Dopamine Replacement Medication Research Articles

A metabolomics study in aqueous humor discloses altered arginine metabolism in Parkinson’s disease

BackgroundThe lack of accessible and informative biomarkers results in a delayed diagnosis of Parkinson’s disease (PD), whose symptoms appear when a significant number of dopaminergic neurons have already disappeared. The retina, a historically overlooked part of the central nervous system (CNS), has gained recent attention. It has been discovered that the composition of cerebrospinal fluid influences the aqueous humor composition through microfluidic circulation. In addition, alterations found in the brain of patients with PD have a correlate in the retina. This new paradigm highlights the potential of the aqueous humor as a sample for identifying differentially concentrated metabolites that could, eventually, become biomarkers if also found altered in blood or CSF of patients. In this research we aim at analyzing the composition of the aqueous humor from healthy controls and PD patients.MethodsA targeted metabolomics approach with concentration determination by mass spectrometry was used. Statistical methods including principal component analysis and linear discriminants were used to select differentially concentrated metabolites that allow distinguishing patients from controls.ResultsIn this first metabolomics study in the aqueous humor of PD patients, elevated levels of 16 compounds were found; molecules differentially concentrated grouped into biogenic amines, amino acids, and acylcarnitines. A biogenic amine, putrescine, alone could be a metabolite capable of differentiating between PD and control samples. The altered levels of the metabolites were correlated, suggesting that the elevations stem from a common mechanism involving arginine metabolism.ConclusionsA combination of three metabolites, putrescine, tyrosine, and carnitine was able to correctly classify healthy participants from PD patients. Altered metabolite levels suggest altered arginine metabolism. The pattern of metabolomic disturbances was not due to the levodopa-based dopamine replacement medication because one of the patients was not yet taking levodopa but a dopamine receptor agonist.

Hopamine as Personalized Medicine for Persons with Parkinson's Disease.

Prescribing dopamine replacement therapy remains the most common approach used by physicians who strive to support persons with Parkinson's disease. In this viewpoint, we argue that instead of merely prescribing dopamine, healthcare professionals should particularly encourage and enable persons with Parkinson's disease to draft their own personalized prescription of "hopamine". The term hopamine is a self-invented neologism representing the uniquely personal set of hopes, desires, experiences, and skills of each individual with a dopamine deficit. As such, the concept of hopamine-as a reflection of the unique personal characteristics of each person with Parkinson's disease-really supplements that of dopamine-as a reflection of each person's unique physical characteristics. Whereas a prescription of dopamine replacement medication necessitates the diagnosed individual to lay his or her fate in the hands of medical professionals, adding a personalized dose of hopamine to the therapeutic mix empowers persons to self-manage daily life with Parkinson's disease. In this viewpoint, we argue that hopamine is a prerequisite for personalized medicine and offer several practical recommendations for how medical professionals can introduce the concept of hopamine in daily clinical practice.

Relating Global Cognition With Upper-Extremity Motor Skill Retention in Individuals With Mild-to-Moderate Parkinson's Disease.

Background and Purpose: Cognition has been linked to rehabilitation outcomes in stroke populations, but this remains unexplored in individuals with Parkinson's disease (PD). The purpose of this secondary data analysis from a recent clinical trial (NCT02600858) was to determine if global cognition was related to skill performance after motor training in individuals with PD.Methods: Twenty-three participants with idiopathic PD completed 3 days of training on an upper-extremity task. For the purposes of the original clinical trial, participants trained either “on” or “off” their dopamine replacement medication. Baseline, training, and 48-h retention data have been previously published. Global cognition was evaluated using the Montreal Cognitive Assessment (MoCA). Linear regression examined whether MoCA score predicted longer-term retention at nine-day follow-up; baseline motor task performance, age, PD severity, depressive symptoms, and group (medication “on”/“off”) were included as covariates. Baseline and follow-up motor task performance were assessed for all participants while “on” their medication.Results: MoCA score was positively related to follow-up motor task performance, such that individuals with better cognition were faster than those with poorer cognition. Baseline task performance, age, PD severity, depressive symptoms, and medication status were unrelated to follow-up performance.Discussion and Conclusions: Results of this secondary analysis align with previous work that suggest cognitive impairment may interfere with motor learning in PD and support the premise that cognitive training prior to or concurrent with motor training may enhance rehabilitative outcomes for individuals with PD. Findings also suggest that assessing cognition in individuals with PD could provide prognostic information about their responsiveness to motor rehabilitation.

