Low-dimensional representations of neural time-series data with applications to peripheral nerve decoding

Bioelectronic medicines, implanted devices that influence physiological states by peripheral neuromodulation, have promise as a new way of treating diverse conditions from rheumatism to diabetes. We here explore ways of creating nerve-based feedback for the implanted systems to act in a dynamically adapting closed loop. In a first empirical component, we carried out decoding studies on in vivo recordings of cat and rat bladder afferents. In a low-resolution data-set, we selected informative frequency bands of the neural activity using information theory to then relate to bladder pressure. In a second high-resolution dataset, we analysed the population code for bladder pressure, again using information theory, and proposed an informed decoding approach that promises enhanced robustness and automatic re-calibration by creating a low-dimensional population vector. Coming from a different direction of more general time-series analysis, we embedded a set of peripheral nerve recordings in a space of main firing characteristics by dimensionality reduction in a high-dimensional feature-space and automatically proposed single efficiently implementable estimators for each identified characteristic. For bioelectronic medicines, this feature-based pre-processing method enables an online signal characterisation of low-resolution data where spike sorting is impossible but simple power-measures discard informative structure. Analyses were based on surrogate data from a self-developed and flexibly adaptable computer model that we made publicly available. The wider utility of two feature-based analysis methods developed in this work was demonstrated on a variety of datasets from across science and industry. (1) Our feature-based generation of interpretable low-dimensional embeddings for unknown time-series datasets answers a need for simplifying and harvesting the growing body of sequential data that characterises modern science. (2) We propose an additional, supervised pipeline to tailor feature subsets to collections of classification problems. On a literature standard library of time-series classification tasks, we distilled 22 generically useful estimators and made them easily accessible.Open Acces

Impacts of Diabetic Neuropathy on the Human Neuromuscular System

Diabetes mellitus (DM) imparts vascular and metabolic stressors that cause damage and dysfunction to the human nervous system. The disorder associated with this dysfunction is termed diabetic polyneuropathy (DPN). Although DPN has been associated with muscle weakness and atrophy, the extent of its impacts on the neuromuscular system is not well understood. The five studies presented in my thesis investigated how DPN affects the neuromuscular system in humans, from the motor neuron to skeletal muscle contractile properties, using a combination of electromyography (EMG), dynamometry and magnetic resonance imaging (MRI) techniques. The purpose of Studies 1 and 2 was to determine whether the neurogenic loss of motor units underlies the muscle weakness and atrophy associated with DPN, and to investigate how these changes may differ in an upper and lower limb muscle. I determined DPN patients feature reduced motor unit estimates (MUNEs) compared to controls, and progression of motor unit loss in DPN may follow a length-dependent pattern. The purpose of Study 3 was to assess the stability of neuromuscular transmission in patients with DPN compared with healthy controls, using a novel set of electrodiagnostic parameters obtained via quantitative EMG. I determined DPN patients have less stable neuromuscular transmission, and the feature intermittent conduction failure at a relatively low contraction intensity. The purpose of Study 4 was to investigate skeletal muscle contractile properties and morphology in DPN patients associated with the severity of muscle denervation. I determined DPN patients possess slowed muscle, with greater proportional amounts of non-contractile muscle tissue compared to controls. The purpose of Study 5 was to explore the fatigability of DPN patients during a sustained, maximal voluntary contraction (MVC). I determined DPN patients have less endurance than controls, and their increased fatigability may be associated with neuromuscular transmission failure. Overall these foundational explorations greatly expand our knowledge of how DPN can impact the neuromuscular system in humans. Furthermore, the studies contained within my thesis may help direct further useful studies and strategies to understand, and direct clinical support in those with DPN

Identification of Point Process Systems With Application to Complex Neuronal Networks

