Predictive coding theorizes the capacity of neural structures to form predictions about forthcoming sensory events based on previous sensory input. This concept increasingly gains attention within experimental psychology and cognitive neuroscience. In auditory research, predictive coding has become a useful model that elegantly explains different aspects of auditory sensory processing and auditory perception. Many of these aspects are backed up by experimental evidence. However, certain fundamental features of predictive auditory processing have not been addressed so far by experimental investigations, like correlates of neural predictions that show up before the onset of an expected event. Four experiments were designed to investigate the proposed mechanism under more realistic conditions as compared to previous studies by manipulating different aspects of predictive (un)certainty, thereby examining the ecological validity of predictive processing in audition. Moreover, predictive certainty was manipulated gradually across five conditions from unpredictable to fully predictable in linearly increasing steps which drastically decreases the risk of discovering incidental findings. The results obtained from the conducted experiments partly confirm the results from previous studies by demonstrating effects of predictive certainty on ERPs in response to omissions of potentially predictable stimuli. Furthermore, results partly suggest that the auditory system actively engages in stimulus predictions in a literal sense as evidenced by gradual modulations of pre-stimulus ERPs associated with different degrees of predictive certainty. However, the current results remain inconsistent because the observed effects were relatively small and could not consistently be replicated in all follow-up experiments. The observed effects could be regained after accumulating the data across all experiments in order to increase statistical power. However, certain questions remain unanswered regarding a valid interpretation of the results in terms of predictive coding. Based on the current state of results, recommendations for future investigations are provided at the end of the current thesis in order to improve certain methodological aspects of investigating predictive coding in audition, including considerations on the design of experiments, possible suitable measures to investigate predictive coding in audition, recommendations for data acquisition and data analysis as well as recommendations for publication of results.

Le prédiabète et le diabète de type 2 (DT2) affectent approximativement 9 millions de canadiens, soit près de 30% de la population. Le DT2 est caractérisé par une résistance à l’insuline (RI) qui ne peut être compensée par une sécrétion d’insuline augmentée. La dysfonction du tissu adipeux blanc (TAB) est centrale à ce phénomène et est caractérisée par de l’inflammation et un flux augmenté de lipides vers les tissus périphériques, dont on sait qu’ils favorisent le développement de RI et une hypersécrétion d’apoB-lipoprotéines (apoB) par le foie menant à une élévation de l’apoB plasmatique. En parallèle, les études épidémiologiques montrent que l’apoB plasmatique prédit le développement du DT2 de 3 à 10 ans avant l’apparition de la maladie, indépendamment de facteurs de risque classiques. Dans cette thèse, nous avons formulé l’hypothèse que l’augmentation de la sécrétion d’apoB-lipoprotéines secondaire à un TAB dysfonctionnel contribue à aggraver cette même dysfonction. En ce sens, les apoB-lipoprotéines et le TAB seraient le centre d’un cercle vicieux menant au développement de facteurs de risque cardiométaboliques. Au courant de cette investigation, nous avons combiné des expériences in vitro, ainsi que des analyses post-hoc sur des données in vivo et ex vivo au sein d’une population d’hommes et de femmes post-ménopausées recrutés à l’Institut de recherches cliniques de Montréal pour deux études métaboliques entre 2006 et 2019. En circulation, 90% de apoB-lipoprotéines sont des LDL. Le nombre d’apoB-lipoprotéines en circulation se mesure par l’apoB plasmatique, qui est associé au développement du TAB dysfonctionnel chez