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1.  Source memory and frontal functioning in Parkinson's disease 
The most extensively described pathological abnormality in Parkinson's disease (PD) is loss of dopaminergic neurons in the substantia nigra pars compacta and the ventral tegmental area, with degeneration of their striatal terminals. Because of the intimate connections between the striatum and the frontal lobes, individuals with PD often demonstrate impairments on those tasks relying on the prefrontal cortex (e.g., tests of executive functioning). Source memory, or memory for context, is believed to rely on the prefrontal cortex and has been previously associated with executive functioning performance, although it has received little attention in the PD literature. Executive functioning and source memory were measured in a group of nondemented PD patients and healthy control participants. Within the PD group, an anti-Parkinson's medication withdrawal manipulation was used to examine whether source memory was affected by phasic changes in dopamine levels. Compared to healthy control participants, PD patients were impaired in source memory (both on- and off-medication) and on a composite measure of executive functioning. Within the PD group, medication administration improved motor performance but did not have a significant effect on source memory.
doi:10.1017/S1355617709090572
PMCID: PMC2735205  PMID: 19402926
Dopamine; Cognition; Frontal lobe; Neuropsychology; Medication; Executive functioning
2.  Nocturnal sleep enhances working memory training in Parkinson's disease but not Lewy body dementia 
Brain  2012;135(9):2789-2797.
Working memory is essential to higher order cognition (e.g. fluid intelligence) and to performance of daily activities. Though working memory capacity was traditionally thought to be inflexible, recent studies report that working memory capacity can be trained and that offline processes occurring during sleep may facilitate improvements in working memory performance. We utilized a 48-h in-laboratory protocol consisting of repeated digit span forward (short-term attention measure) and digit span backward (working memory measure) tests and overnight polysomnography to investigate the specific sleep-dependent processes that may facilitate working memory performance improvements in the synucleinopathies. We found that digit span backward performance improved following a nocturnal sleep interval in patients with Parkinson's disease on dopaminergic medication, but not in those not taking dopaminergic medication and not in patients with dementia with Lewy bodies. Furthermore, the improvements in patients with Parkinson's disease on dopaminergic medication were positively correlated with the amount of slow-wave sleep that patients obtained between training sessions and negatively correlated with severity of nocturnal oxygen desaturation. The translational implication is that working memory capacity is potentially modifiable in patients with Parkinson's disease but that sleep disturbances may first need to be corrected.
doi:10.1093/brain/aws192
PMCID: PMC3577106  PMID: 22907117
consolidation; sleep; working memory; training; Parkinson's disease; dementia with Lewy bodies
3.  Differential Response of Speed, Amplitude, and Rhythm to Dopaminergic Medications in Parkinson’s Disease 
Movement Disorders  2011;26(14):2504-2508.
Although movement impairment in Parkinson’s disease includes slowness (bradykinesia), decreased amplitude (hypokinesia), and dysrhythmia, clinicians are instructed to rate them in a combined 0–4 severity scale using the Unified Parkinson’s Disease Rating Scale motor subscale. The objective was to evaluate whether bradykinesia, hypokinesia, and dysrhythmia are associated with differential motor impairment and response to dopaminergic medications in patients with Parkinson’s disease. Eighty five Parkinson’s disease patients performed finger-tapping (item 23), hand-grasping (item 24), and pronation–supination (item 25) tasks OFF and ON medication while wearing motion sensors on the most affected hand. Speed, amplitude, and rhythm were rated using the Modified Bradykinesia Rating Scale. Quantitative variables representing speed (root mean square angular velocity), amplitude (excursion angle), and rhythm (coefficient of variation) were extracted from kinematic data. Fatigue was measured as decrements in speed and amplitude during the last 5 seconds compared with the first 5 seconds of movement. Amplitude impairments were worse and more prevalent than speed or rhythm impairments across all tasks (P < .001); however, in the ON state, speed scores improved exclusively by clinical (P < 10−6) and predominantly by quantitative (P < .05) measures. Motor scores from OFF to ON improved in subjects who were strictly bradykinetic (P < .01) and both bradykinetic and hypokinetic (P < 10−6), but not in those strictly hypokinetic. Fatigue in speed and amplitude was not improved by medication. Hypokinesia is more prevalent than bradykinesia, but dopaminergic medications predominantly improve the latter. Parkinson’s disease patients may show different degrees of impairment in these movement components, which deserve separate measurement in research studies.
doi:10.1002/mds.23893
PMCID: PMC3318914  PMID: 21953789
Parkinson’s disease; bradykinesia; UPDRS; MBRS; KinetiSense
4.  Dissociation between Active and Observational Learning from Positive and Negative Feedback in Parkinsonism 
PLoS ONE  2012;7(11):e50250.
