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.

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.

Dopaminergic modulation of the updating of stimulus-response episodes in Parkinson's disease.

Increasing evidence suggests that the control of retrieval of episodic feature bindings is modulated by the striatal dopaminergic pathway. The present study investigated whether this may reflect a contribution from the ventral or the dorsal part of the striatum. Along the lines of the overdose hypothesis in Parkinson's disease (PD), functions known to rely on the dorsal striatum are enhanced with dopaminergic medication, while operations relying on the ventral circuitry are impaired. We found that partial mismatches between present and previous stimulus-response relations are, compared to control participants, abnormally low OFF DA medication and normalized ON DA medication. The results suggest that the dorsal striatum, but not (or not so much) the ventral striatum, is driving the flexible control of retrieval of stimulus-response episodes.

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.

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.

Inefficient response inhibition in individuals with mild cognitive impairment.

Individuals diagnosed with mild cognitive impairment (MCI) show primary deficits in memory and are at increased risk for developing Alzheimer's disease (AD). In light of recent evidence that executive cognitive deficits are common in AD and may be detectable in individuals diagnosed with MCI, we extend these findings to the investigation of response inhibition, an essential aspect of executive cognitive control. Twenty MCI patients and 20 healthy controls (HC) completed an arrow version of the flanker task [Eriksen, B. A., & Eriksen, C. W. (1974). Effects of noise letters upon the identification of target letters in a non-search task. Perception & Psychophysics, 16, 143-149] in which participants responded to a target arrow surrounded by distractors (i.e., flankers) that signaled a same (congruent) or a conflicting (incongruent) response. Reaction time (RT) increased in both groups when flankers signaled an incongruent response, but more so among MCI patients. MCI patients taking a cholinesterase inhibitor showed smaller flanker interference effects than those not taking this medication. Analysis of the flanker effect as a function of the entire RT distribution indicated that MCI patients show increasing interference at the slowest segments of the distribution, a finding that implicates deficient inhibition of the incongruent response [Ridderinkhof, K. R. (2002). Activation and suppression in conflict tasks: Empirical clarification through distributional analyses. In W. Prinz & B. Hommel (Eds.), Common mechanisms in perception and action. Attention & performance, Vol. XIX (pp. 494-519). Oxford: Oxford University Press]. These results suggest that deficits in response inhibition are detectable in MCI patients and merit further investigation as to whether these changes aid prediction of which MCI patients convert to AD.

On-line anosognosia: unawareness for chorea in real time but not on videotape delay.

In hemiplegics, anosognosia (unawareness of deficit) rests on a mismatch between expected and actual movement: a feedback hypothesis emphasizes sensory deficits or neglect, a feedforward hypothesis postulates impaired intention to move. Anosognosia for other problems is less studied. The authors report a man without sensory deficits who was unaware of choreiform movements, except on videotape delay. The authors believe that a feed-forward mechanism underlies his "on-line" unawareness.

Influence of Competing Distractors on Response Selection in Huntington's Disease and Parkinson's Disease.

Current theories of the basal ganglia suggest a functional role in filtering stimuli that are competing for response selection. We hypothesised that damage to the basal ganglia, as occurs in Huntington's disease (HD) and Parkinson's disease (PD), may alter the effects of distractors on this filtering process. Fourteen HD subjects, 16 PD subjects, and age-matched healthy controls performed an ignored repetition test of negative priming. Negative priming was defined as a significant time cost in responding to a target that shared features with the distractor from the previous trial. Results indicated that whereas healthy controls and PD subjects showed normal negative priming, HD subjects failed to show negative priming. The results indicate that disruption to cells in the neostriatum, but not necessarily to cells in the substantia nigra, may affect selective attention by altering the influence of distractor stimuli competing for action.

Is the age-complexity effect mediated by reductions in a general processing resource?

The rate of information processing, as revealed in measures of reaction time, slows with advancing age and this slowing is most evident as processing complexity increases. This phenomenon, known as the Age-Complexity effect, has been attributed to general changes in the speed of processing that affect all components of processing indiscriminantly, both within and across tasks in a particular processing domain. That the slowing is thought to be task- and process-independent has led to the additional inference that it reflects reductions in a general processing resource. On the basis of converging evidence identified in a review of both behavioral and chronopsychophysiological studies, we argue that the slowing induced by older age is not generalized, but rather is both task-dependent and process-specific and, as such, cannot be explained in terms of a diminished general processing resource. We close by speculating that elements of the age-induced slowing can be interpreted within the context of the cognitive-energetical model.