Advancements in neural interfacing technologies, such as microelectrode arrays, have significantly contributed to understanding brain function and treating neurological disorders. Decoding the intricacies and functioning of neural circuits is key to further unlocking its potential. Two key approaches, electrical neural recording and optical imaging, have been the basis of stimulating and monitoring neural circuits. Despite the remarkable progress, several key issues such as reliable stimulation of neurons, closed-loop stimulation and monitoring, and undesired background fluorescence during widefield optical imaging remain challenging. After giving a brief background on electrode and microLED arrays, the dissertation delves into the design, microfabrication, and characterization of microelectrode arrays for neural electrical stimulation, recordings, and microLED arrays as a light source for improving optical microscopy. We first discuss a dense conformal electrode array for high spatial resolution stimulation in electrosensory systems. The performance metrics of the integrated system are thoroughly examined through meticulous characterization and optimization processes. Special emphasis is placed on evaluating biocompatibility, electrical properties, and spatial resolution to ensure robust and reliable neural stimulation capability. Next, we discuss a microelectrode device that combines simultaneous electrical recording and 2-photon imaging. We use an Indium Tin Oxide (ITO) material to fabricate a transparent electrode array with a design capable of single neuron recordings. The design, microfabrication, and electrooptical characterization are presented to demonstrate the device’s capability. A system integrating the array with a GRIN lens is also presented to record and image deeper into the brain tissue. Combining both the electrical and optical recordings of neuron ensembles and finding correlations can shed further light on the functioning of neural circuits. To address the problem of unwanted background fluorescence during neural cell imaging, two microLED arrays as light sources are presented. With a microstripe array, we implement optical sectioning structured illumination microscopy (OS-SIM), and with the 2D microLED array, we implemented targeted illumination to reject background fluorescence and improve contrast. We examine the capability of the microLED as a light source with luminance-current-voltage, directivity, and transient measurements. Both implementations highlight the novel non-display application of microLED to address challenges in neural imaging. This research represents a significant contribution to the burgeoning field of neural engineering, offering novel methodologies and technologies that promise to revolutionize our approach to understanding brain functions.

Neuroscience, the study of the brain and nervous system in humans and animals, relies more and more on data acquisition and analysis. Since the first recording of a neuron by Hubel and Wiesel in 1957, using a tungsten electrode probe, neuroscientists have developed a multitude of devices to record neuronal signals at various spans and spatiotemporal resolutions, leading to a rapid, exponential increase in the number of recordable neurons. Methods such as calcium-imaging, multi-electrode arrays (MEAs), or optogenetics are now at the core of research aiming at understanding the processes underlying cognition and the encoding of information by neural populations, improving brain-machine interfaces, and potentially discovering new cures for neurological diseases. Combining multiple advances in probe design, Neuropixels probes, introduced in 2017, have 384 recording channels arranged in a narrow and elongated shape that allows in vivo recordings of a large number of neurons from multiple brain regions, in arbitrary brain locations, with high spatiotemporal resolution, and in many different species of unrestrained animals. Thanks to these advantages as well as their low cost, this technology has been widely adopted by numerous labs that design experiments to record data from various brain regions and species. Multiple laboratories, and in particular the International Brain Laboratory, a group of 22 neuroscience labs, or the Allen Institute, have now released thousands of Neuropixels recordings from multiple brain regions and species. These large-scale experiments, which allow neuroscientists to examine the coordinated action of large neuronal populations in superficial and deep structures of the brain, present a fantastic opportunity for studying global brain dynamics. However, Neuropixels probes produce large volumes of high-dimensional data, and extracting information from these recordings is challenging. The main challenge is spike-sorting, i.e. detecting and assigning spikes to individual neurons. This step is critical to many downstream tasks, such as cell type classification or decoding. Unfortunately, spike sorting algorithms are inacurate and do not generalize well to different brain regions or animals, often requiring manual supervision which makes this process expensive and inefficient. The analysis of large-scale Neuropixels recordings thus requires accurate, robust, modular, and scalable spike sorting algorithms that generalize well across multiple species and brain regions, different existing probes, and even new probe designs. During my thesis, we developed methods for improving spike-sorting in Neuropixels recordings. We specifically tackled the problem