Abnormal temporal coupling of tactile perception and motor action in Parkinson's disease

Evidence shows altered somatosensory temporal discrimination threshold (STDT) in Parkinson's disease in comparison to normal subjects. In healthy subjects, movement execution modulates STDT values through mechanisms of sensory gating. We investigated whether STDT modulation during movement execution in patients with Parkinson's disease differs from that in healthy subjects. In 24 patients with Parkinson's disease and 20 healthy subjects, we tested STDT at baseline and during index finger abductions (at movement onset "0", 100, and 200 ms thereafter). We also recorded kinematic features of index finger abductions. Fifteen out of the 24 patients were also tested ON medication. In healthy subjects, STDT increased significantly at 0, 100, and 200 ms after movement onset, whereas in patients with Parkinson's disease in OFF therapy, it increased significantly at 0 and 100 ms but returned to baseline values at 200 ms. When patients were tested ON therapy, STDT during index finger abductions increased significantly, with a time course similar to that of healthy subjects. Differently from healthy subjects, in patients with Parkinson's disease, the mean velocity of the finger abductions decreased according to the time lapse between movement onset and the delivery of the paired electrical stimuli for testing somatosensory temporal discrimination. In conclusion, patients with Parkinson's disease show abnormalities in the temporal coupling between tactile information and motor outflow. Our study provides first evidence that altered temporal processing of sensory information play a role in the pathophysiology of motor symptoms in Parkinson's disease

Abnormal Temporal Coupling of Tactile Perception and Motor Action in Parkinson’s Disease

Evidence shows altered somatosensory temporal discrimination threshold (STDT) in Parkinson’s disease in comparison to normal subjects. In healthy subjects, movement execution modulates STDT values through mechanisms of sensory gating. We investigated whether STDT modulation during movement execution in patients with Parkinson’s disease differs from that in healthy subjects. In 24 patients with Parkinson’s disease and 20 healthy subjects, we tested STDT at baseline and during index finger abductions (at movement onset “0”, 100, and 200 ms thereafter). We also recorded kinematic features of index finger abductions. Fifteen out of the 24 patients were also tested ON medication. In healthy subjects, STDT increased significantly at 0, 100, and 200 ms after movement onset, whereas in patients with Parkinson’s disease in OFF therapy, it increased significantly at 0 and 100 ms but returned to baseline values at 200 ms. When patients were tested ON therapy, STDT during index finger abductions increased significantly, with a time course similar to that of healthy subjects. Differently from healthy subjects, in patients with Parkinson’s disease, the mean velocity of the finger abductions decreased according to the time lapse between movement onset and the delivery of the paired electrical stimuli for testing somatosensory temporal discrimination. In conclusion, patients with Parkinson’s disease show abnormalities in the temporal coupling between tactile information and motor outflow. Our study provides first evidence that altered temporal processing of sensory information play a role in the pathophysiology of motor symptoms in Parkinson’s disease

The interplay of exercise, placebo and nocebo effects on experimental pain

Over the last few decades, placebo, and nocebo effects in general, have been investigated at rest. This proposed study explores whether they could work even when the experience of pain occurs during a movement. Exercise itself can have a hypoalgesic effect, suggesting that placebo- and exercise-induced hypoalgesia could foster pain reduction. In the present study, we investigated the interplay of exercise, placebo and nocebo effects on pain. To this aim, we developed a machine-controlled isotonic motor task to standardize the exercise across participants and used a well-validated model of placebo and nocebo manipulations with reinforced expectations via a conditioning procedure including visual cues paired with heat painful stimulations. Participants reported expectations and pain on a trial-by-trial basis. We found that the standardized isotonic exercise elicited a reduction of pain intensity. Moreover, both exercise and placebo induced comparable hypoalgesic effects. When the exercise was added, placebo and nocebo effects were influenced by expectations but were not affected by fatigue or sex differences. Exercise-, placebo- and nocebo-induced pain modulation are likely to work through distinct mechanisms and neurophysiological research is needed to fully exploit the implications for sport, rehabilitation and pain management

