Cognitive Training in Parkinson\u27s Disease: A Review of Studies from 2000 to 2014

Cognitive deficits are prevalent among patients with Parkinson\u27s disease (PD), in both early and late stages of the disease. These deficits are associated with lower quality of life, loss of independence, and institutionalization. To date, there is no effective pharmacological treatment for the range of cognitive impairments presented in PD. Cognitive training (CT) has been explored as an alternative approach to remediating cognition in PD. In this review we present a detailed summary of 13 studies of CT that have been conducted between 2000 and 2014 and a critical examination of the evidence for the effectiveness and applicability of CT in PD. Although the evidence shows that CT leads to short-term, moderate improvements in some cognitive functions, methodological inconsistencies weaken these results. We discuss several key limitations of the literature to date, propose methods of addressing these questions, and outline the future directions that studies of CT in PD should pursue. Studies need to provide more detail about the cognitive profile of participants, include larger sample sizes, be hypothesis driven, and be clearer about the training interventions and the outcome measures

Differential effects of dopaminergic therapies on dorsal and ventral striatum in Parkinson\u27s disease: implications for cognitive function.

Cognitive abnormalities are a feature of Parkinson\u27s disease (PD). Unlike motor symptoms that are clearly improved by dopaminergic therapy, the effect of dopamine replacement on cognition seems paradoxical. Some cognitive functions are improved whereas others are unaltered or even hindered. Our aim was to understand the effect of dopamine replacement therapy on various aspects of cognition. Whereas dorsal striatum receives dopamine input from the substantia nigra (SN), ventral striatum is innervated by dopamine-producing cells in the ventral tegmental area (VTA). In PD, degeneration of SN is substantially greater than cell loss in VTA and hence dopamine-deficiency is significantly greater in dorsal compared to ventral striatum. We suggest that dopamine supplementation improves functions mediated by dorsal striatum and impairs, or heightens to a pathological degree, operations ascribed to ventral striatum. We consider the extant literature in light of this principle. We also survey the effect of dopamine replacement on functional neuroimaging in PD relating the findings to this framework. This paper highlights the fact that currently, titration of therapy in PD is geared to optimizing dorsal striatum-mediated motor symptoms, at the expense of ventral striatum operations. Increased awareness of contrasting effects of dopamine replacement on dorsal versus ventral striatum functions will lead clinicians to survey a broader range of symptoms in determining optimal therapy, taking into account both those aspects of cognition that will be helped versus those that will be hindered by dopaminergic treatment

Pramipexole increases go timeouts but not No-go errors in healthy volunteers

Parkinson’s disease (PD) is characterized by motor symptoms, such as resting tremor, bradykinesia and rigidity, but also features non-motor complications. PD patients taking dopaminergic therapy, such as levodopa but especially dopamine agonists (DAs), evidence an increase in impulse control disorders (ICDs), suggesting a link between dopaminergic therapy and impulsive pursuit of pleasurable activities. However, impulsivity is a multifaceted construct. Motor impulsivity refers to the inability to overcome automatic responses or cancel pre-potent responses. Previous research has suggested that PD patients, on dopaminergic medications, have decreased motor impulsivity. Whether effects on impulsivity are main effects of dopaminergic therapies or are specific to PD is unclear. Using a Go No-go task, we investigated the effect of a single dose of the DA pramipexole on motor impulsivity in healthy participants. The Go No-go task consisted of Go trials, for which keystroke responses were made as quickly as possible, and lesser frequency No-go trials, on which motor responses were to be inhibited. We hypothesized that pramipexole would decrease motor impulsivity. This would manifest as: (a) fewer No-go errors (i.e., fewer responses on trials in which a response ought to have been inhibited); and (b) more timed-out Go trials (i.e., more trials on which the deadline elapsed before a decision to make a keystroke occurred). Healthy volunteers were treated with either 0.5 mg of pramipexole or a standard placebo (randomly determined). During the 2-h wait period, they completed demographic, cognitive, physiological and affective measures. The pramipexole group had significantly more Go timeouts (p \u3c 0.05) compared to the placebo group though they did not differ in percent of No-go errors. In contrast to its effect on pursuit of pleasurable activities, pramipexole did not increase motor impulsivity. In fact, in line with findings in PD and addiction, dopaminergic therapy might increase motor impulse control. In these patient groups, by enhancing function of the dorsal striatum (DS) of the basal ganglia in contrast to its effect on impulsive pursuit of pleasurable activities. These findings have implications for use and effects of pramipexole in PD as well as in other conditions (e.g., restless leg, dystonia, depression, addiction-related problems)

Problems with Facial Mimicry Might Contribute to Emotion Recognition Impairment in Parkinson\u27s Disease

Difficulty with emotion recognition is increasingly being recognized as a symptom of Parkinson\u27s disease. Most research into this area contends that progressive cognitive decline accompanying the disease is to be blamed. However, facial mimicry (i.e., the involuntary congruent activation of facial expression muscles upon viewing a particular facial expression) might also play a role and has been relatively understudied in this clinical population. In healthy participants, facial mimicry has been shown to improve recognition of observed emotions, a phenomenon described by embodied simulation theory. Due to motor disturbances, Parkinson\u27s disease patients frequently show reduced emotional expressiveness, which translates into reduced mimicry. Therefore, it is likely that facial mimicry problems in Parkinson\u27s disease contribute at least partly to the emotional recognition deficits that these patients experience and might greatly influence their social cognition abilities and quality of life. The present review aims to highlight the need for further inquiry into the motor mechanisms behind emotional recognition in Parkinson\u27s disease by synthesizing behavioural, physiological, and neuroanatomical evidence

Burning pain secondary to clozapine use: a case report.

