Dopaminergic function in attention deficit hyperactivity disorder in relation to symptomatology, neurocognition and cortical structure

Converging evidence suggests a dysfunction in dopamine (DA) neurotransmission in attention deficit/hyperactivity disorder (ADHD). For example, DA genes are implicated in the etiology of ADHD, and DA augmenting agents, such as methylphenidate (MPH) and dextroamphetamine (d-AMPH) produce significant symptom improvement. In this dissertation, I examined the response of striatal DA to a d-AMPH challenge in treatment-naïve adults with ADHD and control participants, using positron emission tomography (PET) and the radioligand [11C]raclopride. I also examined the relationship between DA response and symptomatology, neurocognitive function, and neuroanatomy. The ADHD group showed greater d-AMPH induced striatal DA responses than controls. A quadratic U-shaped relationship was observed between the d-AMPH induced DA responses and self-reported hyperactivity across both groups, with the largest DA response in individuals reporting moderate levels of activity and smaller responses in both non-hyperactive and highly hyperactive individuals. Compared to Controls, ADHD participants performed more poorly on tests of response inhibition, showing longer inhibitory reaction times on the stop signal reaction time task, a higher error rate on the antisaccade task, and a higher error rate on a version of the go/ no-go task. Inhibitory performance on one measure of the antisaccade task, anticipatory saccades, was linearly related to DA release. Frontal cortical thickness did not differ significantly between ADHD and control participants. Cortical thickness was linearly related to striatal DA response but the direction of the association was opposite in the two groups. In the control group, thicker cortex was associated with smaller d-AMPH-induced DA increases while in the ADHD group thicker cortex was associated with larger d-AMPH-induced DA increases. The findings are consistent with a model of ADHD proposing abnormally low striatal DA tone coupled with an exaggerated phasic DA release (Grace, 2001). The greater d-AMPH induced increases in extracellular DA in the ADHD group likely reflect the exaggerated phasic component. Stimulant medications might acutely increase DA tone and diminish phasic reactivity. Since the most severely hyperactive patients had lower DA responses, the quadratic association may reflect a more rapid increase in DA tone accompanied by a down-modulation of phasic reactivity, effects that would be consistent with reports of the greatest clinical response to stimulants in the most symptomatic patients (Robbins & Sahakian, 1979; Buitelaar et al, 1995). The performance on neuropsychological tests is consistent with previous reports (Nigg, 2005) suggesting an important neurocognitive deficit in the area of inhibitory function. The divergent associations of frontal cortical thickness and d-AMPH induced DA release in the two groups may reflect differences in cortical developmental trajectories in Controls and ADHD participants (Shaw et al. 2007) or differences in cortico-striatal connectivity between the two groups.Plusieurs données semblent suggérer qu'un dérèglement du système dopaminergique pourrait être présent dans le trouble déficitaire d'attention avec hyperactivité (TDAH). Par exemple, les gènes liés au système dopaminergique sont impliqués dans l'étiologie du TDAH et des agents qui augmentent la neurotransmission dopaminergique, tels que le méthylphénidate (MPH) et la dextroamphétamine (d-AMPH), améliorent les symptômes du trouble. Dans la présente thèse, j'ai examiné la réactivité du système dopaminergique à une dose de d-AMPH chez des adultes présentant un TDAH et n'ayant jamais reçu de traitement comparé à un groupe témoin. J'ai également examiné la relation entre la réactivité du système dopaminergique et la symptomatologie, la fonction neurocognitive et la neuroanatomie. Le groupe TDAH a montré une plus grande augmentation de la réactivité du système de neurotransmission dopaminergique que le groupe témoin après une dose de d-AMPH. Une relation quadratique a pu être observée entre les réponses dopaminergiques induites par d-AMPH et les symptômes d'hyperactivité auto-rapportés dans les deux groupes. Les sujets déclarant des niveaux modérés d'activité avaient la plus grande réponse dopaminergique, tandis que les sujets non hyperactifs et les sujets très hyperactifs avaient la réponse moins prononcée. Les participants présentant un TDAH ont obtenu des performances moindres que ceux du groupe témoin dans les taches d'inhibition d'une réponse motrice, y compris la tâche de "signal-arret" (stop-signal), la tâche « antisaccade », et la tâche «go/ no-go». Il y avait une relation linéaire entre un aspect de la performance au niveau de l'inhibition – saccades anticipatifs – et la réactivité dopaminergique à d-AMPH. L'épaisseur du cortex frontal ne différait pas significativement entre les participants TDAH et le groupe témoin. Il y avait une relation linéaire entre l'épaisseur du cortex frontal et la réactivité du système dopaminergique, mais la direction de cette association était opposée dans les deux groupes. Dans le groupe témoin, une plus grande épaisseur du cortex frontal était associée à une réponse dopaminergique moins prononcée, tandis que dans le groupe TDAH, une plus grande épaisseur du cortex frontal était associée à une réponse dopaminergique plus prononcée. Les résultats sont cohérents avec le modèle proposant que le tonus dopaminergique dans le striatum soit diminué et que la libération phasique de la dopamine soit amplifiée chez les individus présentant un TDAH (Grace, 2001). L'administration aiguë des médicaments stimulants pourrait augmenter le tonus dopaminergique et diminuer la libération phasique de la dopamine. Étant donné que les patients les plus hyperactifs avaient la réponse dopaminergique moins prononcée à d-AMPH, la relation quadratique peut refléter une amplification plus rapide du tonus dopaminergique accompagnée par une diminution de réactivité phasique du système. Ces effets sont concordants avec les études ayant démontré une meilleure réponse clinique aux stimulants chez des patients les plus symptomatiques (Robbins & Sahakian, 1979; Buitelaar et al, 1995). De plus, les résultats des tests neuropsychologiques sont compatibles avec les études précédentes (Nigg, 2005), suggérant un déficit neurocognitif important au niveau de l'inhibition. Le fait que l'association entre l'épaisseur du cortex frontal et la réactivité du système dopaminergique soit inverse dans les deux groupes pourrait indiquer des différences dans les trajectoires de développement cortical chez les participants présentant un TDAH comparé aux participants témoins ou des différences dans la connectivité cortico-striatale entre les deux groupes

