Electrical and Electronic Engineering - Theses

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    A predictive model of retinal ganglion cell responses to electrical stimulation
    MATURANA, MATIAS ( 2016)
    Degenerative diseases such as retinitis pigmentosa and age-related macular degeneration result in the loss of photoreceptor cells, which function to transduce light into a neural signal. However, retinal ganglion cells (RGCs), the output cells of the retina, and other cells within the retina often survive in high numbers. Recent developments in visual prostheses have demonstrated that electrical stimulation of the retina is becoming a viable therapy for those blinded through degenerative diseases. While the developments of retinal prostheses are still in their infancy, clinical trials have shown that the vision produced by retinal prostheses can appear complex in both space and time. The development of improved stimulation strategies for the bionic eye requires an understanding of the effects of RGCs to electrical stimulation. This thesis investigates a model that can be used to predict responses of RGCs to arbitrary patterns of electrical stimulation. Intracellular whole cell patch clamp recordings were made in whole mount preparations from normal sighted rats to develop RGC response models to electrical stimulation. Recordings were made at room temperature (~24ºC). Stimulation was applied using a custom-made multi electrode array and consisted of random amplitude biphasic pulses applied at constant frequency. Short-latency responses were correlated with the stimulation applied and a spike triggered covariance technique was used to determine spatial features of the stimulation that resulted in a response. Generally, the spatial arrangements of electrodes that influenced the cell’s response were as expected: the electrodes closest to the recorded cell had largest influence on the cell’s response. An extracellular recording technique was applied to model the long-latency responses to electrical stimulation. Recordings were made close to physiological temperature (~34ºC). The mathematical model used during the intracellular recordings was adapted to also model temporal features of stimulation. Temporal features of stimulation for many cells were complex; the polarity and spatial organisation of stimulation changed over time. Additionally, both excitatory and suppressive features of electrical stimulation were revealed by the model. The effects of temperature were examined to investigate whether some differences observed in results for the two recording techniques could be explained by the temperature used during the two experiments. In vitro recordings at different temperatures were used to investigate how retinal responses changed at different temperatures. The sensitivity of RGCs to electrical stimulation was found to be higher at temperatures closer to physiological temperature. Additionally, a greater amount of long latency activity was observed, suggesting increased activation of the retinal network. Simulations were used to explore an algorithm for achieving spatial control of neural activation. The algorithm made use of the error between recorded and target responses to fine tune the stimulation applied. The simulations suggested that the model can be used to manipulate spatial interactions in a predictable manner, thereby improving spatial fidelity. Additionally, closed loop stimulation may be used to mitigate undesirable effects of stimulation that are observed clinically, such as fading; a phenomena that results in the visual percept produced by electrical stimulation disappearing over time despite constant stimulation. Electrical stimulation of the retina often results in indiscriminate activation of many RGC types. A major goal of electrical stimulation is the targeted activation of certain cell types, such as ON cells or OFF cells. Traditionally, light responses are used to classify cell types. In the degenerate retina, where light responses are not obtainable, other methods are required to identify cells. Analysis of recorded intracellular responses revealed that the action potential waveform may contain identifiable features that could be used to establish the cell type. A previously developed multi compartment model of a RGC was used to relate features in morphology and electrophysiology to features in the action potential waveform. Overall, the results of my investigations demonstrate that RGC responses to electrical stimulation can be accurately modelled and predicted. Complex spatiotemporal features of electrical stimulation can be extracted and explained in a computationally simple model. The work presented here can aid in future developments of improved stimulation strategies that achieve a tighter control of neural activation.
