Proposal of a screening instrument for autism spectrum disorder in children (Mini-TEA Scale).

BACKGROUND: Autism spectrum disorder (ASD) requires trained professionals for its adequate diagnosis. There is a shortage of such professionals in Brazil. Screening tools could identify priority cases. The only instrument for that in Brazilian Portuguese is employed for toddlers up to 2.5 years old. OBJECTIVE: The Mini-TEA scale was conceived and tested as a screening for children from 2.5 to 12 years old. METHODS: After local ethics committee's approval, this study was conducted from December 2022 to April 2023 in the Associação de Pais e Amigos dos Excepcionais, Passo Fundo/RS, of invitations to children's parents/relatives who were under evaluation for ASD and by local advertisement. Inclusion criteria were age from 2.5 to 12 years old; consent from the child's legal guardians. 75 children's parents/relatives were interviewed using the 15-item Mini-TEA scale. After that, children were evaluated for the diagnosis of ASD by a pediatric neurologist. Sensibility and specificity for ASD diagnosis along the Mini-TEA scores were measured. Experts and target population evaluated the validity/reliability of the Mini-TEA scale. The reproducibility of the scores was assessed about 40 days later. RESULTS: From the 75 participants, 28 received a diagnosis of ASD. Scores ≥ 10 on the Mini-TEA scale require further evaluation of the children (sensitivity 100%; specificity 68%). Content validity coefficient (CVC) rendered values > 0.80 (acceptable). Test-retest analyzes with the intraclass correlation coefficient (ICC) indicated excellent reliability (> 0.90). The time spent for applying the screening was about 10 minutes. CONCLUSION: The Mini-TEA scale presents as an easy tool for screening ASD among children.

ANTECEDENTES: O transtorno do espectro autista (TEA) requer profissionais treinados para o diagnóstico, escassos no Brasil. Instrumentos de triagem poderiam identificar casos prioritários para avaliação. O único em português brasileiro é empregado para crianças até 30 meses de idade. OBJETIVO: A escala Mini-TEA foi concebida e testada como triagem para crianças entre 2,5 e 12 anos. MéTODOS: Estudo foi conduzido de dezembro de 2022 a abril de 2023 na Associação de Pais e Amigos dos Excepcionais (APAE) de Passo Fundo/RS, após a aprovação bioética local. O recrutamento consistiu em convite aos familiares de crianças que estavam sendo avaliadas para TEA e por divulgação local. Os critérios de inclusão foram idade entre 2,5 e 12 anos e consentimento do guardião legal. Familiares de 75 crianças foram entrevistados com a escala Mini-TEA (15 itens). Depois, as crianças foram avaliadas para o diagnóstico de TEA por neuropediatra. A sensibilidade e a especificidade do diagnóstico de TEA com os escores da Mini-TEA foram mensuradas. A validade e a confiabilidade da escala Mini-TEA foram avaliadas por experts e pela população alvo. A reprodutibilidade dos escores foi medida após ± 40 dias. RESULTADOS: Dos 75 participantes, 28 receberam diagnóstico de TEA. Escores ≥ 10 na escala Mini-TEA requerem avaliação das crianças (sensibilidade 100%; especificidade 68%). O coeficiente de validação de conteúdo (CVC) rendeu valores > 0,80 (aceitável). Análises de teste-reteste com coeficiente de correlação intraclasse (ICC) indicou excelente confiabilidade (> 0,90). O tempo gasto para a triagem foi cerca de 10 minutos. CONCLUSãO: A escala Mini-TEA constitui ferramenta breve e fácil para triagem de TEA em crianças.

High-beta oscillations at EEG resting state and hyperconnectivity of pain circuitry in fibromyalgia: an exploratory cross-sectional study.

