Focused stimulation of dorsal versus ventral subthalamic nucleus enhances action-outcome learning in patients with Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the clinical motor symptoms of Parkinson's disease, but may alter the ability to learn contingencies between stimuli, actions and outcomes. We investigated how stimulation of the functional subregions in the subthalamic nucleus (motor and cognitive regions) modulates stimulus-action-outcome learning in Parkinson's disease patients. Twelve Parkinson's disease patients with deep brain stimulation of the subthalamic nucleus completed a probabilistic stimulus-action-outcome task while undergoing ventral and dorsal subthalamic nucleus stimulation (within subjects, order counterbalanced). The task orthogonalized action choice and outcome valence, which created four action-outcome learning conditions: action-reward, inhibit-reward, action-punishment avoidance and inhibit-punishment avoidance. We compared the effects of deep brain stimulation on learning rates across these conditions as well as on computed Pavlovian learning biases. Dorsal stimulation was associated with higher overall learning proficiency relative to ventral subthalamic nucleus stimulation. Compared to ventral stimulation, stimulating the dorsal subthalamic nucleus led to a particular advantage in learning to inhibit action to produce desired outcomes (gain reward or avoid punishment) as well as better learning proficiency across all conditions providing reward opportunities. The Pavlovian reward bias was reduced with dorsal relative to ventral subthalamic nucleus stimulation, which was reflected by improved inhibit-reward learning. Our results show that focused stimulation in the dorsal compared to the ventral subthalamic nucleus is relatively more favourable for learning action-outcome contingencies and reduces the Pavlovian bias that could lead to reward-driven behaviour. Considering the effects of deep brain stimulation of the subthalamic nucleus on learning and behaviour could be important when optimizing stimulation parameters to avoid side effects like impulsive reward-driven behaviour.

A new paradigm for investigating real-world social behavior and its neural underpinnings.

Eye tracking and other behavioral measurements collected from patient-participants in their hospital rooms afford a unique opportunity to study natural behavior for basic and clinical translational research. We describe an immersive social and behavioral paradigm implemented in patients undergoing evaluation for surgical treatment of epilepsy, with electrodes implanted in the brain to determine the source of their seizures. Our studies entail collecting eye tracking with other behavioral and psychophysiological measurements from patient-participants during unscripted behavior, including social interactions with clinical staff, friends, and family in the hospital room. This approach affords a unique opportunity to study the neurobiology of natural social behavior, though it requires carefully addressing distinct logistical, technical, and ethical challenges. Collecting neurophysiological data synchronized to behavioral and psychophysiological measures helps us to study the relationship between behavior and physiology. Combining across these rich data sources while participants eat, read, converse with friends and family, etc., enables clinical-translational research aimed at understanding the participants' disorders and clinician-patient interactions, as well as basic research into natural, real-world behavior. We discuss data acquisition, quality control, annotation, and analysis pipelines that are required for our studies. We also discuss the clinical, logistical, and ethical and privacy considerations critical to working in the hospital setting.

Effects of deep brain stimulation target on the activation and suppression of action impulses.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment to improve motor symptoms in Parkinson's disease (PD). The Globus Pallidus (GPi) and the Subthalamic Nucleus (STN) are the most targeted brain regions for stimulation and produce similar improvements in PD motor symptoms. However, our understanding of stimulation effects across targets on inhibitory action control processes is limited. We compared the effects of STN (n = 20) and GPi (n = 13) DBS on inhibitory control in PD patients. METHODS: We recruited PD patients undergoing DBS at the Vanderbilt Movement Disorders Clinic and measured their performance on an inhibitory action control task (Simon task) before surgery (optimally treated medication state) and after surgery in their optimally treated state (medication plus their DBS device turned on). RESULTS: DBS to both STN and GPi targets induced an increase in fast impulsive errors while simultaneously producing more proficient reactive suppression of interference from action impulses. CONCLUSIONS: Stimulation in GPi produced similar effects as STN DBS, indicating that stimulation to either target increases the initial susceptibility to act on strong action impulses while concomitantly improving the ability to suppress ongoing interference from activated impulses. SIGNIFICANCE: Action impulse control processes are similarly impacted by stimulating dissociable nodes in frontal-basal ganglia circuitry.

