Boosting Serotonin Increases Information Gathering by Reducing Subjective Cognitive Costs.

Serotonin is implicated in the valuation of aversive costs, such as delay or physical effort. However, its role in governing sensitivity to cognitive effort, for example, deliberation costs during information gathering, is unclear. We show that treatment with a serotonergic antidepressant in healthy human individuals of either sex enhances a willingness to gather information when trying to maximize reward. Using computational modeling, we show this arises from a diminished sensitivity to subjective deliberation costs during the sampling process. This result is consistent with the notion that serotonin alleviates sensitivity to aversive costs in a domain-general fashion, with implications for its potential contribution to a positive impact on motivational deficits in psychiatric disorders.SIGNIFICANCE STATEMENT Gathering information about the world is essential for successfully navigating it. However, sampling information is costly, and we need to balance between gathering too little and too much information. The neurocomputational mechanisms underlying this arbitration between a putative gain, such as reward, and the associated costs, such as allocation of cognitive resources, remain unclear. In this study, we show that week-long daily treatment with a serotonergic antidepressant enhances a willingness to gather information when trying to maximize reward. Computational modeling indicates this arises from a reduced perception of aversive costs, rendering information gathering less cognitively effortful. This finding points to a candidate mechanism by which serotonergic treatment might help alleviate motivational deficits in a range of mental illnesses.

Acute ischaemic stroke alters the brain's preference for distinct dynamic connectivity states.

Acute ischaemic stroke disturbs healthy brain organization, prompting subsequent plasticity and reorganization to compensate for the loss of specialized neural tissue and function. Static resting state functional MRI studies have already furthered our understanding of cerebral reorganization by estimating stroke-induced changes in network connectivity aggregated over the duration of several minutes. In this study, we used dynamic resting state functional MRI analyses to increase temporal resolution to seconds and explore transient configurations of motor network connectivity in acute stroke. To this end, we collected resting state functional MRI data of 31 patients with acute ischaemic stroke and 17 age-matched healthy control subjects. Stroke patients presented with moderate to severe hand motor deficits. By estimating dynamic functional connectivity within a sliding window framework, we identified three distinct connectivity configurations of motor-related networks. Motor networks were organized into three regional domains, i.e. a cortical, subcortical and cerebellar domain. The dynamic connectivity patterns of stroke patients diverged from those of healthy controls depending on the severity of the initial motor impairment. Moderately affected patients (n = 18) spent significantly more time in a weakly connected configuration that was characterized by low levels of connectivity, both locally as well as between distant regions. In contrast, severely affected patients (n = 13) showed a significant preference for transitions into a spatially segregated connectivity configuration. This configuration featured particularly high levels of local connectivity within the three regional domains as well as anti-correlated connectivity between distant networks across domains. A third connectivity configuration represented an intermediate connectivity pattern compared to the preceding two, and predominantly encompassed decreased interhemispheric connectivity between cortical motor networks independent of individual deficit severity. Alterations within this third configuration thus closely resembled previously reported ones originating from static resting state functional MRI studies post-stroke. In summary, acute ischaemic stroke not only prompted changes in connectivity between distinct networks, but it also caused characteristic changes in temporal properties of large-scale network interactions depending on the severity of the individual deficit. These findings offer new vistas on the dynamic neural mechanisms underlying acute neurological symptoms, cortical reorganization and treatment effects in stroke patients.

Age affects the contribution of ipsilateral brain regions to movement kinematics.

Healthy aging is accompanied by changes in brain activation patterns in the motor system. In older subjects, unilateral hand movements typically rely on increased recruitment of ipsilateral frontoparietal areas. While the two central concepts of aging-related brain activity changes, "Hemispheric Asymmetry Reduction in Older Adults" (HAROLD), and "Posterior to Anterior Shift in Aging" (PASA), have initially been suggested in the context of cognitive tasks and were attributed to compensation, current knowledge regarding the functional significance of increased motor system activity remains scarce. We, therefore, used online interference transcranial magnetic stimulation in young and older subjects to investigate the role of key regions of the ipsilateral frontoparietal cortex, that is, (a) primary motor cortex (M1), (b) dorsal premotor cortex (dPMC), and (c) anterior intraparietal sulcus (IPS) in the control of hand movements of different motor demands. Our data suggest a change of the functional roles of ipsilateral brain areas in healthy age with a reduced relevance of ipsilateral M1 and a shift of importance toward dPMC for repetitive high-frequency movements. These results support the notion that mechanisms conceptualized in the models of "PASA" and "HAROLD" also apply to the motor system.