Background: Electroencephalography (EEG) has identified neural activity in specific brain regions as a potential indicator of the neural signature of chronic pain. This study compared the lagged coherence connectivity between regions of interest (ROIs) associated with the pain connectome in women with fibromyalgia (FM) and healthy women (HC). Methods: We evaluated 64 participants (49 FM and 15 HC) during resting-state EEG sessions under both eyes open (EO) and eyes closed (EC) conditions. In addition to EEG measurements, we assessed clinical and psychological symptoms and serum levels of brain-derived neurotrophic factor (BDNF). The connectivity between eight ROIs was computed across eight different EEG frequencies. Results: The FM group demonstrated increased connectivity between the left dorsolateral prefrontal cortex (DLPFC) and right anterior cingulate cortex (ACC), specifically in the beta-3 frequency band (t = 3.441, p = 0.044). When comparing the EO and EC conditions, FM patients exhibited heightened interhemispheric connectivity between insular areas (t = 3.372, p = 0.024) and between the left insula (INS) and right DLPFC (t = 3.695, p = 0.024) within the beta-3 frequency band. In the EC condition, there was a negative correlation between pain disability and connectivity in the beta-3 frequency band between the left ACC and the left primary somatosensory cortex (SI; r = -0.442, p = 0.043). In the EO condition, there was a negative correlation between central sensitization severity and lagged coherence connectivity in the alpha-2 frequency band between the right ACC and left SI (r = 0.428, p = 0.014). Moreover, in the EO-EC comparison, the lagged coherence connection between the left DLPFC and right INS, indexed by the gamma frequency band, showed a negative correlation with serum BDNF levels (r = -0.506, p = 0.012). Conclusion: These findings indicate that increased connectivity between different pain processing circuits, particularly in the beta-3 frequency band during rest, may serve as neural biomarkers for the chronic pain brain signature associated with neuroplasticity and the severity of FM symptoms.

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.

Primary somatosensory cortex and periaqueductal gray functional connectivity as a marker of the dysfunction of the descending pain modulatory system in fibromyalgia.

Background: Resting-state functional connectivity (rs-FC) may aid in understanding the link between pain-modulating brain regions and the descending pain modulatory system (DPMS) in fibromyalgia (FM). This study investigated whether the differences in rs-FC of the primary somatosensory cortex in responders and non-responders to the conditioned pain modulation test (CPM-test) are related to pain, sleep quality, central sensitization, and the impact of FM on quality of life. Methods: This cross-sectional study included 33 females with FM. rs-FC was assessed by functional magnetic resonance imaging. Change in the numerical pain scale during the CPM-test assessed the DPMS function. Subjects were classified either as non-responders (i.e., DPMS dysfunction, n = 13) or responders (n = 20) to CPM-test. A generalized linear model (GLM) and a receiver operating characteristic (ROC) curve analysis were performed to check the accuracy of the rs-FC to differentiate each group. Results: Non-responders showed a decreased rs-FC between the left somatosensory cortex (S1) and the periaqueductal gray (PAG) (P < 0.001). The GLM analysis revealed that the S1-PAG rs-FC in the left-brain hemisphere was positively correlated with a central sensitization symptom and negatively correlated with sleep quality and pain scores. ROC curve analysis showed that left S1-PAG rs-FC offers a sensitivity and specificity of 85% or higher (area under the curve, 0.78, 95% confidence interval, 0.63-0.94) to discriminate who does/does not respond to the CPM-test. Conclusions: These results support using the rs-FC patterns in the left S1-PAG as a marker for predicting CPM-test response, which may aid in treatment individualization in FM patients.

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].

Association between descending pain modulatory system and cognitive impairment in fibromyalgia: A cross-sectional exploratory study.

