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Bruno Schein,1,2 Gerardo Beltran,1– 3 Bárbara Regina França,1,2 Paulo RS Sanches,4 Danton P Silva Jr,4 Iraci Lucena Torres,5,6 Felipe Fegni,7 Wolnei Caumo1,2,5,8 1Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul (RS), Brazil; 2Laboratory of Pain and Neuromodulation, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; 3Institute of Neurosciences, Universidad Catolica de Cuenca, Cuenca, Ecuador; 4Laboratory of Biomedical Engineer, HCPA, Porto Alegre, RS, Brazil; 5Pain and Palliative Care Service, HCPA, Porto Alegre, RS, Brazil; 6Laboratory of Pharmacology of Pain and Neuromodulation, Experimental Research Center, HCPA, Porto Alegre, RS, Brazil; 7Laboratory of Neuromodulation and Center for Clinical Research Learning, Physics and Rehabilitation Department, Spaulding Rehabilitation Hospital, Boston, MA, USA; 8Department of Surgery, School of Medicine, UFRGS, Porto Alegre, RS, BrazilCorrespondence: Wolnei Caumo, Laboratory of Pain and Neuromodulation, Hospital de Clínicas de Porto Alegre at UFRGS, Ramiro Barcelos, 2350 - CEP 90035-003 Bairro Rio Branco, Porto Alegre, RS, Brazil, Tel/Fax +55 51- 33598083, Email wcaumo@hcpa.edu.brObjective: We compare the effect of HAS, a-tDCS on the left dorsolateral prefrontal cortex (l-DLPFC), and rest-testing on pain measures [(cold pressor test (CPT) (primary outcome) and heat pain threshold]. We also compare their effects on the motor evoked potential (MEP) (primary outcome), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP).Methods: This randomized, blind, crossover trial included 18 women with fibromyalgia, aged from 18 to 65 years old. They received at random and in a crossover order a-tDCS over the l-DLPFC (2mA), HAS, or a rest-testing.Results: HAS compared to a-tDCS increased the pain tolerance with a moderate effect size (ES) [Cohen’s f=− 0.78; (CI 95%; − 1.48 to − 0.12)]. While compared to rest-testing, HAS increased the CPT with a large ES [Cohen’s f=− 0.87; (CI 95%; − 1.84 to − 0.09)]. The a-tDCS compared to HAS increased the MEP amplitude with large ES [Cohen’s f=− 1.73 (CI 95%; − 2.17 to − 0.17)]. Likewise, its ES compared to rest-testing in the MEP size was large [Cohen’s f=− 1.03; (CI 95%; − 2.06 to − 0.08)].Conclusion: These findings revealed that HAS affects contra-regulating mechanisms involved in perception and pain tolerance, while the a-tDCS increased the excitability of the corticospinal pathways. They give a subsidy to investigate their effect as approaches to counter regulate the maladaptive neuroplasticity involved in fibromyalgia.Clinical Trial Registration: www.ClinicalTrials.gov, identifier – NCT05066568.Keywords: tDCS, hypnosis, hypnotic analgesia, chronic pain, fibromyalgia, pain threshold, cold pressor test, CPM-test

Gerardo Beltran Serrano,1– 3 Laura Pooch Rodrigues,2 Bruno Schein,1,2 Maxciel Zortea,1,2 Iraci Lucenada Silva Torres,1,4,5 Felipe Fregni,6 Wolnei Caumo1,2,5 1Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil; 2Laboratory of Pain and Neuromodulation at Hospital De Clínicas De Porto Alegre (HCPA), Porto Alegre, Brazil; 3Psychology Department, Universidad Catolica De Cuenca, UCACUE, Cuenca, Ecuador; 4Department of Pharmacology, Institute of Health Sciences (ICBS), Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil; 5Pharmacology of Pain and Neuromodulation: Pre-Clinical Investigations Research Group, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil; 6Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USACorrespondence: Wolnei Caumo Fax + (55) 51- 3359.8083Email wcaumo@hcpa.edu.brObjective: We evaluated whether active(a)-tDCS combined with hypnotic analgesia suggestion (HS) would be more effective than a single active(a)-tDCS, and/or sham-(s)-tDCS and s-tDCS/HS on the following outcomes: function of descending pain modulatory system (DPMS) during the conditioned pain modulation test (CPM-test) (primary outcome), heat pain threshold (HPT), heat pain tolerance (HPTo) and cold pressor test (CPT) (secondary outcomes). We also examined whether their effects are related to neuroplasticity state evaluated by serum brain-derived-neurotropic factor (BDNF).Materials and Methods: Forty-eight females received one session of one of the four interventions (a-tDCS/HS, s-tDCS/HS, a-tDCS, and s-tDCS) in an incomplete randomized crossover sequence. The a-tDCS or s-tDCS was applied over the left dorsolateral prefrontal cortex (DLPFC) for 30 minutes at 2mA.Results: A generalized linear model revealed a significant main effect for the intervention group (P < 0.032). The delta-(Δ) pain score on the Numerical Pain Scale (NPS0-10) during CPM-test in the a-tDCS/HS group was − 0.25 (0.43). The (Δ) pain score on NPS (0– 10) during CPM-test in the other three groups was a-tDCS=− 0.54 (0.41), HS − 0.01 (0.41) and s-tDCS/HS=− 0.19 (0.43). A-tDCS/HS intervention increased the CPT substantially compared to all other interventions. Also, higher baseline levels of BDNF were associated with a larger change in CPT and HPTo.Conclusion: These findings indicate that the HS combined with a-tDCS mitigated the effect of the a-tDCS on the DPMS. The a-tDCS up-regulates the inhibition on DPMS, and the HS improved pain tolerance. And, together they enhanced the reaction time substantially upon the CPT.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03744897.Keywords: tDCS, hypnotic analgesia, conditioned pain modulation, pain perception