The interplay of exercise, placebo and nocebo effects on experimental pain

Over the last few decades, placebo, and nocebo effects in general, have been investigated at rest. This proposed study explores whether they could work even when the experience of pain occurs during a movement. Exercise itself can have a hypoalgesic effect, suggesting that placebo- and exercise-induced hypoalgesia could foster pain reduction. In the present study, we investigated the interplay of exercise, placebo and nocebo effects on pain. To this aim, we developed a machine-controlled isotonic motor task to standardize the exercise across participants and used a well-validated model of placebo and nocebo manipulations with reinforced expectations via a conditioning procedure including visual cues paired with heat painful stimulations. Participants reported expectations and pain on a trial-by-trial basis. We found that the standardized isotonic exercise elicited a reduction of pain intensity. Moreover, both exercise and placebo induced comparable hypoalgesic effects. When the exercise was added, placebo and nocebo effects were influenced by expectations but were not affected by fatigue or sex differences. Exercise-, placebo- and nocebo-induced pain modulation are likely to work through distinct mechanisms and neurophysiological research is needed to fully exploit the implications for sport, rehabilitation and pain management

The Basal Ganglia Select the Expected Sensory Input Used for Predictive Coding

While considerable evidence supports the notion that lower-level interpretation of incoming sensory information is guided by top-down sensory expectations, less is known about the source of the sensory expectations or the mechanisms by which they are spread. Predictive coding theory proposes that sensory expectations flow down from higher-level association areas to lower-level sensory cortex, and deviations from those expectations (error signals) flow back up to association areas. A separate theory of the role of prediction in cognition describes emulations as linked representations of potential actions and their associated expected sensation that are hypothesized to play an important role in many aspects of cognition. The expected sensations in active emulations are proposed to be the top-down expectation used in predictive coding. Representations of the potential action and expected sensation in emulations are thought to be instantiated in distributed cortical networks. Combining predictive coding with emulations thus provides a theoretical link between the top-down expectations that guide sensory expectations and the cortical networks representing potential actions. Now moving to theories of action selection, the basal ganglia has long been proposed to select between potential actions by reducing inhibition to the cortical network instantiating the desired action plan. Integration of these isolated theorie

Estudos preliminares para o desenvolvimento de um modelo animal alternativo para a doença de Parkinson

