Cortical thickness changes in the non-lesioned hemisphere associated with non-paretic arm immobilization in modified CI therapy

Recent evidence suggests that immobilization of the upper limb for 2–3 weeks induces changes in cortical thickness as well as motor performance. In constraint induced (CI) therapy, one of the most effective interventions for hemiplegia, the non-paretic arm is constrained to enforce the use of the paretic arm in the home setting. With the present study we aimed to explore whether non-paretic arm immobilization in CI therapy induces structural changes in the non-lesioned hemisphere, and how these changes are related to treatment benefit. 31 patients with chronic hemiparesis participated in CI therapy with (N = 14) and without (N = 17) constraint. Motor ability scores were acquired before and after treatment. Diffusion tensor imaging (DTI) data was obtained prior to treatment. Cortical thickness was measured with the Freesurfer software. In both groups cortical thickness in the contralesional primary somatosensory cortex increased and motor function improved with the intervention. However the cortical thickness change was not associated with the magnitude of motor function improvement. Moreover, the treatment effect and the cortical thickness change were not significantly different between the constraint and the non-constraint groups. There was no correlation between fractional anisotropy changes in the non-lesioned hemisphere and treatment outcome. CI therapy induced cortical thickness changes in contralesional sensorimotor regions, but this effect does not appear to be driven by the immobilization of the non-paretic arm, as indicated by the absence of differences between the constraint and the non-constraint groups. Our data does not suggest that the arm immobilization used in CI therapy is associated with noticeable cortical thinning.

Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB 1 receptor-independent mechanism

BACKGROUND AND PURPOSE Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB 1 receptors. EXPERIMENTAL APPROACH The anticonvulsant profiles of two CBDV BDSs (50–422 mg·kg −1 ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB 1 receptors was evaluated using displacement binding assays. KEY RESULTS CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg −1 ) and audiogenic seizure models (≥87 mg·kg −1 ), and suppressed pilocarpine-induced convulsions (≥100 mg·kg −1 ). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ 9 -tetrahydrocannabinol and Δ 9 -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB 1 cannabinoid receptors than purified CBDV. CONCLUSIONS AND IMPLICATIONS CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB 1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.

Development of a wearable assistive soft robotic device for elbow rehabilitation

The loss of motor function at the elbow joint can result as a consequence of stroke. Stroke is a clinical illness resulting in long lasting neurological deficits often affecting somatosensory and motor cortices. More than half of those that recover from a stroke survive with disability in their upper arm and need rehabilitation therapy to help in regaining functions of daily living. In this paper, we demonstrated a prototype of a low-cost, ultra-light and wearable soft robotic assistive device that could aid administration of elbow motion therapies to stroke patients. In order to assist the rotation of the elbow joint, the soft modules which consist of soft wedge-like cellular units was inflated by air to produce torque at the elbow joint. Highly compliant rotation can be naturally realised by the elastic property of soft silicone and pneumatic control of air. Based on the direct visual-actuation control, a higher control loop utilised visual processing to apply positional control, the lower control loop was implemented by an electronic circuit to achieve the desired pressure of the soft modules by Pulse Width Modulation. To examine the functionality of the proposed soft modular system, we used an anatomical model of the upper limb and performed the experiments with healthy participants.

Melanin-concentrating hormone projections to areas involved in somatomotor responses

The lateral hypothalamic area (LHA) participates in the integration of sensory information and somatomotor responses associated with hunger and thirst. Although the LHA is neurochemically heterogeneous, a particularly high number of cells express melanin-concentrating hormone (MCH), which has been reported to play a role in energy homeostasis. Treatment with MCH increases food intake, and MCH mRNA is overexpressed in leptin-deficient (ob/ob) mice. Mice lacking both MCH and leptin present reduced body fat, mainly due to increased resting energy expenditure and locomotor activity. Dense MCH innervation of the cerebral motor cortex (MCx) and the pedunculopontine tegmental nucleus (PPT), both related to motor function, has been reported. Therefore, we postulated that a specific group of MCH neurons project to these areas. To investigate our hypothesis, we injected retrograde tracers into the MCx and the PPT of rats, combined with immunohistochemistry. We found that 25% of the LHA neurons projecting to the PPT were immunoreactive for MCH, and that 75% of the LHA neurons projecting to the MCx also contained MCH. Few MCH neurons were found to send collaterals to both areas. We also found that 15% of the incerto-hypothalamic neurons projecting to the PPT expressed MCH immunoreactivity. Those neurons preferentially innervated the rostral PPT. In addition, we observed that the MCH neurons express glutamic acid decarboxylase mRNA, a gamma-aminobutyric acid (GABA) synthesizing enzyme. We postulate that MCH/GABA neurons are involved in the inhibitory modulation of the innervated areas, decreasing motor activity in states of negative energy balance. (C) 2007 Published by Elsevier B.V.