A computational account of threat-related attentional bias.

Visual selective attention acts as a filter on perceptual information, facilitating learning and inference about important events in an agent's environment. A role for visual attention in reward-based decisions has previously been demonstrated, but it remains unclear how visual attention is recruited during aversive learning, particularly when learning about multiple stimuli concurrently. This question is of particular importance in psychopathology, where enhanced attention to threat is a putative feature of pathological anxiety. Using an aversive reversal learning task that required subjects to learn, and exploit, predictions about multiple stimuli, we show that the allocation of visual attention is influenced significantly by aversive value but not by uncertainty. Moreover, this relationship is bidirectional in that attention biases value updates for attended stimuli, resulting in heightened value estimates. Our findings have implications for understanding biased attention in psychopathology and support a role for learning in the expression of threat-related attentional biases in anxiety.

Functional Connectivity Changes of Key Regions for Motor Initiation in Parkinson's Disease.

Akinesia, a cardinal symptom of Parkinson's disease, has been linked to abnormal activation in putamen and posterior medial frontal cortex (pMFC). However, little is known whether clinical severity of akinesia is linked to dysfunctional connectivity of these regions. Using a seed-based approach, we here investigated resting-state functional connectivity (RSFC) of putamen, pMFC and primary motor cortex (M1) in 60 patients with Parkinson's disease on regular medication and 72 healthy controls. We found that in patients putamen featured decreases of connectivity for a number of cortical and subcortical areas engaged in sensorimotor and cognitive processing. In contrast, the pMFC showed reduced connectivity with a more focal cortical network involved in higher-level motor-cognition. Finally, M1 featured a selective disruption of connectivity in a network specifically connected with M1. Correlating clinical impairment with connectivity changes revealed a relationship between akinesia and reduced RSFC between pMFC and left intraparietal lobule (IPL). Together, the present study demonstrated RSFC decreases in networks for motor initiation and execution in Parkinson's disease. Moreover, results suggest a relationship between pMFC-IPL decoupling and the manifestation of akinetic symptoms.

Modulation of I-wave generating pathways by theta-burst stimulation: a model of plasticity induction.

KEY POINTS: Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of transcranial magnetic stimulation applied to primary motor cortex (M1) at different coil orientations. We found an association between late I-wave recruitment [reflected by anterior-posterior (AP)-lateromedial (LM) latency; i.e. the excess latency of motor-evoked potentials generated by transcranial magnetic stimulation with an AP orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using LM stimulation] and changes in cortical excitability following iTBS, confirming previous studies. AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. Plasticity in the motor network may in part derive from a modulation of excitability and the recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and the underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor-evoked potentials elicited by transcranial magnetic stimulation with an anterior-posterior (AP) orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using lateromedial (LM) stimulation, referred to as the 'AP-LM latency' difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. In 20 healthy subjects, we investigated whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced AP-LM latency, and that this reduction significantly correlated with changes in cortical excitability observed following iTBS: subjects with larger reductions in AP-LM latencies featured larger increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating pathways may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel repetitive transcranial magnetic stimulation protocols.

Functional Connectivity Differences of the Subthalamic Nucleus Related to Parkinson's Disease.

