Cluster analysis in fibromyalgia: a systematic review.

BACKGROUND: The multifaceted nature of Fibromyalgia syndrome (FM) symptoms has been explored through clusters analysis. OBJECTIVE: To synthesize the cluster research on FM (variables, methods, patient subgroups, and evaluation metrics). METHODS: We performed a systematic review following the PRISMA recommendations. Independent searches were performed on PubMed, Embase, Web of Science, and Cochrane Central, employing the terms "fibromyalgia" and "cluster analysis". We included studies dated to January 2024, using the cluster analysis to assess any physical, psychological, clinical, or biomedical variables in FM subjects, and descriptively synthesized the studies in terms of design, cluster method, and resulting patient profiles. RESULTS: We included 39 studies. Most with a cross-sectional design aiming to classify subsets based on the severity, adjustment, symptomatic manifestations, psychological profiles, and response to treatment, based on demographic and clinical variables. Two to four different profiles were found according to the levels of severity and adjustment to FMS. According to symptom manifestation, two to three clusters described the predominance of pain versus fatigue, and thermal pain sensitivity (less versus more sensitive). Other clusters revealed profiles of personality (pathological versus non-pathological) and psychological vulnerability (suicidal ideation). Additionally, studies identified different responses to treatment (pharmacological and multimodal). CONCLUSION: Several profiles exist within FMS population, which point out to the need for specific treatment options given the different profiles and an efficient allocation of healthcare resources. We notice a need towards more objective measures, and the validation of the cluster results. Further research might investigate some of the assumptions of these findings, which are further discussed in this paper.

Resting-state EEG as Biomarker of Maladaptive Motor Function and Depressive Profile in Stroke Patients.

Objective: Investigate the relationship between resting-state EEG-measured brain oscillations and clinical and demographic measures in Stroke patients. Methods: We performed a cross-sectional analysis of a cohort study (DEFINE cohort), Stroke arm, with 85 patients, considering demographic, clinical, and stroke characteristics. Resting-state EEG relative power from delta, theta, alpha, and beta oscillations were measured from the central region. Multivariate regression models were used for both affected and non-affected hemispheres. Results: Motor function was negatively associated with Delta and Theta oscillations, while positively associated with Alpha oscillations (both hemispheres). Similarly, cognition levels measured were negatively associated with Delta activity. Depression levels were negatively associated with Alpha activity specifically in the affected hemisphere, while positively associated with Beta activity in both hemispheres. Regarding pain measures, no significant association was observed, while CPM measure showed a positive association with Alpha activity in the non-affected hemisphere. Finally, we found that theta/alpha ratio was negatively associated with motor function and CPM scores. Conclusion: The results lead us to propose a framework for brain oscillations in stroke, whereas Delta and Beta would represent disrupted mal-adaptive brain plasticity and Theta and Alpha would represent compensatory and functional brain oscillations for motor and sensory deficits in stroke, respectively.

Physical Exercise for Treating the Anxiety and Depression Symptoms of Parkinson's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Depression and anxiety are non-motor symptoms of Parkinson's disease (PD). Physical exercise is a promising approach to reducing neuropsychological burden. We aimed to comprehensively synthesize evidence regarding the use of exercise for treating depression and anxiety symptoms in PD. METHODS: Systematic review and meta-analysis following PRISMA recommendations. Searches on PubMed, Cochrane Library, Scopus, Web of Science, Embase, and Physiotherapy Evidence Database (PEDro) was conducted. The random-effects model was employed for all analyses with the standardized mean difference as the effect estimate. RESULTS: Fifty records were retrieved, but only 17 studies met the criteria for the meta-analyses. A moderate to large effect was observed for depression (-.71 [95% CI = -.96 to -.46], 11 studies, 728 individuals), and a small to moderate effect for anxiety (-.39 [95% CI = -.65 to -.14], 6 studies, 241 individuals), when comparing exercise to non-exercise controls. Subgroup analysis revealed significant effects from aerobic (-.95 [95% CI = -1.60, -.31]), mind-body (-1.85 [95% CI = -2.63, -1.07]), and resistance modalities (-1.61 [95% CI = -2.40, -.83]) for depression, and from mind-body (-.67 [95% CI = -1.19 to -.15]) and resistance exercises (-1.00 [95% CI = -1.70 to -.30]) for anxiety. CONCLUSION: Physical exercise has a relevant clinical impact on depression and anxiety in PD. We discuss the level of the evidence, the methodological limitations of the studies, and give recommendations.

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.

Understanding the Effects of Non-Invasive Transauricular Vagus Nerve Stimulation On EEG and HRV.

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no mechanistic studies have investigated this technique's neural network and autonomic nervous system effects. This study aims to describe how taVNS can affect EEG metrics, HRV, and pain levels. Healthy subjects were randomly allocated into two groups: the active taVNS group and the sham taVNS group. Electroencephalography (EEG) and Heart Rate Variability (HRV) were recorded at baseline, 30 min, and after 60 min of 30 Hz, 200-250 µs taVNS, or sham stimulation, and the differences between the metrics were calculated. Regarding vagal projections, some studies have demonstrated the role of the vagus nerve in modulating brain activity, the autonomic system, and pain pathways. However, more data is still needed to understand the mechanisms of taVNS on these systems. In this context, this study presents methods to provide data for a deeper discussion about the physiological impacts of this technique, which can help future therapeutic investigations in various conditions.

Physical exercise for treating non-motor symptoms assessed by general Parkinson's disease scales: systematic review and meta-analysis of clinical trials.

Introduction: Parkinson's disease is a movement disorder that also manifests non-motor symptoms (NMS). Physical exercise is a prominent strategy that can have an impact on NMS; however, the evidence is limited. Our aim was to verify the effects of exercise on NMS, as assessed using general NMS scales. Methods: This study is a systematic review and meta-analysis. Two searches were conducted on the PubMed, Cochrane Library, Scopus, Web of Science, Embase, Science Direct and PEDro databases from September to December 2022. The PEDro scale was used to assess the methodological quality of the studies. Results: Twenty-three studies were included. The interventions were classified as multimodal, aerobic, resistance, dance, conventional physical therapy and other types. Five studies had high risk of bias. Eight studies were included in the meta-analyses. According to the criteria, four studies compared exercise with non-exercise (n=159), two compared multimodal exercise with cognitive/leisure approaches (n=128), and two compared aerobic with conventional exercise (n=40). No statistical differences were observed between exercise and non-exercise (-0.26 (-0.58 to 0.05)) and between multimodal and cognitive approaches (0.21 (-0.14 to 0.55)). However, trends were observed in the direction of exercise and cognitive approaches. A significant difference was observed favouring aerobic over conventional exercise (-0.72 (-1.36 to -0.08)). Conclusions: Our findings suggest that exercise may have an effect on general NMS compared with non-exercise, although only a trend was observed. It was also observed for cognitive approaches over multimodal exercises. Aerobic exercise showed near-large effects compared with conventional exercise.

Understanding the Neuroplastic Effects of Auricular Vagus Nerve Stimulation in Animal Models of Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Transauricular vagus nerve stimulation (taVNS) is being studied as a feasible intervention for stroke, but the mechanisms by which this non-invasive technique acts in the cortex are still broadly unknown. OBJECTIVES: This study aimed to systematically review the current pre-clinical evidence in the auricular vagus nerve stimulation (aVNS) neuroplastic effects in stroke. METHODS: We searched, in December of 2022, in Medline, Cochrane, Embase, and Lilacs databases. The authors executed the extraction of the data on Excel. The risk of bias was evaluated by adapted Cochrane Collaboration's tool for animal studies (SYRCLES's RoB tool). RESULTS: A total of 8 studies published between 2015 and 2022 were included in this review, including 391 animal models. In general, aVNS demonstrated a reduction in neurological deficits (SMD = -1.97, 95% CI -2.57 to -1.36, I2 = 44%), in time to perform the adhesive removal test (SMD = -2.26, 95% CI -4.45 to -0.08, I2 = 81%), and infarct size (SMD = -1.51, 95% CI -2.42 to -0.60, I2 = 58%). Regarding the neuroplasticity markers, aVNS showed to increase microcapillary density, CD31 proliferation, and BDNF protein levels and RNA expression. CONCLUSIONS: The studies analyzed show a trend of results that demonstrate a significant effect of the auricular vagal nerve stimulation in stroke animal models. Although the aggregated results show high heterogeneity and high risk of bias. More studies are needed to create solid conclusions.

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.

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.

Electroencephalographic Patterns in taVNS: A Systematic Review.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a newer delivery system using a non-invasive stimulation device placed at the ear. taVNS research is focused on clinical trials showing potential therapeutic benefits, however the neurophysiological effects of this stimulation on brain activity are still unclear. We propose a systematic review that aims to describe the effects of taVNS on EEG measures and identify taVNS parameters that can potentially lead to consistent EEG-mediated biomarkers for this therapy. A systematic literature review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and the Cochrane handbook for systematic reviews. Clinical trials examining EEG parameters were considered, including absolute and relative power, coherence, degree of symmetry, evoked potentials, and peak frequency of all bands. According to our criteria, 18 studies (from 122 articles) were included. Our findings show a general trend towards increased EEG power spectrum activity in lower frequencies, and changes on early components of the ERP related to inhibitory tasks. This review suggests that quantitative electroencephalography can be used to assess the effects of taVNS on brain activity, however more studies are needed to systematically establish the specific effects and metrics that would reflect the non-invasive stimulation through the auricular branch of the vagus nerve.

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.

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.

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.

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.

The Effects of Intravermis Cerebellar Microinjections of Dopaminergic Agents in Motor Learning and Aversive Memory Acquisition in Mice.

The cerebellum receives dopaminergic innervation and expresses the five types of described dopaminergic receptors. The cerebellar function involves both motor movement and cognition, but the role of cerebellar dopaminergic system on these processes remain unclear. The present study explores the behavioral responses to intracerebellar microinjection of dopaminergic agents in motor and emotional memory. For this, naïve Swiss mice had their cerebellar vermis implanted with a guide canula, received a intravermis microinjection of Dopamine, D1-like antagonist SCH-23390 or D2-like antagonist Eticlopride, and underwent a behavioral analysis of motor learning (by a Rotarod and balance beam learning protocol) or aversive memory acquisition (by the inhibitory avoidance task). The mixed-effects analysis was used to evaluate groups performance, followed by Tukey's post hoc when appropriated. In this study, Dopamine, SCH-23390 and Eticlopride at the doses used did not affected motor control and motor learning. In addition, the administration of Dopamine and SCH-233390 had no effects on emotional memory acquisition, but the animals that received the highest dose of Eticlopride had an improvement in aversive memory acquisition, shown by a suppression of its innate preference for the dark compartment of the inhibitory avoidance apparatus following an exposure to a foot shock. We propose that cerebellar dopaminergic D2 receptors seem to participate on the modulation of aversive memory processes, without influencing motor performance at the doses used in this study.

Understanding intracortical excitability in phantom limb pain: A multivariate analysis from a multicenter randomized clinical trial.

OBJECTIVES: To explore associations of intracortical excitability with clinical characteristics in a large sample of subjects with phantom limb pain (PLP). METHODS: Ancillary study using baseline and longitudinal data from a large multicenter randomized trial that investigated the effects of non-invasive brain stimulation combined with sensorimotor training on PLP. Multivariate regression modeling analyses were used to investigate the association of intracortical excitability, measured by percentages of intracortical inhibition (ICI) and facilitation (ICF) with clinical variables. RESULTS: Ninety-eight subjects were included. Phantom sensation of itching was positively associated with ICI changes and at baseline in the affected hemisphere (contralateral to PLP). However, in the non-affected hemisphere (ipsilateral to PLP), the phantom sensation of warmth and PLP intensity were negatively associated with ICI (both models). For the ICF, PLP intensity (baseline model only) and age (longitudinal model) were negatively associated, while time since amputation and amputation level (both for longitudinal model only) were positively associated in the affected hemisphere. Additionally, use of antidepressants led to lower ICF in the non-affected hemisphere for the baseline model while higher amputation level also led to less changes in the ICF. CONCLUSION: Results revealed clear associations of clinical variables and cortical excitability in a large chronic pain sample. ICI and ICF changes appear not to be mainly explained by PLP intensity. Instead, other variables associated with duration of neuroplasticity changes (such as age and duration of amputation) and compensatory mechanisms (such as itching and phantom limb sensation) seem to be more important in explaining these variables.