Exploring reward-related\xa0attention selectivity deficits in Parkinson\u2019s disease

An important aspect of managing a limited cognitive resource like attention is to use the reward value of stimuli to prioritize the allocation of attention to higher-value over lower-value stimuli. Recent evidence suggests this depends on dopaminergic signaling of reward. In Parkinson’s disease, both reward sensitivity and attention are impaired, but whether these deficits are directly related to one another is unknown. We tested whether Parkinson’s patients use reward information when automatically allocating their attention and whether this is modulated by dopamine replacement. We compared patients, tested both ON and OFF dopamine replacement medication, to older controls using a standard attention capture task. First, participants learned the different reward values of stimuli. Then, these reward-associated stimuli were used as distractors in a visual search task. We found that patients were generally distracted by the presence of the distractors but that the degree of distraction caused by the high-value and low-value distractors was similar. Furthermore, we found no evidence to support the possibility that dopamine replacement modulates the effect of reward on automatic attention allocation. Our results suggest a possible inability in Parkinson’s patients to use the reward value of stimuli when automatically allocating their attention, and raise the possibility that reward-driven allocation of resources may affect the adaptive modulation of other cognitive processes.

Dopamine replacement improves motor learning of an upper extremity task in people with Parkinson disease

BackgroundDopamine replacement medication has positive effects on existing motor skills for people with Parkinson disease (PD), but may have detrimental effects on the learning of motor skills necessary for effective rehabilitation according to the dopamine overdose hypothesis. ObjectivesThis study aimed to determine whether dopamine replacement medication (i.e. levodopa) affects: learning of a novel upper extremity task, decrements in skill following withdrawal of practice, the rate of learning, and the transfer of movement skill to untrained upper extremity tasks compared to training “off” medication, in people with PD. MethodsParticipants with mild-moderate PD (Hoehn and Yahr stage 2) were randomized to train “on” (n = 12) or “off” (n = 11) levodopa medication. Participants practiced 10 blocks of five trials of a functional motor task with their non-dominant upper extremity over three consecutive days (acquisition period), followed by a single block of five trials two and nine days later. Participants were also assessed “on” levodopa with two transfer tasks (the nine-hole peg test and a functional dexterity task) prior to any practice and nine days after the end of the acquisition period. ResultsParticipants who practiced “on” levodopa medication learned the upper extremity task to a greater extent that those who practiced “off” medication, as determined by retained performance two days after practice. Skill decrement and skill transfer were not significantly different between groups. Rate of learning was unable to be modelled in this sample. ConclusionsLevodopa medication improved the learning of an upper extremity task in people with mild-moderate PD.

Dopamine Replacement Medication Does Not Influence Implicit Learning of a Stepping Task in People With Parkinson’s Disease

Introduction. Treatment of Parkinson’s disease (PD) with exogenous dopamine (ie, levodopa) may positively affect motor symptoms, but may negatively affect other functions such as the learning of motor skills necessary for rehabilitation. This study aimed to determine whether levodopa medication affects general and sequence-specific learning of a stepping task and the transfer of movement skill to untrained balance tasks in people with PD. Methods. Participants with PD were randomized to practice “on” (n = 14) or “off” (n = 13) levodopa medication. Participants practiced 6 blocks of 6 trials of 24 steps of a stepping task over an acquisition period of 3 consecutive days, followed by single retention blocks of 6 trials 2 and 9 days later. Participants were also assessed on untrained balance (ie, transfer) tasks “on” levodopa before practice and following late retention. Results. There were no between-group differences in general learning, sequence-specific learning, or transfer of skill to untrained balance tasks (P > .05). Both groups demonstrated general and sequence-specific learning (P < .001) and trends for improvement in untrained tasks (P < .001 to P = .26) following practice. Detailed analysis of early acquisition revealed no difference between medication groups. Conclusion. People with PD improved performance on the stepping task with practice. The between-group effect sizes were small, suggesting that levodopa medication status (“on” versus “off”) during practice did not significantly affect general or sequence-specific learning of the task or components of early acquisition. The practice dose required to optimally result in functional improvements in untrained balance tasks, including reductions in falls, remains to be determined.