A typical feature of Parkinson's disease (PD) is pathological activity in the subthalamic nucleus (STN). Here, we tested whether in patients with PD under dopaminergic treatment functional connectivity of the STN differs from healthy controls (HC) and whether some brain regions show (anti-) correlations between functional connectivity with STN and motor symptoms. We used functional magnetic resonance imaging to investigate whole-brain resting-state functional connectivity with STN in 54 patients with PD and 55 HC matched for age, gender, and within-scanner motion. Compared to HC, we found attenuated negative STN-coupling with Crus I of the right cerebellum and with right ventromedial prefrontal regions in patients with PD. Furthermore, we observed enhanced negative STN-coupling with bilateral intraparietal sulcus/superior parietal cortex, right sensorimotor, right premotor, and left visual cortex compared to HC. Finally, we found a decline in positive STN-coupling with the left insula related to severity of motor symptoms and a decline of inter-hemispheric functional connectivity between left and right STN with progression of PD-related motor symptoms. Motor symptom related uncoupling of the insula, a key region in the saliency network and for executive function, from the STN might be associated with well-known executive dysfunction in PD. Moreover, uncoupling between insula and STN might also induce an insufficient setting of thresholds for the discrimination between relevant and irrelevant salient environmental stimuli, explaining observations of disturbed response control in PD. In sum, motor symptoms in PD are associated with a reduced coupling between STN and a key region for executive function.

Dopaminergic modulation of motor network dynamics in Parkinson's disease.

Although characteristic motor symptoms of Parkinson's disease such as bradykinesia typically improve under dopaminergic medication, deficits in higher motor control are less responsive. We here investigated the dopaminergic modulation of network dynamics underlying basic motor performance, i.e. finger tapping, and higher motor control, i.e. internally and externally cued movement preparation and selection. Twelve patients, assessed ON and OFF medication, and 12 age-matched healthy subjects underwent functional magnetic resonance imaging. Dynamic causal modelling was used to assess effective connectivity in a motor network comprising cortical and subcortical regions. In particular, we investigated whether impairments in basic and higher motor control, and the effects induced by dopaminergic treatment are due to connectivity changes in (i) the mesial premotor loop comprising the supplementary motor area; (ii) the lateral premotor loop comprising lateral premotor cortex; and (iii) cortico-subcortical interactions. At the behavioural level, we observed a marked slowing of movement preparation and selection when patients were internally as opposed to externally cued. Preserved performance during external cueing was associated with enhanced connectivity between prefrontal cortex and lateral premotor cortex OFF medication, compatible with a context-dependent compensatory role of the lateral premotor loop in the hypodopaminergic state. Dopaminergic medication significantly improved finger tapping speed in patients, which correlated with a drug-induced coupling increase of prefrontal cortex with the supplementary motor area, i.e. the mesial premotor loop. In addition, only in the finger tapping condition, patients ON medication showed enhanced excitatory influences exerted by cortical premotor regions and the thalamus upon the putamen. In conclusion, the amelioration of bradykinesia by dopaminergic medication seems to be driven by enhanced connectivity within the mesial premotor loop and cortico-striatal interactions. In contrast, medication did not improve internal motor control deficits concurrent to missing effects at the connectivity level. This differential effect of dopaminergic medication on the network dynamics underlying motor control provides new insights into the clinical finding that in Parkinson's disease dopaminergic drugs especially impact on bradykinesia but less on executive functions.

Network connectivity and individual responses to brain stimulation in the human motor system.

The mechanisms driving cortical plasticity in response to brain stimulation are still incompletely understood. We here explored whether neural activity and connectivity in the motor system relate to the magnitude of cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Twelve right-handed volunteers underwent functional magnetic resonance imaging during rest and while performing a simple hand motor task. Resting-state functional connectivity, task-induced activation, and task-related effective connectivity were assessed for a network of key motor areas. We then investigated the effects of intermittent theta-burst stimulation (iTBS) on motor-evoked potentials (MEP) for up to 25 min after stimulation over left primary motor cortex (M1) or parieto-occipital vertex (for control). ITBS-induced increases in MEP amplitudes correlated negatively with movement-related fMRI activity in left M1. Control iTBS had no effect on M1 excitability. Subjects with better response to M1-iTBS featured stronger preinterventional effective connectivity between left premotor areas and left M1. In contrast, resting-state connectivity did not predict iTBS aftereffects. Plasticity-related changes in M1 following brain stimulation seem to depend not only on local factors but also on interconnected brain regions. Predominantly activity-dependent properties of the cortical motor system are indicative of excitability changes following induction of cortical plasticity with rTMS.