l’humain via divers mécanismes. Parmi ceux-ci, l’enrichissement postprandial des lipoprotéines riches en triglycérides (TG) par l’apolipoprotéine C-I (apoC-I) sécrétées par le TAB a été suggéré comme un facteur contributoire. Dans un premier manuscrit, nous montrons que les sujets (N=39) avec un TAB dysfonctionnel sécrètent de plus grandes quantités d’apoC-I, ce qui est associé spécifiquement à une clairance postprandiale réduite des chylomicrons. Cette dysfonction semble due à une diminution de l’hydrolyse des TG secondaire à une inhibition de la lipase lipoprotéique (LPL) des adipocytes, ce qui constitue un nouveau mécanisme par lequel le TAB contribue à l’augmentation de l’apoB plasmatique. La proprotéine convertase subtilisin-kexin type 9 (PCSK9) est une enzyme circulante qui cible les récepteurs aux apoB-lipoprotéines comme le récepteur aux LDL (LDLR) et le CD36. Une PCSK9 circulante faible combinée à un haut apoB plasmatique, donc un ratio apoB-sur-PCSK9 élevé, est fortement associée au TAB dysfonctionnel et à la RI, suggérant qu’une augmentation de l’internalisation des apoB-lipoprotéines par voie de récepteurs joue un rôle dans ces pathologies. En parallèle, les apoB-lipoprotéines, principalement les LDL natifs et oxydés, activent l’inflammasome NLRP3 (Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3), le récepteur intracellulaire responsable de la sécrétion d’interleukine 1 bêta (IL-1), dont on sait qu’elle joue un rôle majeur dans le développement de l’inflammation liée au DT2. Dans un deuxième manuscrit, nous montrons que le ratio apoB-sur-PCSK9 plasmatique est un index, dans les états à jeun et postprandial, de l’expression des récepteurs aux apoB-lipoprotéines LDLR et CD36 en surface du TAB chez une population en surpoids ou obèse (N=31). Ce même ratio est aussi indicateur de la régulation à jeun et postprandial de l’expression de l’inflammasome NLRP3 et de l’infiltration de macrophages au sein du TAB. Finalement, les études épidémiologiques récentes suggèrent que le risque de DT2 est aussi augmenté chez les sujets avec un LDL cholestérol (LDL-C) faible causé par des variants génétiques perte-de-fonction dans le gène de la PCSK9 ou suite à une thérapie hypocholestérolémiante. Dans un troisième manuscrit, nous montrons que, chez les sujets avec LDL-C faible (<3.5mM, N=28), une PCSK9 plasmatique plus basse identifie les sujets avec une expression augmentée de LDLR et CD36 en surface de leur TAB. Malgré le LDL-C faible, les sujets avec une PCSK9 faible montraient une dysfonction du TAB et à un indice de disposition diminué et une sécrétion augmentée d’IL-1, suggérant une progression vers le DT2. Dans une exploration mécanistique, une exposition chronique des adipocytes humains SGBS aux LDL natifs induit une différenciation anormale, marquée par une diminution de leur fonction. Bien que ce phénomène soit indépendant de l’inflammasome NLRP3, qui n’est pas exprimé chez ces adipocytes, les LDL natifs induisent une augmentation du ratio de sécrétion d’IL-1 actif relativement à la pro-IL-1 inactive qui suggère une activation du système NLRP3 chez les macrophages humains THP-1. En conclusion, ces données suggèrent que le TAB dysfonctionnel contribue en partie via une sécrétion d’apoC-I à la clairance réduite des lipoprotéines et, donc, à l’hyperapoB et au risque cardiométabolique. En retour, une internalisation plus grande d’apoB-lipoprotéines par voie des récepteurs semble associée au développement d’un TAB dysfonctionnel et aux facteurs de risque cardiométaboliques associés. Au sein du TAB, au niveau cellulaire, ceci pourrait être dû à un effet concomitant des LDL natifs, qui induiraient une baisse de différenciation des préadipocytes menant à leur dysfonction ainsi qu’une activation de l’inflammasome NLRP3 chez les macrophages. / Prediabetes and type 2 diabetes (T2D) affect approximately 9 million Canadians, which represents close to 30% of the population. T2D is characterized by insulin resistance (IR) that cannot be compensated by increased insulin secretion. White adipose tissue (WAT) dysfunction is at the root of this pathology and is characterized by increased lipid flux to peripheral tissues causing IR and hypersecretion of apoB-lipoproteins (apoB) by the liver, contributing to increased plasma apoB. In line, epidemiological studies show that plasma apoB is an independent predictor of T2D development 3 to 10 years before onset. In this thesis, we formulated the hypothesis that increased secretion of apoB-lipoprotein secondary to WAT dysfunction promotes further development of this dysfunction in a feed-forward cycle that contributes to increased metabolic risk. To investigate this, we have combined in vitro experiments as well as post hoc analyses of in vivo and ex vivo data from a cohort of men and postmenopausal women recruited from two metabolic studies conducted at Institut de recherches cliniques de Montréal between 2006 and 2019. In circulation, more than 90% of apoB-lipoproteins are in the form of LDL. The number of apoB-lipoproteins (measured by plasma apoB), is associated to the development of WAT dysfunction in humans via different mechanisms. Postprandial enrichment of triglyceride-rich lipoproteins (TRL) by WAT-secreted apoC-I has been proposed as one of them. In a first manuscript, we show that subjects (N=39) with dysfunctional WAT secrete greater amount of apoC-I, which is associated specifically to delayed postprandial chylomicrons clearance in a mechanism that appears to be dependent on apoC-I-mediated inhibition of adipocyte lipoprotein lipase. This constitutes a new mechanism linking adipose tissue dysfunction to increased plasma apoB. Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a circulatory enzyme that targets apoB-lipoprotein receptors, such as the LDLR and CD36, for degradation. Low circulating PCSK9 relative to high plasma apoB, expressed as a higher apoB-to-PCSK9 ratio, is strongly associated to WAT dysfunction and IR, suggesting that increased receptor-mediated uptake of apoB-lipoproteins plays an important role in these pathologies. In parallel, apoB-lipoproteins, mostly native and oxydized LDL, activate the NLRP3 inflammasome (Nucleotide-binding domain and Leucine-rich repeat Receptor, containing a Pyrin domain 3). The NLRP3 inflammasome is an intracellular receptor responsible for interleukin-1 beta (IL-1) secretion, which is known to be implicated in the pathogenesis of T2D. In a second manuscript, we demonstrate in overweight and obese subjects (N=31) that the apoB-to-PCSK9 is indeed an index of WAT surface-expression of LDLR and CD36 both at fasting and in the postprandial state. Similarly, the apoB-to-PCSK9 ratio is associated with chronic NLRP3 inflammasome priming at fasting and with postprandial macrophage infiltration and concomitant NLRP3 upregulation within WAT. Finally, recent epidemiological studies suggest an increased risk for T2D in subjects with low plasma LDL cholesterol (LDL-C) secondary to loss-of-function genetic variants in PCSK9, or secondary to cholesterol-lowering therapies. In a third manuscript, we show that in subjects with low LDL-C (<3.5mM, N=28), lower plasma PCSK9 identifies subjects with higher WAT LDLR and CD36 surface-expression. Despite having lower LDL-C, subjects with lower plasma PCSK9 show dysfunction WAT and decreased disposition index. Mechanistically, human SGBS adipocytes chronically exposed to native LDL show impaired differentiation and concomitant dysfunction. While this phenomenon cannot be described by NLRP3 inflammasome activation, since it is not expressed in these adipocytes, native human LDL increase the ratio of secreted active Il-1 relative to inactive pro-IL-1 suggesting activation of the NLRP3 inflammasome in human THP-1 macrophages. In conclusion, these observations suggest that dysfunctional WAT promotes delayed postprandial lipoprotein clearance via increased apoC-I secretion, thus promoting hyperapoB and increased cardiometabolic risk. In turn, upregulated receptor-mediated uptake of apoB-lipoproteins appears to be connected to the development of WAT dysfunction and associated cardiometabolic risk factors. At the cellular level within WAT, this could be secondary to a concomitant effect of LDL on preadipocytes inducing their reduced differentiation and function and on macrophage inducing activation of the NLRP3 inflammasome.

Predictive coding theorizes the capacity of neural structures to form predictions about forthcoming sensory events based on previous sensory input. This concept increasingly gains attention within experimental psychology and cognitive neuroscience. In auditory research, predictive coding has become a useful model that elegantly explains different aspects of auditory sensory processing and auditory perception. Many of these aspects are backed up by experimental evidence. However, certain fundamental features of predictive auditory processing have not been addressed so far by experimental investigations, like correlates of neural predictions that show up before the onset of an expected event. Four experiments were designed to investigate the proposed mechanism under more realistic conditions as compared to previous studies by manipulating different aspects of predictive (un)certainty, thereby examining the ecological validity of predictive processing in audition. Moreover, predictive certainty was manipulated gradually across five conditions from unpredictable to fully predictable in linearly increasing steps which drastically decreases the risk of discovering incidental findings. The results obtained from the conducted experiments partly confirm the results from previous studies by demonstrating effects of predictive certainty on ERPs in response to omissions of potentially predictable stimuli. Furthermore, results partly suggest that the auditory system actively engages in stimulus predictions in a literal sense as evidenced by gradual modulations of pre-stimulus ERPs associated with different degrees of predictive certainty. However, the current results remain inconsistent because the observed effects were relatively small and could not consistently be replicated in all follow-up experiments. The observed effects could be regained after accumulating the data across all experiments in order to increase statistical power. However, certain questions remain unanswered regarding a valid interpretation of the results in terms of predictive coding. Based on the current state of results, recommendations for future investigations are provided at the end of the current thesis in order to improve certain methodological aspects of investigating predictive coding in audition, including considerations on the design of experiments, possible suitable measures to investigate predictive coding in audition, recommendations for data acquisition and data analysis as well as recommendations for publication of results.:1. Introduction ... 5 1.1 An introduction to predictive coding theory ... 9 1.2 Predictive coding in audition ... 11 1.3 Electrophysiological correlates of predictive auditory processing ... 14 1.4 Limitations of previous research and aims of the thesis ... 21 2. Traditional correlates of auditory prediction ... 24 2.1 Experiment 1: Reliability of auditory predictions ... 25 2.2 Experiment 2: Accuracy of auditory predictions ... 39 3. Pre-stimulus correlates of auditory prediction ...47 3.1 Pre-stimulus effects in Experiment 1 and 2 ... 48 3.2 Experiment 3: Temporal dynamics of auditory prediction ... 56 3.3 Experiment 4: The influence of omissions on stimulus processing ... 64 4 Results across experiments ... 74 4.1 Methods ... 76 4.2 Results ... 80 4.3 Discussion ... 82 5. General Discussion ... 87 5.1 Implications for current research ... 89 5.2 Recommendations for future investigations ... 93 5.3 Future prospects ... 101 5.4 Conclusion ... 104 References ...106 Appendix ... 116

<p>General Aviation (GA) encompasses all aircraft operations, excluding scheduled, military, and commercial operations. GA accidents comprise approximately 94% of all aviation accidents in the United States annually. 75% of these accidents involve pilot-related factors (pilot actions or conditions). Inflight loss of control means that the flight crew was unable to maintain control of the aircraft in flight. With almost 50% of loss of control accidents being fatal yearly, it continues to be the deadliest cause of GA accidents.</p> <p><br></p> <p>The most common approach to understanding accident causation is analyzing historical data from sources such as the National Transportation Safety Board (NTSB) database. The NTSB database has abundant rich information. In contrast to the extensive investigations into and detailed reports on commercial aviation accidents, GA accident investigations tend to be shorter, and the resulting reports tend to be brief and limited—especially regarding human factors’ role in accidents. Only relying on historical data cannot provide a complete understanding of accident causation.</p> <p><br></p> <p>There is a clear need to better understand the role of human factors involved in GA accidents to prevent such accidents and thus improve aviation safety. In my research, I focus on a specific type of accidents, inflight loss of control (LOC-I), the deadliest cause of GA accidents. I use historical data analysis and human-subjects research with pilots to investigate the role of human factors in loss of control accidents. Building on previous work, I created a state-based modeling framework that maximizes data extraction and insight formation from the NTSB accident reports by (1) developing a structured modeling language to represent accident causation in the form of states and triggers; (2) populating the language lexicon of states and triggers using insights from accident reports and pilots perspectives via surveys and interviews; and (3) applying Natural Language Processing (NLP) and machine learning techniques to automatically translate accident narratives into the language lexicon. The framework is focused on LOC-I but can be extended to other types of accidents. Findings from my study may help in consistent accident analysis, better accident reporting, and improving training methods and operating procedures for GA pilots.</p>