Developing Predictor Models of Postoperative Verbal Fluency After Deep Brain Stimulation Using Preoperative Neuropsychological Assessment.

BACKGROUND: Deep brain stimulation (DBS) for Parkinson disease provides significant improvement of motor symptoms but can also produce neurocognitive side effects. A decline in verbal fluency (VF) is among the most frequently reported side effects. Preoperative factors that could predict VF decline have yet to be identified. OBJECTIVE: To develop predictive models of DBS postoperative VF decline using a machine learning approach. METHODS: We used a prospective database of patients who underwent neuropsychological and VF assessment before both subthalamic nucleus (n = 47, bilateral = 44) and globus pallidus interna (n = 43, bilateral = 39) DBS. We used a neurobehavioral rating profile as features for modeling postoperative VF. We constructed separate models for action, semantic, and letter VF. We used a leave-one-out scheme to test the accuracy of the predictive models using median absolute error and correlation with actual postoperative scores. RESULTS: The predictive models were able to predict the 3 types of VF with high accuracy ranging from a median absolute error of 0.92 to 1.36. Across all three models, higher preoperative fluency, digit span, education, and Mini-Mental State Examination were predictive of higher postoperative fluency scores. By contrast, higher frontal system deficits, age, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease scored by the patient, disease duration, and Behavioral Inhibition/Behavioral Activation Scale scores were predictive of lower postoperative fluency scores. CONCLUSION: Postoperative VF can be accurately predicted using preoperative neurobehavioral rating scores above and beyond preoperative VF score and relies on performance over different aspects of executive function.

Essential tremor impairs the ability to suppress involuntary action impulses.

Essential tremor (ET) is a movement disorder characterized primarily by action tremor which affects the regulation of movements. Disruptions in cerebello-thalamocortical networks could interfere with cognitive control over actions in ET, for example, the ability to suppress a strong automatic impulse over a more appropriate action (conflict control). The current study investigated whether ET impacts conflict control proficiency. Forty-one ET patients and 29 age-matched healthy controls (HCs) performed a conflict control task (Simon task). Participants were instructed to give a left or right response to a spatially lateralized arrow (direction of the arrow). When the action signaled by the spatial location and direction of the arrow were non-corresponding (induced conflict), the inappropriate action impulse required suppression. Overall, ET patients responded slower and less accurately compared to HCs. ET patients were especially less accurate on non-corresponding conflict (Nc) versus corresponding (Cs) trials. A focused analysis on fast impulsive response rates (based on the accuracy rate at the fastest reaction times on Nc trials) showed that ET patients made more fast errors compared to HCs. Results suggest impaired conflict control in ET compared to HCs. The increased impulsive errors seen in the ET population may be a symptom of deficiencies in the cerebello-thalamocortical networks, or, be caused by indirect effects on the cortico-striatal pathways. Future studies into the functional networks impacted by ET (cortico-striatal and cerebello-thalamocortical pathways) could advance our understanding of inhibitory control in general and the cognitive deficits in ET.

Deep brain stimulation effects on verbal fluency dissociated by target and active contact location.

