Neurovascular coupling: In vivo optical techniques for functional brain imaging

10.1186/1475-925X-12-38BioMedical Engineering Online121-BEOI

Photoacoustic Elastography and Next-generation Photoacoustic Tomography Techniques Towards Clinical Translation

Ultrasonically probing optical absorption, photoacoustic tomography (PAT) combines rich optical contrast with high ultrasonic resolution at depths beyond the optical diffusion limit. With consistent optical absorption contrast at different scales and highly scalable spatial resolution and penetration depth, PAT holds great promise as an important tool for both fundamental research and clinical application. Despite tremendous progress, PAT still encounters certain limitations that prevent it from becoming readily adopted in the clinical settings. This dissertation aims to advance both the technical development and application of PAT towards its clinical translation. The first part of this dissertation describes the development of photoacoustic elastography techniques, which complement PAT with the capability to image the elastic properties of biological tissue and detect pathological conditions associated with its alterations. First, I demonstrated vascular-elastic PAT (VE-PAT), capable of quantifying blood vessel compliance changes due to thrombosis and occlusions. Then, I developed photoacoustic elastography to noninvasively map the elasticity distribution in biological tissue. Third, I further enhanced its performance by combing conventional photoacoustic elastography with a stress sensor having known stress–strain behavior to achieve quantitative photoacoustic elastography (QPAE). QPAE can quantify the Young’s modulus of biological tissues on an absolute scale. The second part of this dissertation introduces technical improvements of photoacoustic microscopy (PAM). First, by employing near-infrared (NIR) light for illumination, a greater imaging depth and finer lateral resolution were achieved by near-infrared optical-resolution PAM (NIR-OR-PAM). In addition, NIR-OR-PAM was capable of imaging other tissue components, including lipid and melanin. Second, I upgraded a high-speed functional OR-PAM (HF-OR-PAM) system and applied it to image neurovascular coupling during epileptic seizure propagation in mouse brains in vivo with high spatio-temporal resolution. Last, I developed a single-cell metabolic PAM (SCM-PAM) system, which improves the current single-cell oxygen consumption rate (OCR) measurement throughput from ~30 cells over 15 minutes to ~3000 cells over 15 minutes. This throughput enhancement of two orders of magnitude achieves modeling of single-cell OCR distribution with a statistically meaningful cell count. SCM-PAM enables imaging of intratumoral metabolic heterogeneity with single-cell resolution. The third part of this dissertation introduces the application of linear-array-based PAT (LA-PAT) in label-free high-throughput imaging of melanoma circulating tumor cells (CTCs) in patients in vivo. Taking advantage of the strong optical absorption of melanin and the unique capability of PAT to image optical absorption, with 100% relative sensitivity, at depths with high ultrasonic spatial resolution, LA-PAT is inherently suitable for melanoma CTC imaging. First, with a center ultrasonic frequency of 21 MHz, the LA-PAT system was able to detect melanoma CTCs clusters and quantify their sizes based on the contrast-to-noise ratio (CNR). Second, I developed an LA-PAT system with a center ultrasonic frequency of 40 MHz and imaged melanoma CTCs in patients in vivo with a CNR greater than 12. We successfully imaged 16 melanoma patients and detected melanoma CTCs in 3 of them. Among the CTC-positive patients, 67% had disease progression despite systemic therapy. In contrast, only 23% of the CTC-negative patients showed disease progression. This study lays a solid foundation for translating CTC detection to bedside for clinical care and decision-making