Serotonin modulates asymmetric learning from reward and punishment in healthy human volunteers.

Instrumental learning is driven by a history of outcome success and failure. Here, we examined the impact of serotonin on learning from positive and negative outcomes. Healthy human volunteers were assessed twice, once after acute (single-dose), and once after prolonged (week-long) daily administration of the SSRI citalopram or placebo. Using computational modelling, we show that prolonged boosting of serotonin enhances learning from punishment and reduces learning from reward. This valence-dependent learning asymmetry increases subjects' tendency to avoid actions as a function of cumulative failure without leading to detrimental, or advantageous, outcomes. By contrast, no significant modulation of learning was observed following acute SSRI administration. However, differences between the effects of acute and prolonged administration were not significant. Overall, these findings may help explain how serotonergic agents impact on mood disorders.

Dopamine enhances model-free credit assignment through boosting of retrospective model-based inference.

Dopamine is implicated in representing model-free (MF) reward prediction errors a as well as influencing model-based (MB) credit assignment and choice. Putative cooperative interactions between MB and MF systems include a guidance of MF credit assignment by MB inference. Here, we used a double-blind, placebo-controlled, within-subjects design to test an hypothesis that enhancing dopamine levels boosts the guidance of MF credit assignment by MB inference. In line with this, we found that levodopa enhanced guidance of MF credit assignment by MB inference, without impacting MF and MB influences directly. This drug effect correlated negatively with a dopamine-dependent change in purely MB credit assignment, possibly reflecting a trade-off between these two MB components of behavioural control. Our findings of a dopamine boost in MB inference guidance of MF learning highlight a novel DA influence on MB-MF cooperative interactions.

Human complex exploration strategies are enriched by noradrenaline-modulated heuristics.

An exploration-exploitation trade-off, the arbitration between sampling a lesser-known against a known rich option, is thought to be solved using computationally demanding exploration algorithms. Given known limitations in human cognitive resources, we hypothesised the presence of additional cheaper strategies. We examined for such heuristics in choice behaviour where we show this involves a value-free random exploration, that ignores all prior knowledge, and a novelty exploration that targets novel options alone. In a double-blind, placebo-controlled drug study, assessing contributions of dopamine (400 mg amisulpride) and noradrenaline (40 mg propranolol), we show that value-free random exploration is attenuated under the influence of propranolol, but not under amisulpride. Our findings demonstrate that humans deploy distinct computationally cheap exploration strategies and that value-free random exploration is under noradrenergic control.

A mechanistic account of serotonin's impact on mood.

Selective serotonin reuptake inhibitors (SSRIs) constitute a first-line antidepressant intervention, though the precise cognitive and computational mechanisms that explain treatment response remain elusive. Using week-long SSRI treatment in healthy volunteer participants, we show serotonin enhances the impact of experimentally induced positive affect on learning of novel, and reconsolidation of previously learned, reward associations. Computational modelling indicated these effects are best accounted for by a boost in subjective reward perception during learning, following a positive, but not negative, mood induction. Thus, instead of influencing affect or reward sensitivity directly, SSRIs might amplify an interaction between the two, giving rise to a delayed mood response. We suggest this modulation of affect-learning dynamics may explain the evolution of a gradual mood improvement seen with these agents and provides a novel candidate mechanism for the unfolding of serotonin's antidepressant effects over time.

Distinct Processing of Aversive Experience in Amygdala Subregions.

BACKGROUND: The amygdala is an anatomically complex medial temporal brain structure whose subregions are considered to serve distinct functions. However, their precise role in mediating human aversive experience remains ill understood. METHODS: We used functional magnetic resonance imaging in 39 healthy volunteers with varying levels of trait anxiety to assess distinct contributions of the basolateral amygdala (BLA) and centromedial amygdala to anticipation and experience of aversive events. Additionally, we examined the relationship between any identified functional subspecialization and measures of subjective reported aversion and trait anxiety. RESULTS: Our results show that the centromedial amygdala is responsive to aversive outcomes but insensitive to predictive aversive cues. In contrast, the BLA encodes an aversive prediction error that quantifies whether cues and outcomes are worse than expected. A neural representation within the BLA for distinct threat levels was mirrored in self-reported subjective anxiety across individuals. Furthermore, high trait-anxious individuals were characterized by indiscriminately heightened BLA activity in response to aversive cues, regardless of actual threat level. CONCLUSIONS: Our results demonstrate that amygdala subregions are distinctly engaged in processing of aversive experience, with elevated and undifferentiated BLA responses to threat emerging as a potential neurobiological mediator of vulnerability to anxiety disorders.