OBJECTIVE: Deep brain stimulation (DBS) improves motor symptoms in Parkinson's disease (PD), but it can also disrupt verbal fluency with significant costs to quality of life. The current study investigated how variability of bilateral active electrode coordinates along the superior/inferior, anterior/posterior, and lateral/medial axes in the subthalamic nucleus (STN) or the globus pallidus interna (GPi) contribute to changes in verbal fluency. We predicted that electrode location in the left hemisphere would be linked to changes in fluency, especially in the STN. METHODS: Forty PD participants treated with bilateral DBS targeting STN (n = 23) or GPi (n = 17) completed verbal fluency testing in their optimally treated state before and after DBS therapy. Normalized atlas coordinates from left and right active electrode positions along superior/inferior, anterior/posterior, and lateral/medial axes were used to predict changes in fluency postoperatively, separately for patients with STN and GPi targets. RESULTS: Consistent with prior studies, fluency significantly declined pre- to postsurgery (in both DBS targets). In STN-DBS patients, electrode position along the inferior to superior axis in the left STN was a significant predictor of fluency changes; relatively more superior left active electrode was associated with the largest fluency declines in STN. Electrode coordinates in right STN or GPi (left or right) did not predict fluency changes. INTERPRETATION: We discuss these findings in light of putative mechanisms and potential clinical impact.

Deep-brain stimulation of the subthalamic nucleus improves overriding motor actions in Parkinson's disease.

Findings from previous research using the classic stop-signal task indicate that the subthalamic nucleus (STN) plays an important role in the ability to inhibit motor actions. Here we extend these findings using a stop-change task that requires voluntary action override to stop an ongoing motor response and change to an alternative response. Sixteen patients diagnosed with Parkinson's disease (PD) and 16 healthy control participants (HC) performed the stop-change task. PD patients completed the task when deep-brain stimulation (DBS) of the STN was turned on and when it was turned off. Behavioral results indicated that going, stopping, and changing latencies were shortened significantly among PD patients during STN DBS, the former two reductions replicating findings from previous DBS studies using the classic stop-signal task. The shortened go latencies observed among PD patients fell within the control range. In contrast, stopping latencies among PD patients, although reduced significantly, continued to be significantly longer than those of the HC. Like go latencies, stop-change latencies were reduced sufficiently among PD patients for them to fall within the control range, a novel finding. In conclusion, STN DBS produced a general, but differential, improvement in the ability of PD patients to override motor actions. Going, stopping, and stop-change latencies were all shortened, but only going and stop-change latencies were normalized.

Subthalamic Nucleus Subregion Stimulation Modulates Inhibitory Control.

Patients with Parkinson's disease (PD) often experience reductions in the proficiency to inhibit actions. The motor symptoms of PD can be effectively treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN), a key structure in the frontal-striatal network that may be directly involved in regulating inhibitory control. However, the precise role of the STN in stopping control is unclear. The STN consists of functional subterritories linked to dissociable cortical networks, although the boundaries of the subregions are still under debate. We investigated whether stimulating the dorsal and ventral subregions of the STN would show dissociable effects on ability to stop. We studied 12 PD patients with STN DBS. Patients with two adjacent contacts positioned within the bounds of the dorsal and ventral STN completed two testing sessions (OFF medication) with low amplitude stimulation (0.4 mA) at either the dorsal or ventral contacts bilaterally, while performing the stop task. Ventral, but not dorsal, DBS improved stopping latencies. Go reactions were similar between dorsal and ventral DBS STN. Stimulation in the ventral, but not dorsal, subregion of the STN improved stopping speed, confirming the involvement of the STN in stopping control and supporting the STN functional subregions.

Impaired Action Control in Patients With Functional Movement Disorders.

OBJECTIVE: Despite being a major cause of neurological disability, the neural mechanisms of functional movement disorders (FMDs) remain poorly understood. Recent studies suggest that FMD is linked to dysfunctional motor and prefrontal regions that could lead to motor and cognitive impairments. The aim of this study was to investigate different components of action control in FMD by using choice-reaction, stop-signal, and Simon tasks. METHODS: Thirty patients with an FMD were prospectively recruited from the University of Louisville Movement Disorders Clinic and compared with 53 healthy control subjects, recruited from the Vanderbilt University Medical Center Movement Disorders Clinic. FMD motor symptom severity was rated with the Simplified Functional Movement Disorder Rating Scale (S-FMDRS). By using a computer and handheld response grips, participants completed three action-control tasks (choice-reaction task, stop-signal task, and Simon task) that tested action initiation, action cancelation, and interference control over actions. Action-control measures were compared between groups with analyses of variance. RESULTS: Patients with FMD were less proficient in suppressing incorrect response impulses on the Simon task and were slower to stop on the stop-signal task compared with healthy control subjects. No significant correlation with neuropsychological measurements, S-FMDRS scores, and action-control measurements was observed. CONCLUSIONS: These results suggest that two forms of inhibitory control, selective impulse inhibition and global action cancelation, are impaired in patients with FMD, independent of slowing on go reaction times. Improved understanding of action control in FMD may help in the development of new diagnostic and therapeutic strategies.