Functional Connectivity of the Rodent Brain Using Optical Imaging

RÉSUMÉ L'objectif de cette thèse de doctorat est d’appliquer la connectivité fonctionnelle dans une variété de modèles animaux, à l’aide de plusieurs techniques d’imagerie optique. Le cerveau, même au repos, montre une activité métabolique élevée : la corrélation des fluctuations spontanées lentes permet d’identifier des régions cérébrales distantes mais connectées; d’où le terme connectivité fonctionnelle. Les changements dans l’activité spontanée peuvent donner un aperçu des processus neuronaux qui comprennent la majorité de l’activité métabolique du cerveau, et constituent en conséquent une vaste source de changements reliés aux maladies. L’hémodynamique du cerveau peut être modifiée grâce à des affections neurovasculaires et avoir un effet sur l’activité au repos. Cette thèse vise la compréhension des changements de connectivité fonctionnelle induits par des maladies, à l’aide de l’imagerie optique fonctionnelle. Les techniques d’imagerie explorées dans les deux premières contributions de cette thèse sont l’Imagerie Optique Intrinsèque et l’Imagerie par Granularité Laser. Ensemble, elles peuvent estimer les changements de consommation d'oxygène, étroitement liés à l’activité neuronale. Ces techniques possèdent des résolutions temporelles et spatiales adéquates et bien adaptées pour imager la convexité du cortex cérébral. Dans le dernier article, une modalité d’imagerie en profondeur, la Tomographie Photoacoustique a été utilisée chez le rat nouveau-né. La Tomographie par Cohérence Optique et la Tomographie Laminaire Optique font également partie de la gamme des techniques d’imagerie développées et appliquées dans d’autres collaborations. La première partie des résultats mesure les changements de connectivité fonctionnelle dans un modèle d’activité épileptiforme aiguë chez le rongeur. Il y a des augmentations ainsi que des diminutions entre les corrélations homologues, avec une faible dépendance aux crises épileptiques. Ces changements suggèrent un découplage potentiel entre les paramètres hémodynamiques dans les réseaux au repos, en soulignant l’importance d’investiguer les réseaux épileptiques à l’aide de plusieurs mesures hémodynamiques indépendantes. La deuxième partie des travaux étudie un nouveau modèle de rigidité artérielle chez la souris : la calcification unilatérale de la carotide droite. L’analyse de connectivité basé sur les régions d’intérêt montre une tendance décroissante de corrélation homologue dans les cortex moteur et cingulum. L’analyse de graphes montre une randomisation des réseaux corticaux, ce qui suggère une perte de connectivité; plus spécifiquement, dans le cortex moteur ipsilateral à la carotide----------ABSTRACT The aim of this thesis is to apply functional connectivity in a variety of animal models, using several optical imaging modalities. Even at rest, the brain shows high metabolic activity: the correlation in slow spontaneous fluctuations identifies remotely connected areas of the brain; hence the term “functional connectivity”. Ongoing changes in spontaneous activity may provide insight into the neural processing that takes most of the brain metabolic activity, and so may provide a vast source of disease related changes. Brain hemodynamics may be modified during disease and affect resting-state activity. The thesis aims to better understand these changes in functional connectivity due to disease, using functional optical imaging. The optical imaging techniques explored in the first two contributions of this thesis are Optical Imaging of Intrinsic Signals and Laser Speckle Contrast Imaging, together they can estimate the metabolic rate of oxygen consumption, that closely parallels neural activity. They both have adequate spatial and temporal resolution and are well adapted to image the convexity of the mouse cortex. In the last article, a depth-sensitive modality called photoacoustic tomography was used in the newborn rat. Optical coherence tomography and laminar optical tomography were also part of the array of imaging techniques developed and applied in other collaborations. The first article of this work shows the changes in functional connectivity in an acute murine model of epileptiform activity. Homologous correlations are both increased and decreased with a small dependence on seizure duration. These changes suggest a potential decoupling between the hemodynamic parameters in resting-state networks, underlining the importance to investigate epileptic networks with several independent hemodynamic measures. The second study examines a novel murine model of arterial stiffness: the unilateral calcification of the right carotid. Seed-based connectivity analysis showed a decreasing trend of homologous correlation in the motor and cingulate cortices. Graph analyses showed a randomization of the cortex functional networks, suggesting a loss of connectivity, more specifically in the motor cortex ipsilateral to the treated carotid; however these changes are not reflected in differentiated metabolic estimates. Confounds remain due to the fact that carotid rigidification gives rise to neural decline in the hippocampus as well as unilateral alteration of vascular pulsatility; howeve

