Nonlinear and factorization methods for the non-invasive investigation of the central nervous system

This thesis focuses on the functional study of the Central Nervous System (CNS) with non-invasive techniques. Two different aspects are investigated: nonlinear aspects of the cerebrovascular system, and the muscle synergies model for motor control strategies. The main objective is to propose novel protocols, post-processing procedures or indices to enhance the analysis of cerebrovascular system and human motion analysis with noninvasive devices or wearable sensors in clinics and rehabilitation. We investigated cerebrovascular system with Near-infrared Spectroscopy (NIRS), a technique measuring blood oxygenation at the level of microcirculation, whose modification reflects cerebrovascular response to neuronal activation. NIRS signal was analyzed with nonlinear methods, because some physiological systems, such as neurovascular coupling, are characterized by nonlinearity. We adopted Empirical Mode Decomposition (EMD) to decompose signal into a finite number of simple functions, called Intrinsic Mode Functions (IMF). For each IMF, we computed entropy-based features to characterize signal complexity and variability. Nonlinear features of the cerebrovascular response were employed to characterize two treatments. Firstly, we administered a psychotherapy called eye movement desensitization and reprocessing (EMDR) to two groups of patients. The first group performed therapy with eye movements, the second without. NIRS analysis with EMD and entropy-based features revealed a different cerebrovascular pattern between the two groups, that may indicate the efficacy of the psychotherapy when administered with eye movements. Secondly, we administered ozone autohemotherapy to two groups of subjects: a control group of healthy subjects and a group of patients suffering by multiple sclerosis (MS). We monitored the microcirculation with NIRS from oxygen-ozone injection up 1.5 hours after therapy, and 24 hours after therapy. We observed that, after 1.5 hours after the ozonetherapy, oxygenation levels improved in both groups, that may indicate that ozonetherapy reduced oxidative stress level in MS patients. Furthermore, we observed that, after ozonetherapy, autoregulation improved in both groups, and that the beneficial effects of ozonetherapy persisted up to 24 hours after the treatment in MS patients. Due to the complexity of musculoskeletal system, CNS adopts strategies to efficiently control the execution of motor tasks. A model of motor control are muscle synergies, defined as functional groups of muscles recruited by a unique central command. Human locomotion was the object of investigation, due to its importance for daily life and the cyclicity of the movement. Firstly, by exploiting features provided from statistical gait analysis, we investigated consistency of muscle synergies. We demonstrated that synergies are highly repeatable within-subjects, reinforcing the hypothesis of modular control in motor performance. Secondly, in locomotion, we distinguish principal from secondary activations of electromyography. Principal activations are necessary for the generation of the movement. Secondary activations generate supplement movements, for instance slight balance correction. We investigated the difference in the motor control strategies underlying muscle synergies of principal (PS) and secondary (SS) activations. We found that PS are constituted by a few modules with many muscles each, whereas SS are described by more modules than PS with one or two muscles each. Furthermore, amplitude of activation signals of PS is higher than SS. Finally, muscle synergies were adopted to investigate the efficacy of rehabilitation of stiffed-leg walking in lower back pain (LBP). We recruited a group of patients suffering from non-specific LBP stiffening the leg at initial contact. Muscle synergies during gait were extracted before and after rehabilitation. Our results showed that muscles recruitment and consistency of synergies improved after the treatment, showing that the rehabilitation may affect motor control strategies

A review of wearable sensors based monitoring with daily physical activity to manage type 2 diabetes

Globally, the aging and the lifestyle lead to rabidly increment of the number of type two diabetes (T2D) patients. Critically, T2D considers as one of the most challenging healthcare issue. Importantly, physical activity (PA) plays a vital role of improving glycemic control T2D. However, daily monitoring of T2D using wearable devices/ sensors have a crucial role to monitor glucose levels in the blood. Nowadays, daily physical activity (PA) and exercises have been used to manage T2D. The main contribution of the proposed study is to review the literature about managing and monitoring T2D with daily PA through wearable devices and sensors. Finally, challenges and future trends are also highlighted