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    Safety of a wide-field suprachoroidal retinal prosthesis
    VILLALOBOS VILLA, JOEL ( 2012)
    Retinal prostheses have emerged as a promising therapy for blindness arising from retinal degenerative diseases; the leading cause of untreatable visual impairment. Implantation in the suprachoroidal space is a potentially safer alternative to other modes of intraocular implantation because the choroid provides isolation from the neuroretina. This work aimed to characterise the safety of a suprachoroidal retinal prosthesis covering a wide visual field. For this, surgical implantation trauma was assessed, an implant developed, then the pathological response to chronic implantation was characterised and the efficacy of retinal stimulation evaluated. The initial study with flexible circuit electrode arrays assessed surgical implantation trauma. The 8 mm × 100 mm arrays were implanted suprachoroidally in cats, by vitreoretinal surgeons, through a temporal sclerotomy and then advanced towards area centralis. Subsequent histopathological analysis revealed that the implants were consistently located in the suprachoroidal space, without breaching retina, choroid or sclera. The risks identified were: scleral deformation due to implant stiffness, choroidal incarceration through the wide sclerotomy and subclinical retinal folding as the implant approached the optic disc. A medical grade implant substrate was developed for improved safety and simpler surgery. An array of 21 platinum electrodes (ø 600 μm) was built in a spherically contoured silicone substrate (8 mm × 19 mm). The electrode array was designed to be reliably implanted suprachoroidally, conform to the sclera, minimise the trauma found in the first study and be robust for long-term implantation. The implant had a transscleral cable which terminated in a subcutaneous implantable connector. These contoured wide-field electrode arrays were unilaterally implanted in cats for 3 months to evaluate long term safety. Fundus examination revealed that the implants stabilised and initial oedema resolved within 2 weeks. The retinas were unharmed except for small hyperpigmented regions near the optic disc. Electroretinographic assessment showed hypersensitivity in the implanted eyes at 2 weeks, but retinal function was normal after 3 months. Following 3 months of implantation, efficacy of neural stimulation was characterised by recording cortical potentials. For this, the subcutaneous connector was exposed and the electrodes stimulated with biphasic current pulses. Evoked cortical potentials were reliably recorded on the epidural surface of V1 for 98 out of 100 stimulated electrodes, with a median threshold of 150 nC/phase. The average electrode impedance in vivo of 12.5 kΩ was higher than the preimplantation impedance in saline of 3.13 kΩ, which indicated a stable tissue interface. After termination the eyes were processed for histopathological assessment. Tissue samples from the implant tract revealed a thin layer of fibrous tissue on the implant surface (1–2 cells thick) with sporadic macrophages and giant cells. Presence of active inflammatory cells was scarce. The retina over the electrode array was not altered significantly compared to the control eye. The suprachoroidal electrode array was safe, reliable and well tolerated in the eye during 3 months of implantation. The tissue reaction to the implant was minimal and the undamaged retina was reliably stimulated to evoke cortical activity. The spherically contoured electrode array showed promise for safe clinical use.
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    The condition of the retina in retinitis pigmentosa during late stages of degeneration
    O'BRIEN, EMILY ( 2012)
    Retinitis pigmentosa (RP) is a family of inherited retinal degenerations that are characterised by photoreceptor death resulting in blindness. It was once thought that following photoreceptor death, the inner retina remained unchanged. However, studies have begun to show that there are extensive changes at late stages in the disease process. This thesis further extends these studies by examining the inner retina at various time points after photoreceptor death so that the cellular changes that arise throughout the degenerative process can be characterised. A novel transgenic mouse model, the rd1-FTL, was used to document the condition of the retina. This animal model expresses a mutation which results in retinal degeneration as well as containing an axonal targeted transgenic marker gene that labels all neurons that have the c-fos gene activated. A combination of enzyme histochemistry and fluorescence immunohistochemistry was used to reveal an up-regulation of c-fos in the central retina following complete photoreceptor loss that remained throughout the later stages of degeneration. This was also coupled with a major glial dysfunction in this area. Neurochemical analysis prior to and during c-fos upregulation revealed significant changes in the inner retina. Amino acid immunocytochemistry was used to show that many amino acids in the degenerated retina were altered in patches across the retina. The most significant changes were documented in Müller cells and bipolar cells. Additionally, gross remodelling of neural and glial cells occurred in the retina which worsened as animals aged. A comprehensive morphological analysis of retinal ganglion cells in the degenerated retina showed that the cell types which covered the largest area in the retina were altered whilst the smaller cells types remained unchanged. However, these smaller cells did show altered morphology in regions that also expressed c-fos in late stages of degeneration. Furthermore, there were significant changes in the stratification of many ganglion cells in the degenerated retina that included the loss of certain cell types as well as different branching patterns of dendrites. Overall, this thesis shows that there are extensive changes in the inner retina following photoreceptor loss. It provides a thorough examination at different stages in the degenerative process to highlight the varying conditions that can occur in this disease. Approaches aimed at vision restoration rely on a strong understanding of this underlying cellular anatomy and this work will assist with the design of these approaches.
