Annamária Takáts

Reward-learning and the novelty-seeking personality: a between- and within-subjects study of the effects of dopamine agonists on young Parkinson's patients

Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease patients.

The Effect of Dopamine Agonists on Adaptive and Aberrant Salience in Parkinson's Disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinsons disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus–reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus–reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus–reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward.

Impairment of post-movement beta synchronisation in parkinson's disease is related to laterality of tremor

OBJECTIVE Post-movement beta synchronisation (PMBS) is a physiological indicator of the activity of movement related neural networks. To investigate the pathophysiology of this phenomenon, we examined its characteristics in patients with unilateral tremor-dominant Parkinsons disease (PD). METHODS Movement duration and PMBS was measured after self-paced movement of the thumb at movement-reactive beta frequencies, over the supplementary motor area in 10 PD patients and 8 control subjects. RESULTS Movement duration in PD patients was longer than in controls. In left hand tremor patients, movement of the left hand was significantly longer compared to the right hand. When PD patients moved their non-affected hand, similarly to the controls, PMBS was higher contralateral to the movement. After movement of the tremulous hand, the contralateral PMBS decreased significantly and the contralateral preponderance disappeared. In the same hemisphere, PMBS was higher after contralateral to the non-affected hand movement, than after ipsilateral to the tremulous hand after movement. CONCLUSIONS PMBS in PD is affected by the activity of tremor related neural networks, suggesting that both cortical and subcortical sources are responsible for its generation. Examination of PMBS in various neurological diseases might provide further data on its physiological significance.

Is the MDS-UPDRS a Good Screening Tool for Detecting Sleep Problems and Daytime Sleepiness in Parkinson’s Disease?

Movement Disorder Society-sponsored Unified Parkinsons Disease Rating Scale (MDS-UPDRS) has separate items for measuring sleep problems (item 1.7) and daytime sleepiness (1.8). The aim of our study was to evaluate the screening sensitivity and specificity of these items to the PD Sleep Scale 2nd version (PDSS-2) and Epworth Sleepiness Scale (ESS). In this nationwide, cross-sectional study 460 PD patients were enrolled. Spearmans rank correlation coefficients were calculated between the individual items, domains, and the total score of PDSS-2 and item 1.7 of MDS-UPDRS. Similarly, the items and the total score of ESS were contrasted to item 1.8 of MDS-UPDRS. After developing generalized ordinal logistic regression models, the transformed and observed scores were compared by Lins Concordance Correlation Coefficient. Only item 3 difficulties staying asleep and the “disturbed sleep” domain of PDSS-2 showed high correlation with “sleep problems” item 1.7 of the MDS-UPDRS. Total score of PDSS-2 had moderate correlation with this MDS-UPRDS item. The total score of ESS showed the strongest, but still moderate, correlation with “daytime sleepiness” item 1.8 of MDS-UPDRS. As intended, the MDS-UPDRS serves as an effective screening tool for both sleep problems and daytime sleepiness and identifies subjects whose disabilities need further investigation.

Delayed beta synchronization after movement of the more affected hand in essential tremor.

To investigate the pathomechanism of parkinsonian tremor (PT) and essential tremor (ET) by studying the correlation between tremor asymmetry and post-movement beta synchronization (PMBS) of the human EEG. We recorded the EEG of 10 patients with ET, 10 patients with Parkinsons disease and 10 controls. Subjects pressed an on-off switch in a self-paced manner with the thumb of their less (T+) and more (T++) tremulous hand. After digitalization of the EEG from the Cz, C3, C4 electrodes the movement reactive beta frequency, its maximum peak power value and its latency triggered to movement offset were determined. In ET tremor intensity did not influence the power of PMBS, however it was significantly delayed after the movement of the more tremulous hand. In Parkinsons disease after the movement of the more tremulous hand PMBS power was decreased, but it was not delayed. In controls the side of movement had no effect on the power and latency of the PMBS. The neuronal mechanisms underlying PMBS generation are differently affected in essential tremor and Parkinsons disease. The increase of PMBS latency after movement of the more affected hand in ET indicates possible cortical mechanisms in essential tremor generation.

