The role of dopamine in action control: Insights from medication effects in Parkinson's disease.

Parkinson's disease (PD) is a neurological disorder associated primarily with overt motor symptoms. Several studies show that PD is additionally accompanied by impairments in covert cognitive processes underlying goal-directed motor functioning (e.g., action planning, conflict adaptation, inhibition), and that dopaminergic medication may modulate these action control components. In this review we aim to leverage findings from studies in this domain to elucidate the role of dopamine (DA) in action control. A qualitative review of studies that investigated the effects of medication status (on vs. off) on action control in PD suggests a component-specific role for DA in action control, although the expression of medication effects depends on characteristics of both the patients and experimental tasks used to measure action control. We discuss these results in the light of findings from other research lines examining the role of DA in action control (e.g., animal research, pharmacology), and recommend that future studies use multi-method, within-subject approaches to model DA effects on action control across different components as well as underlying striatal pathways (ventral vs. dorsal).

Focused stimulation of dorsal subthalamic nucleus improves reactive inhibitory control of action impulses.

Frontal-basal ganglia circuitry dysfunction caused by Parkinson's disease impairs important executive cognitive processes, such as the ability to inhibit impulsive action tendencies. Subthalamic Nucleus Deep Brain Stimulation in Parkinson's disease improves the reactive inhibition of impulsive actions that interfere with goal-directed behavior. An unresolved question is whether this effect depends on stimulation of a particular Subthalamic Nucleus subregion. The current study aimed to 1) replicate previous findings and additionally investigate the effect of chronic versus acute Subthalamic Nucleus stimulation on inhibitory control in Parkinson's disease patients off dopaminergic medication 2) test whether stimulating Subthalamic Nucleus subregions differentially modulate proactive response control and the proficiency of reactive inhibitory control. In the first experiment, twelve Parkinson's disease patients completed three sessions of the Simon task, Off Deep brain stimulation and medication, on acute Deep Brain Stimulation and on chronic Deep Brain Stimulation. Experiment 2 consisted of 11 Parkinson's disease patients with Subthalamic Nucleus Deep Brain Stimulation (off medication) who completed two testing sessions involving of a Simon task either with stimulation of the dorsal or the ventral contact in the Subthalamic Nucleus. Our findings show that Deep Brain Stimulation improves reactive inhibitory control, regardless of medication and regardless of whether it concerns chronic or acute Subthalamic Nucleus stimulation. More importantly, selective stimulation of dorsal and ventral subregions of the Subthalamic Nucleus indicates that especially the dorsal Subthalamic Nucleus circuitries are crucial for modulating the reactive inhibitory control of motor actions.

Dopamine and temporal attention: An attentional blink study in Parkinson's disease patients on and off medication.

The current study aimed to shed more light on the role of dopamine in temporal attention. To this end, we pharmacologically manipulated dopamine levels in a large sample of Parkinson's disease patients (n=63) while they performed an attentional blink (AB) task in which they had to identify two targets (T1 and T2) presented in close temporal proximity among distractors. We specifically examined 1) differences in the magnitude of the AB between unmedicated Parkinson patients, who have depleted levels of striatal dopamine, and healthy controls, and 2) effects of two dopaminergic medications (l-DOPA and dopamine agonists) on the AB in the Parkinson patients at the group level and as a function of individual baseline performance. In line with the notion that relatively low levels of striatal dopamine may impair target detection in general, Parkinson patients OFF medications displayed overall poor target perception compared to healthy controls. Moreover, as predicted, effects of dopaminergic medication on AB performance critically depended on individual baseline AB size, although this effect was only observed for l-DOPA. l-DOPA generally decreased the size of the AB in patients with a large baseline AB (i.e., OFF medications), while l-DOPA generally increased the AB in patients with a small baseline AB. These findings may support a role for dopamine in the AB and temporal attention, more generally and corroborate the notion that there is an optimum dopamine level for cognitive function. They also emphasize the need for more studies that examine the separate effects of DA agonists and l-DOPA on cognitive functioning.

Easy to learn, hard to suppress: The impact of learned stimulus-outcome associations on subsequent action control.

