Genetic variation in the dopamine system is associated with mixed-strategy decision-making in patients with Parkinson's disease.

Decision-making during mixed-strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed-strategy decision-making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty-six PD patients (ages 49-85, Hoehn and Yahr Stages 1-3) and 22 healthy controls (ages 54-75) competed in a mixed-strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed-strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within-subject, multi-centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val158 Met), rs6277 (C957T) and rs907094 (encoding DARPP-32). PD and control participants displayed comparable mixed-strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow-up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD.

Integrated robotics platform with haptic control differentiates subjects with Parkinson's disease from controls and quantifies the motor effects of levodopa.

BACKGROUND: The use of integrated robotic technology to quantify the spectrum of motor symptoms of Parkinson's Disease (PD) has the potential to facilitate objective assessment that is independent of clinical ratings. The purpose of this study is to use the KINARM exoskeleton robot to (1) differentiate subjects with PD from controls and (2) quantify the motor effects of dopamine replacement therapies (DRTs). METHODS: Twenty-six subjects (Hoehn and Yahr mean 2.2; disease duration 0.5 to 15 years) were evaluated OFF (after > 12 h of their last dose) and ON their DRTs with the Unified Parkinson's Disease Rating Scale (UPDRS) and the KINARM exoskeleton robot. Bilateral upper extremity bradykinesia, rigidity, and postural stability were quantified using a repetitive movement task to hit moving targets, a passive stretch task, and a torque unloading task, respectively. Performance was compared against healthy age-matched controls. RESULTS: Mean hand speed was 41% slower and 25% fewer targets were hit in subjects with PD OFF medication than in controls. Receiver operating characteristic (ROC) area for hand speed was 0.94. The torque required to stop elbow movement during the passive stretch task was 34% lower in PD subjects versus controls and resulted in an ROC area of 0.91. The torque unloading task showed a maximum displacement that was 29% shorter than controls and had an ROC area of 0.71. Laterality indices for speed and end total torque were correlated to the most affected side. Hand speed laterality index had an ROC area of 0.80 against healthy controls. DRT administration resulted in a significant reduction in a cumulative score of parameter Z-scores (a measure of global performance compared to healthy controls) in subjects with clinically effective levodopa doses. The cumulative score was also correlated to UPDRS scores for the effect of DRT. CONCLUSIONS: Robotic assessment is able to objectively quantify parkinsonian symptoms of bradykinesia, rigidity and postural stability similar to the UPDRS. This integrated testing platform has the potential to aid clinicians in the management of PD and help assess the effects of novel therapies.

Disruption of pupil size modulation correlates with voluntary motor preparation deficits in Parkinson's disease.

Pupil size is an easy-to-measure, non-invasive method to index various cognitive processes. Although a growing number of studies have incorporated measures of pupil size into clinical investigation, there have only been limited studies in Parkinson's disease (PD). Convergent evidence has suggested PD patients exhibit cognitive impairment at or soon after diagnosis. Here, we used an interleaved pro- and anti-saccade paradigm while monitoring pupil size with saccadic eye movements to examine the relationship between executive function deficits and pupil size in PD patients. Subjects initially fixated a central cue, the color of which instructed them to either look at a peripheral stimulus automatically (pro-saccade) or suppress the automatic response and voluntarily look in the opposite direction of the stimulus (anti-saccade). We hypothesized that deficits of voluntary control should be revealed not only on saccadic but also on pupil responses because of the recently suggested link between the saccade and pupil control circuits. In elderly controls, pupil size was modulated by task preparation, showing larger dilation prior to stimulus appearance in preparation for correct anti-saccades, compared to correct pro-saccades, or erroneous pro-saccades made in the anti-saccade condition. Moreover, the size of pupil dilation correlated negatively with anti-saccade reaction times. However, this profile of pupil size modulation was significantly blunted in PD patients, reflecting dysfunctional circuits for anti-saccade preparation. Our results demonstrate disruptions of modulated pupil responses by voluntary movement preparation in PD patients, highlighting the potential of using low-cost pupil size measurement to examine executive function deficits in early PD.

High-throughput classification of clinical populations from natural viewing eye movements.

Many high-prevalence neurological disorders involve dysfunctions of oculomotor control and attention, including attention deficit hyperactivity disorder (ADHD), fetal alcohol spectrum disorder (FASD), and Parkinson's disease (PD). Previous studies have examined these deficits with clinical neurological evaluation, structured behavioral tasks, and neuroimaging. Yet, time and monetary costs prevent deploying these evaluations to large at-risk populations, which is critically important for earlier detection and better treatment. We devised a high-throughput, low-cost method where participants simply watched television while we recorded their eye movements. We combined eye-tracking data from patients and controls with a computational model of visual attention to extract 224 quantitative features. Using machine learning in a workflow inspired by microarray analysis, we identified critical features that differentiate patients from control subjects. With eye movement traces recorded from only 15 min of videos, we classified PD versus age-matched controls with 89.6 % accuracy (chance 63.2 %), and ADHD versus FASD versus control children with 77.3 % accuracy (chance 40.4 %). Our technique provides new quantitative insights into which aspects of attention and gaze control are affected by specific disorders. There is considerable promise in using this approach as a potential screening tool that is easily deployed, low-cost, and high-throughput for clinical disorders, especially in young children and elderly populations who may be less compliant to traditional evaluation tests.

Impaired executive function signals in motor brain regions in Parkinson's disease.

Recent evidence has shown that patients with Parkinson's disease (PD) often display deficits in executive functions, such as planning for future behavior, and these deficits may stem from pathologies in prefrontal cortex and basal ganglia circuits that are critical to executive control. Using the antisaccade task (look away from a visual stimulus), we show that when the preparatory 'readiness' to perform a given action is dissociated from the actual execution of that action, PD patients off and on dopamine medication display behavioral impairments and reduced cortical brain activation that cannot be explained by a pathology related to dysfunction in movement execution. Rather, they show that the appropriate task set signals were not in place in motor regions prior to execution, resulting in impairments in the control of subsequent voluntary movement. This is the first fMRI study of antisaccade deficits in Parkinson's disease, and importantly, the findings point to a critical role of the basal ganglia in translating signals related to rule representation (executive) into those governing voluntary motor behavior.

Tremor during movement correlates well with disability in people with essential tremor.

Essential tremor is the most common movement disorder, typically characterized by the presence of both postural and kinetic tremor of the hand. In recent studies, we described the effects of altering force and load conditions on tremor amplitude and power in people with essential tremor. In the same participants, we also measured tremor-related functional disability. In this article we report on the current study on correlations of measures of tremor severity with those of tremor-related functional disability. Twenty-one participants with essential tremor had tremor measured in their more tremorous hand. Power spectral and amplitude measures of tremor were calculated for each of 16 conditions: force tremor at 4 submaximal force levels, postural tremor in unloaded and 3 submaximal load conditions, and kinetic tremor in unloaded and 3 submaximal load conditions for each of concentric and eccentric contractions of the wrist extensors. Participants were rated on the hand items of the Fahn-Tolosa-Marin rating scale and timed on the unilateral hand tasks of the Test Évaluant la Performance des Membres supérieurs des Personnes Âgées. The most consistently high and significant correlations were found between kinetic tremor measures and the hand task scores and tremor-B scores (r = 0.548-0.780, P < .01). Postural tremor measures correlated with disability measures only in loaded conditions, most consistently with the hand task measures (r = 0.640-0.725, P < .01). Thus, measures of kinetic tremor and loaded postural tremor, but not unloaded postural tremor or force tremor, relate well to disability captured with dynamic tasks.

Executive impairment in Parkinson's disease: response automaticity and task switching.

Patients with Parkinson's disease (PD) show slowed movement initiation and can have deficits in executive function, leading to impairments in controlling involuntary behavior. This results in difficulties performing an antisaccade, which requires one to suppress an automatic eye movement (a prosaccade) to a visual stimulus, and execute a voluntary eye movement in the opposite direction. Antisaccade deficits are similar to those seen in task switching, whereby one is required to change a response after performing a different behavior. Both antisaccade (Hood et al., 2007) and task switching (Cools, Barker, Sahakian, & Robbins, 2001) deficits in PD have been attributed to fronto-basal ganglia (BG) dysfunction. Previously, we demonstrated with functional magnetic resonance imaging that BG circuitry is important to both task switching and voluntary saccade generation, as greater caudate activation was seen when healthy young adults first prepared a prosaccade, but then switched to an antisaccade (Cameron, Coe, et al., 2009). Therefore, we hypothesized that PD patients would have difficulty switching from one saccade response to the other, with particular impairment in switching from a pro to an antisaccade. Here, we not only confirmed this prediction, but also showed that PD patients performed better than controls in switching from an anti to a prosaccade. This suggests that task switching deficits in PD are particularly pronounced when more automatic behavior needs to be overridden with alternative behavior. We suggest that this occurs primarily at the level of establishing the appropriate task set, which is an internalized rule that governs how to respond.

Approach to diagnosis of Parkinson disease.

OBJECTIVE: To review the clinical features of Parkinson disease (PD) and other causes of motor parkinsonism with an emphasis on diagnosis in elderly patients. SOURCES OF INFORMATION MEDLINE: and Google Scholar were searched for original research articles describing clinical diagnosis of parkinsonism. Consensus statements and articles summarizing diagnostic criteria for parkinsonian syndromes were also reviewed. Most evidence was levels II or III. MAIN MESSAGE: Diagnosis of PD is made clinically and can be challenging. In older patients, PD can present with general functional decline and nonspecific symptoms. Clinical criteria for diagnosing PD and the TRAP mnemonic can be helpful. A 2-week trial of levodopa-carbidopa treatment can be considered. Specific signs and a minimal response to levodopa treatment suggest other causes of parkinsonism. Clinical features of other causes of parkinsonism are reviewed in the article. CONCLUSION: Parkinsonism and PD are common in older patients. Family physicians should consider parkinsonism in the differential diagnosis of patients who have falls and exhibit general functional decline.

Effects of Parkinson disease on two putative nondeclarative learning tasks: probabilistic classification and gambling.

OBJECTIVE: To assess performance on two nondeclarative (implicit) memory tasks of Parkinson disease (PD) patients without dementia in the earlier or later stages of the disease (Hoehn and Yahr Scale scores of 1-2.5 or 3-4, respectively). BACKGROUND: Different subtypes of nondeclarative memory appear to depend on different components of frontostriatal circuitry. Performance on a probabilistic classification learning (PCL) task was impaired by striatal damage (eg, in PD or Huntington disease) but not by circumscribed frontal lobe damage. On the other hand, performance on the Iowa Gambling Task (IGT) was impaired by damage to the prefrontal cortex. METHOD AND RESULTS: On the PCL, the learning of the control (age- and education-matched) group (n = 19) and the early PD group (n = 16) was comparable with each other, and both groups showed better performance than the later PD group (n = 16). On the IGT, the control group learned better than both of the PD groups. The control and early PD groups were similar on measures from the Wisconsin Card Sorting Test, Stroop Test, Mini-Mental State Examination, and Beck Depression Inventory II. CONCLUSIONS: The PCL and IGT tasks appear to rely on different parts of the frontostriatal circuitry in patients with early PD. The current finding that IGT performance was impaired in early PD implies ventromedial prefrontal cortical dysfunction early in the disease.

Deficits in saccadic eye-movement control in Parkinson's disease.

In contrast to their slowed limb movements, individuals with Parkinson's disease (PD) produce rapid automatic eye movements to sensory stimuli and show an impaired ability to generate voluntary eye movements in cognitive tasks. Eighteen PD patients and 18 matched control volunteers were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus as soon as it appeared (immediate, gap and overlap conditions) or after a variable delay; or, they made sequential saccades to remembered targets after a variable delay. We found that PD patients made more express saccades (correct saccades in the latency range of 90-140 ms) in the immediate pro-saccade task, more direction errors (automatic pro-saccades) in the immediate anti-saccade task, and were less able to inhibit saccades during the delay period in all delay tasks. PD patients also made more directional and end-point errors in the memory-guided sequential task. Their inability to plan eye movements to remembered target locations suggests that PD patients have a deficit in spatial working memory which, along with their deficit in automatic saccade suppression, is consistent with a disorder of the prefrontal-basal ganglia circuit. Impairment of this pathway may release the automatic saccade system from top-down inhibition and produce deficits in volitional saccade control. Parallel findings across various motor, cognitive and oculomotor tasks suggest a common mechanism underlying a general deficit in automatic response suppression.