Un grand défi des cliniciens dans le domaine des commotions cérébrales est de déterminer le moment où l’athlète est prêt à retourner au jeu. Pour guider cette décision, plusieurs ont recours à l’évaluation cognitive pour accompagner l’évaluation des symptômes de l’athlète. Toutefois, plusieurs études appuient la nécessité de développer des tâches cognitives plus raffinées avec des propriétés psychométriques adéquates. Par ailleurs, une étude récente montre que des déficits cognitifs sont exacerbés par l’exercice physique chez 27,7 % des athlètes ayant reçu l’autorisation médicale de retourner au jeu et montrant des résultats normaux à l’état de repos, suggérant une récupération incomplète. Le but de cette thèse consiste en l’élaboration d’un outil, valide et accessible, pour évaluer la disposition d’un athlète à retourner au jeu à la suite d’une commotion, ainsi que pour évaluer les déficits à long terme (c.-à-d., plus de six mois) associés à la blessure. Cet outil comprend un protocole d’exercice standardisé (20 minutes à 80 % de la fréquence maximale théorique sur vélo) et une tâche cognitive, appelée la tâche d’alternance. Dans l’article I, nous avons examiné les propriétés psychométriques de la tâche cognitive. Les résultats suggèrent que la tâche d’alternance est une mesure valide des fonctions exécutives et montre une bonne fidélité test-retest. Ils indiquent aussi que les coûts d’alternance, traditionnellement calculés pour isoler les différentes composantes des fonctions exécutives, ne montrent pas d’aussi bonnes propriétés psychométriques que les variables primaires (vitesse de réaction, précision des réponses et score d’efficacité inverse). Dans l’article II, nous avons mesuré l’effet de pratique associé à la passation répétée de la tâche à des intervalles de 48 heures, dans le but de répliquer l’administration en série de cette tâche lors du suivi post-commotion. Les résultats indiquent que la performance s’améliore durant les trois premières passations de la tâche et que l’utilisation d’une version alternative ne permet pas d’éliminer l’effet de pratique. Dans l’article III, nous avons déterminé que notre outil détenait la capacité de détecter des déficits cognitifs chez des athlètes ayant réussi le protocole de retour au jeu de Zurich. Spécifiquement, notre outil a permis de créer trois sous-groupes : 80 % des athlètes qui ne montrent aucun déficit ; 20 % des athlètes qui montrent des déficits cognitifs au repos sur la tâche d’alternance ; 10 % des athlètes qui montrent des déficits seulement après l’exercice. Ainsi, lorsqu’utilisés ensemble, la tâche d’alternance et le protocole d’exercice permettent de détecter des déficits chez jusqu’à 30 % des athlètes, qui sont pourtant considérés comme rétablis. Dans l’article IV, nous avons montré que notre outil peut détecter les déficits persistants associés à la commotion. Alors qu’au repos aucun déficit n’est observé, l’évaluation post-exercice révèle des déficits chez 20 % des athlètes avec un historique de commotions. En somme, nos résultats soutiennent l’utilisation de notre outil pour l’évaluation du retour au jeu. Les résultats de cette thèse réaffirment la nécessité de changer la norme pour l’évaluation de la commotion. Sur la base des résultats actuels, l’utilisation de tâches cognitives valides et sensibles aux effets de la commotion au-delà de la phase symptomatique, associée à un protocole d’exercice, devrait devenir l’étalon-or. / Concussion is especially hard to detect because clinicians must rely on self-reported symptoms to diagnose the injury and to determine when an athlete is ready to safely return to play (RTP). To guide the latter decision, many use cognitive testing. However, several studies indicate the need to develop more refined cognitive tasks, with better psychometric properties than those currently used to assess concussion. Another option would be to perform the psychometric validation of experimental tasks frequently used in research settings. Further, a recent study suggests that physical exercise can reveal deficits that were not perceptible at rest in one in four athletes, thus indicating incomplete recovery in a significant minority of the concussed athletes. Accordingly, this dissertation aimed to develop a valid and easily accessible tool to assess the readiness of recently concussed athletes to safely return to play, as well as to assess deficits in