Dirson João Stein, 1, 2,* Liciane Fernandes Medeiros, 1, 3, 4,* Wolnei Caumo, 2 Iraci LS Torres 1– 3 1Laboratório de Farmacologia da Dor e Neuromodulação, Investigações Pré-Clínicas, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil; 2Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; 3Programa de Pós-Graduação em Ciências Biológicas: Farmacologia e Terapêutica, UFRGS, Porto Alegre, RS, Brazil; 4Programa de Pós-Graduação em Saúde e Desenvolvimento Humano, Universidade La Salle, Canoas, RS, Brazil*These authors contributed equally to this workCorrespondence: Iraci LS TorresPharmacology Department, ICBS, UFRGS, Rua Sarmento Leite, 500 - Sala 237, 90.050-170, Porto Alegre, RS, BrazilTel +55 51 3308 3183Fax +55 51 3308 3121Email iltorres@hcpa.edu.brAbstract: Anxiety is one of the most prevalent and debilitating psychiatric conditions worldwide. Pharmaco- and psycho-therapies have been employed in the treatment of human anxiety to date. Yet, either alone or in combination, unsatisfactory patient outcomes are prevalent, resulting in a considerable number of people whose symptoms fail to respond to conventional therapies with symptoms remaining after intervention. The demand for new therapies has given birth to several noninvasive brain stimulation techniques. Transcranial direct current stimulation (tDCS) has arisen as a promising tool and has been proven to be safe and well tolerated for the treatment of many diseases, including chronic pain, depression, and anxiety. Here, reports of the use of tDCS in anxiety disorders in human patients were reviewed and summarized. A literature search was conducted in mid-2019, to identify clinical studies that evaluated the use of tDCS for the treatment of anxiety behavior. The PubMed, Web of Science, and Scielo and PsycInfo databases were explored using the following descriptors: “anxiety”, “anxious behavior”, “tDCS”, and “transcranial direct current stimulation”. Among the selected articles, considerable variability in the type of tDCS treatment applied in interventions was observed. Evidence shows that tDCS may be more effective when used in combination with drugs and cognitive behavioral therapies; however future large-scale clinical trials are recommended to better clarify the real effects of this intervention alone, or in combination with others.Keywords: transcranial electrical stimulation, psychiatric disorder, anxious behavior, humans, clinical research

José Ary Berniger Romariz,1,2 Cássio Nonnemacher,2 Mylena Abreu,2 Joice Dickel Segabinazi,2 Janete Shatkoski Bandeira,2 Gerardo Beltran,1–3 Andressa Souza,4 Iraci LS Torres,5 Wolnei Caumo1,2,6–81Postgraduate Program in Medical Sciences, Faculdade de Medicina,Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 2Laboratory of Pain and Neuromodulation, Hospital de Clinicas de Porto Alegre, Brazil; 3Psychology Department, Cuenca Catholic University, Cuenca, Ecuador; 4Postgraduate Program in Health and Human Development, La Salle Universitary Center, Canoas, Brazil; 5Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 6Pain and Anesthesia,Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 7Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; 8Laboratory of Pain and Neuromodulation, Universidade Federal do Rio Grande do Sul, Porto Alegre, BrazilObjectives: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, criterion validity, criterion-group validity and responsiveness) of the Fear of Pain Questionnaire (FOPQ) for adolescents (FOPQ-A) and parents (FOPQ-P) translated to Brazilian Portuguese (BrP). The secondary aim was to analyze the factor structures and their ability to identify subjects with chronic pain conditions and identify the relationship of the BrP FOPQ-A with saliva brain-derived neurotrophic-factor (BDNF).Methods: A cross-sectional study was conducted with 286 adolescents aged 11 to 18 (257 healthy adolescents [157 females] and 29 adolescents with chronic pain [16 females]). Parents and adolescents completed the BrP-FOPQ. A team of experts translated the FOPQ according to international guidelines. Convergent validity and factor analysis were performed. Later, a subsample (n=146) was used to correlate the BrP-FOPQ-A with saliva BDNF.Results: The BrP-FOPQ for adolescents and parents presented strong psychometric properties (Cronbach’s α equal to 0.92 and 0.91, respectively). BrP-FOPQ-A confirmatory factor analysis yielded a two-factor structure while the factorial analyses of BrP-FOPQ-P demonstrated that the best solution was a three-structure factorial. The BrP-FOPQ-P scores in healthy adolescents and those in chronic pain conditions was 34.13 (16.71) vs 43.14 (18.08), respectively. A generalized mixed model demonstrated that the scores in the BrP-FOPQ-A are higher in those with chronic pain conditions compared to healthy subjects (29.20 [12.77] vs 33.80 [10.76], respectively; Wald χ2= 17.80; df=1, P