EP 54. Alpha activity in Fronto-Parietal Areas is modulated by Dopamine in Switching Visuospatial Attention in Parkinson’s Disease

Alpha-band activity (8–12 Hz) is a prominent electrophysiological signal in the human brain. Alpha power is known to be modulated by visuospatial attention in healthy humans( Thut et al., 2006 , Klimesch, 2012 ). Patients with Parkinson’s disease (PD) show a decrease in attentional control and deficits in switching of attention ( Aarsland et al., 2010 ). Here, we studied the role of alpha power in switching of visuospatial attention in PD. In PD, motor symptoms improve with dopamine replacement medication. We additionally studied whether dopaminergic medication alters the network activity in the alpha band during visuospatial attention. 20 subjects with diagnosed PD (15 male, 55 ± 10 y) performed the task in which they had to attend either to the left or right visual hemifield, indicated by a central cue. After a delay (1200 ms) a visual stimulus was presented in each hemifield. After another randomly chosen time, one of the two stimuli changed its color. A button press was required when the color change appeared on the cued side. We measured reaction times, and brain activity with magnetoencephalography. To analyze frequency bands of brain activity, we applied fast Fourier transform on the neural data. Subjects performed the task after 12 h withdrawal from dopamine replacement medication (“OFF”) and after receiving L-DOPA (“ON”). Before and after receiving L-DOPA, we performed the Unified Parkinson’s Disease Rating Scale (UPDRS) to assess efficiency of L-DOPA. We compared switching with not-switching trials, with “switching” meaning two successive trials required attention to opposite hemifields, “not-switching” meaning two successive trials required attention to the same hemifield. Comparison was done between and within medication factor (ON/OFF).UPDRS scores showed significant improvement of motor symptoms after receiving L-DOPA. During OFF, subjects responded faster in not-switching than in switching, whereas during ON there was no difference in reaction times. During OFF, we found a decrease of alpha power for switching relative to not-switching in right parietal (5–15 Hz) and right frontal areas (10–17 Hz) during the delay period. During ON, we found a decrease of alpha power for switching relative to not-switching in right occipital regions (2.5–15 Hz) during the cue period. Finally, we found a positive correlation between alpha power (8–12 Hz) and reaction times during OFF for switching, but not for not-switching. Faster reaction times for not-switching during OFF might reflect a strong focus on the previously attended side. Switching attention during OFF is therefore more difficult, which is reflected in less relative alpha power for switching, and thus more activity, in the fronto-parietal network. L-DOPA, therefore, increases flexibility for switching by lessening suppressing alpha-band activity in the fronto-parietal network. This could be achieved by better visual processing of the cue, as reflected in less alpha power during the cue period in visual areas.

Dopamine selectively remediates 'model-based' reward learning: a computational approach.

Patients with loss of dopamine due to Parkinson's disease are impaired at learning from reward. However, it remains unknown precisely which aspect of learning is impaired. In particular, learning from reward, or reinforcement learning, can be driven by two distinct computational processes. One involves habitual stamping-in of stimulus-response associations, hypothesized to arise computationally from 'model-free' learning. The other, 'model-based' learning, involves learning a model of the world that is believed to support goal-directed behaviour. Much work has pointed to a role for dopamine in model-free learning. But recent work suggests model-based learning may also involve dopamine modulation, raising the possibility that model-based learning may contribute to the learning impairment in Parkinson's disease. To directly test this, we used a two-step reward-learning task which dissociates model-free versus model-based learning. We evaluated learning in patients with Parkinson's disease tested ON versus OFF their dopamine replacement medication and in healthy controls. Surprisingly, we found no effect of disease or medication on model-free learning. Instead, we found that patients tested OFF medication showed a marked impairment in model-based learning, and that this impairment was remediated by dopaminergic medication. Moreover, model-based learning was positively correlated with a separate measure of working memory performance, raising the possibility of common neural substrates. Our results suggest that some learning deficits in Parkinson's disease may be related to an inability to pursue reward based on complete representations of the environment.

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence.