A Neurophysiologic Study Of Visual Fatigue In Stereoscopic Related Displays

Two tasks were investigated in this study. The first study investigated the effects of alignment display errors on visual fatigue. The experiment revealed the following conclusive results: First, EEG data suggested the possibility of cognitively-induced time compensation changes due to a corresponding effect in real-time brain activity by the eyes trying to compensate for the alignment. The magnification difference error showed more significant effects on all EEG band waves, which were indications of likely visual fatigue as shown by the prevalence of simulator sickness questionnaire (SSQ) increases across all task levels. Vertical shift errors were observed to be prevalent in theta and beta bands of EEG which probably induced alertness (in theta band) as a result of possible stress. Rotation errors were significant in the gamma band, implying the likelihood of cognitive decline because of theta band influence. Second, the hemodynamic responses revealed that significant differences exist between the left and right dorsolateral prefrontal due to alignment errors. There was also a significant difference between the main effect for power band hemisphere and the ATC task sessions. The analyses revealed that there were significant differences between the dorsal frontal lobes in task processing and interaction effects between the processing lobes and tasks processing. The second study investigated the effects of cognitive response variables on visual fatigue. Third, the physiologic indicator of pupil dilation was 0.95mm that occurred at a mean time of 38.1min, after which the pupil dilation begins to decrease. After the average saccade rest time of 33.71min, saccade speeds leaned toward a decrease as a possible result of fatigue on-set. Fourth, the neural network classifier showed visual response data from eye movement were identified as the best predictor of visual fatigue with a classification accuracy of 90.42%. Experimental data confirmed that 11.43% of the participants actually experienced visual fatigue symptoms after the prolonged task

Development of non-invasive, optical methods for central cardiovascular and blood chemistry monitoring.

Cardiovascular disease and sepsis are leading causes of mortality, morbidity and high cost in hospitals around the world. Failure of the circulatory system during cardiogenic shock and sepsis both can significantly impair the perfusion of oxygen through organs, resulting in poor patient outcome if not detected and corrected early. Another common disorder which goes hand-in-hand with cardiovascular disease is Diabetes Mellitus. Diabetes is a metabolic disorder resulting from the inability of the body to regulate the level of glucose in the blood. The prevalence of diabetes worldwide is increasing faster than society’s ability to manage cost effectively, with an estimated 9% of the world population diagnosed with metabolic disease. The current gold standard measurements for venous oxygen saturation, arterial pulse wave velocity (PWV), and diabetes management through blood glucose concentration monitoring are all invasive. Invasive measurements increase risk of infection and com- plications, are often high cost and disposable, and have a low patient compliance to regular measurements. The aim of this thesis is to develop non-invasive methods of monitoring these important dynamic physiological variables, including, venous oxygen saturation, pulse wave velocity, and blood glucose concentration. A novel photoplethysmography-based NIR discrete wavelength spectrometer was developed using LEDs to both emit light, and detect the light reflected back through the tissue. Using LEDs to detect light simplifies sensing circuit design, lowering hardware costs, allowing adaptable sensing specific to the needs of the user. A reflectance pulse oximeter was developed to measure the oxygen saturation at both the external jugular vein, and carotid artery. Measuring the jugular venous pulse (JVP) allows estimation of the venous oxygen saturation through either the JVP, or through breathing induced variation of the JVP. In addition to oxygenation, the de- vice developed is capable of adapting the sensing layout to measure the arterial pulse waveform at multiple sites along a peripheral artery, such as the carotid or radial. The PWV local to the carotid artery, and radial artery can then be measured, providing key information of cardiovascular risk. A novel algorithm for PWV measurement over multiple pulse waveforms was also developed. Expanding the sensor to use multiple different wavelength LEDs allow discrete spectroscopy in pulsatile blood. An absorption model of components in blood at specific wavelengths was created to isolate the spectral fingerprint of glucose. The sensor successfully measured the oxygen saturation at the carotid artery, and external jugular vein across 15 subjects, giving mean oxygen saturations of 92% and 85% respectively, within the expected physiological ranges. Venous oxygen saturation calculated using breathing induced changes to JVP was 3.3% less than when calculated on the JVP alone, with a standard deviation of 5.3%, compared to 6.9%. Thus, future work on the sensor will focus on extraction of the breathing induced venous pulse, rather than measuring from the JVP itself. The PWV on the carotid and radial artery was successfully measured within the ex- pected physiological ranges, with the novel phase difference algorithm proving more robust to noise than the gold standard foot-foot method. The phase difference method returned a mean PWV at the radial artery of 4.7 ±0.6 m s−1, and a mean CoV of 20%, compared to 4.0 ±1.4 m s−1, and a moan CoV of 58% for the foot-foot method. The proof of concept PWV sensor gives promising results, but needs to be calibrated against invasive gold standards, such as aorta and femoral pressure catheters. A glucose trial involving adult and neonatal subjects provided validation of the NIR non-invasive pulse glucometer. The sensor has an R2 of 0.47, and a mean absolute relative difference (MARD) of 19% compared to gold standard reference measurements. Clarke error grid analysis returns 85% of measurements in Zone A, 11% in Zone B, and 4% in Zone C. While the sensor is not as accurate as the gold standard invasive measurements, the ability to constantly measure without any pain or discomfort will help increase measurement compliance, improving user quality of life, plus further development may improve this. Overall, this thesis provided novel contributions in non-invasive venous oxygen saturation, PWV, and glucose concentration monitoring. The adaptability of the sensor shows promise in helping reduce the pain and inconvenience of the current invasive measurements, especially in diabetes management, where the sensor has the most potential for impact

