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 Parkinson's 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

Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory

Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.This research work was funded by a Core Award from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). Also supported by a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) awarded to TWR. CE was supported by the Swiss National Science Foundation (PA00P1_134135) and the Vienna Science and Technology Fund (WWTF VRG13-007)

How does a motor or cognitive dual-task affect our sense of upper limb proprioception?

Data Availability: The authors have no reservation with publicly sharing the data that supports our results. Accession numbers and/or DOIs will be made available upon acceptance of this manuscript. Researchers seeking to have access to our data may also contact the "Commissie Voor Medische Ethiek" Medical Ethics Committee from Ghent University, Belgian Registration Number of this study: 8670201940272. To contact the ethical committee: [email protected], or the lead investigation at [email protected] Daily upper limb activities require multitasking and our division of attention. How we allocate our attention can be studied using dual-task interference (DTi). Given the vital role proprioception plays in movement planning and motor control, it is important to investigate how conscious upper limb proprioception is impacted by DTi through cognitive and motor interference. Purpose To examine how dual-task interference impacts conscious upper limb proprioception during active joint repositioning tasks (AJRT). Methods Forty-two healthy participants, aged between 18 and 35, took part in this cross-sectional study. Participants completed two AJRT during three conditions: baseline (single task), dual-cognitive task (serial subtractions), and dual-motor task (non-dominant hand movements). The proprioceptive error (PE; difference between their estimation and targeted position) was measured using an AJRT of 75% and 90% of maximum internal rotation using the Biodex System IIITM and the Upper Limb Proprioception Reaching Test (PRO-Reach). To determine if PEs differed during dual-task interference, interference change scores from baseline were used with one sample t-tests and analyses of variance. Results The overall mean PE with the Biodex was 4.1̊ ± 1.9 at baseline. Mean change scores from baseline reflect a mean improvement of 1.5̊ ± 1.0 (p < .001) during dual-cognitive task and of 1.5̊ ± 1.2 (p < .001) during dual-motor task. The overall mean PE with the PRO-Reach was 4.4cm ± 1.1 at baseline. Mean change scores from baseline reflect a mean worsening of 1.0cm ± 1.1 (p < .001) during dual-cognitive task and improvement of 0.8cm ± 0.6 (p < .001) during dual-motor task. Analysis of variance with the Biodex PEs revealed an interference effect (p < .001), with the cognitive condition causing greater PEs compared to the motor condition and a criterion position effect (p = .006), where 75% of maximum IR produced larger PEs during both interference conditions. An interference effect (p = .022) with the PRO-Reach PEs was found highlighting a difference between the cognitive and motor conditions, with decreased PEs during the contralateral motor task. Conclusion Interference tasks did impact proprioception. Cognitive interference produced mixed results, whereas improved proprioception was seen during motor interference. Individual task prioritization strategies are possible, where each person may choose their own attention strategy when faced with dual-task interference.The author(s) received no specific funding for this work

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Patients with rare endocrine conditions have corresponding views on unmet needs in clinical research

Purpose European Reference Network on Rare Endocrine Conditions' (Endo-ERN) mission is to reduce and ultimately abolish inequalities in care for patients with rare endocrine conditions in Europe. This study assesses which themes related to rare endocrine conditions are prioritized by patients for clinical research. Methods A survey was developed, translated into 22 different European languages, and distributed to patients with rare endocrine conditions. Patients were asked to give priority scores to listed prespecified topics: fertility, heritability, tiredness, daily medicine intake, sleep quality, physical discomfort, and ability to work, partake in social life, and sports. They were also asked to suggest further important areas for research in open fields. Results After data cleaning, 1378 survey responses were analyzed. Most responses were received from Northern (47%) and Western Europeans (39%), while Southern (11%) and Eastern Europe (2%) were underrepresented. Respondents were most interested in research concerning ability to participate in social life and work. Patients suggested key areas to work: long-term side effects of medical treatments and quality of life. Some priorities differed between disease groups, both for prespecified and open topics and reflected aspects of patients' individual conditions. Conclusions With this large survey, Endo-ERN gained insight into patients' unmet needs in scientific research. Patients prioritized research on ability to work and participation in social activities, though needs differ between the disease groups. Clinical experts should incorporate the results of this survey into the design of future studies on rare endocrine conditions. We aim to utilize these results in designing patient-reported outcome measures for the disease areas covered by Endo-ERN

Measuring upper limb active joint position sense: Introducing a new clinical tool - The Upper Limb Proprioception Reaching Test