Feedback to both actively performed and observed behaviour allows adaptation of future actions. Positive feedback leads to increased activity of dopamine neurons in the substantia nigra, whereas dopamine neuron activity is decreased following negative feedback. Dopamine level reduction in unmedicated Parkinson’s Disease patients has been shown to lead to a negative learning bias, i.e. enhanced learning from negative feedback. Recent findings suggest that the neural mechanisms of active and observational learning from feedback might differ, with the striatum playing a less prominent role in observational learning. Therefore, it was hypothesized that unmedicated Parkinson’s Disease patients would show a negative learning bias only in active but not in observational learning. In a between-group design, 19 Parkinson’s Disease patients and 40 healthy controls engaged in either an active or an observational probabilistic feedback-learning task. For both tasks, transfer phases aimed to assess the bias to learn better from positive or negative feedback. As expected, actively learning patients showed a negative learning bias, whereas controls learned better from positive feedback. In contrast, no difference between patients and controls emerged for observational learning, with both groups showing better learning from positive feedback. These findings add to neural models of reinforcement-learning by suggesting that dopamine-modulated input to the striatum plays a minor role in observational learning from feedback. Future research will have to elucidate the specific neural underpinnings of observational learning.
doi:10.1371/journal.pone.0050250
PMCID: PMC3503978  PMID: 23185586
5.  Differential Effects of Parkinson's Disease and Dopamine Replacement on Memory Encoding and Retrieval 
PLoS ONE  2013;8(9):e74044.
Increasingly memory deficits are recognized in Parkinson's disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients' cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms.
doi:10.1371/journal.pone.0074044
PMCID: PMC3784427  PMID: 24086309
6.  L-dopa impairs learning, but spares generalization, in Parkinson’s disease 
Neuropsychologia  2005;44(5):774-784.
In this study we examined the effect of dopaminergic modulation on learning and memory. Parkinson’s patients were tested ‘on’ versus ‘off’ dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested ‘on’ medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson’s disease.
doi:10.1016/j.neuropsychologia.2005.07.013
PMCID: PMC1626444  PMID: 16150469
Dopamine; Learning; Memory; Basal ganglia; Cognition
7.  Medication and subthalamic nucleus deep brain stimulation similarly improve balance and complex gait in Parkinson disease 
Background
Dopaminergic medications and subthalamic nucleus deep brain stimulation (STN-DBS) alleviate motor symptoms in Parkinson disease, but balance and gait are more variably affected. Balance reports are particularly inconsistent. Further, despite their prevalence in daily life, complex gait situations including backward and dual task gait are rarely studied. We aimed to assess how medications, STN-DBS, and both therapies combined affect balance and complex gait.
Methods
Twelve people with Parkinson disease were evaluated OFF medication with STN-DBS OFF and ON as well as ON medication with STN-DBS OFF and ON. Motor impairment was measured with the Movement Disorder Society Unified Parkinson Disease Rating Scale motor section (MDS-UPDRS-III). The Mini-Balance Evaluations Systems Test, timed-up-and-go, and dual task timed-up-and-go measured balance and mobility. Preferred-pace forward, fast as possible, backward, dual task forward, and dual task backward gait were also analyzed.
Results
Medication improved MDS-UPDRS-III scores, dual task timed-up-and-go, and stride length across all gait tasks. STN-DBS improved MDS-UPDRS-III scores, balance scores, dual task timed-up-and-go, and stride length and velocity across all gait tasks. Medication and STN-DBS combined did not provide additional benefits over either therapy alone.