Maria da Graca-Tarragó,1,2 Mateus Lech,2 Letícia Dal Moro Angoleri,2 Daniela Silva Santos,2 Alícia Deitos,1,2 Aline Patrícia Brietzke,1,2 Iraci LS Torres,1,3 Felipe Fregni,4 Wolnei Caumo1,2,5,6 1Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 2Laboratory of Pain and Neuromodulation, HCPA, Porto Alegre, Brazil; 3Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 4Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA; 5Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 6Pain and Palliative Care Service, HCPA, Porto Alegre, Brazil Background: Neuroplastic changes in nociceptive pathways contribute to severity of symptoms in knee osteoarthritis (KOA). A new look at neuroplastic changes management includes modulation of the primary motor cortex by transcranial direct current stimulation (tDCS). Objectives: We investigated whether tDCS combined with intramuscular electrical stimulation (EIMS) would be more efficacious than a sham (s) intervention (s-tDCS/s-EIMS) or a single active(a)-tDCS/s-EIMS intervention and/or s-tDCS/a-EIMS in the following domains: pain measures (visual analog scale [VAS] score and descending pain modulatory system [DPMS], and outcomes, and analgesic use, disability, and pain pressure threshold (PPT) for secondary outcomes. Registration: The trial is registered in Clinical trials.gov: NCT01747070. Methods: Sixty women with KOA, aged 50–75 years old, randomly received five sessions of one of the four interventions (a-tDCS/a-EIMS, s-tDCS/s-EIMS, a-tDCS/s-EIMS, and s-tDCS/a-EIMS). tDCS was applied over the primary motor cortex (M1), for 30 minutes at 2 mA and the EIMS paraspinal of L1–S2. Results: A generalized estimating equation model revealed the main effect of the a-tDCS/a-EIMS in the VAS pain scores at end treatment compared with the other three groups (P

Wolnei Caumo,1–3 Maria Paz Hidalgo,4,5 Andressa Souza,6 Iraci LS Torres,1,7 Luciana C Antunes8 1School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; 2Pain and Palliative Care Service at Hospital de Clínicas de Porto Alegre (HCPA), Laboratory of Pain and Neuromodulation at UFRGS, Porto Alegre, Brazil; 3Pain and Anesthesia in Surgery Department, School of Medicine, UFRGS, Porto Alegre, Brazil; 4Psychiatry Department, School of Medicine, UFRGS, Porto Alegre, Brazil; 5Laboratorio de Cronobiologia e Sono do Hospital de Clinicas de Porto Alegre; Porto Alegre, Brazil; 6Postgraduate Program in Health and Human Development, La Salle Universitary Center, Canoas, Brazil; 7Pharmacology Department, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Brazil; 8Centro de Ciências da Saúde – Departamento de Nutrição da Universidade Federal De Santa Catarina, Florianopolis, Brazil Objective: This study compared urinary 6-sulfatoxymelatonin (aMT6s) over 24 hours among fibromyalgia (FM), major depression disorder (MDD), and healthy control (HC) groups, and examined whether rhythm is correlated with depressive symptoms. To answer this question we compared the rhythm of urinary aMT6s secretion among each group in four time series: morning (06:00–12:00 hours), afternoon (12:00–18:00 hours), evening (18:00–24:00 hours), and night (24:00–06:00 hours). In the FM subjects, we assessed if the rhythm of urinary aMT6s secretion is associated with pain severity, sleep quality, number of trigger points (NTPs), and the pain pressure threshold (PPT). Patients and methods: We included 54 women, aged 18–60 years with diagnosis of FM (n=18), MDD (n=19), and HC (n =17). The 24-hour urinary aMT6s was evaluated according to four standardized periods. The assessment instruments were the Hamilton Depression Rating Scale (HDRS), Pittsburgh Sleep Quality Index, and Fibromyalgia Impact Questionnaire. Results: A generalized estimating equation revealed no difference in the daily load of aMT6s secretion among the three groups (P=0.49). However, at the daily time (06:00–18:00 hours), the load secretion of aMT6s reached 41.54% and 60.71% in the FM and MDD, respectively, as compared to 20.73% in the HC (P