the protracted phase of the recovery. The tool includes a standardized exercise protocol (20-min on an ergocycle at 80% theoretical maximum heart rate) and a cognitive task (color-shape switch task). In the first manuscript, we examined the construct validity and the test-retest reliability of the switch task. The results suggest that the switch task is a valid measure of executive functions that shows an adequate test-retest reliability. The results also suggest that the switch costs, which are traditionally computed to isolate the different components of executive functions, do not show as good psychometric properties as primary variables do (i.e., reaction time, accuracy, and inverse efficiency score). In the second manuscript, we measured the practice effect associated with serial administration of the switch task. The results indicate that the performance improves during the first three assessments when the task is completed every 48 hours. Also, they do not support the use of alternative versions of the task in order to eliminate the practice effect as it is still present. In the third manuscript, we determined that our tool has the requisite sensitivity for detecting cognitive deficits in recently concussed athletes who had successfully completed the RTP protocol. Specifically, our tool detected deficits in 20% of athletes when the switch task is completed at rest and in an additional 10% when it is completed post-exercise. Thus, our tool can detect deficits in up to 30% of athletes who had received their medical clearance to RTP. In the 4th manuscript, we showed that our tool can detect persistent deficits stemming from sports concussion. The post-exercise testing showed deficits in 20% of athletes, deficits that were not detected at rest. Thus, the use of an acute bout of aerobic exercise may increase the sensitivity of the cognitive testing. The results herein support the use of the switch task, before and after an acute bout of exercise of moderate intensity. Moreover, they reaffirm the necessity to change the standard for assessing sports concussion. Indeed, based on the current results, the use of valid and reliable cognitive tasks, sensitive to the effects of concussion beyond the symptomatic phase, in combination with an exercise protocol, should become the gold standard.

Le fonctionnement du cortex cérébral nécessite l'action coordonnée de deux principaux types de neurones : les cellules principales excitatrices glutamatergiques (PC) (∼80%) et les interneurones inhibiteurs GABAergiques (IN) (∼20%). Le sous-type le plus courant d'interneurones (IN) GABAergiques, les IN exprimant la parvalbumine (Pv+), innervent le soma et les dendrites proximales d'environ 100 PC voisins. Ainsi, ils délivrent une forte impulsion inhibitrice périsomatique et, à ce titre, jouent un rôle essentiel dans l'intégration synaptique et la synchronisation des circuits corticaux. La maturation des Pv+ IN est un processus prolongé, qui n'atteint un plateau qu'après la fin de l'adolescence. Des altérations de la connectivité et de la fonction des Pv+ IN au cours du développement, en particulier dans le cortex préfrontal (PFC), ont été systématiquement signalées dans plusieurs troubles psychiatriques associés à la rigidité cognitive, ce qui suggère que des déficits des Pv+ IN pourraient être un phénotype cellulaire central de ces troubles. Une autre classe d’IN majeure est constituée par les IN exprimant la somatostatine (Sst+). Malgré des origines neurodéveloppementales similaires, les IN Sst+ présentent une morphologie et une physiologie distinctes des IN Pv+. Les IN Sst+ ciblent les dendrites apicales des PC, modulant ainsi directement les entrées excitatrices sous-jacentes aux différentes fonctions corticales. Comme pour les IN Pv+, le dysfonctionnement des IN Sst+ a été associé aux NDD. Ici, nous étudions les mécanismes moléculaires sous-jacents à la maturation de ces circuits d’IN et comment les altérations de ces mécanismes affectent la fonction corticale. Nous avons précédemment montré que la réductionde l'expression du récepteur de la neurotrophine p75 (p75NTR) par les Pv+ IN au cours du premier mois postnatal régule l'évolution temporelle de leur maturation morphologique cellulaire de façon autonome. Toutefois, il restait à déterminer si l'expression de p75NTR au cours du développement postnatal a un effet à long terme sur la connectivité des cellules