Conclusions
Overall, dopaminergic medications and STN-DBS provided similar improvements in balance and gait tasks, although the effects of STN-DBS were stronger, potentially due to reductions in medication doses after surgery. Lack of synergistic effect of treatments may suggest both therapies improve balance and gait by influencing similar neural pathways.
doi:10.1016/j.parkreldis.2012.07.013
PMCID: PMC3508177  PMID: 22885253
Parkinson Disease; Medication; Deep Brain Stimulation; Gait; Balance
8.  Parkinson's disease and dopaminergic therapy—differential effects on movement, reward and cognition 
Brain  2008;131(8):2094-2105.
Cognitive deficits are very common in Parkinson's disease particularly for ‘executive functions’ associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative ‘on’ and ‘off’ states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1–4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico–striato–thalamo–cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease.
doi:10.1093/brain/awn112
PMCID: PMC2494617  PMID: 18577547
Parkinson's disease; reward; task-shift; fMRI; dopamine
9.  Differential Influence of Levodopa on Reward-Based Learning in Parkinson's Disease 
The mesocorticolimbic dopamine (DA) system linking the dopaminergic midbrain to the prefrontal cortex and subcortical striatum has been shown to be sensitive to reinforcement in animals and humans. Within this system, coexistent segregated striato-frontal circuits have been linked to different functions. In the present study, we tested patients with Parkinson's disease (PD), a neurodegenerative disorder characterized by dopaminergic cell loss, on two reward-based learning tasks assumed to differentially involve dorsal and ventral striato-frontal circuits. 15 non-depressed and non-demented PD patients on levodopa monotherapy were tested both on and off medication. Levodopa had beneficial effects on the performance on an instrumental learning task with constant stimulus-reward associations, hypothesized to rely on dorsal striato-frontal circuits. In contrast, performance on a reversal learning task with changing reward contingencies, relying on ventral striato-frontal structures, was better in the unmedicated state. These results are in line with the “overdose hypothesis” which assumes detrimental effects of dopaminergic medication on functions relying upon less affected regions in PD. This study demonstrates, in a within-subject design, a double dissociation of dopaminergic medication and performance on two reward-based learning tasks differing in regard to whether reward contingencies are constant or dynamic. There was no evidence for a dose effect of levodopa on reward-based behavior with the patients’ actual levodopa dose being uncorrelated to their performance on the reward-based learning tasks.
doi:10.3389/fnhum.2010.00169
PMCID: PMC2967381  PMID: 21048900
levodopa; decision-making; reinforcement learning; reversal learning; overdose hypothesis; PD; reward contingencies
10.  Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study 
Brain : a journal of neurology  2009;132(Pt 5):1376-1385.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
doi:10.1093/brain/awp054
PMCID: PMC3479148  PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
11.  Dopaminergic and Clinical Correlates of Pathological Gambling in Parkinson’s Disease: A Case Report 
Dopaminergic medication for motor symptoms in Parkinson’s disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [11C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [11C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.
doi:10.3389/fnbeh.2013.00095
PMCID: PMC3725950  PMID: 23908610
Parkinson’s disease; pathological gambling; impulse control disorders; decision-making; dopamine
12.  Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson's patients* 
Brain  2009;132(9):2385-2395.
Parkinson's disease is characterized by the degeneration of dopaminergic pathways projecting to the striatum. These pathways are implicated in reward prediction. In this study, we investigated reward and punishment processing in young, never-medicated Parkinson's disease patients, recently medicated patients receiving the dopamine receptor agonists pramipexole and ropinirole and healthy controls. The never-medicated patients were also re-evaluated after 12 weeks of treatment with dopamine agonists. Reward and punishment processing was assessed by a feedback-based probabilistic classification task. Personality characteristics were measured by the temperament and character inventory. Results revealed that never-medicated patients with Parkinson's disease showed selective deficits on reward processing and novelty seeking, which were remediated by dopamine agonists. These medications disrupted punishment processing. In addition, dopamine agonists increased the correlation between reward processing and novelty seeking, whereas these drugs decreased the correlation between punishment processing and harm avoidance. Our finding that dopamine agonist administration in young patients with Parkinson's disease resulted in increased novelty seeking, enhanced reward processing, and decreased punishment processing may shed light on the cognitive and personality bases of the impulse control disorders, which arise as side-effects of dopamine agonist therapy in some Parkinson's disease patients.
