To align the neuropsychological functioning of our adult euthymic patient group with that reported in previous studies on euthymic bipolar disorder (BD), we used a neuropsychological battery that examined sustained attention (Rapid Visual Information Processing Task), verbal memory (California Verbal Learning Task), executive functioning (Intradimensional-Extradimensional Shift Task, Barrett Impulsivity Task, and Framing Task), and emotion responsiveness/regulation (Positive Affect/Negative Affect Scales, Behavioral Inhibition/Behavioral Activation Scale, and Affective Lability/Affective Intensity Scales) in patients versus healthy volunteers (HV). Our results corroborated existing evidence of reduced sustained attention, impaired verbal memory and executive functioning, and abnormal emotional responsiveness and regulation in euthymic BD relative to healthy controls (Chapter 2). To investigate how abnormal development of brain function in BD leads to deficits in decision-making, motor inhibition, and response flexibility, we examined child and adult BD using a novel risky decision-making task, and used cross-sectional (age x diagnosis) functional magnetic resonance (fMRI) designs to examine neural activation associated with motor inhibition and response flexibility in BD relative to HV. During the risky decision-making task, adult euthymic BD patients were no different from healthy controls in their proportion of risky lottery choices over a range of competing lotteries. This matched behavioral performance was associated with similar prefrontal and striatal brain activation between the patient and control groups during response, anticipation, and outcome phases of decision-making (Chapter 3). These results are different from previous studies that have shown increased risk taking during decision-making in euthymic BD. Similarly, young BD patients were no different from age-matched healthy and patient controls in their pattern of decision making during the risky choice task. This was evidenced by a similar number of risky lottery selections over the range of changing expected values between the young BD group and control groups (Chapter 4). Using a cross-sectional, fMRI analytic design during the stop signal task, we found that child and adult BD showed similar behavioral performance to child and adult HV during motor inhibition. However, this matched behavioral performance was associated with abnormal neural activation in patients relative to controls. Specifically, during unsuccessful motor inhibition, there was an age group x diagnosis interaction, with BD youth showing reduced activity in left and right ACC compared to both age-matched HV and adult BD, and adult BD showing increased activation in left ACC compared to healthy adults. During successful motor inhibition there was a main effect of diagnosis, with HV showing greater activity in left VPFC and right NAc compared to BD (Chapter 5). These neuroimaging data support existing laboratory-based evidence of motor inhibition impairments in BD relative to HV, and indicate brain dysregulation during motor control is important to BD pathophysiology. A previous behavioral study showed impaired response flexibility in young BD patients relative to age-matched controls when using the change task. Here, we used the change task during fMRI to examine response flexibility in child and adult BD compared to child and adult HV. We found that patient and control groups showed similar change signal reaction times in response to change cues. However, this matched behavioral performance was associated with abnormal age group x diagnosis activations in brain regions important in signal detection, response conflict, response inhibition, and sustained attention. Specifically, during successful change trials, child BD participants showed frontal, parietal, and temporal hyperactivation relative to healthy children and adult BD, while adult BD showed hypoactivation in these regions relative to healthy adults. These novel fMRI findings during the change task indicate impaired neural activation during response flexibility may be important to the pathophysiology of BD development.

L'intégralité de ce projet a été réalisé à l'aide de logiciels sous licence libre. / Une évaluation du nombre de symptômes d'hyperactivité-impulsivité et d'inattention a été faite sur 277 jumeaux au moyen d'une entrevue semi-structurée administré aux parents, basée sur une échelle validée et communément admise, et une tâche de pointage a été demandée à chacun d'eux. La tâche de pointage a été effectuée avec chaque main successivement vers une cible dont la position à 135° ou à 45° était déterminée aléatoirement. Les tracés ont été classés en trois catégories selon le type de la première correction volontaire qu'ils présentaient sur leurs profils cinématiques : absence de correction, correction de position, correction dynamique. Ce projet veut caractériser la relation entre le taux de chaque type de correction et le nombre de symptômes de TDAH chez une population d'enfants ne répondant majoritairement pas à un diagnostic clinique de TDAH. Il a été montré que la présence de corrections de position était fréquemment corrélée à la présence de symptômes d'hyperactivité-impulsivité, mais pas, ou rarement, de symptômes d'inattention. D'autre part, il a été aussi remarqué que le taux de correction augmentait significativement lorsque le mouvement de pointage était effectué de la main gauche, sans égard à la dominance manuelle du sujet. Le premier résultat n'était pas attendu, étant donné la littérature relativement épaisse montrant un lien entre l'inattention et les problèmes de coordination motrice. Le second résultat, par contre, laisse entendre que la différenciation fonctionnelle hémisphérique d'un point de vue de contrôle attentionnel, ou de la motricité de la main gauche, serait affectée par le TDAH. / Symptoms linked to ADHD were assessed on 277 twins according to the commonly recognized dimensions formed by hyperactivity-impulsivity and inattention. A semi-structured interview administered to parents was used for the assessment. Subjects were asked to perform a pointing task. Left and right hands were tested in turn, and to reach a target placed either at 135° or 45°. Order of appearance was randomly determined. All traces were categorized according to the first voluntary correction as shown in their kinematic profiles : no correction, position correction, and dynamic correction. This project proposes to characterize the link between each correction type frequency and hyperactivity-impulsivity and inattention symptoms. The population studied was mostly subclinical and did not reach ADHD diagnosis criteria. Position corrections were shown to be correlated quite reliably to hyperactivity- impulsivity symptoms, but not to inattention symptoms. Deficits were most reliably linked with left hand use. The first result was unexpected considering abundant literature confirming the link between inattention and fine motor deficits, but the second one is more in line with a less exploited hypothesis stating that hemispherical functional differentiation related to control of the hand, or control of attention is affected by ADHD.