of probe motion. Due to their elongated shapes, Neuropixels probes move relative to the brain. The neurons’ spike shapes thus change over time as the probe drifts, making it hard to cluster them properly. Inspired by image registration, we developed a decentralized registration method for Neuropixels recordings to estimate the movement of the probe relative to the brain, by treating the distribution of spike amplitudes as an image. We then developed a localization method to infer the three-dimensional position of the detected spikes relative to the probe using a simple model for the propagation of the electrical field generated by a neuron in the brain. We showed how these locations can be leveraged to improve registration. I then contributed to extending the above methods to developing Dredge, a registration method that shows good performance across a variety of data modalities i.e. different Neuropixels probes, different species, and different frequency bands. We then built a spike sorter, DARTSort, that improved upon existing spike sorters by explicitly modeling the unit’s spike shape variability as a function of probe motion, rather than interpolating the data to correct for drift. Moreover, we aimed at building a modular and interpretable spike sorter, allowing each of its components to be easily isolated, that generalizes well to a variety of probe designs. DARTSort was used to sort Ultra-High Density Neuropixels recordings. These very dense, newly designed probes allow for improved spike detection, yield, and cell-type classification, at the expanse of a shorter recording span. Finally, the localization and registration methods were utilized for building a state-of-the-art decoding model, taking as input the spike density along the probe, acting as an efficient and uncertainty-aware proxy for spike sorting.

Judgments of Learning (JOLs) are judgments of the likelihood of remembering recently studied material on a future test. Although JOLs have been extensively studied, particularly due to their important applications in education, relatively little is known about the cognitive and neural processes supporting JOLs and how these processes relate to actual memory processing. Direct access theories describe JOLs as outputs following direct readings of memory traces and hence predict that JOLs cannot be distinguished from objective memory encoding operations. Inferential theories, by contrast, claim JOLs are products of the evaluation of a number of cues, perceived by learners to carry predictive value. This alternative account argues that JOLs are made on the basis of multiple underlying processes, which do not necessarily overlap with memory encoding. In this thesis, the neural and cognitive bases of JOLs were examined in a series of four ERP experiments. Across experiments the study phase ERP data showed that JOLs produce neural activity that is partly overlapping with, but also partly distinct from, the activity that predicts successful memory encoding. Furthermore, the neural correlates of successful memory encoding appear sensitive to the requirements to make a JOL, emphasising the close interaction between subjective and objective measures of memory encoding. Finally, the neural correlates of both JOLs and successful memory encoding were found to vary depending on the nature of the stimulus materials, suggesting that both phenomena are supported by multiple cognitive and neural systems. Although the primary focus was on the study phase ERP data, the thesis also contains two additional chapters reporting the ERP data acquired during the test phases of three of the original experiments. These data, which examined the relative engagements of retrieval processes for low and high JOL items, suggest that encoding processes specifically resulting in later recollection (as opposed to familiarity) form one reliable basis for making JOLs. Overall, the evidence collected in this series of ERP experiments suggests that JOLs are not pure products of objective memory processes, as suggested by direct access theories, but are supported by neural systems that are at least partly distinct from those supporting successful memory encoding. These observations are compatible with inferential theories claiming that JOLs are supported by multiple processes that can be differentially engaged across stimulus contents.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

La mouche Drosophila melanogaster est un modèle de choix dans l’étude des grandes fonctions neurophysiologiques notamment en raison de la disponibilité d’une importante variété d’outils disponibles (approches génétiques, pharmacologiques et comportementales). Le cerveau de la mouche, malgré sa simplicité apparente, est capable de traiter des fonctions complexes d’intégration des différents paramètres environnementaux nécessaires à sa survie. Dans le cerveau drosophile, les corps pédonculés (CP) sont des structures impliquées dans de nombreuses fonctions neurophysiologiques de premier plan telles que l'apprentissage et la mémoire olfactive, la régulation de l’activité locomotrice, l'orientation spatiale, la régulation du sommeil ou encore la prise de décision. Il a été montré par des approches associant essentiellement observations comportementales et outils génétiques que la voie de signalisation de l'AMPc joue un rôle crucial dans la réalisation des fonctions diverses des CP. Les cellules de Kenyon (CK) qui sont les cellules intrinsèques des CP, reçoivent principalement des afférences du