doi:10.1093/brain/awp094
PMCID: PMC2766178  PMID: 19416950
Parkinson's disease; reward; novelty seeking; dopamine; pramipexole; ropinirole
13.  Risk and learning in impulsive and non-impulsive patients with Parkinson’s disease 
Relatively little is known about the interaction between behavioural changes, medication and cognitive function in Parkinson’s disease. We examined working memory, learning and risk aversion in patients with Parkinson’s disease (PD) with and without impulsive or compulsive behaviour and compared to a group of age-matched control subjects. Parkinson patients with impulsive or compulsive behaviour (PD+ ICB) had poorer working memory performance than either controls or PD patients without ICB. PD+ICB patients also showed decreased learning from negative feedback and increased learning from positive feedback off compared to on dopaminergic medication. This interaction between medication status and learning was the opposite of that found in the PD patients without a diagnosis of ICB. Finally, the PD group showed increased risk preference on medication relative to controls and the subgroup of PD+ICB patients with pathological gambling were overall more risk prone than the PD group. Thus, medication status and an impulsive behavioural diagnosis differentially affect several behaviors in PD.
doi:10.1002/mds.23247
PMCID: PMC3093055  PMID: 20721918
Parkinson’s disease; Impulse control disorder; risk and learning; memory
14.  Cognitive slowing in Parkinson's disease resolves after practice 
Objective: To assess the effect of dopaminergic repletion on working memory in Parkinson's disease.
Methods: The role of dopaminergic state on working memory in patients with Parkinson's disease was determined using the Sternberg item recognition paradigm, a continuous performance task that dissociates the motor and cognitive components of response time. Ten patients with Parkinson's disease were tested in an "on" state (on dopaminergic drug treatment) and a practical "off" state in two sessions held one week apart in counterbalanced order; 10 controls matched for age and education were studied at the same time points.
Results: Patients with Parkinson's disease showed impaired working memory, independent of motor slowing. During session 1, the performance of the patients was worse than the controls, regardless of dopaminergic state. The patients showed a significant improvement in the cognitive component of task performance during the second session, such that they no longer differed from the controls. The performance of the control subjects remained stable over the two sessions.
Conclusions: Working memory performance of patients with Parkinson's disease did not change in association with dopaminergic state; rather, the performance improved over time. The pattern of improvement over time suggests a delay in proceduralising the task, similar to the deficits shown by such patients in procedural learning of other tasks.
doi:10.1136/jnnp.73.5.524
PMCID: PMC1738096  PMID: 12397144
15.  Inverted-U shaped dopamine actions on human working memory and cognitive control 
Biological psychiatry  2011;69(12):e113-e125.
Brain dopamine has long been implicated in cognitive control processes, including working memory. However, the precise role of dopamine in cognition is not well understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum dopamine level for cognitive function implicates the need to take into account baseline levels of dopamine when isolating dopamine’s effects. Second, cognitive control is a multi-factorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum respectively. Manipulating dopamine will thus have paradoxical consequences for distinct cognitive control processes depending on distinct basal or optimal levels of dopamine in different brain regions.
doi:10.1016/j.biopsych.2011.03.028
PMCID: PMC3111448  PMID: 21531388
Working memory; cognitive control; prefrontal cortex; striatum; dopamine; fMRI
16.  Dopamine replacement therapy does not restore the ability of Parkinsonian patients to make rapid adjustments in motor strategies according to changing sensorimotor contexts 
Parkinsonism & related disorders  2007;13(7):425-433.
The ability of dopamine replacement to restore rapid motor adjustments in Parkinson's disease was investigated. Medicated and non-medicated patients performed finger-to-nose movements while simultaneously bending the trunk forward, without vision. Trunk motion was blocked unexpectedly, necessitating rapid adjustments in arm trajectories. Patients exhibited irregular hand paths, plateaus in hand velocity, and prolonged movement times which were significantly greater in perturbed trials. Medication improved kinematics but perturbation-induced disturbances persisted and did not approximate the levels of non-perturbed trials nor those of controls. Dopaminergic replenishment in Parkinson’s disease may therefore have limited restorative benefits for rapid context-specific motor control.
doi:10.1016/j.parkreldis.2007.02.003
PMCID: PMC2211273  PMID: 17446116
Parkinson’s disease; adaptive motor control; dopamine medication; basal ganglia
17.  Dopaminergic modulation of the updating of stimulus–response episodes in Parkinson’s disease 
Behavioural brain research  2011;228(1):82-86.
