Training of executive functions in Parkinson's disease

Cognitive disturbances are common in Parkinson's disease (PD). Examination of cognitive function often reveals deficits in executive functions, including maintenance and inhibition of attention, flexibility in thinking, and planning. The involvement of the dopaminergic system in cognitive executive functions has been suggested by numerous studies. The aim of the present study was to analyze the effect of cognitive training on cognitive performance of PD-patients (N=26). Half of the patients participated in a cognitive training regimen, while the other patients only received standard treatment. The outcome showed improved performance of the group with cognitive treatment in two executive tasks after the training period, while no improvement was seen in the standard-treatment group. The results indicate that specific training is required for improvement of executive functions, while general rehabilitation is not sufficient. Thus, PD-patients might benefit from a short-term cognitive executive function training program that is tailored to the individual patient's needs.     

The evidence for disease modification in Parkinson's disease

Disease modification or slowing the progression of any neurodegenerative disorder represents a dire unmet need. There have been trials for several decades specifically designed to help evaluate whether a specific therapy might be able to slow the progression of Parkinson's disease (PD) or be disease modifying. Trials evaluating the use of coenzyme Q10, pramipexole, and levodopa suggest that these medications offer symptomatic benefit uniquely, while other studies reveal that rasagiline and selegiline may be disease modifying. This review will discuss in detail the design and results of clinical trials for varied medical therapies that were specifically undertaken to discern whether a particular treatment might be disease modifying in the treatment of PD.     

Parkinson's disease and arithmetics: the role of executive functions

Brain imaging studies as well as neuropsychological case studies suggest an important role for basal ganglia in arithmetic processing. Aim of this study was to assess possible numerical deficits in PD and functional relations between numerical and other cognitive deficits. Fifteen non-demented patients with early PD (stable responders treated by l-dopa) were compared to 28 healthy age and education matched controls. Both groups underwent a neuropsychological assessment focussing on numerical abilities (quantity processing, arithmetic fact retrieval, complex mental and written calculation, transcoding, arithmetic set-shifting, calculation span), working memory and executive functions. Patients with PD showed deficits in complex mental calculation and calculation span tasks. Results of this study suggest that impairments in working memory as well as in executive functions, such as inhibition of interference, lead to secondary deficits in numerical processing. The study contributes to better understanding the specific cognitive deficits in early PD and the neurocognitive architecture of arithmetic processing.     

Visuo-spatial processing is linked to cortical glutamate dynamics in Parkinson's disease — a 7-T functional magnetic resonance spectroscopy study

Background and purpose

Cognitive decline is a frequent and debilitating non-motor symptom for patients with Parkinson's disease (PD). Metabolic alterations in the occipital cortex during visual processing may serve as a biomarker for cognitive decline in patients with PD.

Methods

Sixteen patients with PD (Unified Parkinson's Disease Rating Scale Part 3, OFF, 38.69 ± 17.25) and 10 age- and sex-matched healthy controls (HC) underwent 7-T functional magnetic resonance spectroscopy (MRS) utilizing a visual checkerboard stimulation. Glutamate metabolite levels during rest versus stimulation were compared. Furthermore, correlates of the functional MRS response with performance in visuo-cognitive tests were investigated.

Results

No differences in static MRS between patients with PD and HC were detected, but a dynamic glutamate response was observed in functional MRS in HC upon visual stimulation, which was blunted in patients with PD (F_1,22 = 7.13, p = 0.014; ${\eta }_{\mathrm{p}}^2$ = 0.245). A diminished glutamate response correlated with poorer performance in the Benton Judgment of Line Orientation test in PD (r = −0.57, p = 0.020).

Conclusions

Our results indicate that functional MRS captures even subtle differences in neural processing linked to the behavioral performance, which would have been missed by conventional, static MRS. Functional MRS thus represents a promising tool for studying molecular alterations at high sensitivity. Its prognostic potential should be evaluated in longitudinal studies, prospectively contributing to earlier diagnosis and individual treatment decisions.     

Depressed mood and executive dysfunction in early Parkinson's disease

OBJECTIVES: Studies on neuropsychological functions in early Parkinson's disease (PD) have reported changes with respect to memory and executive control related to dysfunction of fronto-striatal circuitry. The question has been raised, however, whether these findings are at least partly influenced by depression, which as such can also lead to cognitive impairments that depend on the functional integrity of the prefrontal cortex. MATERIAL AND METHODS: In the present investigation early non-depressed PD patients (NPD), early PD patients with mild depressive symptoms (DPD), patients with primary depression (DEP) and healthy controls (HC) completed a range of neuropsychological tests. RESULTS: Group comparisons revealed impairments of DPD patients in comparison with HC with respect to verbal fluency, short-term memory and concept formation. In addition they showed mild working-memory deficits. CONCLUSIONS: In summary the present results indicate that depressed mood in early PD may exacerbate cognitive impairments. Thus careful assessment of affective variables in PD should be an integral part of the treatment of PD.     

