The cerebellum and its connections to other brain structures involved in motor and non-motor functions: A comprehensive review.

The cerebellum has a large network of neurons that communicate with several brain structures and participate in different functions. Recent studies have demonstrated that the cerebellum is not only associated with motor functions but also participates in several non-motor functions. It is suggested that the cerebellum can modulate behavior through many connections with different nervous system structures in motor, sensory, cognitive, autonomic, and emotional processes. Recently, a growing number of clinical and experimental studies support this theory and provide further evidence. In light of recent findings, a comprehensive review is needed to summarize the knowledge on the influence of the cerebellum on the processing of different functions. Therefore, the aim of this review was to describe the neuroanatomical aspects of the activation of the cerebellum and its connections with other structures of the central nervous system in different behaviors.

Exercise effects on motor function, manual dexterity, and brain oscillatory activity in individuals with Parkinson's disease: Randomized controlled trial protocol.

BACKGROUND: Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Exercise protocols are promising interventions to improve PD symptoms, however, the best modality and its neural correlates are still unknown. OBJECTIVES: To evaluate the effects of the aerobic, strength and task-oriented upper-limb exercises in motor function, manual dexterity, and brain oscillations of individuals with PD. METHOD: In this clinical trial, 44 PD patients aged 40-80 years will be randomized in four groups: aerobic training (AT), strength training (ST), task-oriented training (TOT), and waiting list group (CG). The AT group will perform 30 min of a cycle ergometer on 50%-70% of the reserve heart rate. The ST group will use equipment for upper limb muscles and will perform two series of 8-12 repetitions for each exercise, and intensity between 50% and 70% of one maximum repetition will be used. The TOT group will perform a program consisting of three activities to enhance reaching, grasping, and manipulation. All the groups will perform three sessions per week for 8 weeks. We will use the UPDRS Motor function section, Nine-Hole Peg Test, and quantitative electroencephalography to measure motor function, manual dexterity, and brain oscillations, respectively. ANOVA and regression models will be used to compare outcomes within and between groups.

Neuronal activation of cerebellum functional circuits in motor and non-motor functions in mice.

The cerebellum is involved in the control of balance, movement and the acquisition of motor skills. Scientific and technological advances have shown that the cerebellum also participates in non-motor functions, such as emotional control, memory and language. However, which cerebellar areas and functional circuits are predominantly activated in these different functions is not known. The current study analyzed the neuronal activation of cerebellar areas and other brain structures (e.g., hippocampus, amygdala, prelimbic cortex and infralimbic cortex) after exposure to rotarod and inhibitory avoidance behavioral models to establish possible neuronal circuits for motor and non-motor functions. Naïve male Swiss albino mice weighing 25 to 35 g were used. The animals were subjected to three conditions for behavioral evaluation: inhibitory avoidance, which is a model used to infer emotional memory; rotarod, which assesses motor performance and motor learning; and housing box/control. The mice remained in their housing box in Condition 1. Mice in Condition 2 were exposed to the inhibitory avoidance box for 2 days, and mice in Condition 3 were exposed to the rotarod for 3 days. The animals were euthanized after the last exposure to the apparatus then perfused with paraformaldehyde. Brains were extracted and sectioned for immunofluorescence analysis of c-Fos protein in pre-established structures. Images of the brain structures were obtained, and neuronal activation was analyzed microscopically. One-way analysis of variance was used, followed by Tukey's post-hoc test. There was no significant difference in c-Fos expression in lobe VI of the cerebellum between the different conditions. Differences in c-Fos expression were observed in the basolateral amygdala, infralimbic cortex and prelimbic cortex, which are relevant to emotional processes, after exposure to the evaluation apparatuses. Pearson's r correlation coefficient test showed a positive correlation between the variables of structures related to emotional processes. We concluded that there was no significant difference in c-Fos expression in lobe VI of the cerebellum after exposure of the animals to the evaluation apparatus. However, there was a difference in c-Fos expression in other brain structures related to emotional processes after exposure of animals to the apparatus.

Home-based transcranial direct current stimulation (tDCS) and motor imagery for phantom limb pain using statistical learning to predict treatment response: an open-label study protocol.

Background: Phantom limb pain (PLP) management has been a challenge due to its response heterogeneity and lack of treatment access. This study will evaluate the feasibility of a remotely home-based M1 anodal tDCS combined with motor imagery in phantom limb patients and assess the preliminary efficacy, safety, and predictors of response of this therapy. Methods: This is a pilot, single-arm, open-label trial in which we will recruit 10 subjects with phantom limb pain. The study will include 20 sessions. All participants will receive active anodal M1 tDCS combined with phantom limb motor imagery training. Our primary outcome will be the acceptability and feasibility of this combined intervention. Moreover, we will assess preliminary clinical (pain intensity) and physiological (motor inhibition tasks and heart rate variability) changes after treatment. Finally, we will implement a supervised statistical learning (SL) model to identify predictors of treatment response (to tDCS and phantom limb motor imagery) in PLP patients. We will also use data from our previous clinical trial (total observations=224 [n=112 x timepoints = 2)) for our statistical learning algorithms. The new prospective data from this open-label study will be used as an independent test dataset. Discussion: This protocol proposes to assess the feasibility of a novel, neuromodulatory combined intervention that will allow the design of larger remote clinical trials, thus increasing access to safe and effective treatments for PLP patients. Moreover, this study will allow us to identify possible predictors of pain response and PLP clinical endotypes.

Effects of Combined and Alone Transcranial Motor Cortex Stimulation and Mirror Therapy in Phantom Limb Pain: A Randomized Factorial Trial.

Phantom limb pain (PLP) is a frequent complication in amputees, which is often refractory to treatments. We aim to assess in a factorial trial the effects of transcranial direct current stimulation (tDCS) and mirror therapy (MT) in patients with traumatic lower limb amputation; and whether the motor cortex plasticity changes drive these results. In this large randomized, blinded, 2-site, sham-controlled, 2 × 2 factorial trial, 112 participants with traumatic lower limb amputation were randomized into treatment groups. The interventions were active or covered MT for 4 weeks (20 sessions, 15 minutes each) combined with 2 weeks of either active or sham tDCS (10 sessions, 20 minutes each) applied to the contralateral primary motor cortex. The primary outcome was PLP changes on the visual analogue scale at the end of interventions (4 weeks). Motor cortex excitability and cortical mapping were assessed by transcranial magnetic stimulation (TMS). We found no interaction between tDCS and MT groups (F = 1.90, P = .13). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = -0.99, P = .04) on phantom pain. The overall effect size was 1.19 (95% confidence interval: 0.90, 1.47). No changes in depression and anxiety were found. TDCS intervention was associated with increased intracortical inhibition (coefficient = 0.96, P = .02) and facilitation (coefficient = 2.03, P = .03) as well as a posterolateral shift of the center of gravity in the affected hemisphere. MT induced no motor cortex plasticity changes assessed by TMS. These findings indicate that transcranial motor cortex stimulation might be an affordable and beneficial PLP treatment modality.

Barriers and facilitators for clinical trial participation of underrepresented and non-underrepresented fibromyalgia patients: A cross-sectional internet survey.

BACKGROUND: There is a need of well-powered randomized clinical trials in fibromyalgia. However, challenges for recruitment are presented. This study aims to describe and assess the perception of barriers and facilitators and the associated factors for the participation of underrepresented and non-underrepresented fibromyalgia patients. METHODS: We performed an online survey through REDCap (Research Electronic Data Capture) targeting fibromyalgia patients from April 7 to July 3, 2020 during the COVID-19 stay home mandate and it was restricted to the United States of America. We described and compared the survey characteristics between underrepresented and non-underrepresented participants, and we performed logistic regression models to assess the associated factors with clinical trial participation. RESULTS: In total, 481 completed the survey including 168 underrepresented fibromyalgia patients. Only (1) 11.09 % reported previous participation in clinical trials and the significant perceived barriers were investigator-related (lack of friendliness of research staff and the opportunity to receive the results) and center-related (privacy and confidentiality policies, and the institution's reputation); (2) the participation rate and perceived barriers and facilitators were similar between underrepresented and non-underrepresented patients; and was positively associated with low income, higher age, and clinical trial awareness from their physician; and negatively associated with the perception of investigator-related barriers; and (4) for the underrepresented population, the presence of emotional support. CONCLUSION: Our findings suggest low rates of participation, regardless of underrepresented population status. Strategies as involving their physician as liaison to increase the awareness of clinical trials, as well as improving patient-researcher communication should be considered in this population.

Recruitment characteristics and non-adherence associated factors of fibromyalgia patients in a randomized clinical trial: A retrospective survival analysis.

INTRODUCTION: Fibromyalgia is a complex pain condition that affects mostly women. Given the disease's lack of understanding, patients report poor adherence to medication and mistrust of medical services. This study aims to describe the recruitment characteristics and non-adherence associated factors of fibromyalgia patients to an RCT. METHODS: We performed a retrospective longitudinal analysis with data from our ongoing RCT. We investigated characteristics of subjects recruited, consented, and randomized. Adherence was studied using survival analysis techniques, and its associated factors were identified using Cox proportional hazards regression model. RESULTS: 524 subjects were contacted, 269 were eligible, 61 consented and 40 subjects were randomized. Thirty-eight percent were non-adherent to the protocol with a median of visits of five. The recruitment survey reported that 90% would likely participate in RCTs, 52% had previous participation, and 19% were aware of RCTs by their physicians. Some barriers were investigator-related (staff's friendliness and receiving the results of their trial participation) and center-related (privacy-confidentiality issues and the institution's reputation), without difference between adherent and non-adherent participants. We report significant factors for non-adherence as VAS anxiety score of 5 or more (5.3 HR, p = 0.01), Body Mass Index (BMI) (0.91 HR, p = 0.041) and Quality of Life (QoL) - Personal development subdomain (0.89 HR, p = 0.046). CONCLUSION: Recruitment and adherence of fibromyalgia patients is a challenge; however, they seem eager to participate in RCTs. We recommend creating a comfortable, friendly and trusting environment to increase the recruitment rate. Higher anxiety, lower BMI and lower quality of life were associated with a higher attrition rate.

The evaluation of non-use of the upper limb in chronic hemiparesis is influenced by the level of motor impairment and difficulty of the activities-proposal of a new version of the Motor Activity Log.

This study aims to evaluate the influence of the degree of difficulty of the activities in Motor Activity Log (MAL) scores for patients with mild, moderate, and severe hemiparesis, and to estimate the correlation between motor impairment levels of hemiparesis and MAL scores in post-stroke patients. Sixty-six patients with chronic hemiparesis (49 with mild-moderate hemiparesis, and 17 with severe hemiparesis) were evaluated by the Fugl-Meyer upper-limb section and versions of MAL for different degrees of motor impairment. The Rasch model was used to analyze the level of difficulty of the activities of the different versions of MAL. The Spearman's correlation tested the relationship between the Fugl-Meyer Assessment upper-limb section and MAL. The MAL version, developed to evaluate patients with severe hemiparesis, does not contain the easier activities as employed by the Rasch analysis. There was positive correlation between the Fugl-Meyer Assessment upper-limb section scores and Amount of Use of the three versions of the MAL (r = 0.76, 0.78, and 0.77). The difficulty of the activities seems to influence the quantity and quality of use of the affected upper limb in individuals with chronic hemiparesis. A new version of MAL is proposed for individuals with severe motor impairment.

Intracerebellar vermis histamine facilitates memory consolidation in the elevated T maze model.

Experimental evidence suggests that the cerebellum plays a more complex role in learning than simply regulating the motor response. Rather, it is thought to play a significant role in the consolidation of emotional memory in mice. Due to the difficulty of interpreting fear and anxiety behaviors-the standard methodology for the study of the histaminergic system and emotional memory-in mice, we propose a behavioral assessment of mice subjected to the Elevated T-maze after histamine microinjection of the cerebellar vermis. Young male Swiss albino mice weighing 25-35g were used. In addition, locomotor activity was tested in an open field test. Our data suggest that histamine did not affect memory consolidation during escape or open field behavior at the doses used in this study. However, we observed a significant increase in inhibitory avoidance on the second day in animals receiving a dose of 6.8nmol/0.5µl, suggesting that histamine facilitates the consolidation of inhibitory avoidance in mice.

Influência da textura na preensão de indivíduos com Síndrome de Down / Influence of the object texture related to the grip in individuals with Síndrome de Down

Diversos estudos disponibilizam evidências sobre características do desempenho motor ecognitivo de indivíduos com Síndrome de Down (SD), porém poucos estudos analisam a força muscular nestes indivíduos. As alterações apresentadas por indivíduos com SD podem manifestar-se funcionalmente e interferir na sua capacidade de desempenhar de forma independente diversas atividades e tarefas da rotina diária. Objetivo: O presente estudo teve como objetivo analisar a influência da textura do objeto na força de preensão palmar em indivíduos com Síndrome de Down. Participaram do estudo dez indivíduos com SD, com idade entre 4 e 30 anos. Método: A análise da força de preensão palmar foi mensurada por meio de um transdutor de força. A tarefa proposta para a coleta dos dados foi realizar a preensão do transdutor, revestido com diferentes texturas, transportá-lo até um ponto previamente demarcado, e posteriormente o retorno à posição inicial. Os dados obtidos foram analisados por meio de estatística descritiva e não-paramétrica. Resultados: Os dados da estatística descritiva permitiram observar que a textura áspera foi a que exigiu menor força de preensão palmar dos participantes neste estudo, no entanto a análise não-paramétrica indicou não haver diferença estatisticamente significativa. Conclusão:Os resultados deste estudo indicam que textura do objeto não influenciou a força de preensão palmar executada pelos indivíduos com Síndrome de Down.

Many studies show evidences about characteristics of the motor and cognitive performance of subjects with Down Syndrome (DS). However, there is lack of studies that analyze the muscular force in these individuals. The alterations found in subjects with DS can impair their function and interfere in the capacity of the subjects to perform many activities and tasks of the daily routine independently. Objective: The purpose of this study was to analyze the influence of object's texture on grip force in subjects with DS. Ten individuals with diagnosis of DS were selected, with age between 4 and 30 years. Methods: The grip force was measured with a transducer with two different textures. The proposed task for data collection was to hold the transducer, covered with two different textures, and carry it until a point previously demarcated, and later return it to the initial position. The data were analyzed through descriptive and nonparametric statistics. Results: It was possible to observe that the rough texture was the one that demanded minor amount of grip force; however the nonparametric analysis indicated that there was no significant difference in grip force among textures. Conclusion: The results of this study indicated that the object's texture did not influence the grip force carried out by individuals with DS.