Increasing evidence suggests that the control of retrieval of episodic feature bindings is modulated by the striatal dopaminergic pathway. The present study investigated whether this may reflect a contribution from the ventral or the dorsal part of the striatum. Along the lines of the overdose hypothesis in Parkinson’s disease (PD), functions known to rely on the dorsal striatum are enhanced with dopaminergic medication, while operations relying on the ventral circuitry are impaired. We found that partial mismatches between present and previous stimulus–response relations are, compared to control participants, abnormally low OFF DA medication and normalized ON DA medication. The results suggest that the dorsal striatum, but not (or not so much) the ventral striatum, is driving the flexible control of retrieval of stimulus–response episodes.
doi:10.1016/j.bbr.2011.11.034
PMCID: PMC3657465  PMID: 22155477
Parkinson’s disease; Event file; Dopamine; Dorsal striatum
18.  Adenosine A2A receptors in Parkinson’s disease treatment 
Purinergic Signalling  2008;4(4):305-312.
Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug.
doi:10.1007/s11302-008-9100-8
PMCID: PMC2583202  PMID: 18438720
Parkinson’s disease; Adenosine; Adenosine receptors; Dopamine receptors; Neuroprotection
19.  Therapeutic effect of Yang-Xue-Qing-Nao granules on sleep dysfunction in Parkinson’s disease 
Chinese Medicine  2013;8:14.
Background
This study aimed to evaluate the effects of add-on Yang-Xue-Qing-Nao granules (YXQN) on sleep dysfunction in patients with Parkinson’s disease (PD).
Methods
PD participants fitted with an actigraph took either YXQN or placebo granules in a randomized manner for 12 weeks while maintaining other anti-parkinsonism medications (e.g., dopaminergic agent, dopamine agonist) unchanged. Additional participants without sleep disturbance or PD served as controls. The changes in detrended fluctuation analysis (DFA) of physical activity with respect to diurnal activity (DA), evening activity (EA), nocturnal activity (NA), Parkinson’s disease sleep scale (PDSS) score and unified Parkinson’s disease rating scale (UPDRS) score were evaluated every 4 weeks during the 12-week YXQN intervention period and again at week 16.
Results
A total of 61 (placebo group, n = 30; YXQN group, n = 31) idiopathic PD participants with sleep dysfunction (mean age ± standard deviation, 63.4 ± 8.6 years; mean duration of illness, 5.8 ± 6.6 years) completed the study. Significant improvements in EA (p = 0.033, 0.037 and 0.029), DA (p = 0.041, 0.038 and 0.027) and PDSS score (p = 0.034, 0.028 and 0.029) were observed in the YXQN group at weeks 8 and 12, and maintained until week 16, respectively.
Conclusion
YXQN improved the DFA parameters, and PDSS and UPDRS scores in PD participants.
doi:10.1186/1749-8546-8-14
PMCID: PMC3733743  PMID: 23890176
20.  Perseveration and Choice in Parkinson's Disease: The Impact of Progressive Frontostriatal Dysfunction on Action Decisions 
Cerebral Cortex (New York, NY)  2012;23(7):1572-1581.
We have previously shown that patients with Parkinson's disease (PD) perseverate in their choice of action relative to healthy controls, and that this is affected by dopaminergic medication (Hughes LE, Barker RA, Owen AM, Rowe JB. 2010. Parkinson's disease and healthy aging: Independent and interacting effects on action selection. Hum Brain Mapp. 31:1886–1899). To understand further the neural basis of these phenomena, we used a new task that manipulated the options to repeat responses. Seventeen patients with idiopathic PD were studied both “on” and “off” dopaminergic medication and 18 healthy adults were scanned twice as controls. All subjects performed a right-handed 3-choice button press task, which controlled the availability of repeatable responses. The frequency of choosing to repeat a response (a form of perseveration) in patients was related to dopamine therapy and disease severity as a “U-shaped” function. For repetitive trials, this “U-shaped” relationship was also reflected in the BOLD response in the caudate nuclei and ventrolateral prefrontal cortex. Our results support a U-shaped model of optimized cortico-striatal circuit function and clearly demonstrate that flexibility in response choice is modulated by an interaction of dopamine and disease severity.
doi:10.1093/cercor/bhs144
PMCID: PMC3673173  PMID: 22661404
Action-selection; Caudate; fMRI; Ventrolateral prefrontal cortex; “U-shaped” function
21.  COGNITIVE DECLINES ONE YEAR AFTER UNILATERAL DEEP BRAIN STIMULATION SURGERY IN PARKINSON’S DISEASE: A CONTROLLED STUDY USING RELIABLE CHANGE 
The Clinical neuropsychologist  2008;23(3):385-405.