Pedal : identification of models for duodenal administration of levodopa

Backgound and aims: The main purpose of the PEDAL study is to identify and estimate sample individual pharmacokinetic- pharmacodynamic (PK/PD) models for duodenal infusion of levodopa/carbidopa (Duodopa®) that can be used for in numero simulation of treatment strategies. Other objectives are to study the absorption of Duodopa® and to form a basis for power calculation for a future larger study. PK/PD based on oral levodopa is problematic because of irregular gastric emptying. Preliminary work with data from [Gundert-Remy U et al. Eur J Clin Pharmacol 1983;25:69-72] suggested that levodopa infusion pharmacokinetics can be described by a two-compartment model. Background research led to a hypothesis for an effect model incorporating concentration-unrelated fluctuations, more complex than standard E-max models. Methods: PEDAL involved a few patients already on Duodopa®. A bolus dose (normal morning dose plus 50%) was given after a washout during night. Data collection continued until the clinical effect was back at baseline. The procedure was repeated on two non-consecutive days per patient. The following data were collected in 5 to 15 minutes intervals: i) Accelerometer data. ii) Three e-diary questions about ability to walk, feelings of “off” and “dyskinesia”. iii) Clinical assessment of motor function by a physician. iv) Plasma concentrations of levodopa, carbidopa and the metabolite 3-O-methyldopa. The main effect variable will be the clinical assessment. Results: At date of abstract submission, lab analyses were currently being performed. Modelling results, simulation experiments and conclusions will be presented in our poster.

A pharmacokinetic-pharmacodynamic model for duodenal levodopa infusion

Objective Levodopa in presence of decarboxylase inhibitors is following two-compartment kinetics and its effect is typically modelled using sigmoid Emax models. Pharmacokinetic modelling of the absorption phase of oral distributions is problematic because of irregular gastric emptying. The purpose of this work was to identify and estimate a population pharmacokinetic- pharmacodynamic model for duodenal infusion of levodopa/carbidopa (Duodopa®) that can be used for in numero simulation of treatment strategies. Methods The modelling involved pooling data from two studies and fixing some parameters to values found in literature (Chan et al. J Pharmacokinet Pharmacodyn. 2005 Aug;32(3-4):307-31). The first study involved 12 patients on 3 occasions and is described in Nyholm et al. Clinical Neuropharmacology 2003:26:156-63. The second study, PEDAL, involved 3 patients on 2 occasions. A bolus dose (normal morning dose plus 50%) was given after a washout during night. Plasma samples and motor ratings (clinical assessment of motor function from video recordings on a treatment response scale between -3 and 3, where -3 represents severe parkinsonism and 3 represents severe dyskinesia.) were repeatedly collected until the clinical effect was back at baseline. At this point, the usual infusion rate was started and sampling continued for another two hours. Different structural absorption models and effect models were evaluated using the value of the objective function in the NONMEM package. Population mean parameter values, standard error of estimates (SE) and if possible, interindividual/interoccasion variability (IIV/IOV) were estimated. Results Our results indicate that Duodopa absorption can be modelled with an absorption compartment with an added bioavailability fraction and a lag time. The most successful effect model was of sigmoid Emax type with a steep Hill coefficient and an effect compartment delay. Estimated parameter values are presented in the table. Conclusions The absorption and effect models were reasonably successful in fitting observed data and can be used in simulation experiments.