The role of dopamine in dynamic effort-reward integration.

When deciding to act, the neurotransmitter dopamine is implicated in a valuation of prospective effort and reward. However, its role in dynamic effort-reward integration during action, a process central to everyday behaviour, remains unclear. In a placebo-controlled, within-subject, study, we probed the impact of increasing brain dopamine levels (150 mg of levodopa) and blocking dopamine receptors (1.5 mg of haloperidol) in the context of a novel dynamic effort task in healthy human subjects. We show that modulating homoeostatic dopamine balance distinctly alters implicit and explicit effort allocation as a function of instantaneous reward. Pharmacologically boosting dopamine enhanced motor vigour, reflected in an implicit increase in effort allocation for high rewards. Conversely, pharmacological blockade of dopamine attenuated sensitivity to differences in reward context, reflected in reduced strategic effort discounting. These findings implicate dopamine in an integration of momentary physical experience and instantaneous reward, suggesting a key role of dopamine in acting to maximise reward on the fly.

The role of the hippocampus in weighting expectations during inference under uncertainty.

Making inference under uncertainty requires an optimal weighting of prior expectations and observations. How this weighting is realized in the brain remains elusive. To investigate this, we recorded functional neuroimaging data while participants estimated a number based on noisy observations. Crucially, the prior expectation about the variability of observations (an expected variability) was manipulated. Consistent with normative models, when novel observations were characterized by higher expected or observed variability, participants' estimates relied more on expectations than novel observations and were characterized by higher stochasticity. Activity in hippocampus increased when novel evidence was characterized by higher expected or observed variability. Response in superior parietal cortex reflected a precision-weighted prediction error signal (i.e., the distance between observations and expectations) that was modulated by hippocampal activity. Our findings implicate the hippocampus during inference under uncertainty, suggesting a role in weighting prior representations over observations and in modulating responsivity of superior parietal cortex to prediction error.

Being on Target: Visual Information during Writing Affects Effective Connectivity in Parkinson's Disease.

A common motor symptom of Parkinson's disease (PD) is micrographia, characterized by a decrease in writing amplitude. Despite the relevance of this impairment for activities of daily living, the underlying neural network abnormalities and the impact of cueing strategies on brain connectivity are unknown. Therefore, we investigated the effects of visual cues on visuomotor network interactions during handwriting in PD and healthy controls (HCs). Twenty-eight patients with early disease, ON dopaminergic medication, and 14 age-matched controls performed a pre-writing task with and without visual cues in the scanner. Patients displayed weaker right visuo-parietal coupling than controls, suggesting impaired visuomotor integration during writing. Surprisingly, cueing did not have the expected positive effects on writing performance. Patients and controls, however, did activate similar networks during cued and uncued writing. During cued writing, the stronger influence of both visual and motor areas on the left superior parietal lobe suggested that visual cueing induced greater visual steering. In the absence of cues, there was enhanced coupling between parietal and supplementary motor areas (SMA) in line with previous findings in HCs during uncued motor tasks. In conclusion, the present study showed that patients with PD, despite their compromised brain function, were able to shift neural networks similar to controls. However, it seemed that visual cues provided a greater accuracy constraint on handwriting rather than offering unequivocal beneficial effects. Altogether, the results suggest that the effectiveness of using compensatory neural networks through applying external stimuli is task dependent and may compromise motor control during writing.

Training for Micrographia Alters Neural Connectivity in Parkinson's Disease.

