Effets électrophysiologiques d’une thérapie cognitivo-comportementale pour traiter le syndrome de Gilles de la Tourette et le trouble de tics chroniques

Les troubles des tics, comme le syndrome de Gilles de la Tourette et le trouble de tics chroniques, sont des conditions neuropsychiatriques impliquant des tics moteurs et/ou phoniques. En plus de nombreuses comorbidités, les patients qui en sont atteints ont aussi des difficultés neuropsychologiques, notamment au niveau de l’inhibition et des fonctions motrices. La thérapie cognitivo-comportementale permet d’améliorer les tics et la condition générale de ces patients. Nous avons donc enregistré, durant une tâche de compatibilité stimulus-réponse, les potentiels évoqués cognitifs et les potentiels de latéralisation motrice (lateralized readiness potential; LRP) chez 20 patients atteints de trouble des tic avant et après une thérapie cognitivo-comportementale, et chez 20 participants contrôles. Chez les patients atteints de trouble des tics, nos résultats ont révélé une apparition plus tardive de l’amorce du LRP moyenné par rapport au stimulus, une amplitude plus élevée du LRP moyenné par rapport à la réponse, et une suractivation frontale liée aux processus d’inhibition. Suite à la thérapie, le retard au niveau de la latence de l’amorce du LRP moyenné par rapport à la réponse est comblé et l’amplitude du LRP moyenné par rapport à la réponse est normalisée, mais pas la suractivation frontale liée à l’inhibition. Cela suggère donc que la thérapie induit une modification des processus prémoteurs de sélection et de préparation de la réponse, ainsi que des processus d’exécution motrice, mais n’altère pas la suractivation frontale reliée aux fonctions inhibitrices. Étant donnés ces résultats, nous suggérons que la thérapie cognitivo-comportementale induit une modification du fonctionnement des aires motrices du cerveau.Gilles de la Tourette syndrome and chronic tic disorder are two neuropsychiatric condition involving motor and/or phonic tics. In the DSM, these two conditions are characterized as “tic disorders”. Patients with such diagnoses face numerous comorbidities, and also show multiple neuropsychological impairments, especially concerning inhibition and motor processing. Tic symptoms, as well as general condition, can be improved with a cognitive-behavioural therapy (CBT). To this end, we recorded, during a stimulus-response compatibility task, event-related potentials and lateralized readiness potentials in 20 patients with tic disorder and 20 healthy controls. Patients and controls were paired on age, sex and hand dominance. Our result revealed a delay in stimulus-locked lateralized readiness potential (LRP) onset latency, higher response-locked LRP peak amplitude and a frontal overactivation related to stimulus inhibition in GTS and CTD patients. Following CBT, stimulus-locked LRP onset latency and response-locked LRP peak amplitude were normalized, but the frontal overactivation related to inhibition processing remained unchanged. These results suggest that CBT induces a modification of pre-motor processes such as response selection and preparation, as well as motor processes like response execution, but does not affect cortical activation related to stimulus inhibition. Since we found a reduction in tic symptoms, as well as a normalization of stimulus-locked LRP onset latency and response-locked LRP peak amplitude, and because LRPs are partly generated by the supplementary motor area, we suggest that CBT leads to a modification of this structure’s functioning

Étude des capacités d’inhibition, des processus moteurs, et de l’impact de la thérapie cognitive-comportementale sur le fonctionnement cérébral des patients atteints du syndrome de Gilles de la Tourette

