The effect of dopaminergic medication on conflict adaptation in Parkinson's disease

Parkinson's disease (PD) is a neurological disorder associated primarily with motor symptoms such as tremor, slowness of movement, and difficulties with gait and balance. Most patients take dopaminergic medication to improve their motor functions. Previous studies reported indications that such medication can impair higher cognitive functions (cf. dopamine overdose hypothesis). In the present study, we examined the effect of medication status on conflict adaptation. PD patients performed a Stroop task in which we manipulated the proportion of congruent and incongruent items, thereby allowing us to explore conflict adaptation. The use of mouse movements allowed us to examine the action dynamics of conflict adaptation in PD, and their sensitivity to dopaminergic medication. Each patient performed the same task twice: once without making changes to their regular medication regime, and once after overnight withdrawal from their medication. Results showed that medication improved mouse movements and alleviated motor symptoms. Moreover, patients' mouse movements were modulated as a function of the proportion congruency manipulation, revealing conflict adaptation in PD, which was unaffected by medication status. The present study extends earlier work on conflict adaptation in PD where reduced transient (trial-by-trial) conflict adaptation was observed ON compared to OFF medication (Duthoo et al., 2013, Neuropsychology, 27, 556). Our findings suggest that more sustained cognitive control processes may not be sensitive to dopamine overdose effects.     

Impact of Parkinson’s disease and dopaminergic medication on adaptation to explicit and implicit visuomotor perturbations

The capacity to learn new visuomotor associations is fundamental to adaptive motor behavior. Evidence suggests visuomotor learning deficits in Parkinson’s disease (PD). However, the exact nature of these deficits and the ability of dopamine medication to improve them are under-explored. Previous studies suggested that learning driven by large and small movement errors engaged distinct neural mechanisms. Here, we investigated whether PD patients have a generalized impairment in visuomotor learning or selective deficits in learning from large explicit errors which engages cognitive strategies or small imperceptible movement errors involving primarily implicit learning processes. Visuomotor learning skills of non-medicated and medicated patients were assessed in two reaching tasks in which the size of visuospatial errors experienced during learning was manipulated using a novel three-dimensional virtual reality environment. In the explicit perturbation task, the visuomotor perturbation was applied suddenly resulting in large consciously detected initial spatial errors, whereas in the implicit perturbation task, the perturbation was gradually introduced in small undetectable steps such that subjects never experienced large movement errors. A major finding of this study was that PD patients in non-medicated and medicated conditions displayed slower learning rates and smaller adaptation magnitudes than healthy subjects in the explicit perturbation task, but performance similar to healthy controls in the implicit perturbation task. Also, non-medicated patients showed an average reduced deadaptation relative to healthy controls when exposed to the large errors produced by the sudden removal of the perturbation in both the explicit and implicit perturbation tasks. Although dopaminergic medication consistently improved motor signs, it produced a variable impact on learning the explicit perturbation and deadaptation and unexpectedly worsened performance in some patients. Considered together, these results indicate that PD selectively impairs the ability to learn from large consciously detected visuospatial errors. This finding suggests that basal ganglia-related circuits are important neural structures for adaptation to sudden perturbations requiring awareness and high-cost action selection. Dopaminergic treatment may selectively compromise the ability to learn from large explicit movement errors for reasons that remain to be elucidated.     

Dopaminergic medication alters auditory distractor processing in Parkinson's disease