Dopamine effects on frontal cortical blood flow and motor inhibition in Parkinson's disease.

Parkinson's disease (PD) is characterized by dysfunction in frontal cortical and striatal networks that regulate action control. We investigated the pharmacological effect of dopamine agonist replacement therapy on frontal cortical activity and motor inhibition. Using Arterial Spin Labeling MRI, we examined 26 PD patients in the off- and on-dopamine agonist medication states to assess the effect of dopamine agonists on frontal cortical regional cerebral blood flow. Motor inhibition was measured by the Simon task in both medication states. We applied the dual process activation suppression model to dissociate fast response impulses from motor inhibition of incorrect responses. General linear regression model analyses determined the medication effect on regional cerebral blood flow and motor inhibition, and the relationship between regional cerebral blood flow and motor inhibitory proficiency. We show that dopamine agonist administration increases frontal cerebral blood flow, particularly in the pre-supplementary motor area (pre-SMA) and the dorsolateral prefrontal cortex (DLPFC). Higher regional blood flow in the pre-SMA, DLPFC and motor cortex was associated with better inhibitory control, suggesting that treatments which improve frontal cortical activity could ameliorate motor inhibition deficiency in PD patients.

Exposing an "Intangible" Cognitive Skill Among Collegiate Football Players: III. Enhanced Reaction Control to Motion.

Football is played in a dynamic, often unpredictable, visual environment in which players are challenged to process and respond with speed and flexibility to critical incoming stimulus events. To meet this challenge, we hypothesize that football players possess, in conjunction with their extraordinary physical skills, exceptionally proficient executive cognitive control systems that optimize response execution. It is particularly important for these systems to be proficient at coordinating directional reaction and counter-reaction decisions to the very rapid lateral movements routinely made by their opponents during a game. Despite the importance of this executive skill to successful on-field performance, it has not been studied in football players. To fill this void, we compared the performances of Division I college football players (n = 525) and their non-athlete age counterparts (n = 40) in a motion-based stimulus-response compatibility task that assessed their proficiency at executing either compatible (in the same direction) or incompatible (in the opposite direction) lateralized reactions to a target's lateral motion. We added an element of decision uncertainty and complexity by giving them either sufficient or insufficient time to preload the response decision rule (i.e., compatible vs. incompatible) prior to the target setting in motion. Overall, football players were significantly faster than non-athlete controls in their choice reactions to a target's lateral motion. The reactions of all participants slowed when issuing incompatible counter-reactions to a target's lateral motion. For football players, this cost was reduced substantially compared to controls when given insufficient time to preload the decision rule, indicating that they exerted more efficient executive control over their reactions and counter-reactions when faced with decision uncertainty at the onset of stimulus motion. We consider putative sources of their advantage in reacting to a target's lateral motion and discuss how these findings advance the hypothesis that football players utilize highly-proficient executive control systems to overcome processing conflicts during motor performance.

Action Control Deficits in Patients With Essential Tremor.

OBJECTIVES: Essential tremor (ET) is a movement disorder characterized by action tremor which impacts motor execution. Given the disrupted cerebellar-thalamo-cortical networks in ET, we hypothesized that ET could interfere with the control mechanisms involved in regulating motor performance. The ability to inhibit or stop actions is critical for navigating many daily life situations such as driving or social interactions. The current study investigated the speed of action initiation and two forms of action control, response stopping and proactive slowing in ET. METHODS: Thirty-three ET patients and 25 healthy controls (HCs) completed a choice reaction task and a stop-signal task, and measures of going speed, proactive slowing and stop latencies were assessed. RESULTS: Going speed was significantly slower in ET patients (649 ms) compared to HCs (526 ms; F(1,56) = 42.37; p <.001; η 2 = .43), whereas proactive slowing did not differ between groups. ET patients exhibited slower stop signal reaction times (320 ms) compared to HCs (258 ms, F(1,56) = 15.3; p <.00; η 2 = .22) and more severe motor symptoms of ET were associated with longer stopping latencies in a subset of patients (Spearman rho = .48; p <.05). CONCLUSIONS: In line with previous studies, ET patients showed slower action initiation. Additionally, inhibitory control was impaired whereas proactive slowing remained intact relative to HCs. More severe motor symptoms of ET were associated with slower stopping speed, and may reflect more progressive changes to the cerebellar-thalamo-cortical network. Future imaging studies should specify which structural and functional changes in ET can explain changes in inhibitory action control. (JINS, 2019, 25, 156-164).

Exposing an "Intangible" Cognitive Skill Among Collegiate Football Players: II. Enhanced Response Impulse Control.

American football is played in a dynamic environment that places considerable demands on a player's ability to make fast, precise reactions while controlling premature, impulsive reactions to spatial misinformation. We investigated the hypothesis that collegiate football players are more proficient than their non-athlete counterparts at controlling impulsive motor actions. National Collegiate Athletic Association (NCAA) Division I football players (n = 280) and non-athlete controls (n = 32) completed a variant of the Simon conflict task, which quantifies choice reaction speed and the proficiency of controlling spatially driven response impulses. Overall, the choice reaction times (RTs) and accuracy rates of football players and controls were equivalent. Similarly, football players and controls were equally susceptible to producing incorrect impulsive motor responses. However, the slowing of RT attributed to the activation and successful inhibition of these impulses (i.e., the Simon effect) was reduced significantly among football players compared to controls. Moreover, differences in impulse control varied by position among the players, with the reduction being greater for offensive than for defensive players. Among offensive players, running backs, wide receivers, and offensive linemen had greater impulse control than did controls, whereas among defensive players only linebackers had greater control. Notably, the Simon effect was reduced by 60% in running backs compared to controls. These results contribute to emerging evidence that elite football players possess more proficient executive control over their motor systems than their age counterparts and suggest that the speed of controlling impulsive motor reactions may represent an enhanced cognitive "intangible" among football players.

Taq1A polymorphism and medication effects on inhibitory action control in Parkinson disease.

BACKGROUND: Dopamine therapy in Parkinson disease (PD) can have differential effects on inhibitory action control, or the ability to inhibit reflexive or impulsive actions. Dopamine agonist (DAAg) medications, which preferentially target D2 and D3 receptors, can either improve or worsen control of impulsive actions in patients with PD. We have reported that the direction of this effect depends on baseline levels of performance on inhibitory control tasks. This observation suggests that there may exist certain biologic determinants that contribute to these patient-specific differences. We hypothesized that one important factor might be functional polymorphisms in D2-like receptor genes. AIM: The goal of this study was to determine whether the direction of DAAg effects on inhibitory control depends on functional polymorphisms in the DRD2 and DRD3 genes. METHODS: Twenty-eight patients with PD were genotyped for known functional polymorphisms in DRD2 (rs6277 and rs1800497) and DRD3 (rs6280) receptors. These patients then completed the Simon conflict task both on and off DAAg therapy in a counterbalanced manner. RESULTS: We found that patients with the rs1800497 Taq1A (A1) polymorphism (A1/A1 or A1/A2: 11 subjects) showed improved proficiency to suppress impulsive actions when on DAAg; conversely, patients with the A2/A2 allele (14 patients) became less proficient at suppressing incorrect response information on DAAg therapy (Group × Medication, F(1, 23) = 5.65, p < 0.05). Polymorphisms in rs6277 and rs6280 were not associated with a differential medication response. CONCLUSION: These results suggest that certain DRD polymorphisms may determine the direction of DAAg effects on critical cognitive control processes impaired in PD. Our findings have implications for understanding pharmacogenomics interactions on a larger scale and the role these may play in the wide variability of treatment effects seen in the PD population.

[18F]fallypride characterization of striatal and extrastriatal D2/3 receptors in Parkinson's disease.

Parkinson's disease (PD) is characterized by widespread degeneration of monoaminergic (especially dopaminergic) networks, manifesting with a number of both motor and non-motor symptoms. Regional alterations to dopamine D2/3 receptors in PD patients are documented in striatal and some extrastriatal areas, and medications that target D2/3 receptors can improve motor and non-motor symptoms. However, data regarding the combined pattern of D2/3 receptor binding in both striatal and extrastriatal regions in PD are limited. We studied 35 PD patients off-medication and 31 age- and sex-matched healthy controls (HCs) using PET imaging with [18F]fallypride, a high affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). PD patients completed PET imaging in the off medication state, and motor severity was concurrently assessed. Voxel-wise evaluation between groups revealed significant BPND reductions in PD patients in striatal and several extrastriatal regions, including the locus coeruleus and mesotemporal cortex. A region-of-interest (ROI) based approach quantified differences in dopamine D2/3 receptors, where reduced BPND was noted in the globus pallidus, caudate, amygdala, hippocampus, ventral midbrain, and thalamus of PD patients relative to HC subjects. Motor severity positively correlated with D2/3 receptor density in the putamen and globus pallidus. These findings support the hypothesis that abnormal D2/3 expression occurs in regions related to both the motor and non-motor symptoms of PD, including areas richly invested with noradrenergic neurons.

Exposing an "Intangible" Cognitive Skill among Collegiate Football Players: Enhanced Interference Control.

American football is played in a chaotic visual environment filled with relevant and distracting information. We investigated the hypothesis that collegiate football players show exceptional skill at shielding their response execution from the interfering effects of distraction (interference control). The performances of 280 football players from National Collegiate Athletic Association Division I football programs were compared to age-matched controls in a variant of the Eriksen flanker task (Eriksen and Eriksen, 1974). This task quantifies the magnitude of interference produced by visual distraction on split-second response execution. Overall, football athletes and age controls showed similar mean reaction times (RTs) and accuracy rates. However, football athletes were more proficient at shielding their response execution speed from the interfering effects of distraction (i.e., smaller flanker effect costs on RT). Offensive and defensive players showed smaller interference costs compared to controls, but defensive players showed the smallest costs. All defensive positions and one offensive position showed statistically smaller interference effects when compared directly to age controls. These data reveal a clear cognitive advantage among football athletes at executing motor responses in the face of distraction, the existence and magnitude of which vary by position. Individual differences in cognitive control may have important implications for both player selection and development to improve interference control capabilities during play.

Nigrostriatal and Mesolimbic D2/3 Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors.

The nigrostriatal and mesocorticolimbic dopamine networks regulate reward-driven behavior. Regional alterations to mesolimbic dopamine D2/3 receptor expression are described in drug-seeking and addiction disorders. Parkinson's disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). Until now, changes in D2/3 receptor binding in both striatal and extrastriatal regions have not been concurrently quantified in this population. We identified 35 human PD patients (both male and female) receiving DAgonist therapy, with (n = 17) and without (n = 18) ICBs, matched for age, disease duration, disease severity, and dose of dopamine therapy. In the off-dopamine state, all completed PET imaging with [18F]fallypride, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Striatal differences between ICB+/ICB- patients localized to the ventral striatum and putamen, where ICB+ subjects had reduced BPND In this group, self-reported severity of ICB symptoms positively correlated with midbrain D2/3 receptor BPND Group differences in regional D2/3 BPND relationships were also notable: ICB+ (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala BPNDs. These findings support the hypothesis that compulsive behaviors in PD are associated with reduced ventral and dorsal striatal D2/3 expression, similar to changes in comparable behavioral disorders. The data also suggest that relatively preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are characteristic of ICB+ patients, and may account for differential DAgonist therapeutic response.SIGNIFICANCE STATEMENT The biologic determinants of compulsive reward-based behaviors have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease patients with impulsive compulsive behaviors (ICBs). This is the first study to image a large cohort of ICB+ patients using positron emission tomography with [18F]fallypride, allowing quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in dopaminergic networks, including (1) D2-like receptor distinctions in the ventral striatum and putamen, and (2) a preservation of widespread dopaminergic projections emerging from the midbrain, which is associated with the severity of compulsive behaviors. This clearly illustrates the roles of D2/3 receptors and medication effects in maladaptive behaviors, and localizes them specifically to nigrostriatal and extrastriatal regions.