A doença de Parkinson é uma doença neurodegenerativa causada pela perda de neurónios dopaminérgicos. Tradicionalmente, têm sido utilizados animais vertebrados, maioritariamente roedores, no estudo desta doença. Existem vários modelos disponíveis, incluindo o modelo com o pesticida paraquato. No entanto, a experimentação animal com vertebrados tem sido objecto de forte regulamentação, só sendo autorizada quando não existe alternativa não animal disponível. Assim, o desenvolvimento e validação de modelos animais alternativos reveste-se de particular importância. A Daphnia magna é um invertebrado aquático, que possui a homologia genética mais elevada com o homem de entre os não vertebrados, e para a qual já foi comprovada a existência de neurónios dopaminérgicos. No âmbito da presente tese, o pesticida paraquato foi usado como substância modelo. Foram realizados testes agudos de acordo com a norma 202 da OECD e foi avaliado o impacto na sobrevivência de Daphnia e em termos de alterações de movimento. Os resultados obtidos demonstram que existe uma grande variação nos valores de EC50 (Concentração responsável pela imobilização de 50% dos animais). Essa variação foi atribuída à idade das Daphnia expostas. Apesar da norma da OCDE indicar que os ensaios devem ser realizados com neonatos com menos de 24h, os resultados obtidos demonstram claramente que esse intervalo deve ser reajustado uma vez que diferenças relativamente reduzidas (i.e., duas horas) na idade dos neonatos são responsáveis por diferenças nos valores de EC50. Relativamente às alterações no movimento foi possível observar uma tendência de aumento no movimento (em termos de deslocamento) em função da idade dos neonatos para a mesma concentração de paraquato. Foi ainda possível observar uma diminuição no movimento com o aumento da concentração de paraquato para neonatos com a mesma idade. De uma forma geral, este trabalho demonstrou a Daphnia magna apresenta várias características que a tornam um bom modelo para o estudo da doença de Parkinson, no entanto, é necessário um ajuste ao protocolo da OECD e são necessários mais estudos particularmente em termos de alterações de movimento.Parkinson disease is a neurodegenerative disease caused by the loss of dopaminergic neurons. Traditionally, vertebrate animals, mostly rodents, have been used to study this disease. There are several models available, including the model with the pesticide paraquat. However, animal experimentation with vertebrates has growingly been regulated, only being authorized when no other alternative is available. Therefore, the development and validation of animal alternative models are of a particular significance. Daphnia magma is an aquatic invertebrate, that has the highest genetic homology with humans among non vertebrates, and for which it has been verified the existence of dopaminergic neurons. In this thesis, the pesticide paraquat had been used as model substance. Acute toxicity tests were performed according to the guideline 202 of OECD and the impact in the survival and motion changes of Daphnia were evaluated. The results obtained demonstrate that the values of EC50 (Concentration responsible for the immobilization of 50% of the animals) vary widely. That variation was attributed to the age of the exposed Daphnia. Although the OECD guideline indicates that the assays must be performed with neonates younger than 24 hours, our results clearly demonstrate that this age range should be narrowed since comparatively small variations (i.e., two hours) in the age of the newborns is responsible for differences in EC50 values. Concerning alterations in movement, it was possible to observe that older Daphnia display higher levels of movement (in terms of displacement). It was also possible to observe that, for neonates with the same age, there was a reduction in movement with increasing concentrations of paraquat. In a general, this work demonstrates that Daphnia magma presents characteristics that makes it a good alternative animal model for the study of Parkinson disease. Although, it is required an adjustment to the OECD’s protocol and further research is necessary, particularly studies related with movement alterations

Efeito de diferentes intervalos de recuperação sobre o desempenho isocinético de indivíduos com doença de Parkinson