Pv+ et la fonction cognitive dans le PFC. En utilisant des stratégies de knock-out conditionnel et virales, nous avons montré que l'expression de p75NTR dans les IN Pv+ du cerveau adolescent contribue à l'établissement de leurs connections afférentes et de leur plasticité dans le PFC. De plus, la délétion postnatale de p75NTR spécifiquement aux cellules Pv+ entraîne 1) une augmentation de la production efférente sur les PC, 2) une augmentation de l'agglomération des PNN autour de leurs corps cellulaires dans le PFC adulte, 3) une altération de l'engagement des cellules Pv+ dans le circuit préfrontal suite à des stimuli sensoriels et 4) une altération des oscillations γ et de la rigidité cognitive chez la souris adulte. Un autre facteur moléculaire qui joue un rôle important dans la connectivité et la fonction des IN est la cadhérine-13 (Cdh13). Cdh13 est un membre unique ancré au glycosylphosphatidylinositol de la famille des cadhérines qui est exprimé à la fois par les IN Pv+ et Sst+ et régule la transmission inhibitrice basale dans l'hippocampe. Cdh13 est un gène à risque pour les NDD ; cependant, le mécanisme par lequel Cdh13 affecte la fonction et la cognition au niveau du réseau cortical et la pathogenèse de ces troubles reste insaisissable. Nous avons utilisé la transcriptomique unicellulaire et montré que l'ARNm de Cdh13 est sélectivement enrichi en Sst+ IN corticaux chez les souris juvéniles. Nous avons ensuite analysé le patrond'expression de Cdh13 dans les IN Pv+ et Sst+ à l'aide de l’hybridation in situ de type RNAscope et avons constaté que les deux types cellulaires expriment Cdh13 à des niveaux différents. Enfin, nous avons généré des modèles de souris knock- out conditionnels SstcKO (Sst_Cre+/-; Cdh13loxP/loxP) et Pv-cKO (PV_Cre+/-; Cdh13loxP/ loxP) et effectué des enregistrements intracorticaux in vivo à partir de souris éveillées. Nous avons identifié des altérations significatives dans le traitement auditif, spécifiquement chez les souris SstcKO. Ainsi, Cdh13 joue un rôle critique et spécifique dans la fonction IN Sst+. En résumé, la compréhension des mécanismes cellulaires et moléculaires régissant le bon développement et la maturation des circuits inhibiteurs met en lumière les mécanismes par lesquels l'inhibition GABAergique contribue aux opérations du réseau cortical et à la fonction cognitive. Ces études indiquent en outre des substrats subcellulaires, potentiellement affectés dans les NDD et les troubles neuropsychiatriques et ouvrent la voie à des stratégies de diagnostic et de traitement plus efficaces. / The proper functioning of the cerebral cortex requires the coordinated action of two main types of neurons: the principal excitatory glutamatergic cells (PCs) (∼80%) and the GABAergic inhibitory interneurons (INs) (∼20%). The most common subtype of GABAergic INs, the parvalbumin-expressing (Pv+) INs, innervate the soma and proximal dendrites of around 100 neighboring PCs. Thus, they deliver a strong perisomatic inhibitory drive and, as such, play an essential role in synaptic integration and cortical circuit synchronization. Pv+ INs maturation is a prolonged process, which reaches a plateau only after the end of adolescence. Alterations in Pv+ INs connectivity and function during development, especially in the prefrontal cortex (PFC), have been consistently reported in several psychiatric disorders associated with cognitive rigidity, suggesting that Pv+ INs deficits may be a core cellular phenotype in these disorders. Another major IN class, not overlapping with Pv+ cells, is constituted by somatostatin-expressing (Sst+) INs. Despite sharing similar neurodevelopmental origins, Sst+ INs exhibit distinct morphology and physiology from Pv+ INs. Sst+ INs target apical dendrites of PCs, thus directly modulating excitatory inputs underlying different cortical functions. Like Pv+ INs, the dysfunction of Sst+ INs has been associated with NDDs. Here, we investigate the molecular mechanisms underlying the maturation of these INs circuits and how alterations of these mechanisms affect cortical function. We have previously shown that the downregulation of the p75 neurotrophin receptor (p75NTR) expression in Pv+INs during the first postnatal month regulates the time course of their morphological maturation in a cell-autonomous fashion. Whether p75NTR expression during postnatal development has a long-term effect on Pv+ cell