Multifunctional photoacoustic materials for neural engineering

Understanding the complex information transfer process of our nervous system is one of the most urgent needs in the biomedical community. Neuromodulation is a technique that can artificially influence or modulate the activity of the target neurons. It's an inevitable tool in both the neuroscience study but also the clinical treatment of neurological diseases. The conventional method for neural modulation is the electrical stimulation using implantable electrodes. However, its intrinsic current leakage problem is an obstacle for further improving its performance in clinical scenarios because of the finite spatial resolution and recording artifacts. In general, an ideal method should be able to modulate neural activities with a high spatial, temporal and functionality specificity but without biocompatibility and reliability issues even in long term. Photoacoustic stimulation is an emerging light-mediated, non-genetic neural modulation method with high spatiotemporal resolution. Multiple devices have been designed in the past few years. But there are still several gaps to be filled to further expand its applications. One is the material mismatch, and another is that more function is needed, for example the capability of simultaneous recording. My research focused on the design and development of two new types of photoacoustic materials to expand the use of photoacoustic stimulation. A soft hydrogel film and a multifunctional fiber-based emitter for photoacoustic neuromodulation have been developed in my Ph.D. research. The study on these materials increased our knowledge to photoacoustic neurostimulation, also help us to investigate the effect of photoacoustic neuromodulation in the treatment of neurological and neurodegenerative diseases