Parkinson's disease (PD) patients show signs of cognitive impairment, such as executive dysfunction, working memory problems and attentional disturbances, even in the early stages of the disease. Though motor symptoms of the disease are often successfully addressed by dopaminergic medication, it still remains unclear, how dopaminergic therapy affects cognitive function. The main objective of this study was to assess the effect of dopaminergic medication on visual and auditory attentional processing. 14 PD patients and 13 matched healthy controls performed a three-stimulus auditory and visual oddball task while their EEG was recorded. The patients performed the task twice, once on- and once off-medication. While the results showed no significant differences between PD patients and controls, they did reveal a significant increase in P3 amplitude on- vs. off-medication specific to processing of auditory distractors and no other stimuli. These results indicate significant effect of dopaminergic therapy on processing of distracting auditory stimuli. With a lack of between group differences the effect could reflect either 1) improved recruitment of attentional resources to auditory distractors; 2) reduced ability for cognitive inhibition of auditory distractors; 3) increased response to distractor stimuli resulting in impaired cognitive performance; or 4) hindered ability to discriminate between auditory distractors and targets. Further studies are needed to differentiate between these possibilities.     

Dopaminergic and cholinergic modulations of visual-spatial attention and working memory: insights from molecular genetic research and implications for adult cognitive development

Attention and working memory are fundamental for selecting and maintaining behaviorally relevant information. Not only do both processes closely intertwine at the cognitive level, but they implicate similar functional brain circuitries, namely the frontoparietal and the frontostriatal networks, which are innervated by cholinergic and dopaminergic pathways. Here we review the literature on cholinergic and dopaminergic modulations of visual-spatial attention and visual working memory processes to gain insights on aging-related changes in these processes. Some extant findings have suggested that the cholinergic system plays a role in the orienting of attention to enable the detection and discrimination of visual information, whereas the dopaminergic system has mainly been associated with working memory processes such as updating and stabilizing representations. However, since visual-spatial attention and working memory processes are not fully dissociable, there is also evidence of interacting cholinergic and dopaminergic modulations of both processes. We further review gene-cognition association studies that have shown that individual differences in visual-spatial attention and visual working memory are associated with acetylcholine- and dopamine-relevant genes. The efficiency of these 2 transmitter systems declines substantially during healthy aging. These declines, in part, contribute to age-related deficits in attention and working memory functions. We report novel data showing an effect of dopamine COMT gene on spatial updating processes in older but not in younger adults, indicating potential magnification of genetic effects in old age.     

Effort responses to suboptimal reward cues are related to striatal dopaminergic functioning

Reward cues have been found to increase the investment of effort in tasks even when cues are presented suboptimally (i.e. very briefly), making them hard to consciously detect. Such effort responses to suboptimal reward cues are assumed to rely mainly on the mesolimbic dopamine system, including the ventral striatum. To provide further support for this assumption, we performed two studies investigating whether these effort responses vary with individual differences in markers of striatal dopaminergic functioning. Study 1 investigated the relation between physical effort responses and resting state eye-blink rate. Study 2 examined cognitive effort responses in relation to individually averaged error-related negativity. In both studies effort responses correlated with the markers only for suboptimal, but not for optimal reward cues. These findings provide further support for the idea that effort responses to suboptimal reward cues are mainly linked to the mesolimbic dopamine system, while responses to optimal reward cues also depend on higher-level cortical functions.     

Revisiting the effects of Parkinson's disease and frontal lobe lesions on task switching: The role of rule reconfiguration

This study investigated the hypothesis that rule reconfiguration in task switching can isolate aspects of intact and impaired control at different stages of Parkinson's disease (PD) by comparing switches between concrete naming rules pertaining to stimulus selection, to switches between abstract rules which allocate categorization responses to these stimuli. Based on previous findings, it was hypothesized that attentional switches, where task set competition emerges at the stimulus but not response set level, highlights striatal dopaminergic function. Conversely, increasing the degree of task set competition to encompass reconfiguration of response set when switching between abstract rules, represents a condition which engages the prefrontal cortex (PFC) and renders this manipulation sensitive to frontal damage. To this end, we investigated task switching with concrete and abstract rules in unilaterally (Hoehn & Yahr stage I) and bilaterally (Hoehn & Yahr stage II) affected PD patients, as well as striatally intact frontal lesion patients. As predicted, frontal lesion patients demonstrated switching deficits only with abstract categorization rules, where switching engendered complete task set reconfiguration and a new response, as did stage II PD patients with presumed frontal cortical pathology. Replicating previous findings, stage I PD patients with relatively circumscribed striatal pathology demonstrated no such impairment. Disease severity also impacted on attentional switching indexed by naming rules, since medicated stage II but not stage I patients demonstrated switching deficits emerging from stimulus set reconfiguration, suggesting that the ameliorative efficacy of dopaminergic medication is inversely related to the severity of the striatal deficit. These findings illustrate that the nature of the rules that are switched, and its implication in terms of reconfiguring different task set elements, highlights different neural characters of cognitive flexibility. These manipulations may help decipher the differential effects of progressive neurodegeneration on parkinsonian cognition, and provide a framework in which to conceptualize the contributions of cortical and subcortical regions to cognitive control.     