The inhibition of impulsive response tendencies that conflict with goal-directed action is a key component of executive control. An emerging literature reveals that the proficiency of inhibitory control is modulated by expected or unexpected opportunities to earn reward or avoid punishment. However, less is known about how inhibitory control is impacted by the processing of task-irrelevant stimulus information that has been associated previously with particular outcomes (reward or punishment) or response tendencies (action or inaction). We hypothesized that stimulus features associated with particular action-valence tendencies, even though task irrelevant, would modulate inhibitory control processes. Participants first learned associations between stimulus features (color), actions, and outcomes using an action-valence learning task that orthogonalizes action (action, inaction) and valence (reward, punishment). Next, these stimulus features were embedded in a Simon task as a task-irrelevant stimulus attribute. We analyzed the effects of action-valence associations on the Simon task by means of distributional analysis to reveal the temporal dynamics. Learning patterns replicated previously reported biases; inherent, Pavlovian-like mappings (action-reward, inaction-punishment avoidance) were easier to learn than mappings conflicting with these biases (action-punishment avoidance, inaction-reward). More importantly, results from two experiments demonstrated that the easier to learn, Pavlovian-like action-valence associations interfered with the proficiency of inhibiting impulsive actions in the Simon task. Processing conflicting associations led to more proficient inhibitory control of impulsive actions, similar to Simon trials without any association. Fast impulsive errors were reduced for trials associated with punishment in comparison to reward trials or trials without any valence association. These findings provide insight into the temporal dynamics of task irrelevant information associated with action and valence modulating cognitive control. We discuss putative mechanisms that might explain these interactions.

Speed pressure in conflict situations impedes inhibitory action control in Parkinson's disease.

The current study investigated the effects of Parkinson's disease (PD) on the ability to resolve conflicts when performance emphasized speed vs. response accuracy. PD patients and healthy controls (HC) completed a Simon task, and a subset of participants provided movement-related potential (MRP) data to investigate motor cortex activation and inhibition associated with conflict resolution. Both groups adjusted performance strategically with speed or accuracy instructions. The groups experienced similar susceptibility to making fast errors in conflict trials, but PD patients were less proficient compared to HC at suppressing incorrect responses, especially under speed pressure. Analysis of MRPs showed attenuated inhibition of the motor cortex controlling the conflicting response in PD patients compared to HC. These results confirm the detrimental effects of PD on inhibitory control mechanisms with speed pressure and also suggest that a downstream effect of inhibitory dysfunction in PD might be due to diminished inhibition of the motor cortex.

Effect of beta and gamma neurofeedback on memory and intelligence in the elderly.

Recent research showed a correlation between cognitive decline and a decrease of EEG gamma activity. In the present double-blind randomized control study, we investigated whether gamma and beta neurofeedback protocols, that have been shown to modulate performance on cognitive control and memory in young adults, also leads to increased brain activity and cognitive performance in elderly. Twenty older adults either performed eight 30-min gamma neurofeedback session or beta neurofeedback session within a period of 21 days. Cognitive performance was determined before and after the training through an IQ and memory task and we added a subjective well-being questionnaire. Both neurofeedback training protocols resulted in a significant increase of the brain activity within each training session, suggesting that the aging brain is still trainable. However, we found no effects on cognitive performance or transfer of the feedback beyond the trainings. We discuss several possible reasons for the lack of training on rest measurements and cognition and ways to improve the feedback protocols for future studies.

Dose dependent dopaminergic modulation of reward-based learning in Parkinson's disease.

Learning to select optimal behavior in new and uncertain situations is a crucial aspect of living and requires the ability to quickly associate stimuli with actions that lead to rewarding outcomes. Mathematical models of reinforcement-based learning to select rewarding actions distinguish between (1) the formation of stimulus-action-reward associations, such that, at the instant a specific stimulus is presented, it activates a specific action, based on the expectation that that particular action will likely incur reward (or avoid punishment); and (2) the comparison of predicted and actual outcomes to determine whether the specific stimulus-action association yielded the intended outcome or needs revision. Animal electrophysiology and human fMRI studies converge on the notion that dissociable neural circuitries centered on the striatum are differentially involved in different components of this learning process. The modulatory role of dopamine (DA) in these respective circuits and component processes is of particular relevance to the study of reward-based learning in patients diagnosed with Parkinson's disease (PD). Here we show that the first component process, learning to predict which actions yield reward (supported by the anterior putamen and associated motor circuitry) is impaired when PD patients are taken off their DA medication, whereas DA medication has no systematic effects on the second processes, outcome evaluation (supported by caudate and ventral striatum and associated frontal circuitries). However, the effects of DA medication on these processes depend on dosage, with larger daily doses leading to a decrease in predictability of stimulus-action-reward relations and increase in reward-prediction errors.