Availability of data materials: All authors consent to all data being openly public and accessible.Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S2468781223001145?via%3Dihub#appsec1 .Background: Proprioception is our sense of body awareness, including the sub-category of active joint position sense (AJPS). AJPS is fundamental to joint stability and movement coordination. Despite its importance, there remain few confident ways to measure upper limb AJPS in a clinic. Objective: To assess a new AJPS clinical tool, the Upper Limb Proprioception Reaching Test (PRO-Reach; seven targets), for discriminant validity, intra-rater and absolute reliability. Design: Cross-sectional measurement study. Methods: Seventy-five healthy participants took part in a single session with 2 consecutive evaluations (E1 and E2) (within-day reliability). Twenty participants were randomly selected to perform a dominant shoulder fatigue protocol (discriminant validity), whereafter a third evaluation was repeated (E3). The PRO-Reach was analyzed with paired t tests (discriminant validity), intra-class correlation coefficients (ICCs) and minimal detectable change [MDC]) (intra-rater: within-day and between-trial relative and absolute reliability). Results: The PRO-Reach supports moderate (mostly superior targets) to excellent (mostly inferior targets) reliability. Between-trial ICCs (T1/T2/T3) varied between 0.72 and 0.90, and within-day (E1/E2) ICCs between 0.45 and 0.72, with associated MDC95 values (3.9–5.0 cm). The overall scores (seven targets) supported the strongest within-day reliability (ICC = 0.77). The inferior targets demonstrated the highest between-trial and within-day reliability (ICCs = 0.90 and 0.72). A fatigue effect was found with the superior and superior-lateral targets (P <.05). Conclusions: The inferior targets and overall scores demonstrate the strongest reliability. The use of the PRO-Reach tool may be suitable for clinical use upon further psychometric testing amongst pathological populations. Level of evidence: Level III cross-sectional study.Financial support was provided by the Centre for Interdisciplinary Research in Rehabilitation and Social Integration (Cirris) and Université Laval in Québec City, Canada in the form of a student bursary

Infraspinatus scapular retraction test: a reliable and practical method to assess infraspinatus strength in overhead athletes with scapular dyskinesis

Background Alteration of normal scapulohumeral rhythm due to the fatigue of scapular-stabilizing muscles induces decrease of rotator cuff strength. In this study we analyzed the interobserver and intraobserver realibility of the infraspinatus strength test (IST) and infraspinatus scapular retraction test (ISRT) in 29 overhead athletes with scapular dykinesis, before and after 6 months of scapular musculature rehabilitation. Materials and methods Subjects with magnetic resonance imaging (MRI) findings of labral injuries (2 cases, 5%) and cuff tears (4 cases, 11%) were excluded. Scapular dyskinesis patterns were evaluated according to Kibler et al. (J Shoulder Elbow Surg 11:550-556, 2002). We found a type I dyskinesis in 24 cases (83%) and a type II in 5 cases (17%). Patients were tested by using IST and ISRT and the maximum infraspinatus strength (kg) was registered by a handheld dynamometer. Changes in shoulder IR were measured by using a standard goniometry. Rehabilitation continued for 6 months and was focused on the restoration of scapular muscular control and balance. We used a paired Student t test for the significance of the force values (alpha = 0.01). Intraclass correlation coefficient (ICC) and standard error (SE) were applied to determine the realibility of repeated values collected within testers and between testers. Results Values of ICC close to 1 at baseline and at 6 months indicated a higher interexaminer and intraexaminer realibility. IST force values registered a significant increase at 6 months for both examiners (P&lt;0.01). The mean difference between IST and ISRT values were not significant at 6 months (P&gt;0.01). The increase of glenohumeral internal rotation was significant at 6 months (P&lt;0.01). Conclusion The good realibility and the easy reproducibility make the ISRT an excellent test to assess patients with infraspinatus weakness due to scapular dyskinesis and address them toward an appropriate program of rehabilitation aimed to restore scapular musculature balance and control. \ua9 The Author(s) 2010

Razão eletromiográfica de músculos estabilizadores do ombro durante a execução de exercícios com haste oscilatória

Os processos de dor e disfunção do ombro são muito comuns e demandam grande atenção por parte dos profissionais que treinam e reabilitam esta articulação. O excesso de ativação do músculo trapézio superior (TS) combinado com a diminuição da ativação do trapézio inferior (TI) têm sido proposto como fator contribuinte para lesões no ombro. Diversos equipamentos são usados no treinamento e reabilitação destes músculos como faixas elásticas, cargas livres e, recentemente, hastes oscilatórias. Apesar de muito utilizada no contexto clínico e desportivo, pouco se sabe acerca dos efeitos destas hastes sobre o recrutamento dos músculos estabilizadores de ombro. Assim, o objetivo do presente estudo foi determinar a razão de ativação entre os músculos TS e TI em diferentes exercícios realizados com haste oscilatória. Participaram do estudo 12 indivíduos do sexo feminino, jovens (20,4 ± 2,0 anos), fisicamente ativas. O sinal eletromiográfico dos músculos TS e TI foi coletado durante a execução de três diferentes exercícios realizados com a haste oscilatória. A análise dos dados eletromiográficos foi feita a partir dos valores de root mean square (RMS) pelo cálculo da razão entre os músculos TS e TI para cada exercício. Para análise estatística foram utilizados os testes ANOVA para medidas repetidas e post hoc de Bonferroni, considerando como nível de significância p < 0,05. O exercício III apresentou menor razão entre os músculos TS e TI (0,722), seguido pelos exercícios I e II, respectivamente (0,876 e 0,995). CONCLUSÃO: O uso da haste oscilatória em exercícios executados unimanualmente no plano sagital e com a haste perpendicular ao solo são recomendados para o treinamento e reabilitação dos músculos estabilizadores da escápula por promoverem menor ativação do TS em relação o T