Neural, Anti-Inflammatory, and Clinical Effects of Transauricular Vagus Nerve Stimulation in Major Depressive Disorder: A Systematic Review.

BACKGROUND: The discovery of effective treatments for major depressive disorder (MDD) may help target different brain pathways. Invasive vagus nerve stimulation (VNS) is an effective neuromodulation technique for the treatment of MDD; however, the effectiveness of the noninvasive technique, transauricular VNS (taVNS), remains unknown. Moreover, a mechanistic understanding of the neural effects behind its biological and therapeutic effects is lacking. This review aimed to evaluate the clinical evidence and the neural and anti-inflammatory effects of taVNS in MDD. METHODS: Two searches were conducted using a systematic search strategy reviewed the clinical efficacy and neural connectivity of taVNS in MDD in humans and evaluated the changes in inflammatory markers after taVNS in humans or animal models of depression. A risk of bias assessment was performed in all human studies. RESULTS: Only 5 studies evaluated the effects of taVNS in patients with depression. Although the studies demonstrated the efficacy of taVNS in treating depression, they used heterogeneous methodologies and limited data, thus preventing the conduct of pooled quantitative analyses. Pooled analysis could not be performed for studies that investigated the modulation of connectivity between brain areas; of the 6 publications, 5 were based on the same experiment. The animal studies that analyzed the presence of inflammatory markers showed a reduction in the level of pro-inflammatory cytokines or receptor expression. CONCLUSIONS: Data on the clinical efficacy of taVNS in the treatment of MDD are limited. Although these studies showed positive results, no conclusions can be drawn regarding this topic considering the heterogeneity of these studies, as in the case of functional connectivity studies. Based on animal studies, the application of taVNS causes a decrease in the level of inflammatory factors in different parts of the brain, which also regulate the immune system. Therefore, further studies are needed to understand the effects of taVNS in patients with MDD.

Evidence of bottom-up homeostatic modulation induced taVNS during emotional and Go/No-Go tasks.

Bilateral transcutaneous auricular vagus nerve stimulation (taVNS) - a non-invasive neuromodulation technique - has been investigated as a safe and feasible technique to treat many neuropsychiatric conditions. such as epilepsy, depression, anxiety, and chronic pain. Our aim is to investigate the effect of taVNS on neurophysiological processes during emotional and Go/No-Go tasks, and changes in frontal alpha asymmetry. We performed a randomized, double-blind, sham-controlled trial with 44 healthy individuals who were allocated into two groups (the active taVNS group and the sham taVNS group). Subjects received one session of taVNS (active or sham) for 60 min. QEEG was recorded before and after the interventions, and the subjects were assessed while exposed to emotional conditions with sad and happy facial expressions, followed by a Go/No-Go trial. The results demonstrated a significant increase in N2 amplitude in the No-Go condition for the active taVNS post-intervention compared to the sham taVNS after adjusting by handedness, mood, and fatigue levels (p = 0.046), significantly reduced ERD during sad conditions after treatment (p = 0.037), and increased frontal alpha asymmetry towards the right frontal hemisphere during the emotional task condition (p = 0.046). Finally, we observed an interesting neural signature in this study that suggests a bottom-up modulation from brainstem/subcortical to cortical areas as characterized by improved lateralization of alpha oscillations towards the frontal right hemisphere, and changes in ERP during emotional and Go/No-Go tasks that suggests a better subcortical response to the tasks. Such bottom-up effects may mediate some of the clinical effects of taVNS.

Effect of transcranial direct current stimulation combined with pelvic muscle training in women: Randomized, controlled, double-blind, and clinical trial.

BACKGROUND: Pelvic floor muscle training (PFMT) is widely used for pelvic floor muscle (PFM) weakness in women; however, it has no prolonged effects. OBJECTIVE: To evaluate the effect of Transcranial Direct Current Stimulation (tDCS) associated with PFMT on PFM contraction, sexual function and quality of life (QoL) in healthy women. STUDY DESIGN: 32 nulliparous women, aged 22.7 ± 0.42 years, were randomized into two groups: G1 (active tDCS combined with PFMT) and G2 (sham tDCS combined with PFMT). The treatment was performed three times a week for 4 weeks, totaling 12 sessions. PFM function was assessed using the PERFECT scheme (P = power, E = endurance, R = repetitions, F = rapid contractions, ECT = each timed contraction) and the perineometer (cmH2O). Sexual function was assessed by The Female Sexual Function Index, and QoL by the SF-36 questionnaire. These assessments were performed before and after the 12nd treatment session and after 30-day follow-up. RESULTS: There was a significant increase (p = 0.037) in the power of G2 compared to G1; repetitions and fast contraction increased in the G1 group, and the resistance increased in both groups, however, without statistical difference between the groups. ECT increased in the G1 group (p = 0.0). CONCLUSION: Active tDCS combined with PFMT did not potentiate the effect of the PFMT to increase the PFM function, QoL, and sexual function in healthy women. However, adjunctive tDCS to PFMT improved the time of contractions, maintaining it during follow-up.

Neuropsychiatric drugs and a neurophysiological marker as predictors of health-related quality of life in patients with phantom limb pain.

OBJECTIVE: To explore the relationship between sociodemographic, clinical, and neurophysiological variables and health-related quality of life (HR-QOL) of patients with phantom limb pain. METHODS: This is a cross-sectional analysis of a previous clinical trial. Univariate and multivariate linear and logistic regression analyses were used to model the predictors of HR-QOL. We utilized a sequential modeling approach with increasing adjustment levels, controlling for age and sex, and other relevant clinical variables (time since amputation, level of amputation, and pain). HR-QOL was assessed by the SF-36 Health Survey and its eight subdomains. RESULTS: We analyzed baseline data from 92 patients with lower-limb amputations. They were mostly male (63%), 45.2 ± 15.6 years, with a mean time since amputation of 82.7 ± 122.4 months, and an overall SF-36 score of 55.9 ± 21.5. We found an association between intracortical facilitation in the affected hemisphere (ICF), gabapentin usage, and HR-QOL. ICF is a predictor of better HRQOL, whereas gabapentin usage was associated with a poorer HR-QOL, with the main model explaining 13.4% of the variance in the outcome. For the SF-36 subdomains, ICF was also a positive predictor for social functioning, bodily pain, and vitality, while medication usage was associated with lower scores in mental health, general health perception, bodily pain, and vitality. CONCLUSION: We found firsthand two new independent predictors of HR-QOL in individuals with PLP, namely, the neurophysiological metric ICF and gabapentin usage. These results highlight the role of the motor cortex excitability in the HR-QOL and stress the need for treatments that favor the neuroplastic adaptation after amputation, for which ICF may be used as a possible marker.

Brain compensatory mechanisms in depression and memory complaints in fibromyalgia: The role of theta oscillatory activity.

BACKGROUND: The different clinical presentations of fibromyalgia (FMS) may play independent roles in the unclear etiology of cognitive impairments and depressive symptoms seen in this population. Understanding how these clinical presentations are associated with FMS's clinical and neurophysiological aspects is important when developing effective treatments. AIM: To explore the relationship between memory complaints and depressive symptoms, and the different clinical and neurophysiological characteristics of FMS. METHODS: Cross-sectional data analysis from a randomized clinical trial. Baseline demographics, physical fitness, sleep, anxiety, depression, cortical excitability, and pain (clinical and mechanistic) data from 63 FMS subjects were used. Multiple linear and logistic association models were constructed. RESULTS: Final regression models including different sets of predictions were statistically significant (p < 0.001), explaining approximately 50% of the variability in cognitive complaints and depression status. Older subjects had higher levels of anxiety, poor sleep quality, lower motor threshold, and higher relative theta power in the central area, are more likely to have clinical depression. Higher anxiety, pain and theta power were associated with an increase memory complaint. CONCLUSION: Depression symptoms seem to be associated with TMS-indexed motor threshold and psychosocial variables, while memory complaints are associated with pain intensity and higher theta oscillations. These mechanisms may be catalyzed and/or triggered by some behavioral and clinical features such as older age, sleep disruption, and anxiety. The correlation with clinical variables suggests the increasing of theta oscillations is a compensatory response in patients with FMS, which can be explored in future studies to improve the treatment for FMS.

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.

The role of clinical and demographic predictors for understanding the cognitive impairment in Spinal Cord Injury (SCI) patients.

STUDY DESIGN: Using a cross-sectional design, we extracted sociodemographic and clinical data from 488 Spinal Cord Injury (SCI) patients during their initial assessment before receiving intensive rehabilitation treatment. OBJECTIVES: The primary objectives of this study were to ascertain the prevalence of cognitive impairment in the study sample and specify the key clinical and demographic predictors of cognitive functioning in SCI patients. SETTING: Lucy Montoro Rehabilitation Institute (LMRI), University of Sao Paulo, Sao Paulo, Brazil. METHODS: We utilized independent univariate and multivariate regression models with the Montreal Cognitive Assessment (MoCA) scale, adapted for individuals with visual impairment. Moreover, we consider scores from the execution tasks (visuospatial/executive) as the dependent variable. RESULTS: Our findings demonstrate that approximately 80% of the evaluated study sample exhibited cognitive impairment. Through the multivariate regression models, we show that several factors, including age, education, depression levels, and the use of analgesics and/or opioids, are significant predictors of total cognitive scores. These factors are independent of the clinical features associated with SCI, such as age, sex, education, and time since the injury. CONCLUSIONS: The results indicate a high prevalence of significant cognitive impairment within the sample, with age, education, depression levels, and the use of analgesics and/or opioids emerging as the primary predictors of total cognitive scores, independent of the clinical features correlated to SCI. These findings hold significant implications for both clinical research and practice, offering valuable guidance for comprehensive management throughout hospitalization and rehabilitation.

A Mechanistic Analysis of the Neural Modulation of the Inflammatory System Through Vagus Nerve Stimulation: A Systematic Review and Meta-analysis.

OBJECTIVE: We aimed to conduct a systematic review and meta-analysis assessing the antiinflammatory effects of various VNS methods while exploring multiple antiinflammatory pathways. MATERIALS AND METHODS: We included clinical trials that used electrical stimulation of the vagus nerve and assessed inflammatory markers up to October 2022. We excluded studies lacking control groups, those with combined interventions, or abstracts without full text. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews. For each inflammatory marker, a random-effects meta-analysis using the inverse variance method was performed. Methods used include transcutaneous auricular VNS (taVNS), transcutaneous cervical VNS (tcVNS), invasive cervical VNS (iVNS), and electroacupuncture VNS (eaVNS). Main reported outcomes included tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, C-reactive protein (CRP), and IL-10. Risk of bias was evaluated using the Cochrane Collaboration Tool (RoB 2.0). RESULTS: This review included 15 studies, involving 597 patients. No statistically significant general VNS effect was observed on TNF-α, IL-6, and IL-1ß. However, CRP, IL-10, and interferon (IFN)-γ were significantly modulated by VNS across all methods. Subgroup analysis revealed specific stimulation techniques producing significant results, such as taVNS effects in IL-1ß and IL-10, and iVNS in IL-6, whereas tcVNS and eaVNS did not convey significant pooled results individually. Cumulative exposure to VNS, higher risk of bias, study design, and pulse width were identified as effect size predictors in our meta-regression models. CONCLUSIONS: Pooling all VNS techniques indicated the ability of VNS to modulate inflammatory markers such as CRP, IL-10, and IFN-γ. Individually, methods such as taVNS were effective in modulating IL-1ß and IL-10, whereas iVNS modulated IL-6. However, different VNS techniques should be separately analyzed in larger, homogeneous, and powerful studies to achieve a clearer and more consistent understanding of the effect of each VNS method on the inflammatory system.

Treating neuropathic pain and comorbid affective disorders: Preclinical and clinical evidence.

INTRODUCTION: Neuropathic pain (NP) significantly impacts quality of life and often coexists with affective disorders such as anxiety and depression. Addressing both NP and its psychiatric manifestations requires a comprehensive understanding of therapeutic options. This study aimed to review the main pharmacological and non-pharmacological treatments for NP and comorbid affective disorders to describe their mechanisms of action and how they are commonly used in clinical practice. METHODS: A review was conducted across five electronic databases, focusing on pharmacological and non-pharmacological treatments for NP and its associated affective disorders. The following combination of MeSH and title/abstract keywords were used: "neuropathic pain," "affective disorders," "depression," "anxiety," "treatment," and "therapy." Both animal and human studies were included to discuss the underlying therapeutic mechanisms of these interventions. RESULTS: Pharmacological interventions, including antidepressants, anticonvulsants, and opioids, modulate neural synaptic transmission to alleviate NP. Topical agents, such as capsaicin, lidocaine patches, and botulinum toxin A, offer localized relief by desensitizing pain pathways. Some of these drugs, especially antidepressants, also treat comorbid affective disorders. Non-pharmacological techniques, including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and photobiomodulation therapy, modulate cortical activity and have shown promise for NP and mood disorders. CONCLUSIONS: The interconnection between NP and comorbid affective disorders necessitates holistic therapeutic strategies. Some pharmacological treatments can be used for both conditions, and non-pharmacological interventions have emerged as promising complementary approaches. Future research should explore novel molecular pathways to enhance treatment options for these interrelated conditions.

Electric Field Navigated 1-Hz rTMS for Poststroke Motor Recovery: The E-FIT Randomized Controlled Trial.

BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training-related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil. METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical trial). The sham coil appearance mimicked the active coil but without the weak electric field in the NICHE trial sham coil. Outcomes measured 1 week, and 1, 3, and 6 months after the end of treatment included the following: upper extremity Fugl-Meyer (primary, 6 months after end of treatment), Action Research Arm Test, National Institutes of Health Stroke Scale, quality of life (EQ-5D), and safety. RESULTS: Of 60 participants randomized, 58 completed treatment and were included for analysis. Bayesian analysis of combined data from the E-FIT and the NICHE trials indicated that active treatment was not superior to sham at the primary end point (posterior mean odds ratio of 1.94 [96% credible interval of 0.61-4.80]). For the E-FIT intent-to-treat population, upper extremity Fugl-Meyer improvement ≥5 pts occurred in 60% (18/30) active group and 50% (14/28) sham group. Participants enrolled 3 to 6 months following stroke had a 67% (31%-91% CI) response rate in the active group at the 6-month end point versus 50% in the sham group (21.5%-78.5% CI). There were significant improvements from baseline to 6 months for both active and sham groups in upper extremity Fugl-Meyer, Action Research Arm Test, and EQ-5D (P<0.05). Improvement in National Institutes of Health Stroke Scale was observed only in the active group (P=0.004). Ten serious unrelated adverse events occurred (4 active group, 6 sham group, P=0.72). CONCLUSIONS: Intensive motor rehabilitation 3 to 12 months after stroke improved clinical impairment, function, and quality of life; however, 1 Hz-repetitive transcranial magnetic stimulation was not an effective treatment adjuvant in the present sample population with mixed lesion location and extent. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03010462.

Primary headache disorders in Latin America and the Caribbean: A meta-analysis of population-based studies.

BACKGROUND: In this manuscript, we aim to systematically estimate the pooled prevalence and incidence of primary headaches and its subtypes (migraine, tension-type headache, and chronic headaches) in Latin America and the Caribbean, describing its epidemiological profile and associated factors. METHODS: We systematically searched PubMed/MEDLINE, Scopus, and LILACS (From conception to March 2021), for populational studies reporting the epidemiology of primary headaches and their associated factors in Latin America and the Caribbean. The data extraction was conducted independently. We performed random-effect model meta-analysis of prevalence (overall primary headaches and by subtypes) and associated factors, assessed potential sources of heterogeneity, the risk of bias, publication bias, and the evidence certainty (GRADE methodology). RESULTS: We included 32 populational studies (38 subpopulations, n = 63,813). The prevalence of primary headaches was 41.4% (95% CI 31.1-52.2%; n = 54,357), 15% for migraine (95% CI 12.0-18.3; n = 53,658 individuals), 20.6% for tension-type headache (95% CI 12.4-30.2; n = 25,840), and 6% for chronic headaches (95% CI 3.3-9.6; n = 21,720), with high between-study heterogeneity. No incidence data was found. Female sex, white ethnicity, high BMI, comorbid mental health disorders, and low-back pain were associated with higher prevalence of primary headaches. The prevalence was less in rural areas. CONCLUSION: In Latin America and the Caribbean, primary headaches are highly prevalent affecting young females disproportionally. The prevalence of chronic headaches is higher than in other systematic global and regional estimations. The presence of comorbidities as modifiable risk factors should encourage their integration as targets for community-based preventive and therapeutic interventions. PROTOCOL REGISTRATION NUMBER: CRD42018105116.

Sham-controlled randomized multicentre trial of transcranial direct current stimulation for prolonged disorders of consciousness.

BACKGROUND AND PURPOSE: Transcranial direct current stimulation (tDCS) has been shown to improve signs of consciousness in a subset of patients with disorders of consciousness (DoC). However, no multicentre study confirmed its efficacy when applied during rehabilitation. In this randomized controlled double-blind study, the effects of tDCS whilst patients were in rehabilitation were tested at the group level and according to their diagnosis and aetiology to better target DoC patients who might repond to tDCS. METHODS: Patients received 2 mA tDCS or sham applied over the left prefrontal cortex for 4 weeks. Behavioural assessments were performed weekly and up to 3 months' follow-up. Analyses were conducted at the group and subgroup levels based on the diagnosis (minimally conscious state [MCS] and unresponsive wakefulness syndrome) and the aetiology (traumatic or non-traumatic). Interim analyses were planned to continue or stop the trial. RESULTS: The trial was stopped for futility when 62 patients from 10 centres were enrolled (44 ± 14 years, 37 ± 24.5 weeks post-injury, 18 women, 32 MCS, 39 non-traumatic). Whilst, at the group level, no treatment effect was found, the subgroup analyses at 3 months' follow-up revealed a significant improvement for patients in MCS and with traumatic aetiology. CONCLUSIONS: Transcranial direct current stimulation during rehabilitation does not seem to enhance patients' recovery. However, diagnosis and aetiology appear to be important factors leading to a response to the treatment. These findings bring novel insights into possible cortical plasticity changes in DoC patients given these differential results according to the subgroups of patients.

Neuroplasticity changes in knee osteoarthritis (KOA) indexed by event-related desynchronization/synchronization during a motor inhibition task.

PURPOSE: Event-related desynchronisation (ERD) and event-related synchronisation (ERS) reflect pain perception and integration of the nociceptive sensory inputs. This may contribute to the understanding of how neurophysiological markers of Knee Osteoarthritis (KOA) patients can differ from control individuals, which would improve aspects such as prediction and prognosis. We performed a cross-sectional analysis of our cohort study (DEFINE cohort), KOA arm, with 71 patients, compared with 65 control participants. The study aimed to examine possible differences between ERD and ERS in control participants compared to Knee Osteoarthritis (KOA) patients when adjusting for important covariates. MATERIALS AND METHODS: We performed independent multivariate regression models considering as dependent variables the power value related to ERD and ERS for four different sensorimotor tasks (Motor Execution, Motor Imagery, Active Observation and Passive Observation) and four sensorimotor oscillations (Alpha, Beta, Low Beta, and High Beta), each model, controlled by age and sex. RESULTS: We demonstrate that the differences between KOA and healthy subjects are frequency specific, as most differences are in the beta bandwidth range. Also, we observed that subjects in the KOA group had significantly higher ERD and ERS. This may be correlated to the amount of lack of brain organisation and a subsequent attempt at compensation induced by KOA. CONCLUSIONS: Our findings strengthen the notion that subjects with KOA have a higher degree of brain plasticity changes that are also likely correlated to the degree of compensation and behavioural dysfunction.

Detangling the Structural Neural Correlates Associated with Resting versus Dynamic Phantom Limb Pain Intensity Using a Voxel-based Morphometry Analysis.

The management of phantom limb pain (PLP) is still challenging due to a partial understanding of its neurophysiological mechanisms. Structural neuroimaging features are potential biomarkers. However, only a few studies assessed their correlations with clinical severity and treatment response. This study aims to explore the association between brain gray matter volume (GMV) with phantom limb manifestations severity and PLP improvement after neuromodulatory treatments (transcranial direct current stimulation and mirror therapy). Voxel-based morphometry analyses and functional decoding using a reverse inference term-based meta-analytic approach were used. We included 24 lower limb traumatic amputees with moderate to severe PLP. We found that alterations of cortical GMV were correlated with PLP severity but not with other clinical manifestations. Less PLP severity was associated with larger brain clusters GMV in the non-affected prefrontal, insula (non-affected mid-anterior region), and bilateral thalamus. However, only the insula cluster survived adjustments. Moreover, the reverse inference meta-analytic approach revealed that the found insula cluster is highly functionally connected to the contralateral insula and premotor cortices, and the decoded psychological processes related to this cluster were "rating," "sustained attention," "impulsivity, " and "suffering." Moreover, we found that responders to neuromodulatory treatment have higher GMV in somatosensory areas (total volume of S1 and S2) in the affected hemisphere at baseline, compared to non-responders, even after adjustments.

The role of symptoms severity, heart rate, and central sensitization for predicting sleep quality in patients with fibromyalgia.

BACKGROUND: Clinical predictors of sleep quality in patients with fibromyalgia syndrome (FMS) are still unknown. By identifying these factors, we could raise new mechanistic hypotheses and guide management approaches. We aimed to describe the sleep quality of FMS patients and to explore the clinical and quantitative sensory testing (QST) predictors of poor sleep quality and its subcomponents. METHODS: This study is a cross-sectional analysis of an ongoing clinical trial. We performed linear regression models between sleep quality (Pittsburgh Sleep Quality Index [PSQI]) and demographic, clinical, and QST variables, controlling for age and gender. Predictors for the total PSQI score and its seven subcomponents were found using a sequential modeling approach. RESULTS: We included 65 patients. The PSQI score was 12.78 ± 4.39, with 95.39% classified as poor sleepers. Sleep disturbance, use of sleep medications, and subjective sleep quality were the worst subdomains. We found poor PSQI scores were highly associated with symptom severity (FIQR score and PROMIS fatigue), pain severity, and higher depression levels, explaining up to 31% of the variance. Fatigue and depression scores also predicted the subjective sleep quality and daytime dysfunction subcomponents. Heart rate changes (surrogate of physical conditioning) predicted the sleep disturbance subcomponent. QST variables were not associated with sleep quality or its subcomponents. CONCLUSIONS: Symptom severity, fatigue, pain, and depression (but no central sensitization) are the main predictors of poor sleep quality. Heart rate changes independently predicted the sleep disturbance subdomain (the most affected one in our sample), suggesting an essential role of physical conditioning in modulating sleep quality in FMS patients. This underscores the need for multidimensional treatments targeting depression and physical activity to improve the sleep quality of FMS patients.

The Analgesic Effect of Transcranial Direct Current Stimulation in Fibromyalgia: A Systematic Review, Meta-Analysis, and Meta-Regression of Potential Influencers of Clinical Effect.

BACKGROUND: There is tentative evidence to support the analgesic effect of transcranial direct current stimulation (tDCS) in fibromyalgia (FM), with large variability in the effect size (ES) encountered in different clinical trials. Understanding the source of the variability and exploring how it relates to the clinical results could characterize effective neuromodulation protocols and ultimately guide care in FM pain. The primary objective of this study was to determine the effect of tDCS in FM pain as compared with sham tDCS. The secondary objective was to explore the relationship of methodology, population, and intervention factors and the analgesic effect of tDCS in FM. MATERIALS AND METHODS: For the primary objective, a systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized clinical trials (RCTs) investigating tDCS as an intervention for FM pain were searched in MEDLINE, Embase, and the Web Of Science. Studies were excluded if they used cross-over designs or if they did not use tDCS as an intervention for pain or did not measure clinical pain. Analysis for the main outcome was performed using a random-effects model. Risk of bias and evidence certainty were assessed for all studies using Cochrane Risk of Bias and Grading of Recommendations Assessment, Development, and Evaluation tools. For the secondary objective, a meta-regression was conducted to explore methodology, population, and intervention factors potentially related to the ES. RESULTS: Sixteen RCTs were included. Six studies presented a high risk of bias. Significant reduction in pain scores were found for FM (standardized mean difference = 1.22, 95% CI = 0.80-1.65, p < 0.001). Subgroup analysis considering tDCS as a neural target revealed no differences between common neural sites. Meta-regression revealed that the duration of the tDCS protocol in weeks was the only factor associated with the ES, in which protocols that lasted four weeks or longer reported larger ES than shorter protocols. CONCLUSIONS: Results suggest an analgesic effect of tDCS in FM. tDCS protocols that last four weeks or more may be associated with larger ESs. Definite conclusions are inadequate given the large heterogeneity and limited quality of evidence of the included studies.

Specific Electroencephalographic Signatures for Pain and Descending Pain Inhibitory System in Spinal Cord Injury.

OBJECTIVES: The pain related to spinal cord injury (SCI) is difficult to treat, and it is associated with significant morbidity. One aspect to improve therapeutics is to explore markers of pain and its correlates in SCI. METHODS: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 39 patients with SCI were included. We analyzed conditioned pain modulation (CPM) efficiency as the index of the descending pain inhibitory system, EEG variables, and clinical pain levels as measured by the Visual Analogue Scale. Regression analyses were performed to assess the relationship among EEG variables, pain levels, and CPM. RESULTS: We included 39 SCI patients, 74% reported SCI-related pain. We found that (1) less alpha and beta power are related to pain presence, (2) less alpha and beta power are associated with higher pain levels among patients with pain, (3) patients with pain have decreased peak alpha-theta frequency compared to no-pain group, (4) more relative theta power are related to the presence of low CPM efficiency, (5) higher relative theta power is associated with lower CPM efficiency. CONCLUSIONS: Our results confirm and provide additional data on the relationship between decreased alpha and beta frequencies and higher pain levels. One important finding, though, was a specific and different EEG signature for the descending inhibitory pain system, as we showed that increased theta EEG power is related to decreased CPM efficiency; suggesting that, although low CPM efficiency plays a major role in pain in these participants, it does seem to be associated with a specific oscillatory brain rhythm different from clinical pain. These findings have significant implications for future research on EEG-based biomarkers of pain in post-SCI and new interventions as neurofeedback to manage pain in this population.

Electroencephalography Signatures for Conditioned Pain Modulation and Pain Perception in Nonspecific Chronic Low Back Pain-An Exploratory Study.

Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship. OBJECTIVE: To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms. DESIGN: Cross-sectional analysis. PARTICIPANTS: Thirty NSCLBP patients participated. METHODS: Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis. RESULTS: CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression. CONCLUSIONS: Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.

Clinical and demographic predictors of symptoms of depression and anxiety in patients with spinal cord injury.

Spinal Cord Injury (SCI) is a condition whose consequences can impact the physical, emotional, and social aspects of patient's life, including Depression and Anxiety disorders. STUDY DESIGN: Using a cross-sectional design, sociodemographic and clinical data were extracted from 556 SCI patients at the time of initial assessment, prior to intensive rehabilitation treatment at the local rehabilitation institute. OBJECTIVES: Identify the predictive and multivariate relationship between different sociodemographic and clinical variables of Depression and Anxiety symptoms in SCI patients. SETTING: Lucy Montoro Rehabilitation Institute (LMRI), University of Sao Paulo, Sao Paulo, Brazil. METHODS: We performed independent univariate and multivariate regression models using the Hospital Anxiety and Depression Scale (HADS) as dependent variable. RESULTS: Symptoms of depression and anxiety present in SCI patients negatively correlate with the level of independence for locomotion, personal hygiene, bowel control, social interaction measured by the Functional Independence Scale (FIM), type of medication in use and the Language subtest of the MoCA Scale. Unlike previous studies, we did not find a relationship with the use of alcohol and illicit drugs, injury levels, etiological diagnosis or duration of injury. For the anxiety models, the main predictor was Depression symptoms, with SCI-related aspects not being significant. It was found that characteristics of the FIM Scale and cognitive aspects of the MoCA Scale were the main predictors of symptoms of Depression. Characteristics of the injury and motor deficit were not statistically significant. CONCLUSIONS: These findings can potentially be used to guide clinical practices to identify patients at higher risk of experiencing symptoms of Depression and Anxiety.

Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders.

BACKGROUND: Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects. OBJECTIVE: We convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson's disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction. METHODS: Experts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies. RESULTS: Although most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson's disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy). CONCLUSION: All recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs.