Medicated Parkinson's Disease Patients Research Articles

The Effect of Encoding Condition on Free Recall in Parkinson's Disease: Incidental and Intentional Memory are Equally Affected

Free recall memory deficits are common at early stages of Parkinson's disease (PD). As most studies have used intentional memory tasks, there is little information on how non-intentional, incidental encoding conditions affect memory performance in PD. We studied possible differences between PD patients and controls on free recall using incidental and intentional visual memory tasks. Free recall was examined in relation to attentive/executive functioning and subjective memory complaints. A total of 29 non-demented, medicated PD patients (age 60, disease duration 19 months) and 29 healthy controls (age 61) participated in the study. Incidental free recall was studied using a memory-modification of the Boston naming test (Memo-BNT) and intentional free recall with the 20 Objects test. There was a significant main effect for group due to worse free recall performances in the PD group. No statistically significant interaction between group and encoding condition was observed. The free recall deficit in the PD group was related to cognitive/psychomotor slowing, but not to attentive/executive task demands, or to subjective memory complaints. The results indicate that PD patients are impaired on free recall irrespective of encoding condition.

A Neurocomputational Model of Dopamine and Prefrontal–Striatal Interactions during Multicue Category Learning by Parkinson Patients

Most existing models of dopamine and learning in Parkinson disease (PD) focus on simulating the role of basal ganglia dopamine in reinforcement learning. Much data argue, however, for a critical role for prefrontal cortex (PFC) dopamine in stimulus selection in attentional learning. Here, we present a new computational model that simulates performance in multicue category learning, such as the "weather prediction" task. The model addresses how PD and dopamine medications affect stimulus selection processes, which mediate reinforcement learning. In this model, PFC dopamine is key for attentional learning, whereas basal ganglia dopamine, consistent with other models, is key for reinforcement and motor learning. The model assumes that competitive dynamics among PFC neurons is the neural mechanism underlying stimulus selection with limited attentional resources, whereas competitive dynamics among striatal neurons is the neural mechanism underlying action selection. According to our model, PD is associated with decreased phasic and tonic dopamine levels in both PFC and basal ganglia. We assume that dopamine medications increase dopamine levels in both the basal ganglia and PFC, which, in turn, increase tonic dopamine levels but decrease the magnitude of phasic dopamine signaling in these brain structures. Increase of tonic dopamine levels in the simulated PFC enhances attentional shifting performance. The model provides a mechanistic account for several phenomena, including (a) medicated PD patients are more impaired at multicue probabilistic category learning than unmedicated patients and (b) medicated PD patients opt out of reversal when there are alternative and redundant cue dimensions.

Iowa Gambling Task in Parkinson's Disease

Cognitive impairments are common in patients with Parkinson's disease (PD) from the early stages. Recent studies reported that medicated PD patients have poor performances, with respect to age-matched healthy controls, in a decision-making task like the Iowa Gambling Task (IGT), which detects the ability to alter choice behavior in response to fluctuations in reward contingencies. The IGT principally activates functions related to the orbitofrontal cortex, which plays a crucial role in the generation of outcome expectancies and processing of rewards. The analysis of IGT performances of PD patients is of particular interest because PD represents a good clinical model to study reward processing when its neural bases are affected by a neuropathology or are overdosed by dopaminergic therapies. As a matter of fact, either PD-related neuropathology in advanced stages of the disease or the dopamine replacement therapy from earlier stages of PD may affect the functioning of the orbitofrontal cortex. Three causal hypotheses on a dysfunctional decision making in PD patients, as assessed by IGT, are discussed. Finally, the possible relation between the phenomenon of decision-making impairment and impulse control disorders, a psychiatric complication observed with increasing frequency in PD patients, is discussed.

Elevation of oxidized DJ-1 in the brain and erythrocytes of Parkinson disease model animals

DJ-1, the causative gene of a familial form of Parkinson's disease (PD), has been reported undergo oxidation preferentially at the 106th cysteine residue (Cys-106) under oxidative stress. Recently, it has been found that the levels of oxidized DJ-1 in erythrocytes of unmedicated PD patients are markedly higher than those in medicated PD patients and healthy subjects. In the present study, we examined the changes in oxidized DJ-1 levels in the brain and erythrocytes of PD animal models using specific antibodies against Cys-106-oxidized DJ-1. Treatment with PD model compounds such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine significantly elevated the levels of oxidized DJ-1 in erythrocytes. Immunohistochemical analysis also revealed that the number of oxidized DJ-1 antibody-positive cells in the substantia nigra of MPTP-treated mouse increased in a dose-dependent manner. These results suggest that the oxidative modification of DJ-1 in the brain and erythrocytes is involved in the pathogenesis of PD in animal models.