Conflicting research suggests that deep brain stimulation surgery, an effective treatment for medication-refractory Parkinson’s disease (PD), may lead to selective cognitive declines. We compared cognitive performance of 22 PD patients who underwent unilateral DBS to the GPi or STN to that of 19 PD controls at baseline and 12 months. We hypothesized that compared to PD controls, DBS patients would decline on tasks involving dorsolateral prefrontal cortex circuitry (letter fluency, semantic fluency, and Digit Span Backward) but not on other tasks (Vocabulary, Boston Naming Test), and that a greater proportion of DBS patients would fall below Reliable Change Indexes (RCIs). Compared to controls, DBS patients declined only on the fluency tasks. Analyses classified 50% of DBS patients as decliners, compared to 11% of controls. Decliners experienced less motor improvement than non-decliners. The present study adds to the literature through its hypothesis-driven method of task selection, inclusion of a disease control group, longer-term follow-up and use of Reliable Change. Our findings provide evidence that unilateral DBS surgery is associated with verbal fluency declines and indicate that while these changes may not be systematically related to age, cognitive or depression status at baseline, semantic fluency declines may be more common after left-sided surgery. Finally, use of Reliable Change highlights the impact of individual variability and indicates that fluency declines likely reflect significant changes in a subset of patients who demonstrate a poorer surgical outcome overall.
doi:10.1080/13854040802360582
PMCID: PMC3045862  PMID: 18821180
Parkinson’s disease; Deep brain stimulation; Reliable Change
22.  Diagnosis and treatment of impulse control disorders in patients with movement disorders 
Impulse control disorders are a psychiatric condition characterized by the failure to resist an impulsive act or behavior that may be harmful to self or others. In movement disorders, impulse control disorders are associated with dopaminergic treatment, notably dopamine agonists (DAs). Impulse control disorders have been studied extensively in Parkinson’s disease, but are also recognized in restless leg syndrome and atypical Parkinsonian syndromes. Epidemiological studies suggest younger age, male sex, greater novelty seeking, impulsivity, depression and premorbid impulse control disorders as the most consistent risk factors. Such patients may warrant special monitoring after starting treatment with a DA. Various individual screening tools are available for people without Parkinson’s disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease has been developed specifically for Parkinson’s disease. The best treatment for impulse control disorders is prevention. However, after the development of impulse control disorders, the mainstay intervention is to reduce or discontinue the offending anti-Parkinsonian medication. In refractory cases, other pharmacological interventions are available, including neuroleptics, antiepileptics, amantadine, antiandrogens, lithium and opioid antagonists. Unfortunately, their use is only supported by case reports, small case series or open-label clinical studies. Prospective, controlled studies are warranted. Ongoing investigations include naltrexone and nicotine.
doi:10.1177/1756285613476127
PMCID: PMC3625015  PMID: 23634190
Impulse control disorders; Parkinson’s disease; restless leg syndrome; parkinsonism; dopamine agonist; non-motor complication; neurobehavioural
23.  Predictors of Mild Cognitive Impairment in Early-Stage Parkinson's Disease 
Aim
The aim of this study was to identify mild cognitive deficits in Parkinson's disease (PD) prior to extensive neurodegeneration and to evaluate the extent to which dopamine depletion and other disease-related predictors can explain cognitive profiles.
Methods
Neuropsychological performances of 40 nondemented early-stage PD patients and 42 healthy controls were compared across on or off dopaminergic medications. Stepwise regression evaluated cognitive predictors of early-stage PD and disease-related predictors of PD cognition (levodopa dose, disease duration, Unified Parkinson's Disease Rating Scale score, sleep, quality of life, and mood) across on and off states.