The main aim of the thesis is to develop and apply statistical and computational techniques for the system identification of the complex interactions that occur between the components of neuronal networks within the central nervous system. An analysis of these interactions will provide a basis for understading the operations that the central nervous system uses to carry out particular tasks. In order to work effectively, it is necessary for a statistician to become familiar with the background for understanding the physiological problems. In Chapter 1, a brief description of the neuromuscular control system followed by a more detailed discussion of the muscle spindle, a particular component of the neuromuscular control system we are interested in, is given. The next section describes the problems we will be studying in this thesis. The final part of this chapter presents the basic data sets mainly obtained on the muscle spindle under different experimental conditions, and which will form the experimental material for our studies. Chapter 2 presents a review of the general theory of point processes. In Chapter 3 we introduce a univariate point process. Certain parameters are defined in both the time and frequency domain. In Chapter 4, Introducing a blvarlate stationary point process, we define certain parameters useful for measuring the association and timing relation between two processes in both domains. The main aim of this chapter is again to compare the procedures in both domains. Chapter 5 presents an extensive development of the wide range of applicability of a Fourier-based approach to measures of association and related problems. In Chapter 6 we extend the linear point process system Identification techniques to the systems which are assumed to be non-linear. The simplest non-linear case is quadratic. Certain third order (quadratic) time domain parameters, e.g., the third order product density, conditional density, and cumulant density, are defined and their estimates are considered. It is shown by a simulated study that all the three parameters give different informations about the non-linearities. The application of these parameters is demonstrated by using the real data on muscle spindle. The third order parameters are further extended to order-4. The aim is to have more insight into the processes under investigation. Estimates of the fourth order product density are considered. Asymptotic confidence intervals are constructed and Illustrated. In the frequency domain, the third order spectrum is defined and illustrated. A quadratic model relating a single output to a single input is introduced and developed which leads to the quadratic coherence, a measure of quadratic effects that the input has on the output. The estimation and application of the quadratic coherence is demonstrated. The final section of this chapter extends the quadratic model in order to include a second input. The model is solved under the assumption that the inputs are two independent Poisson processes, and which leads to a simple solution for the identification of a non-linear system with two inputs (independent Poisson processes). The results obtained in both domains reveal significant non-linear features of the muscle spindle. Chapter 7, considering the situations and problems for future work, gives a list of possible ways in which the work of this thesis may be extended. (Abstract shortened by ProQuest.)

Identifying and Reducing Variability, Improving Scaffold Morphology, and Investigating Alternative Materials for the Blood Vessel Mimic Lab Electrospinning Process