Intact Reward Learning but Elevated Delay Discounting in Parkinson's Disease Patients With Impulsive-Compulsive Spectrum Behaviors

It has been postulated that impulsive-compulsive spectrum behaviors (ICBs) in Parkinson's disease (PD) reflect overvaluation of rewards, resulting from excessive dopaminergic transmission in the ventral striatum. However, as the ventral striatum is also strongly implicated in delay discounting, an alternative explanation would be that, similar to stimulant-dependent individuals, PD patients with ICBs impulsively discount future rewards. To test these hypotheses, we investigated whether 36 medicated PD patients with and without ICBs differed from controls on measures of stimulus-reinforcement learning and delay discounting. There was a clear double dissociation between reward learning and impulsivity in PD patients with and without ICBs. Although PD patients without ICBs were impaired at learning stimulus-reward associations for high-probability stimuli, PD patients with ICBs were able to learn such associations equally as well as controls. By contrast, PD patients with ICBs showed highly elevated delay discounting, whereas PD patients without ICBs did not differ from controls on this measure. These results contradict the hypothesis that ICBs in PD result from overvaluation of rewards. Instead, our data are more consistent with a model in which excessive dopaminergic transmission induces a strong preference for immediate over future rewards, driving maladaptive behavior in PD patients with ICBs.

Dopaminergic medication boosts action–effect binding in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder affecting voluntary motor control. However, little is known about the experience of voluntary action in PD patients. A key component of action experience is the feeling of controlling one's own actions, and through them, external events. In healthy individuals this sense of agency (SoA) is associated with a subjective compression of time, such that actions and their effects are perceived as bound together across time. This action–effect binding provides an indirect measure of SoA. Nine PD patients and age-matched controls judged the time of voluntary actions and of an auditory effect (a tone) of the action. The pattern of results resembled previous studies, with the perceived time of actions showing a shift towards the subsequent tone, relative to a baseline condition involving actions without tones. Similarly, the perceived times of tones showed a shift towards the preceding action that caused the tone, relative to a baseline condition involving tones only. The patients were tested both on and off dopaminergic medication. PD patients off medication showed no significant change in action–effect binding relative to controls. Conversely, PD patients on medication showed a significant increase in action–effect binding relative to their own performance off medication. Increased availability of dopamine strengthened the experience of association between actions and external events, enhancing the sense of agency. These results shed light on the contribution of dopamine to the experience of instrumental action, and also on impulse control disorders and psychosis in medicated PD patients.

Preparation and application of monoclonal antibodies against oxidized DJ-1. Significant elevation of oxidized DJ-1 in erythrocytes of early-stage Parkinson disease patients

DJ-1 was initially identified as a novel oncogene and has recently been found to be a causative gene for a familial form of Parkinson's disease (PD), viz, PARK7. Cysteine residue at position 106 (Cys-106) in DJ-1 was found to be oxidized preferentially under oxidative stress. In the present study, we developed specific antibodies against Cys-106-oxidized DJ-1 using baculovirus particles displaying the surface glycoprotein gp64-fusion protein as the immunizing agent. Western blot analysis combined with two-dimensional gel electrophoresis revealed that these antibodies specifically recognized oxidized DJ-1. Furthermore, we developed a competitive enzyme-linked immunosorbent assay (ELISA) for detecting oxidized DJ-1 and measured blood levels of oxidized DJ-1 in PD patients ( n = 15). It was observed that the levels of oxidized DJ-1 in erythrocytes of unmedicated PD patients were markedly higher without overlap than those of medicated PD patients and healthy subjects. No significant difference was observed in DJ-1 levels between mediated and unmediated PD patient. These results suggest the oxidative modification of DJ-1 in PD patients and the potential application of the antibody for diagnosis of PD at early-stage.