Results
Neuropsychological performance was lower in PD patients across cognitive domains with significant memory, naming, visuomotor, and complex attention/executive deficits, but with intact visuospatial, simple attention, and phonemic fluency functions. However, medication effects were absent except for simple attention. Regression analyses revealed age, working memory, and memory recall to be the best cognitive predictors of PD, while age, quality of life, disease duration, and anxiety predicted PD cognition in the off state.
Conclusion
Nondemented early-stage PD patients presented with extensive mild cognitive deficits including prominent memory impairment. The profile was inconsistent with expected isolated frontostriatal dysfunction previously attributed to dopamine depletion and this highlights the need to further characterize extranigral sources of mild cognitive impairment in PD.
doi:10.1159/000351421
PMCID: PMC3670639  PMID: 23741229
Parkinson's disease; Mild cognitive impairment; Predictors; Neuropsychological performance; Dopaminergic medication
24.  The effects of augmented visual feedback during balance training in Parkinson’s disease: study design of a randomized clinical trial 
BMC Neurology  2013;13:137.
Background
Patients with Parkinson’s disease often suffer from reduced mobility due to impaired postural control. Balance exercises form an integral part of rehabilitative therapy but the effectiveness of existing interventions is limited. Recent technological advances allow for providing enhanced visual feedback in the context of computer games, which provide an attractive alternative to conventional therapy. The objective of this randomized clinical trial is to investigate whether a training program capitalizing on virtual-reality-based visual feedback is more effective than an equally-dosed conventional training in improving standing balance performance in patients with Parkinson’s disease.
Methods/design
Patients with idiopathic Parkinson’s disease will participate in a five-week balance training program comprising ten treatment sessions of 60 minutes each. Participants will be randomly allocated to (1) an experimental group that will receive balance training using augmented visual feedback, or (2) a control group that will receive balance training in accordance with current physical therapy guidelines for Parkinson’s disease patients. Training sessions consist of task-specific exercises that are organized as a series of workstations. Assessments will take place before training, at six weeks, and at twelve weeks follow-up. The functional reach test will serve as the primary outcome measure supplemented by comprehensive assessments of functional balance, posturography, and electroencephalography.
Discussion
We hypothesize that balance training based on visual feedback will show greater improvements on standing balance performance than conventional balance training. In addition, we expect that learning new control strategies will be visible in the co-registered posturographic recordings but also through changes in functional connectivity.
Trial registration
ISRCTN: ISRCTN47046299
doi:10.1186/1471-2377-13-137
PMCID: PMC3852133  PMID: 24093506
Randomized clinical trial; Parkinson’s disease; Physical therapy; Balance training; Postural control; Virtual reality; Visual feedback; Electroencephalography; Posturography; Force plate
25.  Impaired endogenously-evoked automated reaching in Parkinson’s disease 
The Journal of Neuroscience  2011;31(49):17848-17863.
Intended reaches triggered by exogenous targets often coexist with spontaneous, automated movements that are endogenously activated. It has been posited that Parkinson’s disease (PD) primarily impairs automated movements but it is unknown to what extent this may affect multi-joint-limb control, particularly when patients are off their dopaminergic medications. Here we tested 9 human patients with PD while off-dopaminergic medication vs. 9 age-matched normal controls (NC). Participants performed intentional reaches forward to a target in a dark room and then transitioned back to their initial posture. Upon target-flash, three forms of guidance were used: (1) memory with eyes closed; (2) continuous target vision only and (3) vision of their moving finger only. The trajectories of their arm joints were measured and their joint-velocities decomposed into the (intended) task-relevant and the (spontaneous) task-incidental degrees-of-freedom (DOF). We also measured the balance between these two subsets of DOF as these movements unfolded. In PD patients we found that the incidental DOF were abnormally variable during the retracting movements and prevailed over the task-relevant DOF. By contrast, their forward intentional motions were abnormally dominated by the task-relevant components. Moreover, the patients abruptly transitioned between voluntary and automated modes of joint control, and unlike NC, the type of visual guidance differentially affected their postural trajectories. These findings lend support to an emerging view that there is a loss of automated control in PD which contributes to impairments in voluntary control, and that basal-ganglia-cortical circuits are critical for the maintenance and balance of multi-joint control.
doi:10.1523/JNEUROSCI.1150-11.2011
PMCID: PMC3294266  PMID: 22159100
voluntary; automated; joint control; reaches; Parkinson’s disease

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