Validation of the CALUX bioassay for PCDD/F analyses in human blood plasma and comparison with GC-HRMS.

Following the dioxin crisis of 1999, several studies were conducted to assess the impact of this crisis on the dioxin body burden in the Belgian population. The Scientific Institute of Public Health identified a population from whom plasma samples were available and from whom, during the follow up survey, plasma samples were obtained in 2000. In total, 496 samples were collected for GC-HRMS and CALUX analyses to verify statistical assessment conclusions. This study was seen as an opportunity to validate the CALUX bioassay for biological sample analysis and to compare toxic equivalency (TEQ) values obtained by the reference GC-HRMS technique and by the screening method. This article focuses on the validation results of the CALUX bioassay for the analyses of the dioxin fractions of blood plasma. The sample preparation is based on a liquid-liquid extraction, followed by an acid silica in series with an activated carbon clean-up. A good recovery (82%) and reproducibility (coefficient of variation less than 25%) were found for this method. Based on 341 plasma samples, a significant correlation was established between the bioassay and chemical method (R = 0.64). However, a proportional systematic error was observed when the results obtained with the CALUX bioassay were regressed with the results from the GC-HRMS analyses. The limit of quantification (LOQ) used to calculate TEQ values from the GC-HRMS determinations, the use of the relative potency values instead of the toxic equivalent factor and the potential of CALUX bioassay to measure all compounds with affinity for the AhR may partly explain this proportional systematic error. Nevertheless, the present results suggest that the CALUX bioassay could be a promising valid screening method for human blood plasma analyses.

Importance of clean-up for comparison of TEQ-values obtained by CALUX and chemo-analysis.

This paper presents Chemically Activated LUciferine gene eXpression (CALUX) TEQ-values obtained for nine plasma samples following two different purification procedures, one of them involving fractionation. CALUX results obtained for the dioxin (DX) and dioxin + PCB (DX + PCB) fractions were then compared to the GC-HRMS TEQ-values calculated for the 17 polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (17 PCDD/F) and 17 PCDD/F + 4 cPCB congeners, respectively. The overestimation of the CALUX (DX fraction) TEQ-values in comparison with the chemo-analyses of the 17 PCDD/F is mainly explained by the presence of other AhR agonists, like brominated compounds. Otherwise, the constancy of the CALUX (DX + PCB fraction) TEQ-value which compares to increasing the GC-HRMS (17 PCDD/F + 4 cPCB) TEQ results raises questions concerning (1) the significance of CALUX results obtained without fractionation as well as (2) the toxicological effect of a cocktail of contaminants on the human health.

TEQ-value determinations of animal feed; emphasis on the CALUX bioassay validation.

Polyhalogenated aromatic hydrocarbons, such as polychlorinated dibenzo-p-dioxins are a large and diverse group of environmental pollutants. Their tendency to accumulate in the food chain and their toxicity make monitoring necessary. The reference analysis method is laborious and very expensive, therefore cheap and rapid bioassays have been developed. The chemical-activated luciferase bioassay (CALUX) bioassay uses a recombinant cell line, which responds to dioxins and dioxin-like molecules with Ah receptor (AhR)-dependent induction of firefly luciferase in a dose related response. The CALUX was tested for its use in the screening of feed. Aliquots of 20g of enriched feed were extracted with a toluene:methanol mixture (20:4 v/v) and extracts were defatted on 33% H(2)SO(4) silica columns and purified on carbon columns. Only the dioxin and furan fraction was analysed, the PCB fraction was discarded. The precision of the method is acceptable and in compliance with an R.S.D. <30% as suggested for cell-based bioassays in the Commission Directive 2002/70/EC of July 2002. The results evidence good agreement between TEQ-values obtained by either CALUX or GC-HRMS. The method is now routinely in use for a feed screening programme designed by the Federal Agency for the Safety of the Food chain. Approximately, 25 samples are analysed weekly. From the obtained results approximately 10% was confirmed by GC-HRMS. The false positive ratio is 1% and no false negatives were found, making the use of the CALUX technology advantageous.