Microscopic Studies of Neurovascular Coupling During Epilepsy in the Mouse Brain

Les mécanismes liant l’activité neuronale au changement local du flot sanguin sont regroupés dans un ensemble nommé couplage neurovasculaire. Ce lien neurovasculaire, qui est à la base de plusieurs principes d’imagerie fonctionnelle du cerveau, est altéré par l’épilepsie. Ces dernières années, des techniques d’imagerie tel l’IRMf, IOS et la NIRS ont été utilisées pour l’étude de cette maladie, montrant une forte corrélation entre l’activité épileptique et le signal mesuré. Par contre, la plupart de ces travaux se sont concentrés sur les changements d’hémoglobine, qui peuvent être liés à des phénomènes non-linéaires et qui ne renseignent pas directement sur la quantification de l’oxygène délivré localement. Le but de cette thèse est d’investiguer l’utilisation de la microscopie avec de nouvelles sondes moléculaires permettant l’imagerie de l’oxygénation des tissus durant les évènements épileptiques dans le cortex sensori-moteur de la souris. Dans un premier temps, une méthode de mesure de la pression partielle d’oxygène (PO2) en microscopie confocale du temps de vie de phosphorescence fut développée. Ce système permet une mesure minimalement invasive du PO2 dans les tissus corticaux à haute fréquences spatiale et temporelle lorsqu’il est utilisé conjointement avec la sonde phosphorescente OxyphorG4. Les mesures réalisées durant les crises épileptiques, induites avec l’agent 4-aminopyridine (4-AP), montrent des changements significatifs de l’oxygénation tissulaire. De plus, la distribution spatio-temporelle de la chute initiale de la réserve en oxygène, à proximité du point d’injection et le long des artérioles, a été caractérisé durant ces mêmes épisodes épileptiques. Une corrélation positive entre la variation du PO2 durant cette première phase et la durée de la crise épileptique a aussi été mesurée. Cette mesure pourrait s’avérer utile dans la localisation des foyers épileptique et dans la prédiction de la durée des crises. La deuxième étude présentée dans cette thèse se concentre sur le possible rôle joué par les astrocytes, qui sont un des acteurs importants dans le couplage neurovasculaire, dans la propagation des crises épileptiques. La concentration en ions calciques libres à la base axonale des astrocytes, conjointement avec le diamètre des artérioles adjacentes a été mesuré in-vivo en simultané sur des souris durant les épisodes épileptiques. Pour la mesure du calcium, la sonde fluorescente OregonGreen BAPTA-1 AM (OGB-1) a été utilisée en imagerie du temps de demie-vie de fluorescence avec un microscope 2-photons. Les résultats montrent que l’augmentation de calcium induirait une vasodilatation à chaque ictus dans la région du foyer épileptique. Dans les régions plus éloignées, cette même mesure corrèlerait plutôt avec une vasoconstriction dans les premiers moments de la crise, suivi par une vasodilatation selon la durée de l’épisode. De plus, une augmentation lente du niveau absolu de la concentration calcique a été observée lors de longues séquences d’évènements. Cette tendance à la hausse semble induire à son tour une constriction des artérioles dans les régions adjacentes. Ces observations confirment le rôle des astrocytes dans le contrôle local de la microcirculation et suggèrent un second rôle de modulation du niveau de la concentration calcique autour de leur base axonale. Puisqu’il n’a pas été possible de mesurer le PO2 en profondeur dans le cerveau ou de pouvoir imager adéquatement les réseaux de capillaires en microscopie confocale, et suivant le développement d’une sonde sensible aux ions d’oxygène en microscopie 2-photons, il a donc été possible, dans le cadre de la dernière étude de cette thèse, d’acquérir cette mesure en profondeur durant des épisodes épileptiques. Des changements significatifs du PO2 dans les tissus et les vaisseaux ont pu être observés. La distribution spatiale de la chute initiale de ce paramètre autour des artérioles, des capillaires, des veinules et du tissu près du foyer a pu être caractérisée. Les résultats obtenus pourraient avoir des implications profondes dans notre compréhension des mécanismes de livraison de l’oxygène dans les tissus en profondeur et leur capacité à supporter le cortex adéquatement dans les situations pathologiques. Le potentiel de la microscopie dans l’étude du couplage neurovasculaire et des changements liés à des pathologies a pu être pleinement démontré par les travaux de cette thèse.----------ABSTRACT Neurovascular coupling (NVC) is the mechanism that links a transient neural activity to the corresponding increase of cerebral blood flow (CBF). It underlies the local increase in blood flow during neural activity, forms the basis of functional brain imaging and is altered in epilepsy. For the last decades, functional imaging using BOLD fMRI, IOS and fNIRS and others have been applied to epilepsy, and yielded good correlation between epileptic activity and the measured signal. However, most previous work on epilepsy focused on the measurement of hemoglobin changes which sometimes leads to non-linear phenomena and does not quantify oxygen delivery in tissue. The aim of this thesis is to study oxygen delivery using microscopy with new oxygen sensitive molecular probes during epileptic events in the mouse somatosensory cortex. First, a confocal phosphorescence lifetime microscopy system for measuring brain oxygen partial pressure (PO2) was developed. This system enabled minimally invasive measurements of oxygen partial pressure in cerebral tissue with high spatial and temporal resolution using a dendritic phosphorescent probe, Oxyphor G4. Significant changes of PO2 in tissue were found at the epileptic focus and in remote areas during 4-aminopyridine (4-AP) induced epilepsy. The spatio-temporal distribution of the “initial dip” in PO2 near the injection site and along nearby arterioles was characterized by investigating epileptic events. A positive correlation between the percent change in the PO2 signal during the “initial dip” and the duration of seizure-like activity was revealed in this work, which may help localize the epileptic focus and predict the length of seizures. Because astrocytic calcium signalling is involved in neurovascular coupling, the second study investigated the role of this pathway in epilepsy. The free calcium concentration in astrocytic endfeet and diameter of adjacent arterioles were simultaneously monitored with the calcium-sensitive indicator OGB-1 by two-photon fluorescence lifetime measurements following 4-AP injection. Our results revealed that, increases in calcium concentration induced vasodilation for each ictal event in the focus. In the remote area, increases in calcium concentration correlated with vasoconstriction at the onset of seizure and vasodilation during the later part of the seizures. Furthermore, a slow increase in absolute calcium concentration following multiple seizures was observed, which in turn, caused a trend of arteriolar constriction both at the epileptic focus and remote areas. These observations confirmed the role of astrocytes in the control of local microcirculation and suggest a modulating role for baseline absolute calcium concentration in astrocytic endfeet. Since the confocal phosphorescence microscopy system was not able to measure PO2 deep in the cortex or resolve capillaries, two-photon phosphorescence microscopy was then used in the last project to study the PO2 delivery during epilepsy in deep tissue and vessels. Significant changes of PO2 in tissue and vasculature were observed during epileptic events. The spatial landscape of “initial dip” in PO2 signals around arterioles, veins and tissue near the injection site was characterized. These results may have profound implications for evaluating microvascular oxygen delivery capacity to support cerebral tissue in disease. The results of this thesis confirmed the potential of using microscopy to study neurovascular coupling during epilepsy