système olfactif par l’intermédiaire des neurones de projections (PN) en provenance des lobes antennaires et des afférences neuromodulatrices (dopaminergiques et octopaminergiques). Les synapses entres PN et CK se font sur un mode cholinergique grâce à des récepteurs canaux à l’acétylcholine de type nicotinique (nAchR). Nous avons utilisé une technique récente d’imagerie calcique par bioluminescence utilisant une protéine recombinante, la GFP-Aequorine. Cette technique nous a permis de suivre l’activité cellulaire calcique consécutive à l’application de nicotine, un agoniste des nAchR. Grâce à l’observation de ces réponses suite à une combinaison d’approches génétiques corroborée par des approches pharmacologiques, nous avons pu mettre en évidence une modulation complexe et régionalisée de la réponse calcique dans les CP par l’AMPc et d’autres différents partenaires tels que des canaux K+ et Ca2+. Dans un premier temps, nous avons démonté l’existence d’une modulation directe de l’intensité de la réponse par l’AMPc. Nous avons également montré, pour la première fois, que des réponses Ca2+ « spontanées » peuvent être directement inductibles par augmentation de l’AMPc. Nous avons mis en évidence l’existence d’un nouveau partenaire de la modulation de la réponse des CP indépendant de la PKA : les CNG (Cyclic Nucleotides Gated Channels) dont le rôle n’avait jusqu’ici jamais été démontré dans les corps pédonculés. Enfin nous avons pu observer une régionalisation de la régulation de l’activité Ca2+ des CP par l’AMPc. Dans un deuxième temps nous nous somme intéressé aux principales conductances calciques et potassiques. Nous avons mis en évidence que différents canaux calciques voltages dépendants (VGCC) sont impliqués de façon régionalisée et séquentielle dans la formation de la réponse calcique. Il a pu également être démontré que le signal est modulé de façon différentielle dans les calices et les lobes par l’AMPc à travers différents canaux potassiques. Enfin des protocoles originaux ont été développés, tels que la micro application de drogue ou l’électrostimulation permettant d’étudier la neuromodulation dans les CP, à réutiliser pour des travaux ultérieurs du laboratoire. Ce travail est une première étape dans la compréhension des voies de signalisations et des mécanismes intracellulaires impliqués dans l’apprentissage et la mémoire olfactive. / In Drosophila, the Mushroom-Bodies (MBs) are implicated in multiple functions, as olfactory learning and memory, locomotor activity, spatial orientation, sleep, decision making, and up to now but indirectly, in various addiction. Notably, the MBs, which express the nAchR, receive their main inputs from the cholinergic olfactory pathways, through the Projections Neurons (PNs). In this thesis we characterized, at the cellular and molecular levels, the nicotine effect on the Kenyon cells (KCs: the intrinsic neurons) of the Mushroom-Bodies. We used the in-Vivo brain imaging approach, based on the Ca2+-Sensitive bioluminescent probe (GFP-Aequorin), to characterize the nicotinic induced Ca2+-Response on the KCs of the MBs. More specifically we searched the role of different partners involved in the cAMP pathway, in order to understand their roles in the different components of the response and in its modulation. First using both genetics and pharmacological approaches to interfere with different components of the cAMP signaling pathway, we first show that the Ca2+-Response is proportional to the levels of cAMP. Second, we reveal that an acute change in cAMP levels is sufficient to trigger a Ca2+-Response. Third, genetic manipulation of protein kinase A (PKA), a direct effector of cAMP, suggests that cAMP also has a PKA-Independent effect through the cyclic nucleotide-Gated Ca2+-Channel (CNG). Finally, the disruption of calmodulin, one of the main regulators of the rutabaga adenylate cyclase (AC), yields different effects between the calyx/cell-Bodies and the lobes, suggesting a differential and regionalized regulation of ACSecond we exploited both genetic approaches to interfere with different types of Ca2+- and K+-Channels, first we show that the disruption of the VGCC, as cacophony, Dmcα1d and Dmcα1g lead to a striking decrease of the Ca2+-Response both in the CCB and the lobes. Moreover, for two of them, cacophony and Dmcα1d, the duration of the response is importantly increased. Second, the disruption of the fast inactivating K+-Currents, as shaker (sh), shaker-Like (shal) and slowpoke (slo) reveal that the knocked-Down of shal and slo lead to a striking decrease of the Ca2+-Response, while the knocked-Down of sh has only a mild effect. Interestingly, the stimulation of the adenylate cyclase (AC) by the forskolin with the various K+-Channels disruption show an antagonist effect of the cAMP in the CCB between sh (inhibitory) and slow (excitatory) while AC simulation mediate excitatory effects in the ML though both shal and sh. Finally, the knock-Down of the two slow inactivating K+-Currents as shaker w (shaw) and shaker b (shab) also yields to a strong decrease of the Ca2+-Response In conclusion, our results provide new insights into the complexity of the Ca2+-Response in the MBs and are a first step toward deciphering the roles of the VGCC and K+-Channels in the multiples roles of the MBs. Finaly we developed several original protocols to explore the role of the neuromodulation on the KC.This work constitutes an important step toward a better understanding of the pathway required in learning and memory.