Dopaminergic medication shifts the balance between going and stopping in Parkinson's disease.

The present behavioral study delineates the impact of Parkinson's disease (PD) and of dopaminergic medication on action control over voluntary behavior. Previous studies reported either prolonged responding or stopping latencies in PD compared to healthy controls (HC). Few studies investigated the effects of dopaminergic medication on these processes concurrently. We administered a stop-change task, an extended version of the stop task, that required (i) speeded responding to a go signal (i.e., going), (ii) inhibiting ongoing motor responses (i.e., stopping), and (iii) changing to an alternative response. PD performance (n = 33) was collected once during regular dopaminergic medication conditions (On state) and once after a medication washout period (Off state). A group of age-matched HC (n = 21) performed the stop-change task once. Response latencies to go signals were comparable between HC and PD Off, indicative of unimpaired going. Compared to HC, PD Off showed prolonged stopping latencies. Within the clinical group, stopping latencies significantly improved after taking dopaminergic medication. Interestingly, the shorter stopping latencies observed in the On state were paralleled by longer response latencies to go signals. The degree of the inhibition improvement observed in the medication state was correlated with the degree of response slowing. Change RT did not vary between groups or between medication states. These patterns of results are discussed in terms of a tradeoff between going versus stopping of motor responses in PD patients. Shifts of this tradeoff seem to be driven by dopaminergic medication, which has potential clinical implications.

Overriding actions in Parkinson's disease: Impaired stopping and changing of motor responses.

We administered a stop-change paradigm, an extended version of the stop task that requires (a) stopping an ongoing motor response and (b) changing to an alternative (change) response. Performance of a group of patients diagnosed with Parkinson's disease (PD) and taking dopaminergic medication was compared with that of matched healthy control (HC) participants. Behavioral results indicated that response latencies to the initial go signal did not distinguish between the 2 groups, but that stopping latencies were prolonged in PD patients. In addition, the change response was delayed in the clinical group, indicating difficulties in flexibly changing to alternative motor actions upon external cues. The change deficit in PD related to the inhibition deficit. This dependence points to a serial processing architecture in PD according to which the stopping process has to finish before the change process can be initiated. In contrast, the HC group showed parallel stop and change processing. Analyses of sequential trial effects suggest that both HC and PD patients are susceptible to aftereffects of action override, due to the consequences of the automatic retrieval of recent associations between action and goal representations. Interestingly, postchange performance of the clinical group was hampered disproportionately, suggesting that PD is associated with an impairment in overriding previously formed action-goal associations. These findings support the notion that both higher-order cognitive control processes, such as inhibiting and changing actions, as well as lower-order feature binding mechanisms rely on basal ganglia functioning and are compromised by the basal ganglia dysfunction caused by PD. (PsycINFO Database Record

Mesocorticolimbic hemodynamic response in Parkinson's disease patients with compulsive behaviors.

BACKGROUND: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation. OBJECTIVES: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors. METHODS: Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin-labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off-dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity. RESULTS: Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist-induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions. CONCLUSIONS: These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato-nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. © 2017 International Parkinson and Movement Disorder Society.