Trait Extraversion and Dopamine Function

An influential theory within personality neuroscience suggests that trait extraversion is underpinned by individual differences in dopamine function. In a review of the relevant literature, we evaluate this theory in light of the evidence from molecular genetics, neuroimaging, and psychopharmacology. Evidence linking individual differences in extraversion with dopamine‐relevant genes, structural volume of dopamine‐rich brain regions (e.g., in striatal and ventral prefrontal areas), dopamine receptor availability, and frontal alpha asymmetry is mixed at best. Evidence concerning both scalp recorded (electroencephalogram) and hemodynamic (functional magnetic resonance imaging) neural responses to rewards appears somewhat more promising. Perhaps the best evidence concerns extraversion‐dependent responses – both neural and behavioural – to dopaminergic drugs. Future research in this area must go beyond the demonstration of theoretically consistent associations and attempt to provide more specific causal evidence for the dopamine hypothesis of extraversion. A further challenge is to expand this hypothesis to incorporate other neurobiological processes that are likely to underlie this trait.     

Individual Differences in the Context‐Dependent Recruitment of Cognitive Control: Evidence From Action Versus State Orientation

The ability to flexibly adapt to deviations from optimal performance is an important aspect of self‐control. In the present study, the authors present first evidence that the personality trait action versus state orientation (Kuhl, 2000) modulates the ability of adaptive control adjustments in response to experienced conflicts. Sixty‐two German individuals with extreme scores on the action‐state dimension performed a response interference task, that is, 31 extreme action‐oriented individuals (30 females; M_age = 20.35 years) and 31 extreme state‐oriented individuals (20 females; M_age = 23.23 years), respectively. Action‐oriented individuals displayed a stronger conflict adaptation effect as evidenced by a stronger reduction of interference on trials following conflict. These results were further corroborated by a correlational analysis including a sample of 105 participants: the higher the score on the action‐state dimension, the lower the interference effect following conflict (i.e., stronger conflict adaptation). The results provide evidence that even low‐level, bottom‐up‐driven processes of self‐control such as conflict adaptation are systematically moderated by individual differences in control modes and provide insights into the cognitive mechanisms underlying action versus state orientation.     

Executive function in Parkinson’s disease: contributions of the dorsal frontostriatal pathways to action and motivation

Disruption of the dorsal frontostriatal pathways in Parkinson’s disease (PD) is associated with impairments in motivation, as well as in executive function. The goal of this study was to investigate whether these impairments are related and, if so, whether the disruption of frontostriatal pathways compromises the ability to process the motivational aspects of feedback in such tasks. In Experiment 1, informative feedback improved the performance of young, healthy participants in a task-switching paradigm. This task-switching paradigm was then used in Experiment 2 to test whether feedback would improve the performance of 17 PD patients and age-matched controls. The PD group benefitted from feedback to the same degree as control participants; however, depression scores on the Beck Depression Inventory were significantly related to feedback usage, especially when response selection demands were high. Regardless of feedback, PD patients were more impaired when response demands were high than in an equally difficult condition with low action demands. These results suggest that response selection is a core impairment of insufficient dopamine to the dorsal frontal striatal pathways.     