Neuropsychiatric symptoms in untreated parkinson’s disease

Neuropsychiatric and cognitive symptoms are common in Parkinson’s disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.

Contralateral voluntary hand movement inhibits human parkinsonian tremor and variably influences essential tremor

While voluntary movement blocks Parkinsonian rest tremor (PT), essential tremor (ET) is enforced by postural and/or kinetic action. We studied the effect of contralateral externally- and internally triggered hand movement on PT and ET to investigate the transhemispheric influences on tremor genesis. We measured the changes of tremor peak frequency power after flash signal (F), flash triggered (FM) and self-paced (SPM) movement of the contralateral hand in nine PT and seven ET patients using accelerometer. PT significantly decreased both during FM and SPM tasks, suggesting that it is generated by a constant subcortico-cortical network, which includes higher order motor areas. Intensity of ET showed a remarkable intra- and interindividual variability both during FM and SPM reflecting a different generator circuitry with variable functional connections.

Quality of Life and Costs in Parkinson's Disease: A Cross Sectional Study in Hungary

Background Patient reported outcomes and costs of illness are useful to capture some of the multiple effects of a disease and its treatments. Our aim was to assess quality of life (QoL) and costs of Parkinsons disease (PD) in Hungary, and to analyze their associations. Methods A cross-sectional questionnaire survey was conducted in one neurology university clinic. Clinical characteristics, PD related resource utilizations and productivity loss in the past 12 months were recorded; the Hoehn&Yahr (HY) scale, PDQ-39 and EQ-5D questionnaires were applied. Cost calculation was performed from the societal perspective. Results 110 patients (34.5% female) were involved with mean age of 63.3 (SD = 11.3) and disease duration of 8.2 (SD = 5.8) years. PDQ-39 summary score was 48.1 (SD = 13.4). The average EQ-5D score was 0.59 (SD = 0.28), and was significantly lower than the population norm in age-groups 45–74. The correlation was significant between EQ-5D and PDQ-39 (−0.47, p = 0.000), the HY scale and EQ-5D (−0.3416, p = 0.0008) and PDQ-39 (0.3419, p = 0.0006) scores. The total mean cost was €6030.2 (SD = 6163.0)/patient/year (direct medical 35.7%, direct non-medical 29.4%, indirect cost 34.9%). A one year increase in disease duration and 0.1 decrease of the EQ-5D utility score increase the yearly costs by 8 to 10%, and 7.8%, respectively. The effect of the PDQ-39 score on total cost was not significant. Conclusions Disease severity and public health importance of PD are clearly demonstrated by the magnitude of QoL loss. PD-related costs are substantial, but are much lower in Hungary than in Western European countries. Disease duration and EQ-5D score are significant proxy of costs.

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

Background In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD. Clinical trail registration TRN NCT03043768.

Dopamine improves exploration after expectancy violations and induces psychotic-like experiences in patients with Parkinson's disease

Dopamine neurons are sensitive to novel and rewarding events, and dopamine signals can modulate learning in higher-level brain networks. Additionally, dopamine abnormalities appear to be central to the pathophysiology of schizophrenia spectrum disorders. In this study, we investigate the dopaminergic modulation of schizotypal traits and exploration after expectancy violations in Parkinsons disease (PD) patients on dopamine replacement therapy. Exploration after expectancy violations was measured with a latent inhibition and an anomaly categorisation task. Patients with PD had significantly elevated levels of schizotypy and reduced latent inhibition, relative to the controls. Anomaly categorisation was enhanced at trend level among the patients. Dopaminergic antiparkinsonian drugs showed dose-dependent effects: they induced psychotic-like experiences, and at the same time, they disrupted latent inhibition and made categorisation of anomaly more efficient. Most of these findings were replicated in an independent sample of patients with PD. An up-regulated dopamine system in medicated PD patients might tune higher-level brain networks to engage in learning when faced with unexpected information, and therefore hasten the updating of internal models.