Differential executive control impairments in early Parkinson's disease

Investigations concerning cognitive functions in early PD have revealed memory and executive function deficits related to dysfunction of fronto-striatal circuitry. Despite the range of data base, many previous investigations are limited because of methodological questions and inconsistencies. Thus the pattern of executive function impairments in early PD is far from being established. In the present investigation, twenty PD patients in early stages of the disease were compared to control subjects on a comprehensive neuropsychological test battery, aiming to explore their cognitive profile across a range of executive subcomponents. Results revealed impairments with respect to initiation, reasoning and planning. In summary, the present investigation shows that PD is associated with a differential executive impairment pattern which is (partly) related to disease characteristics and affective variables.     

Subjective and objective assessment of executive functions in Parkinson's disease

Impairments in executive functions (EF) in Parkinson's disease (PD) will have a negative influence on daily life. For the assessment objective and subjective measurement approaches are used. It is however unknown whether these approaches contribute in a different way to the assessment of EF in PD. Thirty-nine PD patients and 24 healthy participants completed the Dysexecutive questionnaire (DEX; subjective measure) and the Frontal Assessment Battery (FAB; objective measure). PD patients showed impaired EF (FAB) and reported more problems with EF in daily life (DEX) than healthy participants. The performance on the FAB could however not be explained by the problems with EF that were reported by PD patients (DEX) and vice versa. In conclusion, not all PD patients who show impairments in EF report them and not all PD patients who report problems with EF in daily life show impairments according to objective measurement. Both measures thus contribute in a different way to the assessment of EF in PD patients. However, it has to be considered that the FAB is not a critical test to assess cognition in PD, since these patients also suffer from posterior abnormalities including memory and visuo-spatial deficits which are strong predictors for PD dementia.     

Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day‐to‐day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron‐emission‐tomography using a high‐affinity dopamine D2/D3 receptor tracer, [¹¹C]FLB‐457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [¹¹C]FLB‐457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [¹¹C]FLB‐457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [¹¹C]FLB‐457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Sensitive measures of executive dysfunction in non-demented Parkinson's disease

BackgroundWe examined the sensitivity of different executive function measures for detecting deficits in Parkinson's disease patients without dementia.MethodsTwenty-one non-demented PD subjects and 21 neurologically healthy controls were administered widely used clinical executive functioning measures as well as the NIH EXAMINER battery, which produces Cognitive Control, Working Memory, and Verbal Fluency scores, along with an overall Executive Composite score, using psychometrically matched scales.ResultsNo significant differences between groups were observed on widely used clinical measures. The PD patients scored lower than controls on the EXAMINER Executive Composite, Cognitive Control, and Working Memory Scores.ConclusionsThe NIH EXAMINER Executive Composite and Cognitive Control Scores are sensitive measures of executive dysfunction in non-demented PD, and may be more sensitive than several widely used measures. Results highlight the importance of careful test selection when evaluating for mild cognitive impairment in PD.     

Beta reactivity, prospective facilitation of executive processing, and its dependence on dopaminergic therapy in Parkinson's disease

Oscillatory activity in the beta frequency band has been shown to be modulated during the preparation and execution of voluntary movements at both cortical and subcortical levels. The exaggeration of beta activity in the basal ganglia of patients with Parkinson's disease has heightened interest in this phenomenon. However, the precise function, if any, subserved by modulations in beta activity remains unclear. Here we test the hypothesis that beta reactivity can be dissociated from processing of specific actions and can index the salience of cues with respect to future behavior in a way that might help prospectively prioritize resources. To this end we used an experimental paradigm designed to dissociate salient warning cues from processing of specific motor or cognitive actions. We recorded local field potential activity from the subthalamic nucleus of humans undergoing functional neurosurgery for the treatment of Parkinson's disease, while the same patients were on or off the dopamine prodrug levodopa. In this way we demonstrate that beta reactivity is indeed dependent on the salience of cues with respect to future motor and cognitive action and is promoted by dopamine. The loss of normal beta encoding of saliency may underlie some of the motor and cognitive features of basal ganglia disorders such as Parkinson's disease.     

