Miniaturized Optical Probes for Near Infrared Spectroscopy

RÉSUMÉ L’étude de la propagation de la lumière dans des milieux hautement diffus tels que les tissus biologiques (imagerie optique diffuse) est très attrayante, car elle offre la possibilité d’explorer de manière non invasive le milieu se trouvant profondément sous la surface, et de retrouver des informations sur l’absorption (liée à la composition chimique) et sur la diffusion (liée à la microstructure). Dans la gamme spectrale 600-1000 nm, également appelée gamme proche infrarouge (NIR en anglais), l'atténuation de la lumière par le tissu biologique (eau, lipides et hémoglobine) est relativement faible, ce qui permet une pénétration de plusieurs centimètres dans le tissu. En spectroscopie proche infrarouge (NIRS en anglais), de photons sont injectés dans les tissus et le signal émis portant des informations sur les constituants tissulaires est mesuré. La mesure de très faibles signaux dans la plage de longueurs d'ondes visibles et proche infrarouge avec une résolution temporelle de l'ordre de la picoseconde s'est révélée une technique efficace pour étudier des tissus biologiques en imagerie cérébrale fonctionnelle, en mammographie optique et en imagerie moléculaire, sans parler de l'imagerie de la durée de vie de fluorescence, la spectroscopie de corrélation de fluorescence, informations quantiques et bien d’autres. NIRS dans le domaine temporel (TD en anglais) utilise une source de lumière pulsée, généralement un laser fournissant des impulsions lumineuses d'une durée de quelques dizaines de picosecondes, ainsi qu'un appareil de détection avec une résolution temporelle inférieure à la nanoseconde. Le point essentiel de ces mesures est la nécessité d’augmenter la sensibilité pour de plus grandes profondeurs d’investigation, en particulier pour l’imagerie cérébrale fonctionnelle, où la peau, le crâne et le liquide céphalo-rachidien (LCR) masquent fortement le signal cérébral. À ce jour, l'adoption plus large de ces techniques optique non invasives de surveillance est surtout entravée par les composants traditionnels volumineux, coûteux, complexes et fragiles qui ont un impact significatif sur le coût et la dimension de l’ensemble du système. Notre objectif est de développer une sonde NIRS compacte et miniaturisée, qui peut être directement mise en contact avec l'échantillon testé pour obtenir une haute efficacité de détection des photons diffusés, sans avoir recours à des fibres et des lentilles encombrantes pour l'injection et la collection de la lumière. Le système proposé est composé de deux parties: i) une unité d’émission de lumière pulsée et ii) un module de détection à photon unique qui peut être activé et désactivé rapidement. L'unité d'émission de lumière utilisera une source laser pulsée à plus de 80 MHz avec une largeur d'impulsion de picoseconde.----------ABSTRACT The study of light propagation into highly diffusive media like biological tissues (Diffuse Optical Imaging) is highly appealing due to the possibility to explore the medium non-invasively, deep beneath the surface and to recover information both on absorption (related to chemical composition) and on scattering (related to microstructure). In the 600–1000 nm spectral range also known as near-infrared (NIR) range, light attenuation by the biological tissue constituents (i.e. water, lipid, and hemoglobin) is relatively low and allows for penetration through several centimeters of tissue. In near-infrared spectroscopy (NIRS), a light signal is injected into the tissues and the emitted signal carrying information on tissue constituents is measured. The measurement of very faint light signals in the visible and near-infrared wavelength range with picosecond timing resolution has proven to be an effective technique to study biological tissues in functional brain imaging, optical mammography and molecular imaging, not to mention fluorescence lifetime imaging, fluorescence correlation spectroscopy, quantum information and many others. Time Domain (TD) NIRS employs a pulsed light source, typically a laser providing light pulses with duration of a few tens of picoseconds, and a detection circuit with temporal resolution in the sub-nanosecond scale. The key point of these measurements is the need to increase the sensitivity to higher penetration depths of investigation, in particular for functional brain imaging, where skin, skull, and cerebrospinal fluid (CSF) heavily mask the brain signal. To date, the widespread adoption of the non-invasive optical monitoring techniques is mainly hampered by the traditional bulky, expensive, complex and fragile components which significantly impact the overall cost and dimension of the system. Our goal is the development of a miniaturized compact NIRS probe, that can be directly put in contact with the sample under test to obtain high diffused photon harvesting efficiency without the need for cumbersome optical fibers and lenses for light injection and collection. The proposed system is composed of two parts namely; i) pulsed light emission unit and ii) gated single-photon detection module. The light emission unit will employ a laser source pulsed at over 80MHz with picosecond pulse width generator embedded into the probe along with the light detection unit which comprises single-photon detectors integrated with other peripheral control circuitry. Short distance source and detector pairing, most preferably on a single chip has the potential to greatly expedites the traditional method of portable brain imaging

Nonlinear microscopy for failure analysis of CMOS integrated circuits in the vectorial focusing regime

This thesis focuses on the development of techniques for enhancing the spatial resolution and localisation precision in the sub-surface microscopy for failure analysis in semiconductor integrated circuits (ICs). Highest spatial resolutions are obtained by implementing solid immersion lenses (SIL), which provide unsurpassed numerical aperture (NA) for sub-surface microscopy. These high NA conditions mean that scalar diffraction theory is no longer valid and a vectorial focusing description should be applied to accurately describe the focal plane electric field distribution. Vectorial theory predicts that under high NA conditions a linearly polarised (LP) light focuses to a spot that is extended along the electric field vector, but radially polarised (RP) light is predicted to form a circular spot whose diameter equals the narrower dimension obtained with linear polarisation. By implementing a novel liquid-crystal (LC) radial polarisation converter (RPC) this effect was studied for both two-photon optical-beam-induced current (TOBIC) microscopy and two-photon laser assisted device alteration (2pLADA) techniques, showing a resolution and localisation improvement using the RP beam. By comparing images of the same structural features obtained using linear, circular and radial polarisations imaging and localisation resolutions both approaching 100 nm were demonstrated. The obtained experimental results were in good agreement with modelling and were consistent with theoretically predicted behaviour. Certain artefacts were observed under radial polarisation, which were thought to result from the extended depth of focus and the significant longitudinal field component. In any application these effects must be considered alongside the benefits of the symmetric field distribution in the focal plane. While SIL sub-surface microscopy offers unmatched spatial resolutions, it is prone to being severely degraded by aberrations arising from inaccurate dimensions of the SIL, imprecise substrate thickness or imperfect contact between SIL and substrate. It is in this context that techniques to identify and even mitigate aberrations in the system are important. A simple approach is demonstrated for revealing the presence of chromatic and spherical aberrations by measuring the two-photon autocorrelation of the pulses at the focal plane inside the sample. In the case of aberration free imaging, it was shown both theoretically and experimentally that the planes of the maximum autocorrelation amplitude and shortest pulse duration always coincide. Therefore, the optics of the imaging system can be first adjusted to obtain the minimum autocorrelation duration and then the wavefront of incident light modified to maximise the autocorrelation intensity, iterating this procedure until the positions of minimum pulse duration and maximum autocorrelation amplitude coincide

On-Chip Integrated Functional Near Infra-Red Spectroscopy (fNIRS) Photoreceiver for Portable Brain Imaging