Building And Validating Next-Generation Neurodevices Using Novel Materials, Fabrication, And Analytic Strategies

Technologies that enable scientists to record and modulate neural activity across spatial scales are advancing the way that neurological disorders are diagnosed and treated, and fueling breakthroughs in our fundamental understanding of brain function. Despite the rapid pace of technology development, significant challenges remain in realizing safe, stable, and functional interfaces between manmade electronics and soft biological tissues. Additionally, technologies that employ multimodal methods to interrogate brain function across temporal and spatial scales, from single cells to large networks, offer insights beyond what is possible with electrical monitoring alone. However, the tools and methodologies to enable these studies are still in their infancy. Recently, carbon nanomaterials have shown great promise to improve performance and multimodal capabilities of bioelectronic interfaces through their unique optical and electronic properties, flexibility, biocompatibility, and nanoscale topology. Unfortunately, their translation beyond the lab has lagged due to a lack of scalable assembly methods for incorporating such nanomaterials into functional devices. In this thesis, I leverage carbon nanomaterials to address several key limitations in the field of bioelectronic interfaces and establish scalable fabrication methods to enable their translation beyond the lab. First, I demonstrate the value of transparent, flexible electronics by analyzing simultaneous optical and electrical recordings of brain activity at the microscale using custom-fabricated graphene electronics. Second, I leverage a recently discovered 2D nanomaterial, Ti3C2 MXene, to improve the capabilities and performance of neural microelectronic devices. Third, I fabricate and validate human-scale Ti3C2 MXene epidermal electrode arrays in clinical applications. Leveraging the unique solution-processability of Ti3C2 MXene, I establish novel fabrication methods for both high-resolution microelectrode arrays and macroscale epidermal electrode arrays that are scalable and sufficiently cost-effective to allow translation of MXene bioelectronics beyond the lab and into clinical use. Thetechnologies and methodologies developed in this thesis advance bioelectronic technology for both research and clinical applications, with the goal of improving patient quality of life and illuminating complex brain dynamics across spatial scales

Investigation of neuronal activity in a murine model of Alzheimer’s disease using in vivo two-photon calcium imaging