Wolnei Caumo,1–4 Luciana C Antunes,1 Jéssica Lorenzzi Elkfury,1 Evelyn G Herbstrith,5 Raquel Busanello Sipmann,6 Andressa Souza,7 Iraci LS Torres,1,8 Vinicius Souza dos Santos,1 Randy Neblett9 1Postgraduate Program in Medical Sciences, School of Medicine, 2Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre, 3Laboratory of Pain and Neuromodulation, 4Surgery Department, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, 5School of Psychology, Pontifícia Universidade Católica do Rio Grande do Sul, 6School of Medicine, Universidade Federal do Rio Grande do Sul, 7Postgraduate Program in Health and Human Development, La Salle University Center, Canoas, 8Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 9PRIDE Research Foundation, Dallas, TX, USA Objectives: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, reproducibility, and factor structure) of the Central Sensitization Inventory (CSI), adapted and validated for a Brazilian population (CSI-BP). Additionally, we evaluated the relationship between the CSI-BP and the serum brain-derived neurotrophic factor (BDNF) and determined if the symptoms elicited by the CSI-BP discriminate between subjects who do/do not respond to the conditioned pain modulation (CPM) task, as assessed by change in numeric pain scale (0–10) score. Patients and methods: A cross-sectional study was conducted in a pain clinic in a tertiary teaching hospital. A total of 222 adults with chronic musculoskeletal pain and 63 healthy control subjects completed the CSI-BP and the Brazilian Portuguese pain-catastrophizing scale (BP-PCS). A team of experts translated the CSI according to the international guidelines. Test–retest, item analysis, convergent validity, and factor analysis were performed. Later, a random subsample (n=77) was used to correlate the CSI-BP adjusted index with change in numeric pain-scale score during the CPM task and a BDNF blood sample. Results: The CSI-BP presented strong psychometric properties (test–retest reliability 0.91, Cronbach’s a=0.91). Confirmatory factor analysis yielded a four-factor structure, supporting the original English version. The CSI-BP adjusted index showed moderate positive correlation with the BP-PCS, and classified more than 80% of patients correctly vs healthy controls. Serum BDNF levels explained 27% of the variation in the CSI-BP adjusted index. Subjects with impairment in the descending modulatory system had higher CSI-BP adjusted index scores than subjects who responded normally to the CPM task: 49.35 (12.1) vs 39.5 (12.33), respectively (P

Joanna Ripoll Rozisky,1,2,4,* Yasmine Nonose,1,4,* Gabriela Laste,1,2,4 Vinicius Souza dos Santos,1,4 Isabel Cristina de Macedo,1,2,4 Ana Maria Oliveira Battastini,2,3 Wolnei Caumo,2,4 Iraci LS Torres1,2,41Laboratório de Farmacologia da Dor e Neuromodulação: Modelos Animais, Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, 2Programa de Pós-Graduação em Medicina, Ciências Médicas, 3Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil; 4Unidade de Experimentação Animal e Grupo de Pesquisa e Pós-Graduação, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil *Both authors contributed equally to this workAbstract: Morphine has been widely used in neonatal pain management. However, this treatment may produce adaptive changes in several physiologic systems. Our laboratory has demonstrated that morphine treatment in neonate rats alters nucleoside triphosphate diphosphohydrolase (NTPDase) activity and gene expression in central nervous system structures. Considering the relationship between the opioid and purinergic systems, our aim was to verify whether treatment with morphine from postnatal days 8 (P8) through 14 (P14) at a dose of 5 µg per day alters NTPDase and 5´-nucleotidase activities in rat serum over the short, medium, and long terms. After the in vivo assay, the morphine group showed increased hydrolysis of all nucleotides at P30, and a decrease in adenosine 5´-diphosphate hydrolysis at P60. Moreover, we found that nucleotidase activities change with age; adenosine 5´-triphosphate hydrolysis activity was lower at P16, and adenosine 5'-monophosphate hydrolysis activity was higher at P60. These changes are very important because these enzymes are the main regulators of blood nucleotide levels and, consequently, nucleotide signaling. Our findings showed that in vivo morphine treatment alters nucleotide hydrolysis in rat blood serum, suggesting that purine homeostasis can be influenced by opioid treatment during the neonatal period.Keywords: 5´-nucleotidase, morphine, neonate, NTPDase, rat blood serum