A novel approach to bioelectrical impedance plethysmography for the assessment of arterial and venous circulatory problems in the forearm

Peripheral vascular disease (PVD) and/or peripheral arterial disease (PAD) are sicknesses known to inadequate delivery of either arterial or venous blood towards the extremities. Such sickness may trigger complications owing to the lack of transport of oxygen and nutrients, thus causing hypoxic events that may eventually prompt to ischaemic tissue or even the loss of the compromised limb. One of the most prominent indicators of prosperous health is blood volume and flow. The basic information within these health parameters may show cardiovascular problems or the advance of further complications related to other diseases like diabetes. In clinical setting, there effective methods to measure these parameters like Doppler ultrasound, photoplethysmography or venous occlusion plethysmography. These methods take measurements from either single vessels and/or small volume of tissue. However, it is difficult to establish a relation between the obstruction of arterial and/or venous circulation and the amount of blood received by the tissue. Bioelectrical impedance plethysmography (iPG) measures blood changes by driving a small amount of AC current into the body and after measuring the potential created by fluids flowing through tissue. This technique apart from taking measures within defined volumes of tissue, it is easy to use as only needs four electrodes on the skin. Hence, a bespoken bioelectrical impedance device including hardware and software was built ready to measure changes in blood volume/flow in the upper limbs. The system was assessed in an in-vivo controlled environment with 8 participants. The blood flow towards their left arms was altered by constricting the upper arm with a cuff at three levels: 1) below venous pressure 2) amongst venous and arterial pressure and 3) during total occlusion. Simultaneously, measurements from various instruments like ECG, Doppler ultrasound, laser Doppler flowmetry and PPG were taken and compared to the measurements obtained from the iPG instrument and defining its correlation with the impedimetric signal. The results from the experiments showed that the bioelectrical impedance signal changed in basal and arterial pulses showing specific characteristics for each kind of occlusion. The data indicated that it is possible to differentiate between a venous and arterial occlusion by examining both components of the impedance signal. The impedance during venous occlusion dropped in average 0.658±0.230% from the baseline. On the other hand, during arterial occlusion the base impedance dropped in a higher rate approximately 1.13±04.82%, indicating a differentiator during both type of blood flow disruption. Furthermore, the impedance plethysmography waveform morphology also reshaped during these occlusive periods. The whole waveform during artificial venous obstruction increased in magnitude, the systolic peak rose 31.80%, the dicrotic notch 47.73% and the diastolic point 31.92%, where the value of the latter was higher than the dicrotic notch point. In contrast, in the time of partial arterial occlusion the waveform also increased in size at all these points, but its shape was altered. The impedance magnitude at the diastolic point went below the ones at the dicrotic notch. These fluctuations provided additional further information that it might be possible to differentiate amongst venous and arterial occlusions. By consolidating the data obtained by the iPG device, it is possible to produce an index ratio between the basal impedance and these three reference points which may help to identify early circulatory problems in the arterial and/or venous systems

The use of near infrared spectroscopy (NIRS) to measure vascular haemodynamics in human bone tissue in vivo