To the influence of general slowing and medication on identity‐ and location‐based priming effects in patients with Parkinson's disease

Previous studies on inhibitory mechanisms assessed by negative priming (NP) paradigms in patients suffering from Parkinson's disease (PD) have yielded highly ambiguous results. The present study examined two possible reasons for this heterogeneity: general slowing and anti-Parkinsonian medication. Their effects on identity and location NP and positive priming (PP) were investigated. Twenty medicated PD patients and 20 PD patients after drug withdrawal were compared to 20 sex- and age-matched healthy controls. The influence of PD patients' general slowing on priming effects was statistically controlled. Location NP was found not to be affected by PD, whereas identity NP was reduced in medicated PD patients compared to non-medicated PD patients and healthy controls. At first, identity and location PP appeared to be enhanced in both PD groups. After controlling for general slowing, however, differences between PD patients and healthy controls disappeared. These findings endorse the notion that uncontrolled effects of both, PD-related general slowing and anti-Parkinsonian medication may have contributed to previously conflicting results on priming effects in PD patients.

The recognition of facial emotion expressions in Parkinson's disease

A limited number of studies in Parkinson's Disease (PD) suggest a disturbance of recognition of facial emotion expressions. In particular, disgust recognition impairment has been reported in unmedicated and medicated PD patients. However, the results are rather inconclusive in the definition of the degree and the selectivity of emotion recognition impairment, and an associated impairment of almost all basic facial emotions in PD is also described. Few studies have investigated the relationship with neuropsychiatric and neuropsychological symptoms with mainly negative results. This inconsistency may be due to many different problems, such as emotion assessment, perception deficit, cognitive impairment, behavioral symptoms, illness severity and antiparkinsonian therapy. Here we review the clinical characteristics and neural structures involved in the recognition of specific facial emotion expressions, and the plausible role of dopamine transmission and dopamine replacement therapy in these processes. It is clear that future studies should be directed to clarify all these issues.

Dopaminergic modulation of timing control and variability in the gait of Parkinson's disease

The basal ganglia have been implicated in timing control, yet the nature of timing disturbances in Parkinson's disease (PD) is poorly understood. We evaluated the influence of timing cues on spatiotemporal aspects of gait control and its variability, and the impact of dopaminergic treatment on timing. Three separate groups: 19 PD (OFF state); 24 PD (ON state); and 30 control participants were tested. Participants walked on a computerized carpet at four randomized and metronome-controlled rates: self-paced, 60, 80, or 100 steps/min. To our knowledge, this is the first study to demonstrate that medicated PD patients had poorer timing control than patients withdrawn from medication and healthy participants when modulating timing to an external stimulus. Increased step-to-step timing variability and deficits in mean temporal gait characteristics revealed that the medicated PD group (in contrast to nonmedicated PD group) performed least like healthy participants. This was observable in externally-cued conditions, but not during self-paced gait. Similar to previous research, step length contributed to overall slowness in PD, while temporal characteristics of gait did not. Interestingly, healthy participants increased stride length with each increase in cue rate, whereas both PD groups locked their step length regardless of temporal demand. Step-to-step variability differences between PD and healthy (e.g. step and double-support time measurements) may be indicative of specific basal ganglia involvement in temporal control of gait.

Parkinsonian deficits in sensory integration for postural control: Temporal response to changes in visual input

This study investigated the effect of Parkinson's disease (PD) on the time course for postural control following the removal and reinsertion of visual information. Twelve medicated PD patients (PD) and 12 age matched control (CTRL) subjects performed two 45-s quiet standing trials, during which visual feedback was available (0–15 s), deprived (15–30 s), and then restored (30–45 s). The 45 s test trial was divided into 5 s time bins to compare the time-based effect of sensory reorganization during deprivation and reintegration. Results revealed an increase in Elliptical Sway Area (ESA) following visual deprivation for both groups; this increased ESA remained significantly higher than the baseline level for the duration of the deprivation period among PD patients and returned to baseline the level among CTRL. Despite elevated ESA at the end of visual deprivation among PD patients, neither group showed a change in ESA after visual information was restored. These results indicate a PD-associated deficit with the reorganization of sensory priorities for postural control, and may implicate the basal ganglia as being critical for integration of sensory information for postural control.