Alzheimer’s disease (AD) is one of the biggest challenges for biomedical research nowadays as with the growth of life span more and more people are affected by this disorder. Etiology of AD is unknown, yet growing evidence identifies alterations in neuronal activity as of the great importance for pathology. Although several significant studies of neuronal activity alteration in AD were done during the last decade, none of them addressed the question of the time course of these changes over the disease progression. Alzheimer’s disease (AD) is characterized by impairments of brain neurons that are responsible for the storage and processing of information. Studies have revealed decrease in the activity of neurons (Silverman et al., 2001; Prvulovic et al., 2005) and it was proposed that generalized hypoactivity and silencing of brain circuits takes place as formulated in the synaptic failure hypothesis (Selkoe, 2002). However, more recent studies also reported opposite effects – hyperexcitability and hyperactivity of neurons in the AD models (Busche et al., 2008; Sanchez et al., 2012; Liebscher et al., 2016). It still remains unclear if these are two sides of the same coin or if these are two stages, that follow each other. Moreover, it is not clear if observed neuronal activity alterations are caused by the dysfunction of individual neurons or if overall circuitry is disturbed because the crucial “activity controllers” (most probably - inhibitory neurons) alter their activity. This project aimed to examine spontaneous neuronal activity in the murine model of AD at the early stages of disease progression using chronic in vivo imaging to address the character and the stability of neuronal activity alterations as well relation of the activity alterations to amyloid plaque proximity. Compared to earlier studies the approach of in vivo awake calcium imaging used in the current study has many benefits for brain research. The main advantage is that brain activity can be measured without artifacts generated by anesthesia, which can exaggerate or mitigate experimental readouts. In this project, I used genetically encoded calcium indicator GCaMP6 that enables prolonged repetitive imaging of the same neurons in an intact environment. Recording of calcium transients in cell bodies of neurons was accompanied by in vivo imaging of Aβ plaques and followed by immunohistochemical staining of GCaMP6-expressing neurons to investigate how activity changes are correlated with proximity to the plaque. All the experiments were done in awake mice to ensure the absence of anesthesia-derived impact on spontaneous neuronal activity. My results support previously published reports of the increased proportion of hyperactive excitatory neurons in the AD mouse model. Importantly, my results also demonstrate that this increased activity is present in the awake state, is stable over a longer period of time (one month) and does not depend on the distance to the closest plaque. These findings support the hypothesis of permanent network alterations driving aberrant activity patterns that appear early in the disease progression, resulting in a chronic excitation/inhibition disbalance. Another important finding of my project is that individual neurons do not stay in the silent state and most of them remain functional demonstrating normal activity at the later time points. This finding requires further research as it has important implication for the development of the AD treatment, as in case many neurons remain functional and their normal neuronal activity can be recovered by addressing the cause of the circuit dysfunction with treatment. To summarize, the study presented in this PhD thesis is the first longitudinal study of neuronal activity changes in an AD mouse model, and while it provides important insight into pathology, it also emphasizes the importance of chronic in vivo studies to investigate neuronal activity and its role in the disease progression

Investigation of neuronal activity in a murine model of Alzheimer’s disease using in vivo two-photon calcium imaging

Alzheimer’s disease (AD) is one of the biggest challenges for biomedical research nowadays as with the growth of life span more and more people are affected by this disorder. Etiology of AD is unknown, yet growing evidence identifies alterations in neuronal activity as of the great importance for pathology. Although several significant studies of neuronal activity alteration in AD were done during the last decade, none of them addressed the question of the time course of these changes over the disease progression. Alzheimer’s disease (AD) is characterized by impairments of brain neurons that are responsible for the storage and processing of information. Studies have revealed decrease in the activity of neurons (Silverman et al., 2001; Prvulovic et al., 2005) and it was proposed that generalized hypoactivity and silencing of brain circuits takes place as formulated in the synaptic failure hypothesis (Selkoe, 2002). However, more recent studies also reported opposite effects – hyperexcitability and hyperactivity of neurons in the AD models (Busche et al., 2008; Sanchez et al., 2012; Liebscher et al., 2016). It still remains unclear if these are two sides of the same coin or if these are two stages, that follow each other. Moreover, it is not clear if observed neuronal activity alterations are caused by the dysfunction of individual neurons or if overall circuitry is disturbed because the crucial “activity controllers” (most probably - inhibitory neurons) alter their activity. This project aimed to examine spontaneous neuronal activity in the murine model of AD at the early stages of disease progression using chronic in vivo imaging to address the character and the stability of neuronal activity alterations as well relation of the activity alterations to amyloid plaque proximity. Compared to earlier studies the approach of in vivo awake calcium imaging used in the current study has many benefits for brain research. The main advantage is that brain activity can be measured without artifacts generated by anesthesia, which can exaggerate or mitigate experimental readouts. In this project, I used genetically encoded calcium indicator GCaMP6 that enables prolonged repetitive imaging of the same neurons in an intact environment. Recording of calcium transients in cell bodies of neurons was accompanied by in vivo imaging of Aβ plaques and followed by immunohistochemical staining of GCaMP6-expressing neurons to investigate how activity changes are correlated with proximity to the plaque. All the experiments were done in awake mice to ensure the absence of anesthesia-derived impact on spontaneous neuronal activity. My results support previously published reports of the increased proportion of hyperactive excitatory neurons in the AD mouse model. Importantly, my results also demonstrate that this increased activity is present in the awake state, is stable over a longer period of time (one month) and does not depend on the distance to the closest plaque. These findings support the hypothesis of permanent network alterations driving aberrant activity patterns that appear early in the disease progression, resulting in a chronic excitation/inhibition disbalance. Another important finding of my project is that individual neurons do not stay in the silent state and most of them remain functional demonstrating normal activity at the later time points. This finding requires further research as it has important implication for the development of the AD treatment, as in case many neurons remain functional and their normal neuronal activity can be recovered by addressing the cause of the circuit dysfunction with treatment. To summarize, the study presented in this PhD thesis is the first longitudinal study of neuronal activity changes in an AD mouse model, and while it provides important insight into pathology, it also emphasizes the importance of chronic in vivo studies to investigate neuronal activity and its role in the disease progression