Tese (doutorado)—Universidade de Brasília, Faculdade de Educação Física, Programa de Pós-Graduação em Educação Física, 2019.Introdução: O déficit de força muscular em indivíduos com doença de Parkinson resulta em prejuízo ao desempenho funcional. Entretanto, nestes casos, o treinamento resistido melhora a força muscular e o desempenho funcional. Para que estes benefícios ocorram, é necessário que haja uma adequada organização das variáveis agudas do treinamento resistido. A este respeito, a literatura científica se mostra especialmente limitada no que tange o intervalo de recuperação. Objetivo: Analisar o efeito de diferentes intervalos de recuperação sobre o desempenho isocinético de indivíduos com doença de Parkinson. Materiais e Métodos: O Grupo Parkinson (n=11; 69,73 ± 5,72 anos; 1,73 ± 0,05 m; 74,80 ± 13,10 kg; 24,98 ± 4,62 kg/m²) e o Grupo Controle (n= 11; 73,91 ± 5,86 anos; 1,70 ± 0,05 m; 75,97 ± 12,04 kg; 26,20 ± 3,00 kg/m²) foram submetidos a duas avaliações do desempenho isocinético compostas por três séries de 10 repetições a 60°/s, uma com um e outra com dois minutos de recuperação. O melhor desempenho dos grupos foi comparado com teste-t independente. O desempenho de cada grupo ao longo das séries com os diferentes intervalos de recuperação foi avaliado com análise de variância de dois fatores e três níveis. Adicionalmente, o tamanho do efeito foi calculado. Resultado: O Grupo Parkinson apresentou menor Pico de Torque Absoluto (p=0,04; tamanho do efeito=-1,07), Torque a 18 ms Absoluto (p=0,04; tamanho do efeito=-1,07), Trabalho Total Absoluto (p=0,01; tamanho do efeito:-1,24), Trabalho Total Relativo (p=0,02; tamanho do efeito=-1,37), Potência Média Absoluta (p=0,02; tamanho do efeito=-1,32), e Potência Média Relativa (p=0,02; tamanho do efeito=-1,45). Os grupos não diferiram em Pico de Torque Relativo, Torque a 18 ms Relativo, e Fadiga do Trabalho. Ao longo das séries, não houve diferença os entre os intervalos no Pico de Torque, Torque a 18 ms, Trabalho Total, Potência Média, e Fadiga do Trabalho. Conclusão: Apesar do menor desempenho isocinético de indivíduos com doença de Parkinson, um intervalo com um minuto de recuperação é suficiente para a manutenção de desempenho tanto para indivíduos com doença de Parkinson como para seus pares controle.Background: Muscle weakness in individuals with Parkinson's disease results in consistent funcional impairment. Furthermore, in theses cases, resistance training improves muscle strength and funcional performance. To secure such benefits, it is necessary make an adequate organization of the acute resistance training variables. In this regard, there is a gap in scientific literature about the rest interval. Purpose: To analyze the effect of dirrerent rest intervals over the isokinetic performance of individuals with Parkinson's disease. Material and Methods: Parkinson's Group (n=11; 69,73 ± 5,72 years; 1,73 ± 0,05 m; 74,80 ± 13,10 kg; 24,98 ± 4,62 kg/m²) and Control Group (n= 11; 73,91 ± 5,86 years; 1,70 ± 0,05 m; 75,97 ± 12,04 kg; 26,20 ± 3,00 kg/m²) took part in two isokinetic evaluations with three sets of 10 repetitions at 60°/s, with one and two minutes between the sets. Indepentent t-tests compared the best performance of the groups, and fatorial analyses of variance compared the performance of each group across the sets with diferente rest intervals. Aditionally, the effect size was calculed. Results: Parkinson Group presented lower Absolute Peak Torque (p=0,04; effect size=-1,07), Absolute Torque at 18 ms (p=0,04; effect size=-1,07), Absolute Total Work (p=0,01; effect size:-1,24), Relative Total Work (p=0,02; effect size=-1,37), Absolute Average Power (p=0,02; effect size=-1,32), and Relative Average Power (p=0,02; effect size=-1,45). The groups did not differ on Relative Peak Torque, Relative Torque at 18 ms, and Work Fatigue. Across the sets, there was no difference between the rest intervals for both groups on Peak Torque, Torque at 18 ms, Total Work, Average Power, and Work Fatigue. Conclusion: Despite the lower isokinetic performance of individuals with Parkinson’s disease, rest intervals of one minute are adequate for both individuals with Parkinson’s disease and their matched controls

Effet de l’activation du récepteur mGluR2 par LY-354,740 sur les dyskinésies chez le modèle parkinsonien de rat lésé à la 6-hydroxydopamine

La L-3,4-dihydroxyphénylalanine (L-DOPA) est le traitement symptomatique le plus efficace pour la maladie de Parkinson (MP). Cependant, à long terme, l’utilisation de la L-DOPA est associée au développement de complications motrices telles que des dyskinésies. Ces symptômes entraînent une morbidité significative chez 50-95% des patients atteints de MP avancée et les options de traitement sont peu nombreuses. Récemment, des études ont indiqué que le blocage des récepteurs de la sérotonine 2A (5-HT2AR) interagissait avec le récepteur métabotropique du glutamate 2 (mGluR2), et que ce blocage avait un effet anti-dyskinétique. Se basant sur cette interaction, nous avons émis l’hypothèse que l’activation du mGluR2 soulagerait efficacement la dyskinésie dans la MP. Dans la présente étude, nous avons étudié les effets de l’agoniste orthostérique de mGluR2, LY-354,740, pour soulager et prévenir le développement de la dyskinésie induite par la L-DOPA (DIL) chez le rat lésé à la 6-hydroxydopamine (6-OHDA). Des rats ont été rendus hémi-parkinsoniens par injection stéréotaxique de 6-OHDA dans le faisceau longitudinal médian droit du télencéphale. Après une période de récupération, le degré de parkinsonisme a été évalué en utilisant le test du cylindre et deux études ont ensuite été réalisées. Dans la première série d’expériences, les rats ont été sensibilisés avec l’administration chronique de L-DOPA pour induire des mouvements involontaires anormaux (AIMs). Ensuite, l’effet du LY-354,740 sur l’action anti-parkinsonienne de la L-DOPA a été déterminé par le test du cylindre. Dans la seconde série d’expériences visant à déterminer l’effet du LY-354,740 sur la prévention du développement de la dyskinésie, on a administré de LY-354,740 (0,1 ou 1 mg/kg) ou du véhicule en combinaison avec la L-DOPA, pour 22 jours et évalué la sévérité des DILs. Après une période d’élimination de 3 jours, une dose de L-DOPA a été administrée et la sévérité des AIMs a été évaluée pour déterminer si la réduction de la sévérité des DILs était maintenu. Dans la première série d’expériences, nous avons trouvé que l’administration aiguë de LY-354,740 0,1 mg/kg en combinaison avec L-DOPA réduit significativement l’amplitude et la durée des AIMs de 21% et 18%, respectivement (P < 0,0001) sans altérer l’action anti-parkinsonienne de la L-DOPA. LY-354,740 0,1 mg/kg atténue également le développement des dyskinésies par rapport au groupe L-DOPA/véhicule. Nos résultats suggèrent que l’activation orthostérique sélective du mGluR2 par LY-354,740 est une stratégie thérapeutique efficace et prometteuse pour soulager la sévérité des dyskinésies, et empêcher leur développement.L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective symptomatic treatment for Parkinson’s disease (PD). However, with long term administration, L-DOPA use is associated with the development of motor complications such as dyskinesia. Dyskinesia causes significant morbidity to as many as 50-95% of patients with advanced PD and treatment options are few. Recently, studies have indicated that serotonin 2A receptor (5-HT2AR) blockade has an anti-dyskinetic effect. 5-HT2A receptors interact tightly with metabotropic glutamate receptor 2 (mGluR2); at the downstream signalling level, 5-HT2AR blockade has an effect similar to mGluR2 activation. Based on this, we hypothesised that mGluR2 activation would effectively alleviate dyskinesia in PD. In the present studies, we investigated the effect of the mGluR2 orthosteric agonist LY-354,740 at alleviating established, and preventing the development of, L-DOPA-induced dyskinesia (LID) in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. Rats were rendered hemi-parkinsonian by stereotaxic injection of 6-OHDA into the right medial forebrain bundle. Following a recovery period, degree of parkinsonism was assessed using the cylinder test and two studies were then performed. In the first set of experiments, rats were primed with chronic L-DOPA administration to induce abnormal involuntary movements (AIMs), after which L-DOPA was administered, in combination with LY-354,740 (vehicle, 0.1, 1 and 10 mg/kg). The effect of LY-354,740 on L-DOPA anti-parkinsonian action was subsequently determined by the cylinder test. In the second set of experiments, which sought to determine the effect of LY-354,740 at preventing the development of dyskinesia, hemi-parkinsonian rats were administered a daily dose of LY-354,740 (0.1 or 1 mg/kg) or vehicle, started concurrently with L-DOPA for 22 days and dyskinesia severity was monitored. After a 3-day washout period, an acute challenge of L-DOPA was administered and ALO AIMs severity was assessed to determine if dyskinesia development had indeed been reduced. In the first set of experiments, we found LY-354,740 0.1 mg/kg, in combination with L-DOPA, significantly reduced AIMs amplitude and duration by 21% and 18%, respectively (P < 0.0001) without impairing L-DOPA anti-parkinsonian effect. LY-354,740 0.1 mg/kg also attenuated the priming process leading to the development of dyskinesia when started concurrently with L-DOPA, when compared to the L-DOPA/vehicle group. Our results suggest that selective mGluR2 activation through orthosteric activation is an effective and promising therapeutic strategy to alleviate the severity of established, and attenuate the development of dyskinesia