Une évaluation du nombre de symptômes d'hyperactivité-impulsivité et d'inattention a été faite sur 277 jumeaux au moyen d'une entrevue semi-structurée administré aux parents, basée sur une échelle validée et communément admise, et une tâche de pointage a été demandée à chacun d'eux. La tâche de pointage a été effectuée avec chaque main successivement vers une cible dont la position à 135° ou à 45° était déterminée aléatoirement. Les tracés ont été classés en trois catégories selon le type de la première correction volontaire qu'ils présentaient sur leurs profils cinématiques : absence de correction, correction de position, correction dynamique. Ce projet veut caractériser la relation entre le taux de chaque type de correction et le nombre de symptômes de TDAH chez une population d'enfants ne répondant majoritairement pas à un diagnostic clinique de TDAH. Il a été montré que la présence de corrections de position était fréquemment corrélée à la présence de symptômes d'hyperactivité-impulsivité, mais pas, ou rarement, de symptômes d'inattention. D'autre part, il a été aussi remarqué que le taux de correction augmentait significativement lorsque le mouvement de pointage était effectué de la main gauche, sans égard à la dominance manuelle du sujet. Le premier résultat n'était pas attendu, étant donné la littérature relativement épaisse montrant un lien entre l'inattention et les problèmes de coordination motrice. Le second résultat, par contre, laisse entendre que la différenciation fonctionnelle hémisphérique d'un point de vue de contrôle attentionnel, ou de la motricité de la main gauche, serait affectée par le TDAH. / Symptoms linked to ADHD were assessed on 277 twins according to the commonly recognized dimensions formed by hyperactivity-impulsivity and inattention. A semi-structured interview administered to parents was used for the assessment. Subjects were asked to perform a pointing task. Left and right hands were tested in turn, and to reach a target placed either at 135° or 45°. Order of appearance was randomly determined. All traces were categorized according to the first voluntary correction as shown in their kinematic profiles : no correction, position correction, and dynamic correction. This project proposes to characterize the link between each correction type frequency and hyperactivity-impulsivity and inattention symptoms. The population studied was mostly subclinical and did not reach ADHD diagnosis criteria. Position corrections were shown to be correlated quite reliably to hyperactivity- impulsivity symptoms, but not to inattention symptoms. Deficits were most reliably linked with left hand use. The first result was unexpected considering abundant literature confirming the link between inattention and fine motor deficits, but the second one is more in line with a less exploited hypothesis stating that hemispherical functional differentiation related to control of the hand, or control of attention is affected by ADHD. / L'intégralité de ce projet a été réalisé à l'aide de logiciels sous licence libre.

This PhD thesis investigated the role of the basal ganglia in memory and motor inhibition. Recent neuroimaging evidence suggests a supramodal network of inhibition involving the lateral prefrontal cortex. Here we examined whether this supramodal network also includes subcortical structures, such as the basal ganglia. Despite their well-established role in motor control, the basal ganglia are repeatedly activated but never interpreted during memory inhibition. We first used a series of meta-analyses to confirm the consistent involvement of the basal ganglia across studies using memory and motor inhibition tasks (including the Go/No-Go, Think/No-Think, and Stop-signal tasks), and discovered that there may be different subprocesses of inhibition. For instance, while the Go/No-Go task may require preventing a response from taking place, the Think/No-Think and Stop-signal tasks may require cancelling an emerging or ongoing response. We then conducted an fMRI study to examine how the basal ganglia interact with other putative supramodal regions (e.g., DLPFC) to achieve memory and motor inhibition during prevention and cancellation. Through dynamic causal modelling (DCM), we found that both DLPFC and basal ganglia play effective roles to achieve inhibition in the task-specific regions (hippocampus for memory inhibition; primary motor cortex (M1) for motor inhibition). Specifically, memory inhibition requires a DLPFC-basal ganglia-hippocampus pathway, whereas motor inhibition requires a basal ganglia-DLPFC-M1 pathway. We correlated DCM coupling parameters with behavioural indices to examine the relationship between network dynamics during prevention and cancellation and the successfulness of inhibition. However, due to constraints with DCM parameter estimates, caution is necessary when interpreting these results. Finally, we used diffusion weighted imaging to explore the anatomical connections supporting functions and behaviour. Unfortunately, we were unable to detect any white matter variability in relation to effective connectivity or behaviour during the prevention or cancellation processes of memory and motor inhibition at this stage. This PhD thesis provides essential INITIAL evidence that not only are the basal ganglia consistently involved in memory and motor inhibition, but these structures are effectively engaged in these tasks, achieving inhibition through task-specific pathways. We will discuss our findings, interpretations, and future directions in the relevant chapters.