RÉSUMÉ L'imagerie cérébrale fonctionnelle utilisant la Spectroscopie Fonctionnelle Proche-Infrarouge (SFPI) propose un outil portatif et non invasif de surveillance de l'oxygénation du sang. SFPI est une technique de haute résolution temporelle non invasive, sûr, peu intrusive en temps réel et pour l'imagerie cérébrale à long terme. Il permet de détecter des signaux hémodynamiques à la fois rapides et neuronaux ou lents. Outre les avantages importants des systèmes SFPI, ils souffrent encore de quelques inconvénients, notamment d’une faible résolution spatiale, d’un bruit de niveau modérément élevé et d’une grande sensibilité au mouvement. Afin de surmonter les limites des systèmes actuellement disponibles de SFPI non-portables, dans cette thèse, nous en avons introduit une nouvelle de faible puissance, miniaturisée sur une puce photodétecteur frontal destinée à des systèmes de SFPI portables. Elle contient du silicium photodiode à avalanche (SiAPD), un amplificateur de transimpédance (TIA), et « Quench-Reset », circuits mis en oeuvre en utilisant les technologies CMOS standards pour fonctionner dans les deux modes : linéaire et Geiger. Ainsi, elle peut être appliquée pour les deux fNIRS : en onde continue (CW- SFPI) et pour des applications de comptage de photon unique. Plusieurs SiAPDs ont été mises en oeuvre dans de nouvelles structures et formes (rectangulaires, octogonales, double APDs, imbriquées, netted, quadratiques et hexadecagonal) en utilisant différentes techniques de prévention de la dégradation de bord prématurée. Les principales caractéristiques des SiAPDs sont validées et l'impact de chaque paramètre ainsi que les simulateurs de l'appareil (TCAD, COMSOL, etc) ont été étudiés sur la base de la simulation et de mesure des résultats. Proposées SiAPDs techniques d'exposition avec un gain de grande avalanche, tension faible ventilation et une grande efficacité de détection des photons dans plus de faibles taux de comptage sombres. Trois nouveaux produits à haut gain, bande passante (GBW) et à faible bruit TIA sont introduits basés sur le concept de gain distribué, d’amplificateur logarithmique et sur le rejet automatique du bruit pour être appliqué en mode de fonctionnement linéaire. Le TIA proposé offre une faible consommation, un gain de haute transimpédance, une bande passante ajustable et un très faible bruit d'entrée et de sortie. Le nouveau circuit mixte trempe-reset (MQC) et un MQC contrôlable (CMQC) frontaux offrent une faible puissance, une haute vitesse de comptage de photons avec un commandable de temps de hold-off et temps de réinitialiser. La première intégration sur puce de SiAPDs avec TIA et Photon circuit de comptage a été démontrée et montre une amélioration de l'efficacité de la photodétection, spécialement en ce qui concerne la sensibilité, la consommation d'énergie et le rapport signal sur bruit.----------ABSTRACT Optical brain imaging using functional near infra-red spectroscopy (fNIRS) offers a direct and noninvasive tool for monitoring of blood oxygenation. fNIRS is a noninvasive, safe, minimally intrusive, and high temporal-resolution technique for real-time and long-term brain imaging. It allows detecting both fast-neuronal and slow-hemodynamic signals. Besides the significant advantages of fNIRS systems, they still suffer from few drawbacks including low spatial- resolution, moderately high-level noise and high-sensitivity to movement. In order to overcome the limitations of currently available non-portable fNIRS systems, we have introduced a new low-power, miniaturized on-chip photodetector front-end intended for portable fNIRS systems. It includes silicon avalanche photodiode (SiAPD), Transimpedance amplifier (TIA), and Quench- Reset circuitry implemented using standard CMOS technologies to operate in both linear and Geiger modes. So it can be applied for both continuous-wave fNIRS (CW-fNIRS) and also single-photon counting applications. Several SiAPDs have been implemented in novel structures and shapes (Rectangular, Octagonal, Dual, Nested, Netted, Quadratic and Hexadecagonal) using different premature edge breakdown prevention techniques. The main characteristics of the SiAPDs are validated and the impact of each parameter and the device simulators (TCAD, COMSOL, etc.) have been studied based on the simulation and measurement results. Proposed techniques exhibit SiAPDs with high avalanche-gain (up to 119), low breakdown-voltage (around 12V) and high photon-detection efficiency (up to 72% in NIR region) in additional to a low dark- count rate (down to 30Hz at 1V excess bias voltage). Three new high gain-bandwidth product (GBW) and low-noise TIAs are introduced and implemented based on distributed-gain concept, logarithmic-amplification and automatic noise-rejection and have been applied in linear-mode of operation. The implemented TIAs offer a power-consumption around 0.4 mW, transimpedance gain of 169 dBΩ, and input-output current/voltage noises in fA/pV range accompanied with ability to tune the gain, bandwidth and power-consumption in a wide range. The implemented mixed quench-reset circuit (MQC) and controllable MQC (CMQC) front-ends offer a quenchtime of 10ns, a maximum power-consumption of 0.4 mW, with a controllable hold-off and resettimes. The on-chip integration of SiAPDs with TIA and photon-counting circuitries has been demonstrated showing improvement of the photodetection-efficiency, specially regarding to the sensitivity, power-consumption and signal-to-noise ratio (SNR) characteristics

Characterization, Operation and Wafer-level Testing of an ultra-fast 4k Pixel Readout ASIC for the DSSC X-ray Detector at the European XFEL

The DEPFET sensor with signal compression (DSSC) project develops amegapixel X-ray camera dedicated for ultra-fast imaging at 4.5MHz frame rate at the European X-ray free electron laser facility in Hamburg. Further requirements are single photon resolution for so X-rays and a high dynamic range. The system concept includes a hybrid pixel detector, utilizing a non-linear DEPFET sensor. A dedicated readout ASIC allows full parallel readout of a 64 x 64 sensor pixel matrix by in-pixel filtering, immediate analog-to-digital conversion and storage. This thesis presents the ASIC working principle, architecture and the design of a test environment as well as test results of the electronics. Possible improvements of the circuits are highlighted. Measurements on sensor and ASIC assemblies are shown verifying the low noise and high dynamic range properties. The implementation of large scale tests for Known Good Die selection is reported. An introduction to free electron lasers and photon detection principles is included to put the DSSC system into the scientific context

Nonlinear Dynamics of Semiconductor Lasers and Their Applications

Semiconductor lasers are key components in many optical systems due to their advantages, including their small size, low cost, high efficiency, and low power consumption. It is well-known that semiconductor lasers under external perturbations, such as optical injection, optical feedback, or delayed coupling can exhibit a large variety of complex dynamical behaviors. Nowadays, cutting-edge engineering applications based on the complex dynamics of diode lasers are being conducted in areas, such as optical communications, optical signal processing, encoded communications, neuro-inspired ultra-fast optical computing devices, microwave signal generation, RADAR and LIDAR applications, biomedical imaging, and broadband spectroscopy. The prospects for these applications are even more exciting with the advent of photonic integrated circuits. This Special Issue focuses on theoretical and experimental advances in the nonlinear dynamics of semiconductor lasers subject to different types of external perturbations

Light-Addressing and Chemical Imaging Technologies for Electrochemical Sensing

Visualizing chemical components in a specimen is an essential technology in many branches of science and practical applications. This book deals with electrochemical imaging techniques based on semiconductor devices with capability of spatially resolved sensing. Two types of such sensing devices have been extensively studied and applied in various fields, i.e., arrayed sensors and light-addressed sensors. An ion-sensitive field-effect transistor (ISFET) array and a charge-coupled device (CCD) ion image sensor are examples of arrayed sensors. They take advantage of semiconductor microfabrication technology to integrate a large number of sensing elements on a single chip, each representing a pixel to form a chemical image. A light-addressable potentiometric sensor (LAPS), on the other hand, has no pixel structure. A chemical image is obtained by raster-scanning the sensor plate with a light beam, which can flexibly define the position and size of a pixel. This light-addressing approach is further applied in other LAPS-inspired methods. Scanning photo-induced impedance microscopy (SPIM) realized impedance mapping and light-addressable electrodes/light-activated electrochemistry (LAE) realized local activation of Faradaic processes. This book includes eight articles on state-of-the-art technologies of light-addressing/chemical imaging devices and their application to biology and materials science

Space Communications: Theory and Applications. Volume 3: Information Processing and Advanced Techniques. A Bibliography, 1958 - 1963

Annotated bibliography on information processing and advanced communication techniques - theory and applications of space communication

Dissection of Affective Catecholamine Circuits Using Traditional and Wireless Optogenetics

Parsing the complexity of the mammalian brain has challenged neuroscientists for thousands of years. In the early 21st century, advances in materials science and neuroscience have enabled unprecedented control of neural circuitry. In particular, cell-type selective manipulations, such as those with optogenetics and chemogenetics, routinely provide answers to previously intractable neurobiological questions in the intact, behaving animal. In this two-part dissertation, I first introduce new minimally invasive, wireless technology to perturb neural activity in the ventral tegmental area dopaminergic system of freely moving animals. I report a series of novel devices for studying and perturbing intact neural systems through optogenetics, microfluidic pharmacology, and electrophysiology. Unlike optogenetic approaches that rely on rigid, glass fiber optics coupled to external light sources, these novel devices utilize flexible substrates to carry microscale, inorganic light emitting diodes (μ-ILEDs), multimodal sensors, and/or microfluidic channels into the brain. Each class of device can be wirelessly controlled, enabling studies in freely behaving mice and achieving previously untenable control of catecholamine neural circuitry. In the second part of this dissertation, I apply existing cell-type selective approaches to dissect the role of the locus coeruleus noradrenergic (LC-NE) system in anxiety-like and aversive behaviors. The LC-NE system is one of the first systems engaged following a stressful event. While LC-NE neurons are known to be activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated until now. I demonstrate that increased tonic activity of LC-NE neurons is both necessary and sufficient for stress-induced anxiety; a behavior which is driven by LC projections to the basolateral amygdala. Furthermore, this activity and behavior is elicited by corticotropin releasing hormone-containing afferent inputs into the LC from the central amygdala. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. Together these two objectives provide a rich technological toolbox for neuroscientists and yield important knowledge of how small catecholamine structures with widespread forebrain innervation can selectively mediate higher order behaviors

Analysis of spine plasticity in CA1 hippocampal pyramidal neurons employing live cell nanoscopic imaging

In der Großhirnrinde von Säugetieren befindet sich die Mehrheit erregender Synapsen auf Dornfortsätzen, kleinen dendritischen Ausbuchtungen, die in Größe und Form stark variieren. Die Auslösung aktivitätsabhängiger synaptischer Langzeitplastizität geht mit strukturellen Veränderungen dendritischer Dornen einher. Da das beugungsbegrenzte Auflösungsvermögen konventioneller Lichtmikroskope nicht ausreicht um die Morphologie der Dornen verlässlich zu untersuchen, stellte die Elektronenmikroskopie bisher das wichtigste bildgebende Verfahren zur Erforschung von struktureller Plastizität dar, blieb dabei jedoch auf die Betrachtung fixierter Gewebeproben beschränkt. Die Anwendung hochauflösender Laser-Raster-Mikroskopie mit Stimulierter-Emissions-Auslöschung hat es mir möglich gemacht, die Dynamik dendritischer Dornenmorphologie in lebenden Zellen zu studieren. Die N-Methyl-D-Aspartat-Rezeptor-abhängige Langzeitpotenzierung von Pyramidenzellen der Cornu-Ammonis Region 1 des Hippocampus bildete dabei den Mechanismus, welcher plastische Veränderungen hervorrief. Nach Potenzierung exzitatorischer Synapsen durch die lokale Ultraviolett-Photolyse von caged-Glutamat wurde ein starker, vorübergehender Anstieg des Anteils dendritischer Dornen mit sichelförmigen Köpfen und ein leichter, anhaltender Zuwachs an pilzförmigen Dornfortsätzen über einen Zeitraum von 50 Minuten beobachtet. Meine Untersuchungen ergänzen frühere Studien zur Wechselbeziehung zwischen synaptischer Potenzierung und struktureller Plastizität dendritischer Dornen und korrespondieren mit dem aktuellen Kenntnisstand der zu Grunde liegenden molekularen Mechanismen.The majority of excitatory synapses in the cortex of mammalian brains is situated on dendritic spines, small protrusions, heterogeneous in size and shape. The induction of activity-dependent long-term synaptic plasticity has been associated with changes in the ultrastructure of spines, particularly in size, head shape and neck width. Since the dimensions of dendritic spines are at the border of the diffraction-limited resolving power of conventional light microscopes, until recently, electron microscopy on fixed tissue constituted the primary method for investigations on spine morphology. I have employed live cell stimulated emission depletion imaging to analyse spine motility and structural transitions in response to n-methyl-d-aspartate receptor dependent long-term potentiation over time at super-resolution in Cornu Ammonis area 1 pyramidal neurons of the hippocampus. Local induction of long-term potentiation via ultraviolet photolysis of caged glutamate facilitated a strong transient increase in the proportion of spines with curved heads and a subtle persistent growth in the amount of mushroom spines over a time course of 50 minutes. My findings reinforce previous investigations on the relation of synaptic potentiation and spine motility, and are in good agreement with the current knowledge of the molecular mechanisms underlying long-term plasticity

Spectrally and temporally resolved single photon counting in advanced biophotonics applications

Biomedicine requires highly sensitive and efficient light sensors to analyse light-tissue or light-sample interactions. Single-photon avalanche diode (SPAD) sensors implemented with complementary metal-oxide-semiconductor (CMOS) technology have a growing range of applications in this field. Single-photon detection coupled with integrated timing circuits enables us to timestamp each detected photon with high temporal resolution (down to picoseconds). Arrays of SPAD based pixels and CMOS technology offer massively parallel time-resolved single-photon counting for spectrally and temporally resolved analysis of various light phenomena.This thesis examines how time-resolved CMOS SPAD based line sensors with per pixel timing circuits can be utilized to advance biophotonic applications. The study focuses on improving the existing techniques of fluorescence and Raman spectroscopy, and demonstrates for the first time CMOS SPAD based detection in optical coherence tomography (OCT). A novel detection scheme is proposed combining low-coherence interferometry and time-resolved photon counting. In this approach the interferometric information is revealed from spectral intensity measurements, which is supplemented by time-stamping of the photons building up the spectra.Two CMOS SPAD line sensors (Ra-I and its improved version, Ra-II) were characterized and the effect of their parameters on the selected techniques was analysed. The thesis demonstrates the deployment of the Ra-I line sensor in time-resolved fluorescence spectroscopy with indications of the applicability in time-resolved Raman spectroscopy. The work includes integration of the sensor with surrounding electrical and optical systems, and the implementation of firmware and software for controlling the optical setup. As a result, a versatile platform is demonstrated capable of micro- and millisecond sampling of spectral fluorescence lifetime changes in a single transient of fast chemical reactions.OCT operating in the spectral domain traditionally uses CMOS photodiode and charge-coupled device (CCD) based detectors. The applicability of CMOS SPAD sensors is investigated for the first time with focus on the main limitations and related challenges. Finally, a new detection method is proposed relying on both the wave and particle nature of light, recording time-resolved interferometric spectra from a Michelson interferometer. This method offers an alternative approach to analyse luminous effects and improves techniques based on the light’s time of flight. As an example, a proof of concept study is presented for the removal of unwanted reflections from along the sample and the optical path in an OCT setup