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    A highly flexible stimulator for a high acuity retinal prosthesis implemented in 65 nm CMOS process
    TRAN, NHAN ( 2011)
    This thesis presents a design of a flexible stimulator in 65 nm Complementary Metal Oxide Semiconductor (CMOS) as part of a 1024-electrode epiretinal prosthesis to restore partial vision in patients suffering from eye diseases such as retinitis pigmentosa (RP) and age-related macular degradation (AMD). The stimulator design is to support as many different stimulation strategies as possible. In particular, a wide variety of current amplitudes and stimulation frequencies is called for. Bipolar as well as monopolar stimulation strategies are also catered for. The selection of electrodes is fully flexible where any electrodes and any number of them can be selected as active or return at any time slice. The separation of image data update rate and stimulation refresh rate helps reduce data bandwidth by a half, which is very beneficial because the bandwidth for the data receiver of the stimulator chip is limited to 300 kHz in Medical Implant Communication Service (MICS) band. A distributed design where data is mainly processed at the local controller of every electrode driver simplifies signal routing, which is critical when the number of electrodes goes up to 1024. Global controlling circuits which help realizing some of the flexibility were designed, fabricated and tested with good performance. A novel electrode driver topology was proposed. Each electrode is controlled by its own driver, which helps selecting electrodes independently. The proposed electrode driver allows its electrode to act as active or return. The novel electrode driver operates in an alternately push-pull manner where only one current sink or source works at a time when doing stimulation. This results in a reduction of headroom voltage by a half, or equivalently more voltage can be used for stimulation, which is extremely advantageous as the maximum supply voltage of the implemented 65 nm CMOS process is limited to 3.3V. In order to verify the feasibility of the flexibility in terms of the ability of circuit implementation and power consumption, a prototype stimulator with 64 outputs was designed, fabricated, and tested. This prototype stimulator supports all the targeted stimulation flexibility. The verification of this prototype stimulator is a very useful and important preparation stage in designing a fully integrated high acuity epiretinal stimulator. The prototype stimulator was extensively tested and expected performance has been achieved. The power consumption of the prototype stimulator is 400 µW excluding the stimulus power, which makes the power consumption of the ultimate 1024-electrode stimulator just a few mW.
