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

Diagnostic Capabilities of the Dichotic Listening in Clinical Research of Local Brain Damage

Статья ретрагирована по просьбе авторов 24.02.201

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

Is there a relation between novelty seeking, striatal dopamine release and frontal cortical thickness?

<div><p>Background</p><p>Novelty-seeking (NS) and impulsive personality traits have been proposed to reflect an interplay between fronto-cortical and limbic systems, including the limbic striatum (LS). Although neuroimaging studies have provided some evidence for this, most are comprised of small samples and many report surprisingly large effects given the challenges of trying to relate a snapshot of brain function or structure to an entity as complex as personality. The current work tested <i>a priori</i> hypotheses about associations between striatal dopamine (DA) release, cortical thickness (CT), and NS in a large sample of healthy adults.</p><p>Methods</p><p>Fifty-two healthy adults (45M/7F; age: 23.8±4.93) underwent two positron emission tomography scans with [¹¹C]raclopride (specific for striatal DA D_2/3 receptors) with or without amphetamine (0.3 mg/kg, p.o.). Structural magnetic resonance image scans were acquired, as were Tridimensional Personality Questionnaire data. Amphetamine-induced changes in [¹¹C]raclopride binding potential values (ΔBP_ND) were examined in the limbic, sensorimotor (SMS) and associative (AST) striatum. CT measures, adjusted for whole brain volume, were extracted from the dorsolateral sensorimotor and ventromedial/limbic cortices.</p><p>Results</p><p>BP_ND values were lower in the amphetamine <i>vs</i>. no-drug sessions, with the largest effect in the LS. When comparing low <i>vs</i>. high LS ΔBP_ND groups (median split), higher NS2 (impulsiveness) scores were found in the high ΔBP_ND group. Partial correlations (age and gender as covariates) yielded a negative relation between ASTS ΔBP_ND and sensorimotor CT; trends for inverse associations existed between ΔBP_ND values in other striatal regions and frontal CT. In other words, the greater the amphetamine-induced striatal DA response, the thinner the frontal cortex.</p><p>Conclusions</p><p>These data expand upon previously reported associations between striatal DA release in the LS and both NS related impulsiveness and CT in the largest sample reported to date. The findings add to the plausibility of these associations while suggesting that the effects are likely weaker than has been previously proposed.</p></div