Individual differences in cognitive-flexibility: the influence of spontaneous eyeblink rate, trait psychoticism and working memory on attentional set-shifting

Individual differences in psychophysiological function have been shown to influence the balance between flexibility and distractibility during attentional set-shifting [e.g., Dreisbach et al. (2005). Dopamine and cognitive control: The influence of spontaneous eyeblink rate and dopamine gene polymorphisms on perseveration and distractibility. Behavioral Neuroscience, 119(2), 483-490]. Here we replicate both the facilitatory and detrimental influence of spontaneous eyeblink rate upon switch costs across the two distinct conditions of a set-shifting task. We extend this by presenting additional, putatively dopamine related, individual differences that also influence attentional control. Whereas trait psychoticism showed a pattern of effects opposite to that of eyeblink rate, greater working memory served to decrease switch costs across both conditions. These results highlight the need for further exploration of the role of dopaminergic neurotransmission and component processes involved in such attentional paradigms, and illustrates the importance of considering individual differences in cognitive control.     

The effects of clinical motor variables and medication dosage on working memory in Parkinson’s disease

In this study, we investigate the interrelationship between clinical variables and working memory (WM) in Parkinson’s disease (PD). Specifically, the aim of the study was to investigate the relationship between disease duration, dopaminergic medication dosage, and motor disability (UPDRS score) with WM in individuals with PD. Accordingly, we recruited three groups of subjects: unmedicated PD patients, medicated PD patients, and healthy controls. All subjects were tested on three WM tasks: short-delay WM, long-delay WM, and the n-back task. Further, PD encompasses a spectrum that can be classified either into akinesia/rigidity or resting tremor as the predominant motor presentation of the disease. In addition to studying medication effects, we tested WM performance in tremor-dominant and akinesia-dominant patients. We further correlated WM performance with disease duration and medication dosage. We found no difference between medicated and unmedicated patients in the short-delay WM task, but medicated patients outperformed unmedicated patients in the long-delay WM and n-back tasks. Interestingly, we also found that akinesia-dominant patients were more impaired than tremor-dominant patients at various WM measures, which is in agreement with prior studies of the relationship between akinesia symptom and basal ganglia dysfunction. Moreover, the results show that disease duration inversely correlates with more demanding WM tasks (long-delay WM and n-back tasks), but medication dosage positively correlates with demanding WM performance. In sum, our results show that WM impairment in PD patients depend on cognitive domain (simple vs. demanding WM task), subtype of PD patients (tremor- vs. akinesia-dominant), as well as disease duration and medication dosage. Our results have implications for the interrelationship between motor and cognitive processes in PD, and for understanding the role of cognitive training in treating motor symptoms in PD.     

Dopaminergic modulation of prospective memory in Parkinson's disease

Growing interest is present in literature on the study of prospective memory functioning in Parkinson's disease (PD). Current data indicate that prospective memory may be impaired in PD and a relationship with general executive dysfunctioning has been suggested. However, although the dopamine dependency of cognitive dysfunction in PD has been widely investigated, poor is known on the dopaminergic modulation of PM. In the present study we explored the effect of acute administration of levodopa on the performance of a PD sample (n=20) in a time-based prospective memory task. PD patients were evaluated in the morning after a 12-hour therapy wash-out in two experimental conditions: i) after levodopa assumption ("on"); ii) without drug administration ("off"). The experimental task required to execute three uncorrelated actions after 10' for three consecutive trials. Distinct scores for the spontaneous recall of the intention to perform the actions (prospective component) and for the correct execution of the actions (retrospective component) have been computed. Results showed that in the "off" condition PD patients were selectively impaired on the prospective component of the task. However, L-dopa administration significantly improved PD patients' performance actually restoring the prospective memory deficit. These results support a critical role of dopaminergic modulation in prospective memory processes in PD patients, possibly through the replacement of dopamine levels in fronto-striatal pathways.     

Both Risk and Reward are Processed Differently in Decisions Made Under Stress

Years of research show that stress influences cognition. Most of this research has focused on how stress affects memory and the hippocampus. However, stress impacts other regions involved in cognitive and emotional processing, including the prefrontal cortex, striatum, and insula. New research examining how stress affects decision processes reveals two consistent findings. First, acute stress enhances selection of previously rewarding outcomes but impairs selection of previously negative outcomes, possibly due to stress-induced changes in dopamine in reward-processing brain regions. Second, stress amplifies gender differences in strategies during risky decisions, with males taking more risk and females less risk under stress. These gender differences in behavior are associated with differences in activity in the insula and dorsal striatum, brain regions involved in computing risk and preparing to take action.     

Basal ganglia, dopamine and temporal processing: performance on three timing tasks on and off medication in Parkinson's disease

A pervasive hypothesis in the timing literature is that temporal processing in the milliseconds and seconds range engages the basal ganglia and is modulated by dopamine. This hypothesis was investigated by testing 12 patients with Parkinson's disease (PD), both 'on' and 'off' dopaminergic medication, and 20 healthy controls on three timing tasks. In a seconds range (30-120 s) time production task, patients tested 'on' medication showed a significantly different accuracy profile compared to controls and when tested 'off' medication. However, no group or on vs off medication differences in accuracy were found on a time reproduction task and a warned reaction time task requiring temporal processing within the 250-2000 ms range. Variability was measured using the coefficient of variation, with the performance of the patient group on the time reproduction task violating the scalar property, suggesting atypical temporal processing mechanisms. The data suggest that the integrity of the basal ganglia is necessary for 'typical' time production in the seconds range as well as for time reproduction at shorter intervals. Exploratory factor analysis suggested that the time production task uses neural mechanisms distinct from those used in the other two timing tasks. The dissociation of the effects of dopaminergic medication and nature of task on performance in PD raises interesting questions about the pharmacological mediation and task-specificity of deficits in temporal processing.     

Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging

Recent brain imaging studies in Huntington's disease (HD) and normal aging suggest a relationship between central dopaminergic neurotransmission and cognitive performance. Results demonstrate substantial losses in dopamine (DA) function in both HD and aging. Moreover, HD patients and older adults show deficits across multiple cognitive domains, including episodic memory, speed of processing, and executive functioning. Although few studies are available at present, there is converging evidence that multiple measures of pre- and postsynaptic DA biochemistry are (a) highly interrelated, and (b) strongly associated with the cognitive deficits that accompany HD and aging. There is also emerging evidence that DA neurotransmission influences cognitive performance independent of HD or age. In general, the research reviewed in this article indicates that the nigrostriatal DA system is an important component of a frontostriatal circuitry that is critically involved in cognitive functioning.     

Cognitive Differences Between Patients with Left-sided and Right-sided Parkinson’s Disease. A Review

At disease onset, patients with Parkinson’s disease (PD) typically report one side of the body to be more affected than the other. Previous studies have reported that this motor symptom asymmetry is associated with asymmetric dopaminergic degeneration in the brain. Research on the cognitive repercussions of this asymmetric degeneration has yielded inconsistent results. Here, we review studies that reported on the cognitive performance of patients with left-sided (LPD) or right-sided (RPD) motor symptom predominance. We present evidence that patients with RPD typically experience problems with language-related tasks and verbal memory, whereas patients with LPD more often perform worse on tasks of spatial attention, visuospatial orienting and memory and mental imagery. In general, no differences were found between both groups on tasks measuring attention and executive function. The association between motor asymmetry and cognitive performance indicates that PD does not lead to one typical cognitive profile. The effect of symptom laterality on the cognitive complaints should be considered in the assessment and treatment of each individual patient.     

Dynamic adjustments of cognitive control during economic decision making

Decision making in the Ultimatum game requires the resolution of conflicts between economic self-interest and fairness intuitions. Since cognitive control processes play an important role in conflict resolution, the present study examined how control processes that are triggered by conflicts between fairness and self-interest in unfair offers affect subsequent decisions in the Ultimatum game. Our results revealed that more unfair offers were accepted following previously unfair, compared to previously fair offers. Interestingly, the magnitude of this conflict adaptation effect correlated with the individual subjects' focus on economic self-interest. We concluded that conflicts between fairness and self-interest trigger cognitive control processes, which reinforce the focus on the current task goal.     

Dopamine,depressive symptoms,and decision-making: the relationship between spontaneous eye blink rate and depressive symptoms predicts Iowa Gambling Task performance

Depressive symptomatology has been associated with alterations in decision-making, although conclusions have been mixed, with depressed individuals showing impairments in some contexts but advantages in others. The dopaminergic system may link depressive symptoms with decision-making performance. We assessed the role of striatal dopamine D₂ receptor density, using spontaneous eye blink rates, in moderating the relationship between depressive symptoms and decision-making performance in a large undergraduate sample that had not been screened for mental illness (N?=?104). The regression results revealed that eye blink rate moderated the relationship between depressive symptoms and advantageous decisions on the Iowa Gambling Task, in which individuals with more depressive symptomatology and high blink rates (higher striatal dopamine D₂ receptor density) performed better on the task. Our computational modeling results demonstrated that depressive symptoms alone were associated with enhanced loss-aversive behavior, whereas individuals with high blink rates and elevated depressive symptoms tended to persevere in selecting options that led to net gains (avoiding options with net losses). These findings suggest that variation in striatal dopamine D₂ receptor availability in individuals with depressive symptoms may contribute to differences in decision-making behavior.     

Parkinsonian speech disfluencies: effects of L-dopa-related fluctuations

The excess dopamine theory of stuttering (Wu et al., 1997) contends that stuttering may be related to excess levels of the neurotransmitter dopamine in the brain. As Parkinson's disease (PD) patients commonly exhibit changes in dopamine levels accompanied by changes in motor performance, the present study examined disfluency in PD patients to gain information on the role of dopamine in speech disfluencies. Nine PD patients with no history of developmental stuttering were recorded once before and twice after taking their morning medication (on separate days). They read a passage and produced a monologue. Within-word and overall speech disfluencies were calculated at each recording. Through motor testing, it was inferred that participants had relatively low dopamine levels before taking medication, and relatively high dopamine levels after taking medication. There were no group changes in disfluency levels when the low-dopamine and high-dopamine states were compared. There were, however, significant differences in percent disfluencies between the PD participants and age-matched controls. The results of this study do not strongly support the excess dopamine theory of stuttering. Rather, the disfluency changes exhibited by individual participants support a hypothesis that speech disfluencies may be related to increases or decreases in dopamine levels in the brain. EDUCATIONAL OBJECTIVES: The reader will learn about: (1). the characteristics of disfluent speech exhibited by speakers with Parkinson's disease. (2). The effect of L-dopa based medications on disfluencies of Parkinsonian speakers. (3). The complex role brain dopamine levels may play in disfluent speaking behavior.     

Self-unawareness of levodopa induced dyskinesias in patients with Parkinson’s disease

The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson’s disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon.PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to assess the executive functions of the prefrontal-ventral-striatal circuitry.Data showed that a reduction of self-awareness using the Dyskinesia rating scale was associated with global monitoring (p = .04), monitoring resolution (p = .04) and control sensitivity (p = .04). Patients failed to perceive their performance, distinguish between correct and incorrect sorts, be confident in their choice and consequently decide to gamble during the task.We did not find any association with executive functions using the hypo-bradykinesia rating scale.Our findings indicate that when the comparator mechanism for monitoring attentive performance is compromised at a prefrontal striatal level, patients lose the ability to recognize their motor disturbances that do not achieve conscious awareness.