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    A super low power MICS band receiver on 65 nm CMOS for high resolution retinal prosthesis
    YANG, JIAWEI ( 2011)
    Implantable biomedical communication devices are now at the forefront of extensive research. These devices may effectively capture vital information from the outside environment for patients to use as substitutes of human organs (e.g. bionic ear, bionic eye, etc.), and/or record real-time physiological parameters from a patient (e.g. electrocardiogram, electroencephalogram, electromyogram, blood pressure, etc.). Transceivers for these purposes require extremely low power consumption, since batteries are undesirable due to their limited lifetime and the possibility of infections, and hence power is preferably acquired by wireless coupling. Moreover, these transceivers are usually preferred to be fully integrated on a single chip for easier surgery and better biocompability. Medical Implant Communication Service (MICS) band (402 MHz - 405 MHz with 10 channels), which was established by the Federal Communications Commission (FCC) of the United States in 1999, is widely used as the operation frequency band for biomedical devices. This thesis presents a super low power MICS band receiver for a fully integrated retinal prosthesis (Bionic Eye). In order to achieve super low total power consumption, all the analog blocks in this work are operated in subthreshold region and various low power techniques are applied. The fully subthreshold operation in MICS band is become possible due to the use of sub-70 nm Complementary Metal Oxide Semiconductor (CMOS) technology. This thesis starts with the power considerations in deep sub-micron CMOS and analyses the limits and challenges in low power radio frequency (RF) and analog design. It then considers subthreshold operation and provides parameter extraction approaches for the Enz-Krummenacher-Vittoz (EKV) model, as well as the modeling of transconductance efficiencies for various types of field-effect transistor (FET) devices. A literature review of MICS receivers is also included, in order to gain an intuitive insight into the current state of the art and the basic approaches that can be used for low power design. After presenting the system architecture and system level calculations, the individual block designs are reported one by one. The first block is the front-end down converter. This down converter, including a low-noise amplifier (LNA) and a quadrature mixer, only draws 500-μA bias current under 1-V supply. With a small differential local oscillation (LO) swing of 300 mV, it provides a voltage conversion gain of 34 dB and a noise figure of 7 dB, while a -27.5-dBm input-referred third-order intercept point (IIP3) is obtained. A power-constrained noise optimization technique is applied to this subthreshold down converter to optimize the matching parameters and transistor sizes. The second block is the channel selection filter. A 5th-order elliptic operational transconductance amplifier-capacitor (OTA-C) bandpass filter utilizes subthreshold inverter-based OTAs is designed. In order to broaden input range of the filter, the first OTA stage is linearized by using the active-error feedforward technique. The overall filter only draws 320-μA bias current under 1-V supply, while having an input range up to 0.6 Vpp and an in-band spurious free dynamic range (SFDR) of 41 dB. By using N-type FET capacitors as OTAs’ load, the chip area of this filter is minimized. Apart from the real bandpass filter, a 7th-order complex filter that has 48-dB image rejection at cost of 500-μW power dissipation is also constructed for the occasions that there exist image frequency interferences. As MICS band channel selection filters, both the real and complex filters have approximately 300-kHz bandwidths and exhibit more than 40-dB attenuations to the adjacent channel. The third block is the intermediate frequency (IF) variable gain amplifier (VGA). This VGA consists of a variable gain stage, followed by a fixed gain stage. It has a 32 dB log-linear tuning range and only requires 46-μA bias current under 1-V supply. The above three blocks constitute the receiver chain, which has a tunable total voltage gain of 36.8-68.9 dB on 50-Ω load and a noise figure of 17.2-15.1 dB. The measured gain and noise figure at designed normal operation condition, for a RF input power of -70 dBm, are 57.3 dB and 15.7 dB respectively. This thesis also reports on a subthreshold voltage-controlled oscillator (VCO) and a low power phase-locked loop (PLL), which are designed to provide LO signals for both receiver and transmitter in multi-channel operation. Current-reuse topology that uses N-type and P-type CMOS cross-coupled pairs is chosen for the core VCO design to save power. Cascade on-chip inductors are used and a pair of ”nCap” varactors (N-type FET in N-well) is configured to give a VCO gain of 12 MHz/V. The VCO is able to produce 600-mVpp quadrature signal whilst only dissipating 220 μW. The PLL utilizes digital frequency synthesizer and can settle within 350 μS while possessing a low phase noise, less than -102 dBc/Hz at 200-kHz offset. The average power dissipation of the entire PLL is a mere 400 μW. A 300-MHz microelectromechanical (MEMS) resonator is proposed to generate the system’s frequency reference. After comparing different types of MEMS devices and their post-CMOS micro-machining processes, a contour mode nickel disk resonator is selected. The precise modeling and simulations ensure it has a quality factor as high as 9000. The integration of the receiver chain with the PLL, including electrostatic discharge (ESD) protections, are demonstrated on a test chip using IBM 10cmoslpe 65-nm process. The performances of all individual blocks are measured and documented. Finally, experimental results of the entire receiver are reported and block power consumptions are experimentally established. The extremely low power dissipation and MICS band operation ensure that this receiver is very suitable for biomedical applications such as the Bionic Eye.