Analysis of tapping test results in a test battery for advanced PD patients

Objective: To compare results from various tapping tests with diary responses in advanced PD. Background: A home environment test battery for assessing patient state in advanced PD, consisting of diary assessments and motor tests was constructed for a hand computer with touch screen and mobile communication. The diary questions: 1. walking, 2. time in off , on and dyskinetic states, 3. off at worst, 4. dyskinetic at worst, 5. cramps, and 6. satisfied with function, relate to the recent past. Question 7, self-assessment, allows seven steps from -3 ( very off ) to +3 ( very dyskinetic ) and relate to right now. Tapping tests outline: 8. Alternately tapping two fields (un-cued) with right hand 9. Same as 8 but using left hand 10. Tapping an active field (out of two) following a system-generated rhythm (increasing speed) with the dominant hand 11. Tapping an active field (out of four) that randomly changes location when tapped using the dominant hand Methods: 65 patients (currently on Duodopa, or candidates for this treatment) entered diary responses and performed tapping tests four times per day during one to six periods of seven days length. In total there were 224 test periods and 6039 test occasions. Speed for tapping test 10 was discardedand tests 8 and 9 were combined by taking means. Descriptive statistics were used to present the variation of the test variables in relation to self assessment (question 7). Pearson correlation coefficients between speed and accuracy (percent correct) in tapping tests and diary responses were calculated. Results: Mean compliance (percentage completed test occasions per test period) was 83% and the median was 93%. There were large differences in both mean tapping speed and accuracy between the different self-assessed states. Correlations between diary responses and tapping results were small (-0.2 to 0.3, negative values for off-time and dyskinetic-time that had opposite scale directions). Correlations between tapping results were all positive (0.1 to 0.6). Conclusions: The diary responses and tapping results provided different information. The low correlations can partly be explained by the fact that questions related to the past and by random variability, which could be reduced by taking means over test periods. Both tapping speed and accuracy reflect the motor function of the patient to a large extent.

Spiral drawing during self-rated dyskinesia is more impaired than during self-rated off

Background: A mobile device test battery, consisting of a patient diary collection section with disease-related questions and a fine motor test section (including spiral drawing tasks), was used by 65 patients with advanced Parkinson's disease (PD)(treated with intraduodenal levodopa/carbidopa gel infusion, Duodopa®, or candidates for this treatment) on 10439 test occasions in their home environments. On each occasion, patients traced three pre-drawn Archimedes spirals using an ergonomic stylus and self-assessed their motor function on a global Treatment Response Scale (TRS) ranging from -3 = very 'off' to 0 = 'on' to +3 = very dyskinetic. The spirals were processed by a computer-based method that generates a "spiral score" representing the PD-related drawing impairment. The scale for the score was based on a modified Bain & Findley rating scale in the range from 0 = no impairment to 5 = moderate impairment to 10 = extremely severe impairment. Objective: To analyze the test battery data for the purpose to find differences in spiral drawing performance of PD patients in relation to their self-assessments of motor function. Methods: Three motor states were used in the analysis; OFF state (including moderate and very 'off'), ON state ('on') and a dyskinetic (DYS) state (moderate and very dyskinetic). In order to avoid the problem of multiple test occasions per patient, 200 random samples of single test occasions per patient were drawn. One-way analysis of variance, ANOVA, test followed by Tukey multiple comparisons test was used to test if mean values of spiral test parameters, i.e. the spiral score and drawing completion times (in seconds), were different among the three motor states. Statistical significance was set at p<0.05. To investigate changes in the spiral score over the time-of-day test sessions for the three motor states, plots of statistical summaries were inspected. Results: The mean spiral score differed significantly across the three self-assessed motor states (p<0.001, ANOVA test). Tukey post-hoc comparisons indicate that the mean spiral score (mean ± SD; [95% CI for mean]) in DYS state (5.2 ± 1.8; [5.12, 5.28]) was higher than the mean spiral score in OFF (4.3 ± 1.7; [4.22, 4.37]) and ON (4.2 ± 1.7; [4.17, 4.29]) states. The mean spiral score was also significantly different among individual TRS values of slightly 'off' (4.02 ± 1.63), 'on' (4.07 ± 1.65) and slightly dyskinetic (4.6 ± 1.71), (p<0.001). There were no differences in drawing completion times among the three motor states (p=0.509). In the OFF and ON states, patients drew slightly more impaired spirals in the afternoon whereas in the DYS state the spiral drawing performance was more impaired in the morning. Conclusion: It was found that when patients considered themselves as being dyskinetic spiral drawing was more impaired (nearly one unit change in a 0-10 scale) compared to when they considered themselves as being 'off' and 'on'. The spiral drawing at patients that self-assessed their motor state as dyskinetic was slightly more impaired in the morning hours, between 8 and 12 o'clock, a situation possibly caused by the morning dose effect.