connectivity and cognitive function in the PFC is unknown. Using conditional knock-out and viral strategies, we showed that p75NTR expression in adolescent Pv+ INs contributes to the establishment of their output and plasticity in the PFC. In addition, Pv cell-specific postnatal deletion of p75NTR leads to 1) increased efferent output onto PCs, 2) increased perineuronal net (PNN) agglomeration around their somata in adult PFC, 3) altered Pv+ cell engagement in the prefrontal circuit following sensory stimuli and 4) altered γ oscillations and cognitive rigidity in adult mice. Another molecular factor that plays a significant role in the connectivity and function of INs is Cadherin-13 (Cdh13). Cdh13 is a unique glycosylphosphatidylinositol-anchored member of the cadherin family that is expressed by both Pv+ and Sst+ INs and regulates basal inhibitory transmission in the hippocampus. Cdh13 is a risk gene for NDDs; however, the mechanism whereby Cdh13 affects cortical network function and cognition and how its dysfunction influences the pathogenesis of these disorders remains elusive. We used single-cell transcriptomics and showed that Cdh13 mRNA is selectively enriched in juvenile mice's cortical Sst+ INs. We then analyzed the expression pattern of Cdh13 in cPv+ and cSst+ INs using RNAscope and found that both cell types express Cdh13 at different levels. Finally, we generated conditional knock-out mice models (Sst_Cre+/-; Cdh13loxP/loxP; Sst-cKO and Pv_Cre+/-; Cdh13 loxP/loxP; Pv-cKO mice) and performed in vivo intracortical recording from awake mice. This approach identified significant alterations in auditory processing, specifically in Sst-cKO mice. Thus, Cdh13 plays a critical and specific role in the Sst+ INs function. In summary, understanding the cellular and molecular rules governing proper inhibitory circuitry development and maturation shed light on the mechanisms by which GABAergic inhibition contributes to cortical network operations and cognitive function. These studies further indicate subcellular substrates, potentially affected in NDDs and neuropsychiatric disorders and pave the road for more effective diagnosis and treatment strategies.

[pt] O envelhecimento em todo o mundo é um dos maiores desafios da saúde. Nesse contexto, condições clínicas como demências e Comprometimento Cognitivo Leve (CCL) também aumentam suas prevalências. A causa de demência mais frequente e estudada é demência de Alzheimer (DA). Tradicionalmente, DA é caracterizada pelo déficit precoce na memória episódica. Entretanto, estudos atuais mostram que a DA apresenta heterogeneidade neuropsicológica e alguns pacientes apresentam déficits cognitivos precoces não-amnésticos. Essas apresentações são chamadas por alguns autores de DA atípica. Dessa forma, a primeira parte dessa tese dedicou-se a estudar a heterogeneidade neuropsicológica na DA através de dois estudos: uma revisão sistemática sobre heterogeneidade neuropsicológica na DA (publicado) e um estudo de casos sobre perfis típico e atípico na DA (publicado). A revisão sistemática tornou-se necessária já que foi a primeira revisão sistemática publicada sobre o tema. Os achados dos dois estudos mostraram que aspectos atípicos na DA precisam ser mais explorados, já que DA não é uma condição homogênea. Compreender esses perfis cognitivos na DA irá interferir nos métodos diagnósticos e intervenções terapêuticas, seja farmacológica ou comportamental. A segunda parte dessa tese explora esses aspectos atípicos em três amostras: envelhecimento normal, CCL e AD. Assim, um estudo transversal foi realizado para comparar medidas de velocidade de processamento (VP), controle inibitório e automonitoramento nas três amostras. Os resultados desse estudo mostram que medidas de VP podem ser indicadores precoces do declínio cognitivo envelhecimento. Ao comparar CCL com o grupo de envelhecimento saudável, os dados mostram diferença nas medidas de VP e erros cometidos nos testes de VP. Entretanto, as duas amostras não apresentaram diferenças nas medidas de funções executivas (FEs) e nas medidas de funcionalidade. CCL versus AD mostraram diferenças nas medidas de VP, funções executivas e funcionalidade. Dessa forma, esse estudo traz resultados relevantes para o diagnóstico precoce de CCL e novas diretrizes para o cenário clínico e pesquisa. Além disso, na segunda parte desta tese foi realizado um artigo sobre acurácia diagnóstica das medidas de VP nos casos de CCL e AD. A literatura mostra falta de estudos sobre diferenças nas medidas de VP no envelhecimento e parâmetros diagnósticos dos instrumentos de VP. Esse estudo mostrou que medidas de VP apresentam habilidades discriminativas, para DA e CCL. Esses dados são necessários, já que apresentamos um cenário de escassez de instrumentos com elevados parâmetros diagnósticos para medidas de VP no envelhecimento. Esse cenário torna-se ainda mais drástico, quando falamos de Brasil. / [en] Aging is a major healthcare challenge worldwide. With aging, the prevalence of conditions such as dementia and Mild Cognitive Impairment increase. The most frequent and studied cause of dementia is Alzheimer s dementia (AD). Traditionally, AD is characterized by early deficit in episodic memory. However, current studies show that AD presents heterogeneity in clinical manifestations, especially cognitive manifestations. Thus, some patients present a non-amnestic cognitive profile. These profiles are called by some authors as atypical AD. The first part of this thesis was aimed at studying the neuropsychological heterogeneity in AD by means of 2 studies: a systematic review on neuropsychological heterogeneity in AD (published) and cases of study with typical and atypical AD patients (published). The systematic review was necessary, as it was the first published review about the topic. The findings of the two studies show that atypical aspects in AD need to be further explored, since AD is not a homogeneous condition. Understanding these cognitive profiles in AD will interfere in diagnostic methods and therapeutic interventions, either pharmacological or behavioral ones. The second part of this thesis explores atypical aspects in three samples: normal aging, MCI and AD. Thus, a cross-sectional study was conducted to compare measures of processing speed (PS), inhibitory control, working memory and cognitive flexibility in the three samples. The results of this study showed that PS measures may be early indicators of cognition decline in aging. MCI versus normal aging showed differences in PS measures and errors in tests of PS. However, these samples did not show differences in executive function measures (EFs) and functional measures. Nevertheless, MCI versus AD show differences in PS measures, executive functions and functionality. Thus, this study showed relevant results for the diagnosis process of MCI and new guidelines for clinical settings and research. In addition, in the second part of this thesis an article was written on diagnostic accuracy of the PS measures used in cases of MCI and AD. The literature shows a lack of studies on differences in PS measures in aging and diagnostic parameters of PS instruments. This study showed that PS measures present discriminative abilities in AD and MCI. These data are important, as there is a lack of diagnostic tools for PS in aging, especially in the Brazilian scenario.

The purpose of this three-article dissertation was to expand knowledge and theory regarding digital tool use in biology laboratory courses, such as microbiology, which requires specific laboratory skill development through the perception of instructors and students. Article 1 establishes the broad digital literacy and fluency problem in education by providing definitions and the context behind digital literacy fluency and its impact on acquisition of knowledge in digital learning environments. The study provided a picture of the lack of knowledge about the use of digital tools in education and practical problems around appropriate implementation, infrastructure, and preparedness. Article 2 presents results of a literature research study about the foundational, pandemic-induced, and current digital tool use in biology and microbiology lab courses. Recommendations for improvement in digital tool implementation, pedagogical approach, and appropriate selection to meet learning outcomes were provided. Article 3 describes a 3-layered study to build a new instrument to understand minority-student perceptions of identity and digital literacy and technology barriers on student success in STEM courses. The study identified challenges and benefits of digital tool use in virtual microbiology lab courses, unique challenges of underrepresented populations, and the need to develop an instrument to capture the context of this unique population.