Identifying targets in cluttered scenes is critical for our interactions in complex environments. Our visual system is challenged to both detect elusive targets that we may want to avoid or chase and discriminate between targets that are highly similar. These tasks require our visual system to become an expert at detecting distinctive features that help us differentiate between indistinguishable targets. As the human brain is trained on this type of visual tasks, we observe changes in its function that correspond to improved performance. We use functional brain imaging, to measure learning-dependent modulations of brain activation and investigate the processes that mediate functional brain plasticity. I propose that dissociable brain mechanisms are engaged when detecting targets in clutter vs. discriminating between highly similar targets: for the former, background clutter needs to be suppressed for the target to be recognised, whereas for the latter, neurons are tuned to respond to fine differences. Although GABAergic inhibition is known to suppress redundant neuronal populations and tune neuronal representations, its role in visual learning remains largely unexplored. Here, I propose that GABAergic inhibition plays an important role in visual plasticity through training on these tasks. The purpose of my PhD is to investigate the inhibitory mechanisms that mediate visual perceptual learning; in particular, learning to detect patterns in visual clutter and discriminate between highly similar patterns. I show that BOLD signals as measured by functional Magnetic Resonance Imaging (fMRI) do not differentiate between the two proposed mechanisms. In contrast, Magnetic Resonance Spectroscopy (MRS) provides strong evidence for the distinct involvement of GABAergic inhibition in visual plasticity. Further, my findings show GABA changes during the time-course of learning providing evidence for a distinct role of GABA in learning-dependent plasticity across different brain regions involved in visual learning. Finally, I test the causal link between inhibitory contributions and visual plasticity using a brain stimulation intervention that perturbs the excitation-inhibition balance in the visual cortex and facilitates learning.

The proportion of older adults living with cognitive impairments is increasing rapidly. This shift will likely increase mortality rates, reduce perceived quality of life, and cause economic burden to patients and health care systems. Currently evidence of highly effective and noninvasive interventions that prevent or slow the onset of cognitive impairment are limited. This study aims to better understand what drives cognitive aging variability among musicians versus non-musicians. Music playing has been shown to improve brain and cognitive functions by engaging networks of brain areas, simultaneously involving cortical mechanisms associated with executive, high-level cognitive and motor functions, and multiple sensory systems. Literature suggests strong correlations between cognition and music ability. However, studies in the past have not concretely operationalized music training. Here we test the general hypothesis that music training improves neural mechanisms associated with core cognitive functions (e.g. working-memory and attention). A multi-source study was designed to control level of music involvement and genre by examining professional, classically trained orchestral musicians, establishing cognitive and neuropsychological profiles in an effort to better understand the potential for music training to protect older adults from cognitive decline. Specific hypotheses involved attentional inhibition theory and increased ability of musicians to perform attention and working memory tasks. Twenty-nine professional musicians were recruited who completed five neuropsychological exams. The scalp electrophysiological signals from 14 channels were recorded wirelessly while each musician performed a modified delayed match-to-sample task, imagination of music playing, and resting states. Musicians completed neuropsychological screening (MoCA) a music and life span questionnaire as well. Musicians tested above normative ranges in cognitive ability indicated through MoCA. Musicians’ scores were compared with average or normative scores of participants at similar ages in previous studies using the same measures and current musicians performed significantly faster and more accurately on four of five neuropsychological measures. Regression and ANCOVA showed strong positive correlations between theta oscillation in bilateral frontal sites (F3, F4) and both number of years of private music lessons and number of hours of music practice. Correlations between EEG recordings taken during music imagination exercise at posterior (01, 02) sites and the number of years of private music lessons participants took, the age participant started to take music lessons and the number of years they played their musical instrument were found. Current new findings reveal that professional musician’s cognitive scores and neural activity are associated with superior cognitive ability via enhancement of neural mechanisms of current target material and inhibition of distractions. Music training is apromising noninvasive method to control cognitive challenge, which merits further research to determine how it can be used as a beneficial cognitive training method for aging individuals. Future studies should examine neuro-cognitive differences between professional musicians and individuals with lower levels of music involvement to examine dose effects of music or the amount of music needed to protect aging adults from cognitive decline.

