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.

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.

Deep brain stimulation of the subthalamic nucleus improves reward-based decision-learning in Parkinson's disease.

Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinson's disease (PD). We determined computational measures of outcome evaluation and reward prediction from PD patients who performed a probabilistic reward-based decision-learning task. In previous work, these measures covaried with activation in the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that stimulation of the STN motor regions in PD patients served to improve reward-based decision-learning, probably through its effect on activity in frontostriatal motor loops (prominently involving the putamen and, hence, reward prediction). In a subset of relatively younger patients with relatively shorter disease duration, the effects of DBS appeared to spread to more cognitive regions of the STN, benefiting loops that connect the caudate to various prefrontal areas importantfor outcome evaluation. These results highlight positive effects of STN stimulation on cognitive functions that may benefit PD patients in daily-life association-learning situations.

Genetic markers of striatal dopamine predict individual differences in dysfunctional, but not functional impulsivity.

Various psychiatric disorders are characterized by elevated levels of impulsivity. Although extensive evidence supports a specific role of striatal, but not frontal dopamine (DA) in human impulsivity, recent studies on genetic variability have raised some doubts on such a role. Importantly, impulsivity consists of two dissociable components that previous studies have failed to separate: functional and dysfunctional impulsivity. We compared participants with a genetic predisposition to have relatively high striatal DA levels (DAT1 9-repeat carriers, DRD2 C957T T/T homozygotes, and DRD4 7-repeat carriers) with participants with other genetic predispositions. We predicted that the first group would show high scores of dysfunctional, but not functional, self-reported impulsivity and greater difficulty in inhibiting a behavioral response to a stop-signal, a behavioral measure of impulsivity. In a sample of 130 healthy adults, we studied the relation between DAT1, DRD4, and C957T polymorphism at the DRD2 gene (polymorphisms related to striatal DA) and catechol-Omethyltransferase (COMT) Val158Met (a polymorphism related to frontal DA) on self-reported dysfunctional and functional impulsivity, assessed by the Dickman impulsivity inventory (DII), and the efficiency of inhibitory control, assessed by the stop-signal paradigm. DRD2 C957T T/T homozygotes and DRD4 7-repeat carriers indeed had significantly higher scores on self-reported dysfunctional, but not functional, impulsivity. T/T homozygotes were also less efficient in inhibiting prepotent responses. Our findings support the claim that dopaminergic variation affects dysfunctional impulsivity. This is in line with the notion that the over-supply of striatal DA might weaken inhibitory pathways, thereby enhancing the activation of, and the competition between responses.

Estrogen modulates inhibitory control in healthy human females: evidence from the stop-signal paradigm.

Animal studies point to a role of estrogen in explaining gender differences in striatal dopaminergic functioning, but evidence from human studies is still lacking. Given that dopamine is crucial for controlling and organizing goal-directed behavior, estrogen may have a specific impact on cognitive control functions, such as the inhibition of prepotent responses. We compared the efficiency of inhibitory control (as measured by the stop-signal task) in young women across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men. Women were less efficient in inhibiting prepotent responses in their follicular phase, which is associated with higher estradiol levels and with higher dopamine turnover rates, than in their luteal or menstruation phase. Likewise, women showed less efficient inhibitory control than men in their follicular phase but not in their luteal or menstruation phase. Our results are consistent with models assuming that the over-supply of striatal dopamine in the follicular phase weakens inhibitory pathways, thus leading to enhanced competition between responses. We conclude that gender differences in response inhibition are variable and state dependent but not structural.

The effect of speed-accuracy strategy on response interference control in Parkinson's disease.

Studies that used conflict paradigms such as the Eriksen Flanker task show that many individuals with Parkinson's disease (PD) have pronounced difficulty resolving the conflict that arises from the simultaneous activation of mutually exclusive responses. This finding fits well with contemporary views that postulate a key role for the basal ganglia in action selection. The present experiment aims to specify the cognitive processes that underlie action selection deficits among PD patients in the context of variations in speed-accuracy strategy. PD patients (n=28) and healthy controls (n=17) performed an arrow version of the flanker task under task instructions that either emphasized speed or accuracy of responses. Reaction time (RT) and accuracy rates decreased with speed compared to accuracy instructions, although to a lesser extent for the PD group. Differences in flanker interference effects among PD and healthy controls depended on speed-accuracy strategy. Compared to the healthy controls, PD patients showed larger flanker interference effects under speed stress. RT distribution analyses suggested that PD patients have greater difficulty suppressing incorrect response activation when pressing for speed. These initial findings point to an important interaction between strategic and computational aspects of interference control in accounting for cognitive impairments of PD. The results are also compatible with recent brain imaging studies that demonstrate basal ganglia activity to co-vary with speed-accuracy adjustments.

The effect of Parkinson's disease on interference control during action selection.

Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson's disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, due presumably to considerable inter-individual variability among PD patients. In an attempt to help resolve this controversy, we measured the performance of 50 PD patients and 25 healthy controls on an arrow version of the Eriksen flanker task in which participants were required to select a response based on the direction of a target arrow that was flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. Consistent with previous findings, reaction time (RT) increased with incongruent flankers compared to congruent or neutral flankers, and this cost of incongruence was greater among PD patients. Two novel findings are reported. First, distributional analyses, guided by dual-process models of conflict effects and the activation-suppression hypothesis, revealed that PD patients are less efficient at suppressing the activation of conflicting responses, even when matched to healthy controls on RT in a neutral condition. Second, this reduced efficiency was apparent in half of the PD patients, whereas the remaining patients were as efficient as healthy controls. These findings suggest that although poor suppression of conflicting responses is an important feature of PD, it is not evident in all medicated patients.