Despite recent advances in clarifying the neural networks underlying rehabilitation in Parkinson's disease (PD), the impact of prolonged motor learning interventions on brain connectivity in people with PD is currently unknown. Therefore, the objective of this study was to compare cortical network changes after 6 weeks of visually cued handwriting training (= experimental) with a placebo intervention to address micrographia, a common problem in PD. Twenty seven early Parkinson's patients on dopaminergic medication performed a pre-writing task in both the presence and absence of visual cues during behavioral tests and during fMRI. Subsequently, patients were randomized to the experimental (N = 13) or placebo intervention (N = 14) both lasting 6 weeks, after which they underwent the same testing procedure. We used dynamic causal modeling to compare the neural network dynamics in both groups before and after training. Most importantly, intensive writing training propagated connectivity via the left hemispheric visuomotor stream to an increased coupling with the supplementary motor area, not witnessed in the placebo group. Training enhanced communication in the left visuomotor integration system in line with the learned visually steered training. Notably, this pattern was apparent irrespective of the presence of cues, suggesting transfer from cued to uncued handwriting. We conclude that in early PD intensive motor skill learning, which led to clinical improvement, alters cortical network functioning. We showed for the first time in a placebo-controlled design that it remains possible to enhance the drive to the supplementary motor area through motor learning.

Differential Functional Connectivity Alterations of Two Subdivisions within the Right dlPFC in Parkinson's Disease.

Patients suffering from Parkinson's disease (PD) often show impairments in executive function (EF) like decision-making and action control. The right dorsolateral prefrontal cortex (dlPFC) has been strongly implicated in EF in healthy subjects and has repeatedly been reported to show alterations related to EF impairment in PD. Recently, two key regions for cognitive action control have been identified within the right dlPFC by co-activation based parcellation. While the posterior region is engaged in rather basal EF like stimulus integration and working memory, the anterior region has a more abstract, supervisory function. To investigate whether these functionally distinct subdivisions of right dlPFC are differentially affected in PD, we analyzed resting-state functional connectivity (FC) in 39 PD patients and 44 age- and gender-matched healthy controls. Patients were examined both after at least 12 h withdrawal of dopaminergic drugs (OFF) and under their regular dopaminergic medication (ON). We found that only the posterior right dlPFC subdivision shows FC alterations in PD, while the anterior part remains unaffected. PD-related decreased FC with posterior right dlPFC was found in the bilateral medial posterior parietal cortex (mPPC) and left dorsal premotor region (PMd) in the OFF state. In the medical ON, FC with left PMd normalized, while decoupling with bilateral mPPC remained. Furthermore, we observed increased FC between posterior right dlPFC and the bilateral dorsomedial prefrontal cortex (dmPFC) in PD in the ON state. Our findings point to differential disturbances of right dlPFC connectivity in PD, which relate to its hierarchical organization of EF processing by stronger affecting the functionally basal posterior aspect than the hierarchically higher anterior part.

Differential effects of dopaminergic medication on basic motor performance and executive functions in Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) often show deficits in the self-initiation and selection of movements, which can be partly compensated for by external cues. We here investigated impairments in the initiation and selection of self-initiated or externally cued movements in PD. Specifically, we assessed how behavioral changes relate to medication, disease severity, and basic motor or cognitive deficits. METHODS: Seventeen akinetic-rigid PD patients and 16 healthy controls (HC) performed a computerized motor task assessing differences between internally and externally triggered movements and reaction times. Patients performed the task twice in a randomized fashion, once with their regular dopaminergic medication and once 12h after withdrawal of medication. Additionally, all subjects underwent comprehensive neuropsychological and motor assessments. RESULTS: Compared to HC, patients showed a significant slowing across all tasks. Furthermore, patients showed a selective deficit of movement initiation as indexed by longer reaction times when movement lateralization was internally chosen as opposed to being externally cued. This deficit correlated significantly with motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). Notably, there was no main effect of dopaminergic medication ("ON"/"OFF") on internally and externally triggered movements despite significant improvement of UPDRS and maximum finger tapping frequency in the "ON" state. DISCUSSION: Our results suggest that disease severity in PD patients is related to disturbances in internal action initiation, selection and simple decision processes. Moreover, the data add further support to the notion that dopaminergic medication differentially affects motor and cognitive performance in PD. These findings imply that disturbances in executive functions in PD are also influenced by factors other than reduced dopaminergic activity.