Rationale: Poor cardiovascular health is associated with reduced bone strength and increased risk of fragility fracture. However, direct measurement of intraosseous vascular health is difficult due to the density and mineral content of bone. The aim of this PhD project was to investigate the feasibility of near infrared spectroscopy (NIRS) for the investigation of vascular haemodynamics in human bone in vivo. NIRS provides inexpensive, non-invasive, safe, and real time data on changes in oxygenated and deoxygenated haemoglobin concentration at superficial anatomical sites. NIRS utilises a source optode of near infrared (NIR) light and detector optode that obtains representative data of the interactions of NIR photons with tissue. Method: A systematic review was performed identifying the current existing applications of NIRS (and similar technologies) for measuring human bone tissue in vivo. This review informed the development of an arterial occlusion protocol for obtaining haemodynamic measurements of the proximal tibia and lateral calf, including assessment of the protocol’s reliability. For thirty-six participants, NIRS results were also compared to alternative tests of bone haemodynamics involving dynamic contrast enhanced MRI (DCE-MRI), and measures of general bone health based on dual x-ray absorptiometry testing and blood markers of bone metabolism. Results: This thesis presents novel data demonstrating NIRS can obtain acceptably reliable markers of haemodynamics at the proximal tibia in vivo, comparable with reliability assessments of alternative modalities measuring intraosseous haemodynamics, and the use of NIRS for measuring muscle. Novel associations have been demonstrated between haemodynamic markers measured with NIRS and DCE-MRI, giving confidence NIRS truly represents bone haemodynamics. Increased NIRS markers of oxygen extraction during occlusion, and greater post-ischaemic vascular response to occlusion, were both associated with greater bone mineral density. Conclusion: As a feasibility study, this PhD project has demonstrated the potential for NIRS to contribute to research around the potential pathophysiological role of vascular dysfunction within bone tissue, but also the limitations and need for further development of NIRS technology.The Royal College of Radiologist

Development of Graphene Nanostructures for Use in Anti-cancer Nanomedicine

Nanomedicine utilises biocompatible nanomaterials for therapeutic as well as imaging purposes, for the treatment of various diseases including cancer, neurological disorders and wound infections. Graphene, a material composed of a single layer of carbon atoms, has recently shown great potential to improve diagnostics and therapeutics, owing to its small size, large surface-area-to-volume ratio and unique physicochemical properties. However, the limited fabrication, in vitro and in vivo functionalities published in the literature indicate inconsistencies regarding the factors affecting metabolic fate, biodistribution as well as toxicity patterns of graphene. This thesis focuses on the biological effects of graphene-based materials, including graphene oxide (GO), reduced graphene oxide (rGO), graphene nanopores (GNPs), graphene quantum dots (GQDs) and three-dimensional graphene foam (GF). These can be used to closely mimic therapeutic functions and thereby open up new pathways to anticancer nanomedicine. In this work, a biocompatible GO-based anti-metastatic enzyme cancer therapy approach has been introduced for the first time to target the extracellular pro-metastatic and pro- tumourigenic enzymes of cathepsin D and cathepsin L, which are typically overexpressed in ovarian and breast cancers. Definitive binding and modulation of cathepsin- D and -L with GO has revealed that both of the enzymes were adsorbed onto the surface of GO through its cationic and hydrophilic residues under the biologically relevant condition of acidic pH. It has been demonstrated that low concentrations of rGO were shown to significantly produce late apoptosis and necrosis rather than early apoptotic events in lung cancer cells (A549 and SKMES-1), suggesting that it was able to disintegrate the cellular membranes in a dose-dependent manner. GNPs at lower concentrations (250µg/ml) induce upregulation of phosphatidylserine on cell surface membrane (i.e. early apoptotic event), which does not significantly disintegrate the cell membrane in the aforementioned lung cancer cells, while higher concentrations of GNPs (5 and 15 mg/kg) in rats (when intraperitoneally injected) exhibited sub-chronic toxicity in a period of 27 days. The interaction of GQDs and trypsin has revealed the strong bonding capacity of GQDs with trypsin, owing to their surface charge and surface functionalities evidencing the high bioavailability of GQDs in enzyme engineering. Finally, 3D GF was developed to probe the role of graphene-based scaffold cues in the field of regenerative medicine revealing their cell attachment to in vitro cell cultures. Furthermore, GF was shown to maintain remarkable biocompatibility with in vitro and in vivo toxicity screening models when exposed for 7 days at doses of 5, 10 and 15 mg/l. Taken together, graphene and its modified structures developed in this thesis promise to revolutionise clinical settings across the board in nanomedicine which include, but are not limited to, ultra-high sensitive enzyme adsorbents, high throughput biosensors, enzyme modulators and smart scaffolds for tissue regeneration.EPSRC Centre for Doctoral Training in Metamaterials, XM2 (Grant no. EP/L015331/1) the University Of Exeter EX4, United Kingdom