The work of the Cal Poly Tissue Engineering Lab is primarily focused on the fabrication, characterization, and improvement of “Blood Vessel Mimics” (BVMs), tissue engineered constructs used to evaluate cellular response to vascular medical devices. Currently, cells are grown onto fibrous, porous tubes made using an in-house electrospinning process from PLGA, a biocompatible co-polymer. The adhesion and proliferation of cells in a BVM is reliant on the micro-scale structure of the PLGA scaffold, and as such it is of great importance for the electrospinning process to consistently produce scaffolds of similar morphologies. Additionally, it has been shown that cell proliferation increases with scaffolds of smaller fibers and pores than the current electrospinning protocol can produce. Finally, the Tissue Engineering Lab has interest in testing devices in more tortuous BVM bioreactor designs, however the use of relatively rigid PLGA scaffolds has severely limited the ability to construct more complicated vessel geometries. The overall goal of this thesis was to improve fabrication and characterization of electrospun polymer scaffolds for BVM use. The specific aims of this thesis were to: 1) Improve scaffold characterization by comparing two techniques for fiber diameter measurement and implementing a technique for pore area measurement. 2) Reduce scaffold fiber diameter and pore area by investigating humidity and solvent composition electrospinning parameters. 3) Reduce process variability by developing a more specific electrospinning protocol. 4) Improve scaffold consistency and use by understanding and reducing PLGA scaffold shrinkage. 5) Identify and evaluate more flexible polymers as potential alternatives for electrospun BVM scaffolds. In order to accomplish these aims, first, several BVM and outside literature images were taken and evaluated with current and prospective fiber diameter techniques, and with 2 prospective pore area techniques to characterize accuracy and consistency of each method. It was found that the prospective fiber diameter measurement technique was not superior to the current method. The techniques developed for pore area measurement were found to produce results that differed significantly from each other and from the published value for a given image. Next, changes to environmental and solution composition parameters were made with the hopes of reducing fiber diameter and pore area of electrospun PLGA scaffolds. Changes in relative humidity did not appear to significantly affect scaffold fiber diameter while changes to solvent composition, specifically the use of acetone, resulted in fibers significantly smaller than those regularly achieved in the BVM lab. Next, several sources of variability in the electrospinning protocol were identified and subsequently altered to improve consistency and usability. Specifically, this included redefining the precision with which PLGA mass was measured, repositioning electrical equipment to reduce the effect of stray electrostatic forces on the polymer solution jet, attempting to control the temperature and humidity inside the electrospinning enclosure, and improving the ease with which scaffolds are removed from their mandrels through alternative mandrel surface treatments. In addition to overall process variability, the issue of scaffold shrinkage during BVM use was investigated and two possible treatments, exposure to either ethanol or elevated temperatures, were proposed based on previous electrospinning literature results. Each was tested for their effectiveness in mitigating shrinkage through exposure to BVM setup-mimicking conditions. It was found that both treatments reduced scaffold shrinkage compared to control samples when exposed to BVM setup-mimicking conditions. Finally, 3 flexible polymers were selected and electrospun to compare against typical PLGA results and to conduct a kink radius test as a metric for measuring flexibility as it pertains to the proposed BVM lab application. It was concluded that two types of thermoplastic polyurethane (tPU) were not acceptable electrospinning materials for use in the BVM lab. Additionally, while polycaprolactone (PCL) could be successfully electrospun it could not undergo the amount bending required for more tortuous BVM bioreactor designs without kinking. Overall, the work in this thesis provided insight into multiple scaffold characterization techniques, reduced overall electrospinning variability in the fabrication and use of PLGA scaffolds, and defined processing parameters that have been shown to yield scaffolds with smaller morphological features than all prior Tissue Engineering Lab work. By creating better, more effective scaffolds, researchers in the Tissue Engineering Lab can more accurately mimic the structure and properties of native blood vessels; this, in turn, will result in BVM cell responses that more closely resemble that of native tissue. Creating consistent and appropriate BVMs will then lead to impactful contributions to the existing body of tissue engineering research and to better preclinical device testing

Sewage sludge heavy metal analysis and agricultural prospects for Fiji

Insoluble residues produced in Waste Water Treatment Plants (WWTP) as by products are known as sewage sludge (SS). Land application of SS, particularly in agricultural lands, is becoming an alternative disposal method in Fiji. However, currently there is no legislative framework governing its use. SS together with its high nutrient and organic matter contents, constitutes some undesired pollutants such as heavy metals, which may limit its extensive use. The focus of this study therefore was to determine the total concentrations of Pb, Zn, Cd, Cu, Cr, Ni and Mn in the SS produced at the Kinoya WWTP (Fiji) and in the non-fertile soil amended with the SS at 20, 40, 60, 80% application rates and in the control (100% Soil). The bioavailable heavy metals were also determined as it depicts the true extent of metal contamination. The treatment mixtures were then used to cultivate cabbage plants in which the total heavy metal uptake was investigated. Total Zn (695.6 mg/kg) was present in the highest amounts in the 100% SS (control), followed by Pb (370.9 mg/kg), Mn (35.0 mg/kg), Cu (65.5 mg/kg), Cr (20.5 mg/kg) and finally Cd (13.5 mg/kg) and hence a similar trend was seen in all treatment mixtures. The potential mobility of sludgeborne heavy metals can be classified as Ni > Cu > Cd > Zn > Mn > Cr > Pb. Total metal uptake in plant leaves and stems showed only the bioavailable metals Cu, Cd, Zn and Mn, with maximum uptake occurring in the leaves. Ni, despite being highly mobile was not detected, due to minute concentrations in the SS treatments. Optimum growth occurred in the 20 and 40% SS treatments. However maximum Cu and Mn uptake occurred in the 40% SS treatment thereby making the 20% treatment the most feasible. Furthermore the total and bioavailable metal concentrations observed were within the safe and permitted limits of the EEC and USEPA legislations