Do pupillary responses during authentic slot machine use reflect arousal or screen luminance fluctuations? A proof-of-concept study

Modern slot machines are among the more harmful forms of gambling. Psychophysiological measures may provide a window into mental processes that underpin these harms. Here we investigated pupil dilation derived from eye tracking as a means of capturing changes in sympathetic nervous system arousal following outcomes on a real slot machine. We hypothesized that positively reinforcing slot machine outcomes would be associated with increases in arousal, reflected in larger pupil diameter. We further examined the contribution of game luminance fluctuations on pupil diameter. In Experiment 1A, experienced slot machine gamblers (N = 53) played a commercially-available slot machine in a laboratory for 20 minutes while wearing mobile eye tracking glasses. Analyses differentiated loss outcomes, wins, losses-disguised-as-wins, and (free-spin) bonus features. Bonus features were associated with rapid increases in pupil diameter following the onset of outcome-related audiovisual feedback, relative to losses. In Experiment 1B, luminance data were extracted from captured screen videos (derived from Experiment 1A) to characterize on-screen luminance changes that could modulate pupil diameter. Bonus features and wins were associated with pronounced and complex fluctuations in screen luminance (≈50 L and ≈25L, respectively). However, the pupil dilation that was observed to bonus features in Experiment 1A coincided temporally with only negligible changes in screen luminance, providing partial evidence that the pupil dilation to bonus features may be due to arousal. In Experiment 2, 12 participants viewed pairs of stimuli (scrambled slot machine images) at luminance difference thresholds of ≈25L, ≈50L, and ≈100L. Scrambled images presented at luminance differences of ≈25L and greater were sufficient to cause pupillary responses. Overall, pupillometry may detect event-related changes in sympathetic nervous system arousal following gambling outcomes, but researchers must pay careful attention to substantial in-game luminance changes that may confound arousal-based interpretations

Terahertz spectroscopy of diabetic and non-diabetic human blood plasma pellets

Significance: The creation of fundamentally new approaches to storing various biomaterial and estimation parameters, without irreversible loss of any biomaterial, is a pressing challenge in clinical practice. We present a technology for studying samples of diabetic and non-diabetic human blood plasma in the terahertz (THz) frequency range. Aim: The main idea of our study is to propose a method for diagnosis and storing the samples of diabetic and non-diabetic human blood plasma and to study these samples in the THz frequency range. Approach: Venous blood from patients with type 2 diabetes mellitus and conditionally healthy participants was collected. To limit the impact of water in the THz spectra, lyophilization of liquid samples and their pressing into a pellet were performed. These pellets were analyzed using THz time-domain spectroscopy. The differentiation between the THz spectral data was conducted using multivariate statistics to classify non-diabetic and diabetic groups’ spectra. Results:We present the density-normalized absorption and refractive index for diabetic and nondiabetic pellets in the range 0.2 to 1.4 THz. Over the entire THz frequency range, the normalized index of refraction of diabetes pellets exceeds this indicator of non-diabetic pellet on average by 9% to 12%. The non-diabetic and diabetic groups of the THz spectra are spatially separated in the principal component space. Conclusion: We illustrate the potential ability in clinical medicine to construct a predictive rule by supervised learning algorithms after collecting enough experimental data

Enhancement of COPD biological networks using a web-based collaboration interface

The construction and application of biological network models is an approach that offers a holistic way to understand biological processes involved in disease. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease of the airways for which therapeutic options currently are limited after diagnosis, even in its earliest stage. COPD network models are important tools to better understand the biological components and processes underlying initial disease development. With the increasing amounts of literature that are now available, crowdsourcing approaches offer new forms of collaboration for researchers to review biological findings, which can be applied to the construction and verification of complex biological networks. We report the construction of 50 biological network models relevant to lung biology and early COPD using an integrative systems biology and collaborative crowd-verification approach. By combining traditional literature curation with a data-driven approach that predicts molecular activities from transcriptomics data, we constructed an initial COPD network model set based on a previously published non-diseased lung-relevant model set. The crowd was given the opportunity to enhance and refine the networks on a website (https://bionet.sbvimprover.com/) and to add mechanistic detail, as well as critically review existing evidence and evidence added by other users, so as to enhance the accuracy of the biological representation of the processes captured in the networks. Finally, scientists and experts in the field discussed and refined the networks during an in-person jamboree meeting. Here, we describe examples of the changes made to three of these networks: Neutrophil Signaling, Macrophage Signaling, and Th1-Th2 Signaling. We describe an innovative approach to biological network construction that combines literature and data mining and a crowdsourcing approach to generate a comprehensive set of COPD-relevant models that can be used to help understand the mechanisms related to lung pathobiology. Registered users of the website can freely browse and download the networks