We previously reported very low levels of dopamine in post-mortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to the living brain, we tested whether striatal [(11)C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [(11)C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [(11)C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n=28; 2.6 days after last use) relative to controls (n=22) (+28%, p<0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [(11)C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent ~10 days following last use (n=17) were normal at the follow-up scan. Our imaging data support post-mortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication.

Does Dopamine Replacement Medication Affect Postural Sequence Learning in Parkinson's Disease?

Deficits in sequence-specific learning (SSL) may be a product of Parkinson's disease (PD) but this deficit could also be related to dopamine replacement. The purpose of this study was to determine whether dopamine replacement affected acquisition and retention of a standing Continuous Tracking Task in individuals with PD. SSL (difference between random/repeated Root Mean Square Error across trials) was calculated over 2 days of practice and 1 day of retention for 4 groups; 10 healthy young (HY), 10 healthy elders, 10 individuals with PD on, 9 individuals with PD off their usual dosage of dopamine replacement. Improvements in acquisition were observed for all groups; however, only the HY demonstrated retention. Therefore, age appeared to have the largest effect on SSL with no significant effect of medication. Additional research is needed to understand the influence of factors such as practice amount, task difficulty, and dopamine replacement status on SSL deficits during postural tasks.

Examining dorsal striatum in cognitive effort using Parkinson's disease and fMRI.

ObjectiveUnderstanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson's disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions.MethodsTwenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI.ResultsThe symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI.InterpretationThese findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment.

Clinical syndromes: Parkinsonian gait

Disturbances of gait manifest in almost all cases of Parkinson's disease (PD), often leading to loss of mobility and increased mortality. In this review a clinically oriented approach to gait disorders in different stages of PD is presented. In addition, interactions between motor behavior and mental processing will be discussed. Analyzing the clinical features of gait can be helpful to differentiate PD from atypical forms of parkinsonism. Bedside tests to distinguish parkinsonian gait disorders are reviewed. There is still an unmet need to effectively treat complex gait disturbances, which are frequently not responsive to dopamine replacement medication. We thus present current approaches for the management of dopa-refractory gait disorders.

Effects of dopamine replacement therapy on lower extremity kinetics and kinematics during a rapid force production task in persons with Parkinson disease

Postural instability appears to be a dopamine resistance motor deficit in persons with Parkinson disease (PD); however, little is known about the effects of dopamine replacement on the relative biomechanical contributions of individual lower extremity joints during postural control tasks. To gain insight, we examined persons with PD using both clinical and laboratory measures. For a clinical measure of motor severity we utilized the Unified Parkinson Disease Rating Scale motor subsection during both OFF and ON medication conditions. For the laboratory measure we utilized data gathered during a rapid lower extremity force production task. Kinematic and kinetic variables at the hip, knee, and ankle were gathered during a counter movement jump during both OFF and ON medication conditions. Sixteen persons with PD with a median Hoehn and Yahr severity of 2.5 completed the study. Medication resulted in significant improvements of angular displacement for the hip, knee, and ankle. Furthermore, significant improvements were revealed only at the hip for peak net moments and average angular velocity compared to the OFF medication condition. These results suggest that dopamine replacement medication result in decreased clinical motor disease severity and have a greater influence on kinetics and kinematics proximally. This proximally focused improvement may be due to active recruitment of muscle force and reductions in passive restraint during lower extremity rapid force production.

Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease

The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson’s disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning.

Effects of Levodopa on Vividness of Motor Imagery in Parkinson Disease

Motor imagery during functional magnetic resonance imaging is commonly used to understand the neural underpinnings of complex movements. This approach has recently been applied to individuals with Parkinson disease (PD) to better understand how brain function may relate to movement dysfunction. However, the ability of individuals with PD to imagine movements when "Off" dopamine replacement medication is poorly understood. Therefore, the primary purpose of the current study is to test the ability of people with PD to imagine movements while "On" and "Off" anti-Parkinson medication. Vividness of imagery was assessed in 28 individuals with mild to moderate PD (Hoehn and Yahr stages 1-3) via the Kinesthetic Visual Imagery Questionnaire (KVIQ-20) both "On" and "Off" anti-Parkinson medication. Vividness of imagery of 32 age-matched older adults was also assessed. No differences in vividness of imagery were observed between "Off" and "On" medication states (p = 0.15). Imagery was similar between controls and PD both "Off" (p = 0.25) and "On" (p = 0.46) anti-Parkinson medication. A significant correlation was observed between imagery and disease severity while "On" anti-Parkinson medication (r = -0.49; p = 0.008). Vividness of movement imagery was not different between "Off" and "On" anti-Parkinson medications or between PD and controls. These results suggest that people with PD are able to imagine similarly to older adults both when "On" and "Off" anti-Parkinson medication, and supports the use of motor imagery in the "Off" medication state.