Background: The successful regulation of sensory input to the central nervous system depends on the descending pain modulatory system (DPMS). For the effective regulation of sensory input to the central nervous system and behavioral responses to pain, the DPMS is required. Its connection to fibromyalgia (FM)-related cognitive dysfunction has not yet been investigated. Therefore, this study tested whether measures of verbal fluency, sustained attention, and short-term and working memory could distinguish FM patients from healthy controls (HC). Additionally, it investigated, using a standardized paradigm, the link between cognitive ability and the function of the DPMS in responders and non-responders to the conditioned pain modulation test (CPM-test). Materials and methods: We enrolled 21 HC women and 69 FM patients, all of whom ranged in age from 30 to 65. We employed scores from the Trail Making Test (TMTB-A) (sustained and divided attention), the Controlled Oral Word Association Test (COWAT) (orthographic and semantic fluency), and the Digits subtest of the Wechsler Adult Intelligence Scale (WAIS-III) as dependent variables. Results: A generalized linear model (GLM) adjusted by educational level revealed significantly lower scores in FM than HC on the Span digits forward, COWAT-orthographic, and TMTB-A. For FM patients, multilevel MANCOVA revealed that the cognitive performance of non-responders compared to responders to CPM-test showed lower adjusted scores in Span digits forward (Partial-η2 = 0.358, P = 0.001), Span digits backward (Partial-η2 = 0.358, P = 0.001), COWAT-orthographic (Partial-η2 = 0.551, P = 0.001), COWAR-semantic (Partial-η2 = 0.355, P = 0.001), and TMTB-A (Partial-η2 = 0.360, P = 0.001). The association between the cognitive tests and the DPMS is moderated by the serum level of brain-derived neurotrophic factor (BDNF). Additionally, these cognitive assessments had a positive correlation with antidepressant use and pain threshold. The cognitive assessments, on the other hand, were conversely associated with a life of quality. Conclusion: Based on these findings, it can be shown that HC performed substantially better on cognitive exams than FM did. They demonstrated a link between clinical complaints about attention and memory and decreased DPMS effectiveness. Additionally, they demonstrated that the BDNF is a moderating element in a potential relationship between the severity of cognitive impairment and DPMS dysfunction.

Spectral Power Density analysis of the resting-state as a marker of the central effects of opioid use in fibromyalgia.

Spectral power density (SPD) indexed by electroencephalogram (EEG) recordings has recently gained attention in elucidating neural mechanisms of chronic pain syndromes and medication use. We compared SPD variations between 15 fibromyalgia (FM) women in use of opioid in the last three months (73.33% used tramadol) with 32 non-users. EEG data were obtained with Eyes Open (EO) and Eyes Closed (EC) resting state. SPD peak amplitudes between EO-EC were smaller in opioid users in central theta, central beta, and parietal beta, and at parietal delta. However, these variations were positive for opioid users. Multivariate analyses of variance (ANOVAs) revealed that EO-EC variations in parietal delta were negatively correlated with the disability due to pain, and central and parietal beta activity variations were positively correlated with worse sleep quality. These clinical variables explained from 12.5 to 17.2% of SPD variance. In addition, central beta showed 67% sensitivity / 72% specificity and parietal beta showed 73% sensitivity/62% specificity in discriminating opioid users from non-users. These findings suggest oscillations in EEG might be a sensitive surrogate marker to screen FM opioid users and a promising tool to understand the effects of opioid use and how these effects relate to functional and sleep-related symptoms.

The mapping of cortical activation by near-infrared spectroscopy might be a biomarker related to the severity of fibromyalgia symptoms.

The delta value of oxyhemoglobin (Δ-HbO) determined by functional near-infrared spectroscopy at prefrontal cortex (PFC) and motor cortex (MC) based on primary (25 °C) and secondary (5 °C) thermal stimuli presented a larger peak latency at left MC in fibromyalgia than in controls. The difference between HbO concentration 15 s after the thermal stimuli ending and HbO concentration before the thermal stimuli onset (Δ-HbO*) at left PFC increased 47.82% in fibromyalgia and 76.66% in controls. This value had satisfactory discriminatory properties to differentiate cortical activation in fibromyalgia versus controls. A receiver operator characteristics (ROC) analysis showed the Δ-HbO* cutoffs of - 0.175 at left PFC and - 0.205 at right PFC offer sensitivity and specificity of at least 80% in screening fibromyalgia from controls. In fibromyalgia, a ROC analysis showed that these cutoffs could discriminate those with higher disability due to pain and more severe central sensitization symptoms (CSS). The ROC with the best discriminatory profile was the CSS score with the Δ-HbO* at left PFC (area under the curve = 0.82, 95% confidence interval = 0.61-100). These results indicate that cortical activation based on Δ-HbO* at left PFC might be a sensitive marker to identify fibromyalgia subjects with more severe clinical symptoms.