Gabriela Laste,1–3 Isabel Cristina de Macedo,1,3 Joanna Ripoll Rozisky,1–3 Fernanda Ribeiro da Silva,1,3 Wolnei Caumo,1,2 Iraci LS Torres1–31Laboratório de Farmacologia da Dor, Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, 2Programa de Pós-Graduação em Medicina, Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 3Unidade de Experimentação Animal e Grupo de Pesquisa e Pós-Graduação, Hospital de Clínicas de Porto Alegre, Porto Alegre, BrazilAbstract: In view of the broad range of effects attributed to melatonin, this study evaluated its analgesic effect on inflammatory pain induced by complete Freund's adjuvant (CFA) in Wistar rats. Inflammation was induced by intradermal CFA injection in the hind paw of all animals, which were then divided into two groups that received either 60 mg/kg of melatonin or vehicle (1% alcohol in saline), intraperitoneally, for three days. The analgesic effect of melatonin was assessed by the hot-plate test, immediately and thereafter at 30, 60, 90, and 120 minutes after the first administration and 24 hours after once-daily administration for 2 more days. After CFA injection, melatonin administration increased withdrawal latency at 60 minutes after the first dose. After the end of treatment, melatonin showed a significant analgesic effect on inflammatory pain. This study paves the way for exploration of how brief courses of treatment could improve this analgesic effect in the late phases of inflammatory pain.Keywords: analgesic response, complete Freund's adjuvant, hot-plate test, inflammation, melatonin, nociception

Summary: Mortality and morbidity for high‐risk surgical patients are often high, especially in low‐resource settings. Enhanced peri‐operative care has the potential to reduce preventable deaths but must be designed to meet local needs. This before‐and‐after cohort study aimed to assess the effectiveness of a postoperative 48‐hour enhanced care pathway for high‐risk surgical patients ('high‐risk surgical bundle') who did not meet the criteria for elective admission to intensive care. The pathway comprised of six elements: risk identification and communication; adoption of a high‐risk post‐anaesthesia care unit discharge checklist; prompt nursing admission to ward; intensification of vital signs monitoring; troponin measurement; and prompt access to medical support if required. The primary outcome was in‐hospital mortality. Data describing 1189 patients from two groups, before and after implementation of the pathway, were compared. The usual care group comprised a retrospective cohort of high‐risk surgical patients between September 2015 and December 2016. The intervention group prospectively included high‐risk surgical patients from February 2019 to March 2020. Unadjusted mortality rate was 10.5% (78/746) for the usual care and 6.3% (28/443) for the intervention group. After adjustment, the intervention effect remained significant (RR 0.46 (95%CI 0.30–0.72). The high‐risk surgical bundle group received more rapid response team calls (24% vs. 12.6%; RR 0.63 [95%CI 0.49–0.80]) and surgical re‐interventions (18.9 vs. 7.5%; RR 0.41 [95%CI 0.30–0.59]). These data suggest that a clinical pathway based on enhanced surveillance for high‐risk surgical patients in a resource‐constrained setting could reduce in‐hospital mortality. [ABSTRACT FROM AUTHOR]

The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. Therefore, a group of research and clinician experts on tDCS were convened to review the research and clinical use of tDCS. This report reviews the regulatory status of tDCS and summarizes the results according to research, off-label, and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan, and the US. Research use, off label treatment, and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials. [ABSTRACT FROM AUTHOR]

Background: Transcranial direct current stimulation (tDCS) might modulate neural activity and promote neural plasticity in patients with fibromyalgia (FM). This multi-group randomized clinical trial compared home-based active tDCS (HB-a-tDCS) on the left dorsolateral prefrontal cortex (l-DLPFC) or home-based sham tDCS (HB-s-tDCS), and HB-a-tDCS or HB-s-tDCS on the primary motor cortex (M1) in the connectivity analyses in eight regions of interest (ROIs) across eight resting-state electroencephalography (EEG) frequencies., Methods: We included 48 women with FM, aged 30 to 65, randomly assigned to 2:1:2:1 to receive 20 sessions during 20 minutes of HB-a-tDCS 2mA or HB-s-tDCS, over l-DLPFC or M1, respectively. EEG recordings were obtained before and after treatment with eyes open (EO) and eyes closed (EC)., Results: In the EC condition, comparing pre to post-treatment, the HB-a-tDCS on l-DLPFC decreased the lagged coherence connectivity in the delta frequency band between the right insula and left anterior cingulate cortex (ACC) (t = -3.542, p = .048). The l-DLPFC HB-a-tDCS compared to HB-s-tDCS decreased the lagged coherence connectivity in the delta frequency band between the right insula and left ACC (t = -4.000, p = .017). In the EO condition, the l-DLPFC HB-a-tDCS compared to M1 HB-s-tDCS increased the lagged coherence connectivity between the l-DLPFC and left ACC in the theta band (t = -4.059, p = .048). Regression analysis demonstrated that the HB-a-tDCS effect on the l-DLPFC was positively correlated with sleep quality. On the other hand, the HB-a-tDCS on l-DLPFC and HB-s-tDCS on M1 were positively correlated with pain catastrophizing., Conclusions: These results show that HB-a-tDCS affects the neural connectivity between parts of the brain that control pain's emotional and attentional aspects, which are most noticeable at lower EEG frequencies in a rest state. This effect on neural oscillations could serve as a neural marker associated with its efficacy in alleviating fibromyalgia symptoms., Clinical Trial Registration: identifier [NCT03843203]., Competing Interests: WC, National Council for Scientific and Technological Development - (CNPq), Brazil, ILST reported grants from National Council for Scientific and Technological Development, and Fundación de Amparo à Pesquisa do Estado do Rio Grande do Sul during the conduct of the study and PRSS grants from National Council for Scientific and Technological Development during the conduct of the study. PRSS reported grants from Financiadora de Estudos e Projetos during the conduct of the study; in addition, WC, ILST, PRSS had a patent for BR 20 2015 016450 0 licensed to Quark Medical. The tDCS device used in this study was developed and patented by PRSS, DPSJ, ILST, and WC, and these authors received royalties from Quark Medical (patent for BR 20 2015 016450 0 licensed to Quark Medical). DPSJ reported grants from Financiadora de Estudos e Projetos during the conduct of the study. No other competing interests were reported. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Lopes Alves et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Considering the growing evidence that psychological variables might contribute to fibromyalgia syndrome (FMS), our study aims to understand the impact of psychological factors in quantitative sensory testing (QST) in FMS patients by performing a systematic review with meta-analysis., Methods: A systematic search was carried out in PubMed/MEDLINE, EMBASE, Web of Science, and PsycINFO databases for records up until January 2024. We included 20 studies ( n = 1623, 16 randomized controlled trials, and 4 nonrandomized controlled trials) with low or moderate risk of bias included., Results: From nonrandomized evidence, our meta-analysis found a baseline relationship between anxiety, depression, and pain catastrophizing and QST measures in FMS patients. Higher pain catastrophizing levels were associated with less efficient conditioned pain modulation. Higher anxiety and depression were associated with lower pain threshold (PT). Randomized evidence showed a statistically significant increase in PT after fibromyalgia treatments (effect size = 0.29, 95% confidence interval = 0.03-0.56). The effect was not influenced by treatment type. Moreover, we found that only anxiety levels before treatment negatively influenced the PT improvements after treatment., Conclusion: FMS patients with higher anxiety levels at baseline showed a smaller increase in PT after the intervention. Depression factor was not significant in either changes in anxiety or depression. Baseline anxiety levels should be monitored as possible confounders of QST measurements. Understanding how psychological factors and QST are related in FMS patients is critical for improving the syndrome's management and treatment.Protocol Registration: CRD42023429397., (Copyright © 2024 by the American Psychosomatic Society.)

Objective: To examine the effect of nutritional counseling therapy (NCT) combined with transcranial direct current stimulation (tDCS) on Binge Eating Disorder (BED) symptoms., Methods: 40 women with BED were randomly (ratio of 2:2:2) allocated to one of the groups: active tDCS (a-tDCS), NCT, sham tDCS (s-tDCS) with NCT, and a-tDCS with NCT. Home-based tDCS was applied to the dorsolateral prefrontal cortex for 28 sessions., Results: A mixed analysis of variance showed no main effect between groups or a time × group interaction. However, a significant main effect was found for time on the primary outcome: Binge Eating Scale (p = 0.001; eta2p= 0.325), which tended to decrease during treatment and follow-up. A significant main effect was found on the secondary outcome: short-interval intracortical inhibition (SICI) (p = 0.02; eta2p= 0.112), a measure of inhibitory function, which increased from baseline to the final period in the a-tDCS group, without significant differences between groups., Conclusions: These findings reveal that the combined therapy did not have a synergic effect on BED symptoms. Since this is a pilot study and this is a promising area, we provide data to plan future larger-scale studies investigating the effects of tDCS and behavioral interventions in BED treatment., Competing Interests: The authors report no conflicts of interest.

The present study examined the medium- and long-term effects of early environmental enrichment (EE) on neuromotor, nociceptive, cognitive, behavioral, and neurochemical parameters in newborn rats repeatedly exposed to morphine. The study employed 90 Wistar rats: 10 adult nulliparous females and 80 male pups. Litter was split into standard and EE housing. Following, half of each litter received saline (S) or morphine (M) injections, resulting in four groups: SC + S, EE + S, SC + M, and EE + M. EE was applied from PND1 to PND21, while morphine or saline was given daily (5 μg/s.c.) from PND8 to PND14. Neuromotor development was similar between groups. In the OF test, morphine reduced outer and total crossings, whereas EE increased inner crossings and rearings. Adult rats showed a decrease in outer and total crossings and grooming and an increase in rearing. EE increased the number of protected and unprotected head dipping. Adult rats showed an increase in protected head dipping. Adult rats showed a lower recognition index, and, when exposed to EE, a lower anxiety index and analgesia. EE increased brainstem and hippocampal BDNF levels. Adult rats had increased hypothalamus, spinal cord, and brainstem BDNF levels, an increase in the spinal cord, and decreased hypothalamus TNF-α levels. This study demonstrated that early-life EE raises BDNF levels in the brainstem and hippocampus of rats and modifies their behaviors (such as nociception, exploration, and anxiety) in a state-dependent manner (morphine and age)., (© 2024 International Society for Developmental Neuroscience.)

Background: Home-based transcranial direct current stimulation (Hb-tDCS) is a non-invasive brain stimulation technique that utilizes low-intensity electric currents delivered via scalp electrodes to modulate brain activity. It holds significant promise for addressing inattention in adults with attention-deficit/hyperactivity disorder (ADHD). However, its effectiveness varies among individuals, and predicting outcomes remains uncertain, partially due to the influence of individual differences in ADHD-related brain anatomy., Methods: We analyzed data from a subsample, composed by twenty-nine adult patients with ADHD, of the Treatment of Inattention Symptoms in Adult Patients with ADHD (TUNED) trial. Fourteen patients underwent active anodal right cathodal left dorsolateral prefrontal cortex (DLPFC) Hb-tDCS for 4 weeks and fifteen received sham-related tDCS intervention. Inattention outcome was evaluated at both baseline and endpoint (4th week). Baseline structural measures of the DLPFC, anterior cingulate cortex (ACC) and subcortical structures, previously associated with ADHD, were quantified. Several linear mixed models, with a three-way interaction between the fixed predictors brain volume or thickness, time, and treatment were calculated. Multiple comparison corrections were applied using the Benjamini-Hochberg method., Results: Baseline volume of the left DLPFC regions middle frontal gyrus (t (25) = 3.33, p-adjusted = 0.045, Cohen's d = 1.33, 95% CI = [0.45, 2.19]), inferior frontal gyrus (orbital part) (t (25) = 3.10, p-adjusted = 0.045, Cohen's d = 1.24, 95% CI = [0.37, 2.08]), and of the left ACC supragenual (t (25) = 3.15, p-adjusted = 0.045, Cohen's d = 1.26, 95% CI = [0.39, 2.11]) presented significant association with the inattentive score improvement only in the active tDCS group. More specifically, the smaller these regions were, the more the symptoms improved following anodal right cathodal left DLPFC Hb-tDCS., Conclusion: Hb-tDCS was associated with greater improvement in brain areas related to attention regulation. Brain MRI can be potentially used to predict clinical response to tDCS in ADHD adults., Competing Interests: Declaration of Competing interest All authors report no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study had the aim of examining the relationships between variations in estrogen levels resulting from ovariectomy, and estrogen hormone replacement therapy (HRT) in rats subjected to an orofacial inflammatory pain model. Eighty adult female Wistar rats were initially divided into 2 groups: Sham or ovariectomy (OVX-D1). Seven days later (D7), the rats were subjected to an unilateral infiltration of Freund's Complete Adjuvant (CFA) or saline solution into the right temporomandibular joint (TMJ). Then, rats received 17β-estradiol (28 µg/kg/day) or placebo for 21 days (D10-D31). Nociception was evaluated by the von Frey (VF) and the Hot Plate (HP) tests, and depressive-like behavior by the Forced Swimming (FS) test. On D32 all rats were euthanized and serum, hippocampus and brainstem were collected. The CFA groups presented a mechanical hyperalgesia until day 21 (p ≤ 0.05). No differences were observed among groups in the HP (p = 0.735), and in the immobility and swimming time of the FS (p = 0.800; p = 0.998, respectively). In the brainstem, there was a significant difference in the TNF-ɑ levels (p = 0.043), and a marginal significant difference in BDNF levels (p = 0.054), without differences among groups in the hippocampal BDNF and TNF-ɑ levels (p = 0.232; p = 0.081, respectively). In conclusion, the hormone replacement therapy did not alleviate orofacial pain in ovariectomized rats. However, there is a decrease in brainstem TNF-ɑ levels in the animals submitted to both models, which was partially reverted by HRT., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

This study aimed to investigate clinical and physiological predictors of brain oscillatory activity in patients with fibromyalgia (FM), assessing resting-state power, event-related desynchronization (ERD), and event-related synchronization (ERS) during tasks. We performed a cross-sectional analysis, including clinical and neurophysiological data from 78 subjects with FM. Multivariate regression models were built to explore predictors of electroencephalography bands. Our findings show a negative correlation between beta oscillations and pain intensity; fibromyalgia duration is positively associated with increased oscillatory power at low frequencies and in the beta band; ERS oscillations in the theta and alpha bands seem to be correlated with better symptoms of FM; fatigue has a signature in the alpha band-a positive relationship in resting-state and a negative relationship in ERS oscillations. Specific neural signatures lead to potential clusters of neural adaptation, in which beta oscillatory activity in the resting state represents a more adaptive activity when pain levels are low and stimulus-evoked oscillations at lower frequencies are likely brain compensatory mechanisms. These neurophysiological changes may help to understand the impact of long-term chronic pain in the central nervous system and the descending inhibitory system in fibromyalgia subjects.