Local field potential beta activity in the subthalamic nucleus of patients with Parkinson's disease is associated with improvements in bradykinesia after dopamine and deep brain stimulation

Parkinson's disease is treated pharmacologically with dopamine replacement medication and, more recently, by stimulating basal-ganglia nuclei such as the subthalamic nucleus (STN). Depth recordings after this procedure have revealed excessive activity at frequencies between 8 and 35 Hz ( Brown et al., 2001; Kuhn et al., 2004; Priori et al., 2004) that are reduced by dopamine therapy in tandem with improvements in bradykinesia/rigidity, but not tremor ( Kuhn et al., 2006). It has also been shown that improvements in motor symptoms after dopamine correlate with single unit activity in the beta range ( Weinberger et al., 2006). We recorded local field potentials (LFPs) from the subthalamic nucleus of patients with Parkinson's disease (PD) after surgery to implant deep brain stimulating electrodes while they were on and off dopaminergic medication. As well as replicating Kuhn et al., using the same patients we were able to extend Weinberger et al. to show that LFP beta oscillatory activity correlated with the degree of improvement in bradykinesia/rigidity, but not tremor, after dopamine medication. We also found that the power of beta oscillatory activity uniquely predicted improvements in bradykinesia/rigidity, but again not tremor, after stimulation of the STN in a regression analysis. However improvements after STN stimulation related inversely to beta power, possibly reflecting the accuracy of the electrode placement and/or the limits of STN stimulation in patients with the greatest levels of beta oscillatory activity.

Whole Body Vibration Versus Conventional Physiotherapy to Improve Balance and Gait in Parkinson’s Disease

Ebersbach G, Edler D, Kaufhold O, Wissel J. Whole body vibration versus conventional physiotherapy to improve balance and gait in Parkinson’s disease. Objective To compare the effects of whole body vibration (WBV) and conventional physiotherapy (PT) on levodopa-resistant disturbances of balance and gait in idiopathic Parkinson’s disease (PD). Design Randomized controlled rater-blinded trial comparing 2 active interventions, final follow-up assessment 4 weeks after termination of active intervention. Setting Specialized referral center, hospitalized care. Participants Patients with PD and dopa-resistant imbalance on stable dopamine replacement medication (N=27) were randomized (intent-to-treat population) to receive WBV (n=13) or conventional PT (controls, n=14). Twenty-one patients (per protocol population) completed follow-up (14 men, 7 women; mean age, 73.8y; age range, 62–84y; mean disease duration, 7.2y; mean dopa-equivalent dose, 768mg/d). Intervention Subjects were randomized to receive 30 sessions (two 15-min sessions a day, 5 days a week) of either WBV on an oscillating platform or conventional balance training including exercises on a tilt board. Twenty-one subjects (10 with WBV, 11 controls) were available for follow-up 4 weeks after treatment termination. Main Outcome Measures The primary measure was Tinetti Balance Scale score. Secondary clinical ratings included stand-walk-sit test, walking velocity, Unified Parkinson’s Disease Rating Scale (section III motor examination) score, performance in the pull test, and dynamic posturography. Results The Tinetti score improved from 9.3 to 12.8 points in the WBV group and from 8.3 to 11.7 in the controls. All secondary measures, except posturography, likewise improved at follow-up compared with baseline in both groups. Quantitative dynamic posturography only improved in patients with WBV (1937–1467mm) whereas there was no significant change in controls (1832–2030mm). Conclusions Equilibrium and gait improved in patients with PD receiving conventional WBV or conventional PT in the setting of a comprehensive rehabilitation program. There was no conclusive evidence for superior efficacy of WBV compared with conventional balance training.