Implementação de classificador de tarefas mentais baseado em EEG

BARBOSA, André F. ; SOUZA, Bryan C. ; PEREIRA JUNIOR, Antônio ; MEDEIROS, Adelardo A. D.de, . Implementação de Classificador de Tarefas Mentais Baseado em EEG. In: CONGRESSO BRASILEIRO DE REDES NEURAIS, 9., 2009, Ouro Preto, MG. Anais... Ouro Preto, MG, 2009

Efeitos do treinamento de marcha sobre superfícies inclinadas em indivíduos com hemiparesia crônica: ensaio clínico controlado randomizado

Among the therapeutic approaches that can be used to achieve this goal is the gait training on sloping surfaces, but there are few scientific findings that elucidate the results of this practice. OBJECTIVE: To evaluate the effects of training on sloping surfaces on the gait of subjects with chronic hemiparesis. MATERIALS AND METHODS: A controlled, randomized, blinded clinical trial was conducted. Concluded the study twenty-four subjects with age between 40 and 70 years (54,91±9,3). Their neurological function, functional independence, motor function and balance assessed, besides the gait evaluation through kinemetry. The subjects were allocated into two groups: control group (CG) underwent gait training on treadmill with partial body weight support (PBWS) without inclination; and the experimental group (EG) submitted to gait training on treadmill with PBWS and inclination of 10%. Twelve training sessions were performed. The paired t Student test and Wilcoxon test were used in statistical analysis to compare findings before and after training for each group, and the t student test for independent samples and Mann-Whitney.test were used to compare the to groups. RESULTS: After training within-group changes were observed on balance recovery, motor function and functionality, in both experimental conditions. The EG showed changes after training on speed, stride length, step length of paretic and non-paretic side, paretic single support, double support time and non-paretic swing time. The CG the differences were detected on double support, paretic single support and hip range of movement. The EG showed better results when compared to CG on the variables: speed (p=0,034), non-paretic single support (p=0,02) and paretic swing time (p=0,02). CONCLUSION: gait training on sloping surfaces represents a promising strategy for gait training of subjects with chronic hemiparesis since it is can influence a greater number of gait variables, when compared with gait training on flat surface

Efeitos da adição de carga no treino de marcha na esteira em indivíduos com Doença de Parkinson: ensaio clínico controlado randomizado

Introduction: The intrinsic gait disorders in individuals with Parkinson's disease (PD) are one of the most disabling motor symptoms. Among the therapeutic approaches used in attempts to improve the motor function, especially the gait pattern of individuals, stands out the treadmill gait training associated with the addition of load. However, there are few findings that elucidate the benefits arising from such practice. Objective: To assess the effects of adding load on the treadmill gait training in individuals with PD. Material and Methods: A controlled, randomized and blinded clinical trial, was performed with a sample of 27 individuals (18 men and 9 women) with PD, randomly assigned to three experimental conditions, namely: treadmill gait training (n=9), treadmill gait training associated with addition of 5% load (n=9) and treadmill gait training associated with addition of 10% load (n=9). All volunteers were assessed, during phase on of Parkinson's medication, regarding to demographic, clinical and anthropometric (identification form) data, level of disability (Hoehn and Yahr Modified Scale), cognitive function (Mini Mental State Examination), clinical functional - in those areas activity of daily living and motor examination (Unified Parkinson's Disease Rating Scale - UPDRS) and gait cinematic analysis was performed through Qualisys Motion Capture System®. The intervention protocol consisted of gait training in a period of 4 consecutive weeks, with three weekly sessions, lasting 30 minutes each. The post-intervention assessment occurred the next day after the last training session, which was performed cinematic analysis of gait and the UPDRS. Data analysis was performed using the software Statistical Package for Social Sciences® (SPSS) 17.0. Results: The age of volunteers ranged from 41 to 75 years old (62,26 ± 9,07) and the time of clinical diagnosis of PD between 2 to 9 years (4,56 ± 2,42). There was a reduction regarding the score from motor exam domain (p=0,005), only when training with the addition of a 5% load. As for the space-time variables there was no significant difference between groups (p>0,120); however, the training with addition of 5% load presented the following changes: increase in stride length (p=0,028), in step length (p=0,006), in time balance of the most affected member (p=0,006) and reduction in support time of the referred member (p=0,007). Regarding angular variables significant differences between groups submitted to treadmill gait training without addition load and with 5% of load were observed in angle of the ankle at initial contact (p=0,019), in plantar flexion at toe-off (p=0,003) and in the maximum dorsiflexion in swing (p=0,005). While within groups, there was a reduction in amplitude of motion of the ankle (p=0,048), the only workout on the treadmill. Conclusion: The treadmill gait training with addition of 5% load proved to be a better experimental condition than the others because it provided greater gains in a number of variables (space-time and angular gait) and in the motion function, becoming a therapy capable of effectively improving the progress of individuals with PD

Administração repetida de baixas doses de reserpina: um possível modelo para o estudo de déficits cognitivos e motores associados à Doença de Parkinson