Objectives: Despite the fact that fibromyalgia, a widespread disease of the musculoskeletal system, has no specific treatment, patients have shown improvement after pharmacological intervention. Pregabalin has demonstrated efficacy; however, its adverse effects may reduce treatment adherence. In this context, neuromodulatory techniques such as transcranial direct current stimulation (tDCS) may be employed as a complementary pain-relieving method. Consequently, the purpose of this study was to evaluate the effect of pregabalin and tDCS treatments on the behavioral and biomarker parameters of rats submitted to a fibromyalgia-like model., Methods: Forty adult male Wistar rats were divided into two groups: control and reserpine. Five days after the end of the administration of reserpine (1 mg/kg/3 days) to induce a fibromyalgia-like model, rats were randomly assigned to receive either vehicle or pregabalin (30 mg/kg) along with sham or active- tDCS treatments. The evaluated behavioral parameters included mechanical allodynia by von Frey test and anxiety-like behaviors by elevated plus-maze test (time spent in opened and closed arms, number of entries in opened and closed arms, protected head-dipping, unprotected head-dipping [NPHD], grooming, rearing, fecal boluses). The biomarker analysis (brain-derived neurotrophic factor [BDNF] and tumor necrosis factor-α [TNF-α]) was performed in brainstem and cerebral cortex and in serum., Results: tDCS reversed the reduction in the mechanical nociceptive threshold and the decrease in the serum BDNF levels induced by the model of fibromyalgia; however, there was no effect of pregabalin in the mechanical threshold. There were no effects of pregabalin or tDCS found in TNF-α levels. The pain model induced an increase in grooming time and a decrease in NPHD and rearing; while tDCS reversed the increase in grooming, pregabalin reversed the decrease in NPHD., Conclusions: tDCS was more effective than pregabalin in controlling nociception and anxiety-like behavior in a rat model-like fibromyalgia. Considering the translational aspect, our findings suggest that tDCS could be a potential non-pharmacological treatment for fibromyalgia., (© 2024 the author(s), published by De Gruyter.)

Background and Purpose: Fibromyalgia (FM) is associated with altered descending pain modulatory pathways, which can be assessed through Conditioned Pain Modulation (CPM). In this study, we aimed to explore the relationship between CPM and self-reported baseline characteristics in patients with fibromyalgia. We also performed a longitudinal analysis exploring CPM as a potential predictor of clinical improvement over time in individuals with FM., Methods: We performed cross-sectional univariable and multivariable analyses of the relationship between CPM and other variables in 41 FM patients. We then performed longitudinal analyses, building linear mixed effects models with pain in the Visual Analogue Scale (VAS) as the dependent variable, and testing for the interaction between time and CPM. We also tested the interaction between CPM and time in models using other outcomes, such as the revised Fibromyalgia Impact Questionnaire (FIQR) and Quality of Life Scale (QOLs)., Results: We found no association between CPM and other demographic and clinical variables in the univariable analysis. We found a statistically significant association in the multivariable linear regression model between CPM and the QOLs at baseline, after controlling for age, sex, and duration of symptoms. In the longitudinal analyses, we found that CPM is an effect modifier for clinical improvement over time for the pain VAS, QOLs and FIQR: individuals with low-efficient CPM at baseline have a different (improved) pattern of response over time when compared to those with high-efficient CPM., Conclusions: Our findings suggest that CPM is not a reliable biomarker of clinical manifestations in chronic pain patients during cross-sectional assessments. However, our results are consistent with previous findings that CPM can be used to predict the evolution of clinical pain over time. We expect that our findings will help in the selection of patients with the best profile to respond to specific interventions and assist clinicians in tailoring pain treatments., Competing Interests: Conflict of interest disclosure Authors state no conflict of interest.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low-amplitude direct currents to alter cortical excitability. Previous trials have established the safety and tolerability of tDCS, and its potential to mitigate symptoms. However, the effects are cumulative, making it more difficult to have adherence to the treatment since frequent visits to the clinic or outpatient center are required. Moreover, the time needed for transportation to the center and the related expenses limit the accessibility of the treatment for many participants. Following guidelines for remotely supervised transcranial direct current stimulation (RS-tDCS) implementation, we propose a protocol designed for remotely supervised and home-based participation that uses specific devices and materials modified for patient use, with real-time monitoring by researchers through an encrypted video conferencing platform. We have developed detailed instructional materials and structured training procedures to allow for self- or proxy-administration while supervised remotely in real time. This protocol has a specific design to have a series of checkpoints during training and execution of the visit. This protocol is currently in use in a large pragmatic study of RS-tDCS for phantom limb pain (PLP). In this article, we will discuss the operational challenges of conducting a home-based RS-tDCS session and show methods to enhance its efficacy with supervised sessions.