Age as a Mediator of tDCS Effects on Pain: An Integrative Systematic Review and Meta-Analysis.

Introduction: The transcranial direct current stimulation (tDCS) is a neuromodulatory technique with the potential to decrease pain scores and to improve chronic pain treatment. Although age is an essential factor that might impact the tDCS effect, most studies are solely conducted in adults. Therefore, the age limitation presents a critical research gap in this field and can be shown by only a handful of studies that have included other age groups. To examine the evidence upon the tDCS effect on pain scores on children, adolescents, or elderly, and indirectly, to infer the age-dependent impact on tDCS effects, we conducted a systematic review and meta-analysis. Methods: A systematic review searching the following databases: PubMed, EMBASE, and Science Direct using the following search terms adapted according to MeSh or Entree: [("Adolescent" OR "Children" OR "Elderly") AND ("tDCS") AND ("Pain" OR "Pain threshold") AND ("dorsolateral prefrontal cortex" OR "Motor cortex)] up to April 20th, 2020. We retrieved 228 articles, 13 were included in the systematic review, and five studies with elderly subjects that had their outcomes assessed by pain score or pain threshold were included in the meta-analysis. Results: For the analysis of pain score, 96 individuals received active stimulation, and we found a favorable effect for active tDCS to reduce pain score compared to sham (P = 0.002). The standardized difference was -0.76 (CI 95% = -1.24 to -0.28). For the pain threshold, the analysis showed no significant difference between active and sham tDCS. We reviewed two studies with adolescents: one study using anodal tDCS over the prefrontal cortex reported a reduction in pain scores. However, the second study reported an increase in pain sensitivity for the dorsolateral prefrontal cortex (DLPFC) stimulation. Conclusion: Our findings suggest tDCS may reduce pain levels in the elderly group. Nevertheless, the small number of studies included in this review-and the considerable heterogeneity for clinical conditions and protocols of stimulation present-limits the support of tDCS use for pain treatment in elderly people. Larger studies on the tDCS effect on pain are needed to be conducted in elderly and adolescents, also evaluating different montages and electrical current intensity.

The Hypnotic Analgesia Suggestion Mitigated the Effect of the Transcranial Direct Current Stimulation on the Descending Pain Modulatory System: A Proof of Concept Study.

OBJECTIVE: 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.

Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. METHODS: In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II - BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS: Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. CONCLUSIONS: The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.

Impact of Age on tDCS Effects on Pain Threshold and Working Memory: Results of a Proof of Concept Cross-Over Randomized Controlled Study.