BACKGROUND: The first of the atypical antipsychotics introduced in the 1970s, clozapine remains the most efficacious neuroleptic to this day. However, serious and potentially fatal side effects have necessitated careful regular monitoring among prescribing clinicians. Some adverse effects (e.g. ischaemic bowel) remain under recognized, while newly identified adverse effects continue to be described in the literature. CASE PRESENTATION: In this report, we describe a healthy 43-year old Caucasian male who experienced onset of a full body deep burning pain several months after the onset of treatment with clozapine. The pain worsened over time, ceased with cessation of treatment, and returned soon after the patient was rechallenged. CONCLUSION: We describe an unusual adverse effect from clozapine treatment that has not been described elsewhere to our knowledge. We present the time course of the pain symptom, relationship to dose, associated laboratory results, and ultimately how it was dealt with and how it improved for the benefit of clinicians who may encounter it in the future

Pramipexole impairs stimulus-response learning in healthy young adults

Dopaminergic therapy has paradoxical effects on cognition in Parkinson\u27s disease (PD) patients, with some functions worsened and others improved. The dopamine overdose hypothesis is proposed as an explanation for these opposing effects of medication taking into account the varying levels of dopamine within different brain regions in PD. The detrimental effects of medication on cognition have been attributed to exogenous dopamine overdose in brain regions with spared dopamine levels in PD. It has been demonstrated that learning is most commonly worsened by dopaminergic medication. The current study aimed to investigate whether the medication-related learning impairment exhibited in PD patients is due to a main effect of medication by evaluating the dopamine overdose hypothesis in healthy young adults. Using a randomized, double-blind, placebo-controlled design, 40 healthy young undergraduate students completed a stimulus-response learning task. Half of the participants were treated with 0.5 mg of pramipexole, a dopamine agonist, whereas the other half were treated with a placebo. We found that stimulus-response learning was significantly impaired in participants on pramipexole relative to placebo controls. These findings are consistent with the dopamine overdose hypothesis and suggest that dopaminergic medication impairs learning independent of PD pathology. Our results have important clinical implications for conditions treated with pramipexole, particularly PD, restless leg syndrome, some forms of dystonia, and potentially depression

Dopaminergic therapy increases Go timeouts in the Go/No-Go task in patients with parkinson’s disease

Parkinson’s disease (PD) is characterized by resting tremor, rigidity and bradykinesia. Dopaminergic medications such as L-dopa treat these motor symptoms, but can have complex effects on cognition. Impulse control is an essential cognitive function. Impulsivity is multifaceted in nature. Motor impulsivity involves the inability to withhold pre-potent, automatic, erroneous responses. In contrast, cognitive impulsivity refers to improper risk-reward assessment guiding behavior. Informed by our previous research, we anticipated that dopaminergic therapy would decrease motor impulsivity though it is well known to enhance cognitive impulsivity. We employed the Go/No-go paradigm to assess motor impulsivity in PD. Patients with PD were tested using a Go/No-go task on and off their normal dopaminergic medication. Participants completed cognitive, mood, and physiological measures. PD patients on medication had a significantly higher proportion of Go trial Timeouts (i.e., trials in which Go responses were not completed prior to a deadline of 750 ms) compared to off medication (p = 0.01). No significant ON-OFF differences were found for Go trial or No-go trial response times (RTs), or for number of No-go errors. We interpret that dopaminergic therapy induces a more conservative response set, reflected in Go trial Timeouts in PD patients. In this way, dopaminergic therapy decreased motor impulsivity in PD patients. This is in contrast to the widely recognized effects of dopaminergic therapy on cognitive impulsivity leading in some patients to impulse control disorders. Understanding the nuanced effects of dopaminergic treatment in PD on cognitive functions such as impulse control will clarify therapeutic decisions

Differential effects of Parkinson\u27s disease and dopamine replacement on memory encoding and retrieval.

Increasingly memory deficits are recognized in Parkinson\u27s 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\u27 cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms

The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson\u27s disease: support from functional MRI.

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson\u27s disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson\u27s disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson\u27s disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson\u27s disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities

Dorsal striatum mediates deliberate decision making, not late-stage, stimulus–response learning

We investigated a controversy regarding the role of the dorsal striatum (DS) in deliberate decision-making versus late-stage, stimulus–response learning to the point of automatization. Participants learned to associate abstract images with right or left button presses explicitly before strengthening these associations through stimulus–response trials with (i.e., Session 1) and without (i.e., Session 2) feedback. In Session 1, trials were divided into response-selection and feedback events to separately assess decision versus learning processes. Session 3 evaluated stimulus–response automaticity using a location Stroop task. DS activity correlated with response-selection and not feedback events in Phase 1 (i.e., Blocks 1–3), Session 1. Longer response times (RTs), lower accuracy, and greater intertrial variability characterized Phase 1, suggesting deliberation. DS activity extinguished in Phase 2 (i.e., Blocks 4–12), Session 1, once RTs, response variability, and accuracy stabilized, though stimulus–response automatization continued. This was signaled by persisting improvements in RT and accuracy into Session 2. Distraction between Sessions 1 and 2 briefly reintroduced response uncertainty, and correspondingly, significant DS activity reappeared in Block 1 of Session 2 only. Once stimulus–response associations were again refamiliarized and deliberation unnecessary, DS activation disappeared for Blocks 2–8, Session 2. Interference from previously learned right or left button responses with incongruent location judgments in a location Stroop task provided evidence that automaticity of stimulus–specific button-press responses had developed by the end of Session 2. These results suggest that DS mediates decision making and not late-stage learning, reconciling two, independently evolving and well-supported literatures that implicate DS in different cognitive functions. Hum Brain Mapp 38:6133–6156, 2017. © 2017 Wiley Periodicals, Inc