Parkinson's disease (PD) is one of the most common neurodegenerative brain disorders and is characterized primarily by a progressive degeneration of dopaminergic neurons nigroestriatais. The main symptoms of this disease are motor alterations (bradykinesia, rigidity, tremor at rest), which can be highly disabling in advanced stages of the condition. However, there are symptomatic manifestations other than motor impairment, such as changes in cognition, mood and sensory systems. Animal models that attempt to mimic clinical features of PD have been used to understand the behavioral and neural mechanisms underlying neurophysiological disturbance of this disease. However, most models promote an intense and immediate motor impairment, consistent with advanced stages of the disease, invalidating these studies for the evaluation of its progressive nature. The administration of reserpine (a monoamine depletor) in rodents has been considered an animal model for studying PD. Recently we found that reserpine (in doses lower than those usually employed to produce the motor symptoms) promotes a memory deficit in an aversive discrimination task, without changing the motor activity. It was suggested that the administration of this drug in low doses can be useful for the study of memory deficits found in PD. Corroborating this data, in another study, acute subcutaneous administration of reserpine, while preserving motor function, led to changes in emotional context-related (but not neutral) memory tasks. The goal of this research was to study the cognitive and motor deficits in rats repeatedly treated with low doses of reserpine, as a possible model that simulates the progressive nature of the PD. For this purpose, 5-month-old male Wistar rats were submitted to a repeated treatment with vehicle or different doses of reserpine on alternate days. Cognitive and motor parameters and possible changes in neuronal function were evaluated during treatment. The main findings were: repeated administration of 0.1 mg / kg of reserpine in rats is able to induce the gradual appearance of motor signs compatible with progressive features found in patients with PD; an increase in striatal levels of oxidative stress and changes in the concentrations of glutamate in the striatum were observed five days after the end of treatment; in animals repeatedly-treated with 0. 1 mg/kg, cognitive deficits were observed only after the onset of motor symptoms, but not prior to the onset of these symptoms; 0.2 mg / kg reserpine repeated treatment has jeopardized the cognitive assessment due to the presence of severe motor deficits. Thus, we suggest that the protocol of treatment with reserpine used in this work is a viable alternative for studies of the progressive appearance of parkinsonian signs in rats, especially concerning motor symptoms. As for the cognitive symptoms, we suggest that more studies are needed, possibly using other behavioral models, and / or changing the treatment regimen

Déficits de memória induzidos por baixas doses de reserpina em ratos: possível relação com prejuízos no processamento emocional na Doença de Parkinson

We have recently verified that the monoamine depleting drug reserpine at doses that do not modify motor function - impairs memory in a rodent model of aversive discrimination. In this study, the effects of reserpine (0.1-0.5 mg/kg) on the performance of rats in object recognition, spatial working memory (spontaneous alternation) and emotional memory (contextual freezing conditioning) tasks were investigated. While object recognition and spontaneous alternation behavior were not affected by reserpine treatment, contextual fear conditioning was impaired. Together with previous studies, these results suggest that mild monoamine depletion would preferentially induce deficits in tasks involved with emotional contexts. Possible relationships with cognitive and emotional processing deficits in Parkinson disease are discussed

Função motora fina, sensorial e perceptiva de escolares com transtorno do déficit de atenção com hiperatividade

OBJETIVO: Caracterizar e comparar as funções motoras fina, sensorial e perceptiva de escolares com Transtorno do Déficit de Atenção com Hiperatividade (TDAH) e escolares com bom desempenho escolar sem alterações de comportamento. MÉTODOS: Participaram 22 escolares do ensino fundamental, de gênero masculino, distribuídos em: GI - 11 escolares com Transtorno do Déficit de Atenção com Hiperatividade; e GII - 11 escolares com bom desempenho acadêmico e sem alterações de comportamento. Os escolares foram submetidos à aplicação do Protocolo de Avaliação da Função Motora Fina, Sensorial e Perceptiva e da Escala de Disgrafia. RESULTADOS: Houve diferença nas tarefas de função motora fina, função sensorial e função perceptiva entre o GI e o GII, com desempenho inferior do GI. Todos os escolares de GI apresentaram disgrafia. CONCLUSÃO: Escolares com Transtorno do Déficit de Atenção com Hiperatividade apresentam desempenho inferior aos escolares com bom desempenho acadêmico em relação às funções motoras fina, sensorial e perceptiva. Tais dificuldades podem causar impacto significativo sobre o desempenho acadêmico, uma vez que comprometem o desenvolvimento da linguagem escrita, ocasionando disgrafia nesses escolares.

The Neuraxial Effects of Intraspinal Amitriptyline at Low Concentrations

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