Visual search deficits in Parkinson's disease are attenuated by bottom-up target salience and top-down information

Patients with Parkinson's disease (PD), a degenerative disorder primarily affecting the nigrostriatal dopamine system, exhibit deficits in selecting task-relevant stimuli in the presence of irrelevant stimuli, such as in visual search tasks. However, results from previous studies suggest that these deficits may vary as a function of whether selection must rely primarily on the “bottom-up” salience of the target relative to background stimuli, or whether “top-down” information about the identity of the target is available to bias selection. In the present study, moderate-to-severe medicated PD patients and age-matched controls were tested on six visual search tasks that systematically varied the relationship between bottom-up target salience (feature search, noisy feature search, conjunction search) and top-down target knowledge (Target Known versus Target Unknown). Comparison of slope and intercepts of the RT × set size function provided information about the efficiency of search and non-search (e.g., decision, response) components, respectively. Patients exhibited higher intercepts than controls as bottom-up target salience decreased, however these deficits were disproportionately larger under Target Unknown compared to Target Known conditions. Slope differences between PD and controls were limited to the Target Unknown Conjunction condition, where patients exhibited a shallower slope in the target absent condition, indicating that they terminated search earlier. These results suggest that under conditions of high background noise, medicated PD patients were primarily impaired in decision and/or response processes downstream from the target search itself, and that the deficit was attenuated when top-down information was available to guide selection of the target signal.

A meta-analysis on cognitive slowing in Parkinson's disease: are simple and choice reaction times differentially impaired?

Meta-analysis was conducted to determine whether patients with Parkinson's disease (PD) are differentially affected when confronted with choice reaction time (RT) tasks as compared to simple RT tasks (1548 PD patients compared to 1648 age-matched controls). While medicated PD patients were slower than controls in all RT conditions, their simple, choice, and discrimination RT followed the same patterns as controls. Severity of disease was found to affect RT but precue availability and tremor did not. Overall findings indicate that movement initiation slowing remained constant across response uncertainty conditions, suggesting that medicated PD patients do not have a response selection impairment.

Refversal of the Bicycle Drawing Direction in Parkinson's Disease by AC Pulsed Electromagnetic Fields

The Draw-a-Bicycle Test is employed in neuropsychological testing of cognitive skills since the bicycle design is widely known and also because of its complex structure. The Draw-a-Bicycle Test has been administered routinely to patients with Parkinson's disease (PD) and other neurodegenerative disorders to evaluate the effect of transcranial applications of AC pulsed electromagnetic fields (EMFs) in the picotesla flux density on visuoconstructional skills. A seminal observation is reported in 5 medicated PD patients who demonstrated reversal of spontaneous drawing direction of the bicycle after they received a series of transcranial treatments with AC pulsed EMFs. In 3 patients reversal of the bicycle drawing direction was observed shortly after the administration of pulsed EMFs while in 2 patients these changes were observed within a time lag ranging from several weeks to months. All patients also demonstrated a dramatic clinical response to the administration of EMFs. These findings are intriguing because changes in drawing direction do not occur spontaneously in normal individuals as a result of relateralization of cognitive functions. This report suggests that administration of AC pulsed EMFs may induce in some PD patients changes in hemispheric dominance during processing of a visuoconstructional task and that these changes may be predictive of a particularly favourable response to AC pulsed EMFs therapy.

Visuospatial memory deficits at different stages of Parkinson's disease

Groups of patients with idiopathic Parkinson's disease (PD), either medicated or unmedicated, were compared with matched groups of normal controls on a computerised battery of tests designed to investigate spatial working memory, visuospatial recognition memory and learning. The medicated PD patients were subdivided into those with mild and severe clinical disability on the basis of Hoehn and Yahr ratings, thus making three groups of PD patients in all. In a test of spatial recognition memory, a significant impairment was only evident in those PD patients who were medicated and had severe clinical symptoms (Hoehn and Yahr stage III–IV). In contrast, none of the three patient groups were impaired in a complementary test of visual pattern recognition memory. Whilst all three patient groups performed well in a test of simultaneous visual matching to sample, medicated patients (MED PD) with severe clinical symptoms were significantly impaired when a short (0–12 sec) delay was introduced. In a test of paired associates learning requiring both visual pattern and visuospatial memory, deficits in learning and memory were only evident in the severely impaired MED PD group. In contrast, in a test of spatial working memory known to be sensitive to frontal lobe damage, significant impairments were found in both groups of medicated PD patients and particularly in those patients with more severe clinical symptoms. Taken together, the results suggest that there are multiple memory impairments in PD which may differentially depend on the clinical severity of the disease.