Actigraphic evidence for night-time hyperkinesia in Parkinson's disease

Parkinson's disease is a common motor disorder that not only leads to motor symptoms but also autonomic dysregulation, mental changes, sensory disturbances, and sleep disorders such as increased daytime sleepiness and sleep fragmentation. The aim of this study was to find out how the daytime and night-time motor activity levels in individuals without motor disorders differ from patients with Parkinson's disease. Daytime and night-time motor activity levels in 17 PD patients and 69 controls were measured for three consecutive days and nights via actigraphy, a method of continuous long-term assessment of activity levels. A ratio between night-time and daytime motor activity was calculated. PD patients had a 1.5-2-fold lower daytime motor activity but also showed 1.5-2-fold higher motor activity at night time. Older controls showed a lower daytime but similar night-time motor activity when compared to younger controls. A ratio of night-time to daytime motor activity could clearly distinguish controls and patients. The possibility to distinguish patients and controls by the ratio of night-time to daytime motor activity is worth further investigation.     

Motor sequencing in Parkinson's disease: relationship to executive function and motor rigidity

Parkinson's disease (PD) is a movement disorder that also affects central cognitive processing; however, the extent to which high-order cognitive processes disrupted by PD affect complex motor function is incompletely explicated. The present analysis provides an examination of the relative contributions of simple motor versus complex cognitive functions involving sequencing, problem solving, and overall cognitive status to complex motor movements involving sequencing and temporal ordering in PD. Motor sequencing performance was videotaped for quantitative scoring. Compared with an age-matched control group, the PD group was impaired on motor agility and motor sequencing tasks in addition to cognitive sequencing and set shifting tasks. Neither current cognitive functioning, age, disease duration, nor overall intellectual abilities accounted for the relationships between motor sequencing and cognitive sequencing abilities in PD. By contrast, both sequencing and nonsequencing executive functions predicted motor sequencing performance as well as or better than motor rigidity or overall cognitive status. These relationships were strongest for the most challenging motor sequencing task, fist-edge-palm, and did not apply to the least challenging task, which required simple alternations of hand movements. Unlike PD, controls showed correlations between motor sequencing tests and executive functioning only tapping nonsequencing abilities. Thus, despite the predominant motor feature of PD, executive functions, as assessed by sequencing and set formation, predicted motor sequencing performance as well as or better than simple motor performance. The results further suggest that the more complex the motor sequencing task, the more susceptible it is to influence from generalized cognitive sequencing ability.     

Visuo-spatial cognition in schizophrenia: confirmation of a preference for local information processing

During visuo-spatial cognitive tasks, patients with schizophrenia show a preference for local (detailed) rather than global (holistic) information processing. The efficiency of such information processing is influenced by task difficulty. We tested whether patients' preference for local processing would persist if task demands favored global or local processing. Twenty-four stabilized patients with schizophrenia (SZ) and 25 healthy, matched controls (C) were tested in a mental mirroring task. Task difficulty was manipulated while stimulus surface structures were maintained unchanged. Information processing was assessed by recording eye movements. SZ were slower than C in the easiest condition but they made more errors than C in the more difficult conditions. Further, SZ did not adapt their average fixation duration to task demands resulting in longer fixation duration in the easiest condition and shorter fixation duration in the most difficult condition compared to C. These findings suggest that patients employ local information processing even when it is maladaptive for task demands. That is, patients do not adapt their fixation duration to task demands implicating (i) a preference for scanning local stimuli features and (ii) information processing inflexibility. These features need to be taken into account when evaluating visuo-spatial cognitive performance in schizophrenia.     

Reward processing abnormalities in Parkinson's disease

The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward. Pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid–A–mediated inhibition in the motor cortex, measured by paired transcranial magnetic stimulation, changes with expectation and uncertainty of money rewards generated by a slot machine simulation. We examined the role of dopamine in this phenomenon by testing 13 mildly affected patients with Parkinson's disease, off and on dopaminergic medications, and 13 healthy, age‐matched controls. Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired transcranial magnetic stimulation in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired transcranial magnetic stimulation response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk‐taking behavior on the Iowa Gambling Task. However, pramipexole increased risk‐taking behavior more in patients showing lower paired transcranial magnetic stimulation response amplitude during low expectation. These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that the physiological state of the motor cortex changes with risk‐taking tendency in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk‐taking behavior in patients on agonist treatment. © 2011 Movement Disorder Society