascicular electrodes can achieve levels of subfasciclular selectivity greater than that of intrafascicular electrodes even when placed 50 ¿¿m off the surface of the perineurium. A bio-inspired FEM model was created to compare the selectivity of interfascicular and intrafascicular electrodes in a more realistic environment. In each simulation, directed intrfascicular electrodes placed directly on the surface of the perineurium were able to achieve selectivity levels equal the intrafascicular electrodes. The results of the previous model were also corroborated, as the interfascicular contact-fascicle distance increased, the select (open full item for complete abstract)

Committee: Dustin Tyler Ph.D (Committee Chair); Kenneth Gustafson Ph.D (Committee Member); Ronald Triolo Ph.D (Committee Member) Subjects: Biomedical Engineering