Background: Age is an important factor that impacts the variability of tDCS effects. Objective/Hypothesis: To compare effects of anodal (a)-tDCS over the left dorsolateral prefrontal cortex (DLPFC), and primary motor cortex (M1) in adolescents, adults, and elderly on heat pain threshold (HPT; primary outcome) and the working memory (WM; secondary outcome). We hypothesized that the effect of tDCS on HPT and WM performance would be the largest in adolescents because their pre-frontal cortex is more prone to neuroplasticity. Methods: We included 30 healthy women within the age ranges of 15-16 (adolescents, n = 10), 30-40 (adults, n = 10), and 60-70 (elderly, n = 10) years. In this crossover single-blinded study, participants received three interventions applied over the DLPF and M1. The active stimulation intensity was two mA for 30 min. From 20 min of stimulation onset, the tDCS session was coupled with an online n-back task. The a-tDCS and sham were applied in a random sequence, with a washout time of a minimum 7 days between each trial. HPT was evaluated before and after stimulation. The WM performance with an n-back task was assessed after the tDCS session. Results: A Generalized Estimating Equation (GEE) model revealed a significant effect of the a-tDCS over the left DLPFC to reduce the HPT in adolescents compared with sham. It increased the pain perception significantly [a large effect size (ES) of 1.09)]. In the adults, a-tDCS over M1 enhanced the HPT significantly (a large ES of 1.25) compared to sham. No significant effect for HPT was found in the elderly. Response time for hits was reduced for a-tDCS over the DLPFC in adolescents, as compared to the other two age groups. Conclusions: These findings suggest that a-tDCS modulates pain perception and WM differentially according to age and target area of stimulation. In adolescents, anodal stimulation over the DLPFC increased the pain perception, while in adults, the stimulation over the M1 increased the pain threshold. Thus, they elucidate the impact of tDCS for different age groups and can help to define what is the appropriate intervention according to age in further clinical trials. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier: NCT04328545.

Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: A randomized, double-blind, placebo-controlled trial.

This randomized, double-blinded, placebo-controlled trial tested the hypothesis that 20mg of melatonin before and during the first cycle of adjuvant chemotherapy for breast cancer (ACBC) reduced the side effects associated with cognitive impairment. We evaluated the effects of melatonin on cognition, depressive symptoms and sleep quality, and whether these effects were related to serum levels of Brain Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin kinase B (TrkB). Thirty-six women were randomly assigned to receive melatonin or placebo for 10 days. To evaluate cognitive performance, we used the Trail-Making-Test Parts A and B (A-B), Rey Auditory-Verbal Learning Test (RAVLT), Controlled Oral Word Association Test (COWAT) and an inhibitory task type Go / No-Go. Our results revealed that melatonin improved executive function on TMT scores, enhanced episodic memory (immediate and delayed) and recognition on RAVLT, and increased verbal fluency in the orthographic COWAT. The TMT-A-B(A-B) were negatively correlated with baseline levels of TrkB and BDNF, respectively. At the end of treatment, changes in TrkB and BDNF were inversely associated with depressive symptoms and sleep quality, but not with the TMT scores. These results suggest a neuroprotective effect of melatonin to counteract the adverse effects of ACBC on cognitive function, sleep quality and depressive symptoms.

Brain-Derived Neurotrophic Factor Modulates the Effect of Sex on the Descending Pain Modulatory System in Healthy Volunteers.

OBJECTIVES: We investigated sex differences and the influence of brain-derived neurotrophic factor (BDNF) in the descending pain modulatory system (DPMS), as measured by change on the numerical pain scale (NPS; 0-10) during conditioned pain modulation (CPM task; primary outcome) and by function of the corticospinal motor pathway and heat pain thresholds (HPTs; secondary outcomes). METHODS: This cross-sectional study included healthy volunteers ranging in age from 18 to 45 years (32 male and 24 female). Assessment included serum BDNF, HPT, change on the NPS (0-10) during the CPM task, and motor-evoked potential (MEP) using transcranial magnetic stimulation (TMS). RESULTS: The MEP (Mv) amplitude was larger in male participants compared with female participants (mean [SE] = 1.55 [0.34] vs mean [SE] = 1.27 [0.27], respectively, P = 0.001). The mean NPS (0-10) during CPM task changed more substantially for female compared with male participants (mean [SE] = -3.25 [2.01] vs mean [SE] = -2.29 [1.34], respectively, P = 0.040). In addition, a higher serum BDNF (adjusted index for age) was associated with a larger decrease of the NPS during CPM task (P = 0.003), although further regression analyses by sex showed that this was only significant for females (P = 0.010). CONCLUSIONS: Significant sex differences were identified in DPMS function and corticospinal motor pathway integrity. Nevertheless, BDNF was associated with the function of the DPMS in female but not male participants, indicating that sex and neuroplasticity state are crucial factors for pain perception in healthy subjects.

Large Treatment Effect With Extended Home-Based Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex in Fibromyalgia: A Proof of Concept Sham-Randomized Clinical Study.

This randomized, double-blind controlled trial tested the hypothesis that 60 sessions of home-based anodal (a)-transcranial direct current stimulation (tDCS) over dorsolateral prefrontal cortex (DLPFC) would be better than home-based sham-tDCS to improve the widespread pain and the disability-related to pain. The anodal-tDCS (2 mA for 30 minutes) over the left DLPFC was self-administered with a specially developed device following in-person training. Twenty women, 18 to 65 years old were randomized into 2 groups [active-(a)-tDCS (n = 10) or sham-(s)-tDCS (n = 10)]. Post hoc analysis revealed that after the first 20 sessions of a-tDCS, the cumulative pain scores reduced by 45.65% [7.25 (1.43) vs 3.94 (1.14), active vs sham tDCS, respectively]. After 60 sessions, during the 12-week assessment, pain scores reduced by 62.06% in the actively group [visual analogue scale reduction, 7.25 (1.43) to 2.75 (.85)] compared to 24.92% in the s-tDCS group, [mean (SD) 7.10 (1.81) vs 5.33 (.90)], respectively. It reduced the risk for analgesic use in 55%. Higher serum levels of the brain-derived neurotrophic factor predicted higher decreases on the pain scores across of treatment. PERSPECTIVE: These findings bring 3 important insights: 1) show that an extended period of treatment (60 sessions, to date the largest number of tDCS sessions tested) for fibromyalgia induces large pain decreases (a large effect size of 1.59) and 2) support the feasibility of home-based tDCS as a method of intervention; 3) provide additional data on DLPFC target for the treatment of fibromyalgia. Finally, our findings also highlight that brain-derived neurotrophic factor to index neuroplasticity may be a valuable predictor of the tDCS effect on pain scores decreases across the treatment.

Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia

Abstract Background: Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. Methods: In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II -BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. Results: Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. Conclusions: The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.(AU)

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.

PER3 variable number tandem repeat (VNTR) polymorphism modulates the circadian variation of the descending pain modulatory system in healthy subjects.

We evaluated the circadian pattern of variation of the descending pain modulatory system (DPMS) using a conditioned pain modulation (CPM) paradigm according to the variable-number tandem-repeat (VNTR) of the clock gene PER3 polymorphism. We assessed the relationship between the genotypes PER34/4 and PER35/5 and the temporal pattern of variation across the day using the following measures: the heat pain threshold (HPT), the cold pressure test (CPT), and the serum levels of BDNF and S100-B protein. The ∆-values (from afternoon to morning) of these measures were used for the analysis. The circadian phenotype was according to the mid-point sleep time established by the Munich ChronoType Questionnaire (MCTQ). We included 18 healthy volunteers (15 women) ages 18 to 30. A Generalized Linear Model (GLM) revealed a significant difference in the ∆-CPM-task between Per34/4 and Per35/5 genotypes, with means (SDs) of -0.41 (0.78) vs. 0.67 (0.90) (χ2 = 7.256; df = 1' P = 0.007), respectively. Both sleep deprivation of at least 2 h/day (B = -0.96, 95% confidence interval (CI) = -1.86 to -0.11)) and the ∆-S100-B protein (-0.03, 95% CI = -0.06 to -0.02) were negatively correlated with the ∆-CPM-task, while the ∆-BDNF was positively correlated with the ∆-CPM-task (0.015, 95% CI = 0.01 to 0.03). We observed a difference in the ∆-CPT between PER34/4 and PER35/5 (0.11 (4.51) vs. 4.00 (2.60), respectively) (χ2 = 22.251; df = 1 P = 0.001). These findings suggest that the polymorphism of PER35/5 is associated with a decrease in the inhibitory function of the DPMS over the course of the day. However, sleep deprivation is an independent factor that also reduces the inhibitory function of the DPMS, regardless of the PER3 VNTR polymorphism.