The aim of this doctoral thesis was to study neuropsychological function in relation to structural and functional brain changes in Alzheimer´s disease (AD). In the first study relations between hippocampal volume, neuropsychological function and limbic-hypothalamic-pituitary-adrenal (LHPA) axis disturbances in AD were investigated with magnetic resonance imaging (MRI). Reduced hippocampal CA1 volume and suppressed cortisol levels in combination, best predicted the variation in neuropsychological performance. The conclusion was that reduced hippocampal volume and LHPA axis disturbances are associated to level of cognitive function in AD. The second study focused on whether patients with early AD showed an altered regional cerebral blood flow (rCBF) pattern compared to control persons, correlation between performance on memory tests and rCBF in sub-lobar volumes of the brain were investigated. The rCBF was measured with single photon emission computed tomography (SPECT). AD-patients showed a significantly lower rCBF in temporoparietal regions including left hippocampus compared to controls. The diagnostic sensitivity and specificity for AD was high in temporoparietal regions. AD-patients had significantly lower performance on semantic and, in particular, episodic memory-tests compared to the controls, and their performance on several episodic tests correlated with rCBF in parietal and temporal regions including left hippocampus, which suggest that abnormalities in the rCBF pattern underlie impaired episodic memory functioning in AD. The conclusion was that an observer-independent analyzing method for SPECT with sub-lobar volumes VOI´s is promising in the diagnosis of AD. In a third study possible differences in memory-related functional brain activation between persons with high versus low risk for AD were examined with functional magnetic resonance imaging (fMRI). The high-risk individuals performed worse than low-risk individuals on tests of episodic memory. Patterns of brain activity during episodic encoding and retrieval showed significant group differences. During both encoding and retrieval, the low-risk persons showed increased activity relative to a baseline condition in prefrontal and hippocampal brain regions that previously have been implicated in episodic memory. By contrast, the high-risk persons did not significantly activate any prefrontal regions, but instead showed increased activity in visual occipito-temporal regions. The conclusion was that patterns of prefrontal brain activity related to episodic memory differed between persons with high versus low risk for AD, and lowered prefrontal activity may predict subsequent disease. In a final study SPECT was used to map patterns of rCBF in an activated state (an episodic encoding task) and in a rest condition in persons with mild AD and in healthy elderly control persons. A reduction of rCBF in temporoparietal regions that was more pronounced in mild AD in the activated encoding task was observed. The conclusion was that there are rCBF differences between mild AD patients and healthy controls in temporoparietal regions, and the temporoparietal reduction is more pronounced during activation than during rest which might be important in the early diagnosis of AD. Taken together, these findings show that level of neuropsychological function, notably episodic memory, can be systematically related to functional disturbances in the LHPA axis and to the function of temporoparietal and prefrontal brain regions in AD patients. These changes are detectable in patients with risk for AD and in an early phase of AD which suggests that the obtained results might be important for early diagnosis of AD.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

This thesis is an exploratory study of the factors that account for the construction of a local social world around a frontier medical technology. The analysis is based on participant-centred accounts of the structuring of a PET world in the MNI&H. According to local actors, the following factors can be identified to have played a role in the birth, promotion, structuring, and maintenance of the local PET world: the personalities; the institution; the resulting tradition; the assessment of PET; the sense of quality; the size of the local PET world and of the institution; elements of the environment such as cost, finding sources, and manufacturers. The data show that the structuration of the PET world in this elitist research cum hospital institution cannot serve as a model for the diffusion of this frontier technology, although the demarcated pattern exhibits some characteristics common with those described in the literature for similar innovations.