Electronic Skin in Robotics and Healthcare: Towards Multimodal Sensing and Intelligent Analysis

Skin-interfaced electronics is gradually transforming robotic and medical fields by enabling noninvasive and continuous monitoring of physiological and biochemical information. Despite their promise, current wearable technologies face challenges in several disciplines: Physical sensors are prone to motion-induced noise and lack the capability for effective disease detection, while existing wearable biochemical sensors suffer from operational instability in biofluids, limiting their practicality. Conventional electronic skin contains only a limited category of sensors that are not sufficient for practical applications, and conventional data processing methods for these wearables necessitate manual intervention to filter noise and decipher health-related information. This thesis presents advances in electronic skin within robotics and healthcare, emphasizing multimodal sensing and data analysis through machine intelligence. Chapter 1 introduces the concept of electronic skin, outlining the emerging sensor technologies and a general machine learning pipeline for data processing. Chapter 2 details the development of multimodal physiological and biochemical sensors that enable long-term continuous monitoring with high sensitivity and stability. Chapter 3 explores the application of integrated electronic skin in robotics, prosthetics, and human machine interactions. Chapter 4 showcases practical implementations of integrated electronic skin with robust sensors for wound monitoring and treatment. Chapter 5 highlights the transformative deployment of artificial intelligence in deconvoluting health profiles on mental health. The last chapter, Chapter 6, delves into the challenges and prospects of artificial intelligence-powered electronic skins, offering predictions for the evolution of smart electronic skins. We envision that multimodal sensing and machine intelligence in electronic skin could significantly advance the field of human machine interactions and personalized healthcare.</p

Methodology of optical topography measurements for functional brain imaging and the development and implementation of functional optical signal analysis software.

Near-infrared spectroscopy (N1RS) has been used extensively in recent years as a non invasive tool for investigating cerebral hemodynamics and oxygenation. The technique exploits the different optical absorption of oxy-haemoglobin and deoxy-haemoglobin in the near infrared region to measure changes in their concentrations in tissue. By making multiple NIRS measurement simultaneously, optical topography (OT) provides spatial maps of the changes in haemoglobin concentration levels from specific regions of the cerebral cortex. The thesis describes several key developments in optical topography studies of functional brain activation. These include the development of a novel data analysis software to process the experimental data and a new statistical methodology for examining the spatial and temporal variance of OT data. The experimental work involved the design of a cognitive task to measure the haemodynamic response using a 24-channeI Hitachi ETG-100 OT system. Following a series of pilot studies, a study on twins with opposite handedness was conducted to study the functional changes in the parietal region of the brain. Changes in systemic variables were also investigated. A dynamic phantom with optical properties similar to those of biological tissues was developed with the use of liquid crystals to simulate spatially varying changes in haemodynamics. A new software tool was developed to provide a flexible processing approach with real time analysis of the optical signals and advanced statistical analysis. Unlike conventional statistical measures which compare a pre-defined activation and task periods, the thesis describes the incorporation of a Statistical Parametric Mapping toolbox which enables statistical inference about the spatially-resolved topographic data to be made. The use of the general linear model computes the temporal correlations between the defined model and optical signals but also corrects for the spatial correlations between neighbouring measurement points. The issues related to collecting functional activation data using optical topography are fully discussed with a view that the work presented in this thesis will extend the applicability of this technology