Ce qui caractérise principalement le syndrome de Gilles de la Tourette (SGT), c’est la présence de tics moteurs et vocaux chez les individus qui en sont atteints. Toutefois, les tics ne sont que la pointe de l’iceberg pour plusieurs patients. Le SGT s’accompagne souvent de troubles concomitants. Les plus fréquents sont le trouble obsessionnel-compulsif et le trouble du déficit de l’attention avec ou sans hyperactivité. De plus, certaines études neuropsychologiques ont rapporté que les patients atteints du SGT présentaient des capacités d’inhibition réduites, ce qui seraient directement associées à la difficulté de contrôler les tics. Toutefois, plusieurs résultats contradictoires ont été publiés à ce sujet. Aussi, plusieurs hypothèses ont été avancées pour expliquer la génération des tics. Parmi celles-ci, on retrouve notamment certaines études qui ont identifié une suractivité des régions motrices du cerveau. Encore ici, il n’existe pas de conclusion définitive au sein de la littérature. On ne peut guérir du SGT, mais il existe plusieurs traitements qui permettent de diminuer la sévérité des symptômes. La pharmacothérapie est généralement efficace, mais s’accompagne souvent d’effets secondaires indésirables. La thérapie cognitive-comportementale s’avère est une avenue de traitement intéressante, car elle n’entraîne pas d’effets secondaires sur le plan physique. Bien que son efficacité ait été maintes fois démontrée, on ne connaît toujours pas les mécanismes neuronaux impliqués dans son fonctionnement. L’objectif général de cette thèse était de mieux comprendre le fonctionnement cognitif des patients atteints du SGT et d’identifier les substrats neurobiologiques qui sous-tendent ces fonctions. Nous souhaitions observer comment ces fonctions évoluent suite à une thérapie cognitive-comportementale permettant de diminuer les tics. Cet objectif général a été divisé en trois volets. Le premier volet visait à mieux comprendre et à quantifier les déficits d’inhibition retrouvés au sein du SGT, ainsi que les facteurs qui les modulent. Nous voulions également identifier les corrélats électrophysiologiques des capacités d’inhibition. Le deuxième volet concernait les processus de préparation et d’exécution des mouvements et leur lien avec la symptomatologie du SGT. Dans le troisième volet, nous avons investigué l’impact d’une thérapie cognitive-comportementale sur le fonctionnement cérébral des patients atteints du SGT. Nous avons tenté également d’identifier des prédicteurs du succès thérapeutique. Pour répondre à ces objectifs, nous avons d’abord réalisé une méta-analyse pour déterminer si les patients atteints du SGT présentaient des déficits d’inhibition et pour comprendre quels facteurs influençaient les capacités d’inhibition. À l’aide des potentiels évoqués, nous avons aussi évalué les corrélats électrophysiologiques des capacités d’inhibition (P300 No-Go) à l’aide d’une tâche de compatibilité stimulus-réponse qui incluait une composante No-Go. Nous avons aussi évalué les corrélats électrophysiologiques des processus de préparation et d’exécution motrice (sLRP et rLRP) durant cette même tâche. Finalement, nous avons investigué comment une thérapie cognitive-comportementale pouvait modifier l’activité du cerveau, à la fois durant la tâche de compatibilité stimulus-réponse (sLRP et rLRP) et durant une tâche oddball (P300; onde positive apparaissant environ 300 ms après la présentation d’un stimulus et associée à l’évaluation et à la catégorisation des stimuli). Nos résultats ont d’abord démontré que les patients atteints du SGT présentaient des déficits d’inhibition durant les tâches de Stroop, de complétion de phrases, de tracement de cercles, et la Continuous Performance Task. Toutefois, la performance durant les tâches de compatibilité stimulus-réponse et Go/No-Go était quant à elle normale. La présence d’un TDAH ainsi que des tics plus sévères étaient associés à des déficits d’inhibition plus importants. Notre étude électrophysiologique a révélé une P300 No-Go plus ample au niveau frontal chez les patients atteints du SGT, en comparaison avec des sujets sains. Ensuite, dans les conditions compatibles et incompatibles, les patients atteints du SGT ont présenté un délai relatif à l’amorce du sLRP ainsi qu’une plus grande amplitude du rLRP, suggérant ainsi un délai quant à la préparation des mouvements, ainsi qu’une plus grande activité des aires motrices du cerveau lors de l’exécution des mouvements. Cette activité s’est toutefois normalisée suite à la thérapie. La latence de l’amorce du sLRP incompatible combinée à l’amplitude de la N200 (onde négative apparaissant environ 200 ms après la présentation d’un stimulus et associée au contrôle cognitif) incompatible ont permis de prédire 43% de la variance associée à la diminution des tics après le traitement. Finalement, nous avons aussi observé que la thérapie permettait une normalisation de la P300 dans une tâche oddball, ce qui suggère que davantage de ressources cognitives sont désormais mobilisées dans les processus de mémoire de travail. Cette normalisation était localisée au niveau du cortex pariétal. Toutefois, l’activité cérébrale mesurée durant cette tâche ne permettait pas de prédire le succès thérapeutique. Nous avons donc démontré que les patients atteints du SGT présentaient un patron d’activité corticale différent de celui des participants contrôles, en lien avec les fonctions motrices et l’inhibition. Les changements relatifs à la symptomatologie du SGT induits par la thérapie cognitive-comportementale se reflètent aussi au niveau du fonctionnement cérébral des patients, où certaines modifications spécifiques peuvent être vues.Tourette syndrome (TS) is mainly characterized by the presence of motor and vocal tics. However, tics are just the tip of the iceberg for many patients. TS often comes with concomitant disorders, such as obsessive-compulsive disorder and attention deficit hyperactivity disorder. In addition, some neuropsychological studies have reported that TS patients show diminished inhibitory functions, which could be reflected in an incapacity to inhibit tics. However, no consensus has been reached on the matter of inhibitory functions in TS. Also, several hypotheses have been advanced to explain the generation of tics. Some studies that have identified overactivity of motor regions of the brain as a cause of tic generation. Here again, there is no definitive conclusion in the literature. While TS cannot be fully cured, several treatment options exist. These treatments have been shown to reduce tic severity. Pharmacotherapy is usually effective in most patients but is often accompanied by unwanted side effects. Cognitive-behavioral therapy was found to be an interesting treatment avenue since it does not cause physical side effects. Although its effectiveness has been demonstrated many times, its neural mechanisms are still poorly understood. The objective of this thesis was to give a better understanding of the cognitive functioning of TS patients and to investigate the neurofunctional substrates underlying these functions. We also wanted to evaluate the impact of a cognitive-behavioral therapy on these functions. This general objective was divided into three specific objectives. The first objective was to better understand inhibitory deficits found in TS. We also wanted to identify the electrophysiological correlates of inhibitory functions. The second objectives concerned movement preparation and execution processes, as well as the link between these processes and the symptomatology of TS. For the third objective, we investigated the impact of a cognitive-behavioral therapy on the brain function of TS patients and tried to identify predictors of treatment outcome. To this end, we first performed a meta-analysis of inhibitory functions in TS patients. This meta-analysis first aimed to determine if TS patients truly exhibited inhibitory deficits, and then to understand the factors influencing such deficits. Using event-related potentials, we also evaluated the electrophysiological correlates of inhibitory function (P300 No-Go) using a stimulus-response compatibility task that included a No-Go component. We also evaluated the electrophysiological correlates of motor preparation and execution processes (sLRP and rLRP) during the same task. Finally, we investigated how cognitive-behavioral therapy could alter brain activity, both during the stimulus-response compatibility task (sLRP and rLRP) and during an oddball task (P300; a positive wave peaking approximately 300 ms after stimuls onset and associated to stimulus evaluation and categorization). Our results first showed that TS patients had inhibitory deficits during the Stroop task, sentence completion paradigm, circle tracing task, and the Continuous Performance Task. The performance during the stimulus-response compatibility and Go/No-Go compatibility tasks was however normal. The concomitant presence of ADHD as well as more severe tics were associated with greater inhibitory deficits. Our electrophysiological study revealed a larger frontal No-Go P300 in TS patients. Then, in compatible and incompatible conditions, TS patients presented a delayed sLRP onset, as well as a larger rLRP peak. This suggests a delay in movement preparation, as well as an overactivation of motor areas during movement execution. These measures were however normalized following cognitive-behavioral therapy. The latency of the incompatible sLRP onset and the incompatible N200 (a negative wave peaking approximately 200 ms after stimuls onset and associated to cognitive control) amplitude predicted 43% of the variance associated with the decrease in tic severity after treatment. Finally, we also observed that the therapy allowed a normalization of the P300 in an oddball task, which suggests that more cognitive resources are now mobilized by working memory processes. This normalization was localized to the parietal cortex. However, brain activity measured during this task was not predictive of treatment outcome. With regards to motor function and inhibition, TS patients display a pattern of cortical activity that differs from that of control participants. Changes in the symptomatology of TS induced by cognitive-behavioral therapy are also reflected in the cerebral functioning of patients, where specific normalization in brain activity can be found

An analysis-ready and quality controlled resource for pediatric brain white-matter research

We created a set of resources to enable research based on openly-available diffusion MRI (dMRI) data from the Healthy Brain Network (HBN) study. First, we curated the HBN dMRI data (N = 2747) into the Brain Imaging Data Structure and preprocessed it according to best-practices, including denoising and correcting for motion effects, susceptibility-related distortions, and eddy currents. Preprocessed, analysis-ready data was made openly available. Data quality plays a key role in the analysis of dMRI. To optimize QC and scale it to this large dataset, we trained a neural network through the combination of a small data subset scored by experts and a larger set scored by community scientists. The network performs QC highly concordant with that of experts on a held out set (ROC-AUC = 0.947). A further analysis of the neural network demonstrates that it relies on image features with relevance to QC. Altogether, this work both delivers resources to advance transdiagnostic research in brain connectivity and pediatric mental health, and establishes a novel paradigm for automated QC of large datasets

Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract

Cataract is one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Mechanisms related to glucose toxicity, namely oxidative stress, processes of non-enzymatic glycation and enhanced polyol pathway significantly contribute to the development of eye lens opacity under conditions of diabetes. There is an urgent need for inexpensive, non-surgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in the prevention of cataract since flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of diabetic cataract. In the present paper, natural flavonoids are reviewed as potential agents that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification. In addition, the bioavailability of flavonoids for the lens is considered

A Review of the Neuropsychological Dimensions of Tourette Syndrome

Neurocognitive functioning in Tourette syndrome (TS) has been the subject of intensive research in the past 30 years. A variety of impairments, presumably related to frontal and frontostriatal dysfunctions, have been observed. These impairments were found in various domains, such as attention, memory, executive functions, language, motor and visuomotor functions, among others. In line with contemporary research, other neurocognitive domains have recently been explored in TS, bringing evidence of altered social reasoning, for instance. Therefore, the aims of this review are to give an overview of the neuropsychological dimensions of TS, to report how neuropsychological functions evolve from childhood to adulthood, and to explain how various confounding factors can affect TS patients’ performance in neuropsychological tasks. Finally, an important contribution of this review is to show how recent research has confirmed or changed our beliefs about neuropsychological functioning in TS

Glucocorticoid-induced leucine zipper (GILZ) regulates testicular FOXO1 activity and spermatogonial stem cell (SSC) function

Spermatogonia stem cell (SSC) self-renewal and differentiation are tightly regulated processes that ensure a continued production of mature sperm throughout male adulthood. In the present study, we investigated the role of glucocorticoid-induced leucine zipper (GILZ) in maintenance of the male germline and spermatogenesis. GILZ was detectable in germ cells of wild type mice on the day of birth, suggesting a role for GILZ in prospermatogonia and SSC pool formation. Gilz KO mice were generated and adult males were azoospermic and sterile. During the first wave of spermatogenesis in Gilz KO mice, spermatogenesis arrested part way through pachytene of meiosis I. Subsequent waves resulted in a progressive depletion of germ cells through apoptosis to ultimately produce a Sertoli cell-only phenotype. Further, in contrast to wild type littermates, PLZF(+) cells were detected in the peri-luminal region of Gilz KO mice at day 6 post-natal, suggesting a defect in prospermatogonia migration in the absence of GILZ. At age 30 days, transient accumulation of PLZF(+) cells in a subset of tubules and severely compromised spermatogenesis were observed in Gilz KO mice, consistent with defective SSC differentiation. GILZ deficiency was associated with an increase in FOXO1 transcriptional activity, which leads to activation of a selective set of FOXO1 target genes, including a pro-apoptotic protein, BIM. On the other hand, no evidence of a heightened immune response was observed. Together, these results suggest that GILZ suppresses FOXO1 nuclear translocation, promotes SSC differentiation over self-renewal, and favours germ cell survival through inhibition of BIM-dependent pro-apoptotic signals. These findings provide a mechanism for the effects of GILZ on spermatogenesis and strengthen the case for GILZ being a critical molecule in the regulation of male fertility

Macrophage Migration Inhibitory Factor Inhibits the Antiinflammatory Effects of Glucocorticoids via Glucocorticoid-Induced Leucine Zipper

Objective. Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid-induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF. Methods. GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function. Results. GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release. Conclusion. MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity