Efficacy of Home-Based Transcranial Direct Current Stimulation Over the Primary Motor Cortex and Dorsolateral Prefrontal Cortex in the Disability Due to Pain in Fibromyalgia: A Factorial Sham-Randomized Clinical Study.

This randomized, double-blind, controlled clinical trial compared the effectiveness of home-based-(HB) active transcranial direct current stimulation (a-tDCS) over the left dorsolateral prefrontal cortex (l-DLPFC) or primary motor cortex (M1) with their respective sham-(s)-tDCS to determine whether a-tDCS would be more effective than s-tDCS in reducing pain and improving disability due to pain. The study included 102 patients with fibromyalgia aged 30 to 65 years old randomly assigned to 1 of 4 tDCS groups using a ratio of 2:1:2:1. The groups included l-DLPFC (a-tDCS, n = 34) and (s-tDCS, n = 17), or tDCS on the M1 (a-tDCS, n = 34) or (s-tDCS, n = 17). Patients self-administered 20 sessions of tDCS, with 2 mA for 20 minutes each day under remote supervision after in-person training. The Mixed Model for Repeated Measurements revealed that a-tDCS on DLPFC significantly reduced pain scores by 36.53% compared to 25.79% in s-tDCS. From baseline to the fourth week of treatment, a-tDCS on M1 reduced pain scores by 45.89% compared to 22.92% over s-tDCS. A generalized linear model showed a significant improvement in the disability scale in the groups that received a-tDCS compared to s-tDCS over M1 20.54% versus 2.49% (χ2 = 11.06, df = 1, P < .001]), while on DLPFC the improvement was 14.29% and 5.77%, with a borderline significance (χ2 = 3.19, df = 1, P = .06]), respectively. A higher reduction in serum brain-derived neurotrophic factor from baseline to treatment end was positively correlated with decreased pain scores regardless of the treatment group. The application of a-tDCS over M1 increased the heat pain threshold and the function of the descending pain inhibitory system. PERSPECTIVE: These findings provide important insights: (1) HB-tDCS has effectively reduced pain scores and improved disability due to fibromyalgia. (2) The study provides evidence that HB-a-tDCS is a viable and effective therapeutic approach. (3) HB-a-tDCS over M1 improved the function of the descending pain inhibitory system and increased the heat pain threshold. Finally, our findings also emphasize that brain-derived neurotrophic factor, as an index of neuroplasticity, may serve as a valuable marker associated with changes in clinical pain measures. TRIAL REGISTRATION: Number NCT03843203.

Peripheral body temperature rhythm as a marker of the severity of depression symptoms in fibromyalgia.

BACKGROUND: Circadian rhythm alterations have been reported in fibromyalgia (FM) and depression. Peripheral body temperature (PBT) is a reliable measure of the circadian system, so we compared the PBT rhythm between persons with FM and controls. We evaluated PBT correlation with depression symptoms and pain severity in women with FM. METHODS: We included 101 women aged 30-65 with FM diagnosis (FM group, n = 83) and controls (n = 18). Twenty-four-hour PBT was assessed by actigraphy. For the analysis, in the FM group, the PBT measurement was divided into four periods: morning (6 a.m.-noon), afternoon (noon-6 p.m.), evening (6 p.m.-midnight), and night (midnight-6 a.m.). According to their scores on the Hamilton Depression Rating Scale (HDRS), participants were classified as having mild or moderate to severe depression symptoms. RESULTS: There was no difference in PBT between FM and controls. Subjects with FM and moderate to severe depression symptoms showed a higher PBT (p = .003) during the evening period (p = .004). The analysis of PBT rhythm revealed an interaction between time and group according to mild or moderate to severe depression symptoms (χ2 (3) = 12.79, p < .005). The pain severity was positively correlated with PBT (ß=0.22, [CI 95%, 0.07-0.37], p = .003). CONCLUSIONS: PBT rhythm was not a sensitive measure for discriminating persons with FM from controls. In FM, PBT is related to the severity of depression symptoms and pain intensity.

The effect of home-based transcranial direct current stimulation in cognitive performance in fibromyalgia: A randomized, double-blind sham-controlled trial.

Background: Transcranial Direct Current Stimulation (tDCS) is a promising approach to improving fibromyalgia (FM) symptoms, including cognitive impairment. So, we evaluated the efficacy and safety of home-based tDCS in treating cognitive impairment. Besides, we explored if the severity of dysfunction of the Descendant Pain Modulation System (DPMS) predicts the tDCS effect and if its effect is linked to changes in neuroplasticity as measured by the brain-derived neurotrophic factor (BDNF). Methods: This randomized, double-blind, parallel, sham-controlled clinical trial, single-center, included 36 women with FM, aged from 30 to 65 years old, assigned 2:1 to receive a-tDCS (n = 24) and s-tDCS (n = 12). The primary outcome was the Trail Making Test's assessment of executive attention, divided attention, working memory (WM), and cognitive flexibility (TMT-B-A). The secondary outcomes were the Controlled Oral Word Association Test (COWAT), the WM by Digits subtest from the Wechsler Adult Intelligence Scale (WAIS-III), and quality of life. Twenty-minute daily sessions of home-based tDCS for 4 weeks (total of 20 sessions), 2 mA anodal-left (F3) and cathodal-right (F4) prefrontal stimulation with 35 cm2 carbon electrodes. Results: GLM showed a main effect for treatment in the TMT-B-A [Wald χ2 = 6.176; Df = 1; P = 0.03]. The a-tDCS improved cognitive performance. The effect size estimated by Cohen's d at treatment end in the TMT-B-A scores was large [-1.48, confidence interval (CI) 95% = -2.07 to-0.90]. Likewise, the a-tDCS effects compared to s-tDCS improved performance in the WM, verbal and phonemic fluency, and quality-of-life scale. The impact of a-tDCS on the cognitive tests was positively correlated with the reduction in serum BDNF from baseline to treatment end. Besides, the decrease in the serum BDNF was positively associated with improving the quality of life due to FM symptoms. Conclusion: These findings revealed that daily treatment with a home-based tDCS device over l-DLPFC compared to sham stimulation over 4 weeks improved the cognitive impairment in FM. The a-tDCS at home was well-tolerated, underlining its potential as an alternative treatment for cognitive dysfunction. Besides, the a-tDCS effect is related to the severity of DPMS dysfunction and changes in neuroplasticity state. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT03843203].

Functional connectivity response to acute pain assessed by fNIRS is associated with BDNF genotype in fibromyalgia: an exploratory study.

Fibromyalgia is a heterogenous primary pain syndrome whose severity has been associated with descending pain modulatory system (DPMS) function and functional connectivity (FC) between pain processing areas. The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism has been linked to vulnerability to chronic pain. In this cross-sectional imaging genetics study, we investigated fibromyalgia, the relationship between BDNF Val66Met heterozygous genotypes (Val/Met), and the functional connectivity (FC) response pattern to acute pain stimulus in the motor (MC) and prefrontal (PFC) cortex assessed by near-infrared spectroscopy (fNIRS) before and after a cold pressor test utilizing water (0-1 °C). Also, we assessed the relationship between this genotype with the DPMS function and quality of life. We included 42 women (Val/Val = 30; Val/Met = 12) with fibromyalgia, ages 18-65. The MANCOVA comparing Val/Met to Val/Val genotypes showed higher ΔFC between left(l)-PFC-l-MC (ß = 0.357, p = 0.048), l-PFC-right(r)-PFC (ß = 0.249, p = 0.012), l-PFC-r-MC (ß = 0.226, p = 0.022), and l-MC-r-PFC (ß = 0.260, p = 0.016). Val/Met genotypes showed higher efficiency of the DPMS and lower disability due to pain. Here we show that fibromyalgia patients carrying the Val/Met BDNF genotype presented an increased ΔFC across MC and PFC in response to acute pain associated with differences in acute pain perception and fibromyalgia symptoms.

Impact of Bifrontal Home-Based Transcranial Direct Current Stimulation in Pain Catastrophizing and Disability due to Pain in Fibromyalgia: A Randomized, Double-Blind Sham-Controlled Study.

This randomized, double-blind trial tested the hypothesis that 20 sessions of home-based anodal(a)-transcranial direct current stimulation (tDCS) (2mA for 20 minutes) bifrontal, with anodal on the left dorsolateral prefrontal cortex (l-DLPFC) would be better than sham-(s)-tDCS to reduce scores on Pain Catastrophizing Scale and disability-related to pain assessed by the Profile of Chronic Pain: Screen (primary outcomes). Secondary outcomes were depressive symptoms, sleep quality, heat pain threshold , heat pain tolerance , and serum brain-derived-neurotrophic-factor (BDNF). Forty-eight women with fibromyalgia, 30 to 65 years-old were randomized into 2:1 groups [a-tDCS (n = 32) or s-tDCS (n = 16)]. Post hoc analysis revealed that a-tDCS reduced the Pain Catastrophizing Scale total scores by 51.38% compared to 26.96% in s-tDCS, and a-tDCS reduced Profile of Chronic Pain: Screen total scores by 31.43% compared to 19.15% in s-tDCS. The a-tDCS improved depressive symptoms, sleep quality and increased the heat pain tolerance. The delta-value in the serum BDNF (mean post treatment end minus pretreatment) was conversely correlated with the a-tDCS effect in pain catastrophizing. In contrast, the a-tDCS impact on reducing the disability-related to pain at the treatment end was positively associated with a reduction in the serum BDNF and improvement of depressive symptoms, sleep quality and pain catastrophizing symptoms. PERSPECTIVE: Home-based bifrontal tDCS with a-tDCS on the l-DLPFC are associated with a moderate effect size (ES) in the following outcomes: 1) Decreased rumination and magnification of pain catastrophizing. 2) Improved the disability for daily activities due to fibromyalgia symptoms. Overall, these findings support the feasibility of self-applied home-based tDCS on DLPFC to improve fibromyalgia symptoms.

Transcranial Direct Current Stimulation to Improve the Dysfunction of Descending Pain Modulatory System Related to Opioids in Chronic Non-cancer Pain: An Integrative Review of Neurobiology and Meta-Analysis.

Background: Opioid long-term therapy can produce tolerance, opioid-induced hyperalgesia (OIH), and it induces dysfunction in pain descending pain inhibitory system (DPIS). Objectives: This integrative review with meta-analysis aimed: (i) To discuss the potential mechanisms involved in analgesic tolerance and opioid-induced hyperalgesia (OIH). (ii) To examine how the opioid can affect the function of DPIS. (ii) To show evidence about the tDCS as an approach to treat acute and chronic pain. (iii) To discuss the effect of tDCS on DPIS and how it can counter-regulate the OIH. (iv) To draw perspectives for the future about the tDCS effects as an approach to improve the dysfunction in the DPIS in chronic non-cancer pain. Methods: Relevant published randomized clinical trials (RCT) comparing active (irrespective of the stimulation protocol) to sham tDCS for treating chronic non-cancer pain were identified, and risk of bias was assessed. We searched trials in PubMed, EMBASE and Cochrane trials databases. tDCS protocols accepted were application in areas of the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), or occipital area. Results: Fifty-nine studies were fully reviewed, and 24 with moderate to the high-quality methodology were included. tDCS improved chronic pain with a moderate effect size [pooled standardized mean difference; -0.66; 95% confidence interval (CI) -0.91 to -0.41]. On average, active protocols led to 27.26% less pain at the end of treatment compared to sham [95% CI; 15.89-32.90%]. Protocol varied in terms of anodal or cathodal stimulation, areas of stimulation (M1 and DLPFC the most common), number of sessions (from 5 to 20) and current intensity (from 1 to 2 mA). The time of application was 20 min in 92% of protocols. Conclusion: In comparison with sham stimulation, tDCS demonstrated a superior effect in reducing chronic pain conditions. They give perspectives that the top-down neuromodulator effects of tDCS are a promising approach to improve management in refractory chronic not-cancer related pain and to enhance dysfunctional neuronal circuitries involved in the DPIS and other pain dimensions and improve pain control with a therapeutic opioid-free. However, further studies are needed to determine individualized protocols according to a biopsychosocial perspective.

S-Ketamine's Effect Changes the Cortical Electrophysiological Activity Related to Semantic Affective Dimension of Pain: A Placebo- Controlled Study in Healthy Male Individuals.

BACKGROUND: Previous studies using the electroencephalogram (EEG) technique pointed out that ketamine decreases the amplitude of cortical electrophysiological signal during cognitive tasks, although its effects on the perception and emotional-valence judgment of stimuli are still unknown. OBJECTIVE: We evaluated the effect of S-ketamine on affective dimension of pain using EEG and behavioral measures. The hypothesis was that S-ketamine would be more effective than placebo, both within and between groups, to attenuate the EEG signal elicited by target and non-target words. METHODS: This double-blind parallel placebo-controlled study enrolled 24 healthy male volunteers between 19 and 40 years old. They were randomized to receive intravenous S-ketamine (n = 12) at a plasmatic concentration of 60 ng/ml or placebo (n = 12). Participants completed a computerized oddball paradigm containing written words semantically related to pain (targets), and non-pain related words (standard). The volunteers had to classify the words either as "positive," "negative" or "neutral" (emotional valence judgment). The paradigm consisted in 6 blocks of 50 words each with a fixed 4:1 target/non-target rate presented in a single run. Infusion started during the interval between the 3rd and 4th blocks, for both groups. EEG signal was registered using four channels (Fz, Pz, Pz, and Oz, according to the 10-20 EEG system) with a linked-earlobe reference. The area under the curve (AUC) of the N200 (interval of 100-200 ms) and P300 (300-500 ms) components of event-related potentials (ERPs) was measured for each channel. RESULTS: S-ketamine produced substantial difference (delta) in the AUC of grand average ERP components N200 (P = 0.05) and P300 (P = 0.02) at Pz during infusion period when compared to placebo infusion for both targets and non-targets. S-ketamine was also associated with a decrease in the amount of pain-related words judged as negative from before to after infusion [mean = 0.83 (SD = 0.09) vs. mean = 0.73 (SD = 0.11), respectively; P = 0.04]. CONCLUSION: Our findings suggest that S-ketamine actively changed the semantic processing of written words. There was an increase in electrophysiological response for pain-related stimuli and a decrease for standard stimuli, as evidenced by the increased delta of AUCs. Behaviorally, S-ketamine seems to have produced an emotional and discrimination blunting effect for pain-related words. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03915938.

Correlation of shift work and waist circumference, body mass index, chronotype and depressive symptoms.

OBJECTIVE: Correlate shift work with body mass index (BMI), waist circumference, chronotype and depressive symptoms. SUBJECTS AND METHODS: This study comprising 14 shift workers and 13 day workers. Subjects were workers from the health area aged 25 to 60 years. Minor psychiatric disorders were accessed by Self Report Questionnaire (SRQ-20) and depressive symptoms by Beck Depression Inventory (BDI). Chronotype was accessed using Morningness-Eveningness Questionnaire (MEQ). Anthropometric measures were taken. RESULTS: Shift workers presented higher BMI (P = 0.03) and waist circumference (P = 0.004) than day workers. Years on shift work were significantly correlated to waist circumference (r = 0.43; P = 0.03) and age (r = 0.47; P = 0.02). Shift work was not correlated with depressive symptoms and chronotype. CONCLUSION: These results may suggest a role played by shift work on the development and/or the early clinic manifestations of metabolic disturbances, becoming a risk factor to metabolic syndrome.

Correlation of shift work and waist circumference, body mass index, chronotype and depressive symptoms / Correlação entre trabalho de turno e circunferência abdominal, índice de massa corporal, cronotipo e sintomas depressivos

OBJECTIVE: Correlate shift work with body mass index (BMI), waist circumference, chronotype and depressive symptoms. SUBJECTS AND METHODS: This study comprising 14 shift workers and 13 day workers. Subjects were workers from the health area aged 25 to 60 years. Minor psychiatric disorders were accessed by Self Report Questionnaire (SRQ-20) and depressive symptoms by Beck Depression Inventory (BDI). Chronotype was accessed using Morningness-Eveningness Questionnaire (MEQ). Anthropometric measures were taken. RESULTS: Shift workers presented higher BMI (P = 0.03) and waist circumference (P = 0.004) than day workers. Years on shift work were significantly correlated to waist circumference (r = 0.43; P = 0.03) and age (r = 0.47; P = 0.02). Shift work was not correlated with depressive symptoms and chronotype. CONCLUSION: These results may suggest a role played by shift work on the development and/or the early clinic manifestations of metabolic disturbances, becoming a risk factor to metabolic syndrome.

OBJETIVO: Correlacionar o trabalho de turno com índice de massa corporal (IMC), circunferência abdominal, cronotipo e sintomas depressivos. SUJEITOS E MÉTODOS: Amostra de 14 trabalhadores de turno e 13 diurnos, com idade entre 25 e 60 anos. Transtornos psiquiátricos menores foram aferidos pelo Self Report Questionnaire (SRQ-20), sintomas depressivos pelo inventário de Depressão de Beck (BDI) e o cronotipo pelo Morningness-Eveningness Questionnaire (MEQ). As medidas antropométricas foram mensuradas. RESULTADOS: Trabalhadores de turno apresentaram maior IMC (P = 0,03) e circunferência abdominal (P = 0,004) quando comparados aos diurnos. O tempo de trabalho de turno foi correlacionado à circunferência abdominal (r = 0,43; P = 0,03). Não houve correlação entre trabalho e sintomas depressivos e cronotipo. CONCLUSÃO: Os resultados podem sugerir que o trabalho de turno desempenhe um papel no desenvolvimento e/ou nas precoces manifestações clínicas de distúrbios metabólicos, tornando-se um fator de risco para a síndrome metabólica.