Evidence of Anti-Inflammatory Effect of Transcranial Direct Current Stimulation in a CFA-Induced Chronic Inflammatory Pain Model in Wistar Rats.

INTRODUCTION: Given that chronic inflammatory pain is highly prevalent worldwide, it is important to study new techniques to treat or relieve this type of pain. The present study evaluated the effect of transcranial direct current stimulation (tDCS) in rats submitted to a chronic inflammatory model by nociceptive response, biomarker levels (brain-derived neurotrophic factor [BDNF] and interleukin [IL]-6 and IL-10), and by histological parameters. METHODS: Sixty-day-old male Wistar rats were used in this study and randomized by weight into 6 major groups: total control, control + sham-tDCS, control + active tDCS, total CFA, CFA + sham-tDCS, and CFA + active tDCS. After inflammatory pain was established, the animals were submitted to the treatment protocol for 8 consecutive days, according to the experimental group. The nociceptive tests (von Frey and hot plate) were assessed, and euthanasia by decapitation occurred at day 8 after the end of tDCS treatment, and the blood serum and central nervous structures were collected for BDNF and IL measurements. All experiments and procedures were approved by the Institutional Committee for Animal Care and Use (UFPel #4538). RESULTS: The tDCS treatment showed a complete reversal of the mechanical allodynia induced by the pain model 24 h and 8 days after the last tDCS session, and there was partial reversal of the thermal hyperalgesia at all time points. Serum BDNF levels were decreased in CFA + sham-tDCS and CFA + tDCS groups compared to the control + tDCS group. The control group submitted to tDCS exhibited an increase in serum IL-6 levels in relation to the other groups. In addition, there was a significant decrease in IL-10 striatum levels in control + tDCS, CFA, and CFA + sham-tDCS groups in relation to the control group, with a partial tDCS effect on the CFA pain model. Local histology demonstrated tDCS effects in decreasing lymphocytic infiltration and neovascularization and tissue regeneration in animals exposed to CFA. CONCLUSION: tDCS was able to reverse the mechanical allodynia and decrease thermal hyperalgesia and local inflammation in a chronic inflammatory pain model, with a modest effect on striatum IL-10 levels. As such, we suggest that analgesic tDCS mechanisms may be related to tissue repair by modulating the local inflammatory process.

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.

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.

Short-term effectiveness of transcranial direct current stimulation in the nociceptive behavior of neuropathic pain rats in development.

Neuropathic pain (NP) is caused by a lesion that triggers pain chronification and central sensitization and it can develop in a different manner, dependent of age. Recent studies have demonstrated the efficacy of transcranial direct current stimulation (tDCS) for treating NP. Then, we aimed to investigate the effects of tDCS and BDNF levels in neuropathic pain rats in development, with 30 days old in the beginning of experiments. Eight-five male Wistar rats were subjected to chronic constriction injury. After establishment of NP, bimodal tDCS was applied to the rats for eight consecutive days, for 20 minutes each session. Subsequently, nociceptive behavior was assessed at baseline, 14 days after surgery, 1 day and 7 days after the end of tDCS. The rats were sacrificed 8 days after the last session of tDCS. An increase in the nociceptive threshold was observed in rats in development 1 day after the end of tDCS (short-term effect), but this effect was not maintained 7 days after the end of tDCS (long-term effect). Furthermore, brain derived neurotrophic factor (BDNF) levels were analyzed in the frontal cortex, spinal cord and serum using ELISA assays. The neuropathic pain model showed an effect of BDNF in the spinal cord of rats in development. There were no effects of BNDF levels of pain or tDCS in the frontal cortex or serum. In conclusion, tDCS is an effective technique to relieve nociceptive behavior at a short-term effect in neuropathic pain rats in development, and BDNF levels were not altered at long-term effect.

Physiological level of norepinephrine increases adenine nucleotides hydrolysis in rat blood serum.

Extracellular adenosine 5'-triphosphate (ATP) and its breakdown products, adenosine 5'-diphosphate (ADP) and adenosine, have significant effects on a variety of biological processes. NTPDase enzymes, responsible for adenine nucleotides hydrolysis, are considered the major regulators of purinergic signaling in the blood. Previous work by our group demonstrated that ATP and ADP hydrolysis in rat blood serum are higher during the dark (activity) phase compared to the light (rest) phase. In nocturnal animals (e.g., rats), important physiological changes occur during the dark phase, such as increased circulating levels of melatonin, corticosterone, and norepinephrine (NE). This study investigated the physiological effects, in vivo and in vitro, of melatonin, dexamethasone, and NE upon nucleotides hydrolysis in rat blood serum. For in vivo experiments, the animals received a single injection of saline (control), melatonin (0.05 mg/kg), dexamethasone (0.1 mg/kg), or NE (0.03 mg/kg). For in vitro experiments, melatonin (1.0 nM), dexamethasone (1.0 µM), or NE (1.0 nM) was added directly to the reaction medium with blood serum before starting the enzyme assay. The results demonstrated that ATP and ADP hydrolysis in both in vitro and in vivo experiments were significantly higher with NE treatment compared to control (in vitro: ATP = 36.63%, ADP = 22.43%, P < 0.05; in vivo: ATP = 44.1%, ADP = 37.28%, P < 0.001). No significant differences in adenine nucleotides hydrolysis were observed with melatonin and dexamethasone treatments. This study suggests a modulatory role of NE in the nucleotidases pathway, decreasing extracellular ATP and ADP, and suggests that NE might modulate its own release by increasing the activities of soluble nucleotidases.

6­Sulfatoxymelatonin as a predictor of clinical outcome in depressive patients.

OBJECTIVES: This study established the value of the 6­sulfatoxymelatonin (aMT6s) urine concentration as a predictor of the therapeutic response to noradrenaline reuptake inhibitors in depressive patients. METHODS: Twenty-two women aged 18-60 years were selected. Depressive symptoms were assessed by using the Hamilton Depression Scale. Urine samples were collected at 0600-1200 h, 1200-1800 h, 1800-2400 h, and 2400-0600 h intervals, 1 day before and 1 day after starting on the nortriptyline treatment. Urine aMT6s concentration was analyzed by a one-way analysis of variance/Bonferroni test. Spearman's rank correlation coefficient was used to analyze the correlation between depressive symptoms after 2 weeks of antidepressant treatment and the increase in aMT6s urine concentration. RESULTS: Higher and lower size effect groups were compared by independent Student's t-tests. At baseline, the 2400­ to 0600­h interval differed from all other intervals presenting a significantly higher aMT6s urine concentration. A significant difference in aMT6s urine concentrations was found 1 day after treatment in all four intervals. Higher size effect group had lower levels of depressive symptoms 2 weeks after the treatment. A positive correlation between depressive symptoms and the delta of aMT6s in the 2400-0600 h interval was observed. CONCLUSION: Our results reinforce the hypothesis that aMT6s excretion is a predictor of clinical outcome in depression, especially in regard to noradrenaline reuptake inhibitors.

Central Post-Stroke Pain: An Integrative Review of Somatotopic Damage, Clinical Symptoms, and Neurophysiological Measures.

Introduction: The physiopathology of central post-stroke pain (CPSP) is poorly understood, which may contribute to the limitations of diagnostic and therapeutic advancements. Thus, the current systematic review was conducted to examine, from an integrated perspective, the cortical neurophysiological changes observed via transcranial magnetic stimulation (TMS), focusing on the structural damage, and clinical symptoms in patients with CPSP. Methods: The literature review included the databases EMBASE, PubMed, and ScienceDirect using the following search terms by MeSH or Entree descriptors: [("Cerebral Stroke") AND ("Pain" OR "Transcranial Magnetic Stimulation") AND ("Transcranial Magnetic Stimulation")] (through September 29, 2020). A total of 297 articles related to CPSP were identified. Of these, only four quantitatively recorded cortical measurements. Results: We found four studies with different methodologies and results of the TMS measures. According to the National Institutes of Health (NIH) guidelines, two studies had low methodological quality and the other two studies had satisfactory methodological quality. The four studies compared the motor threshold (MT) of the stroke-affected hemisphere with the unaffected hemisphere or with healthy controls. Two studies assessed other cortical excitability measures, such as cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). The main limitations in the interpretation of the results were the heterogeneity in parameter measurements, unknown cortical excitability measures as potential prognostic markers, the lack of a control group without pain, and the absence of consistent and validated diagnosis criteria. Conclusion: Despite the limited number of studies that prevented us from conducting a meta-analysis, the dataset of this systematic review provides evidence to improve the understanding of CPSP physiopathology. Additionally, these studies support the construction of a framework for diagnosis and will help improve the methodological quality of future research in somatosensory sequelae following stroke. Furthermore, they offer a way to integrate dysfunctional neuroplasticity markers that are indirectly assessed by neurophysiological measures with their correlated 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.

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.

Longer Cortical Silent Period Length Is Associated to Binge Eating Disorder: An Exploratory Study.

Introduction: Although binge eating disorder (BED) is an eating disorder and obesity is a clinical disease, it is known that both conditions present overlapped symptoms related to, at least partially, the disruption of homeostatic and hedonistic eating behavior pathways. Therefore, the understanding of neural substrates, such as the motor cortex excitability assessed by transcranial magnetic stimulation (TMS), might provide new insights into the pathophysiology of BED and obesity. Objectives: (i) To compare, among BED, obesity, ex-obese, and HC (healthy control) subjects, the cortical excitability indexed by TMS measures, such as CSP (cortical silent period; primary outcome), SICI (intracortical inhibition), and ICF (intracortical facilitation; secondary outcome). (ii) To explore the relationship of the CSP, eating behavior (e.g., restraint, disinhibition, and hunger), depressive symptoms, and sleep quality among the four groups (BED, obesity, ex-obese, and HC). Methods: Fifty-nine women [BED (n = 13), obese (n = 20), ex-obese (n = 12), and HC (n = 14)] comprise the total sample for this study. Assessments: cortical excitability measures (CSP, SICI, and ICF), inhibition response task by the Go/No-go paradigm, and instruments to assess the eating psychopathology (Three-Factor Eating Questionnaire, Eating Disorder Examination Questionnaire, and Binge Eating Scale) were used. Results: A MANCOVA analysis revealed that the mean of CSP was longer in the BED group compared with other three groups: 24.10% longer than the obesity group, 25.98% longer than the HC group, and 25.41% longer than the ex-obese group. Pearson's correlations evidenced that CSP was positively associated with both eating concern and binge eating scores. Conclusion: The findings point out that BED patients present longer CSP, which might suggest an upregulation of intracortical inhibition. Additionally, CSP was positively correlated with Binge Eating Scale and eating concern scores. Further studies are needed.

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.

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.

Long-term effect of morphine administration in young rats on the analgesic opioid response in adult life.

Neonates, infants and children are often exposed to pain from invasive procedures during intensive care and during the post-operative period. Opioid anesthesia and post-operative opioid analgesia have been used in infants and result in clinical benefits. The objectives of this study were to verify the effect of repeated 5 microg morphine administration (subcutaneous), once a day for 7 days in 8-day-old rats, at P8 until P14. To verify the long-term effect of morphine, the animals were submitted to a second exposure of 5mg/kg (intraperitoneal) of morphine at P80 until P86. Animals that received morphine for 7 days, at P14 did not develop tolerance, however at P80, rats demonstrated greater morphine analgesia. At P86, after 7 days of morphine administration, animals showed classical tolerance. These findings may have important implications for the human neonate, suggesting a possible explanation for the differences in the requirements of morphine observed in the youngest patients.

Cognitive effects of transcranial direct current stimulation combined with working memory training in fibromyalgia: a randomized clinical trial.

Cognitive dysfunction in fibromyalgia has been reported, especially memory. Anodal transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) has been effective in enhancing this function. We tested the effects of eight sessions of tDCS and cognitive training on immediate and delayed memory, verbal fluency and working memory and its association with brain-derived neurotrophic factor (BDNF) levels. Forty females with fibromyalgia were randomized to receive eight sessions of active or sham tDCS. Anodal stimulation (2 mA) was applied over the DLPFC and online combined with a working memory training (WMT) for 20 minutes. Pre and post-treatment neurocognitive tests were administered. Data analysis on deltas considering years of education and BDNF as covariates, indicated active-tDCS + WMT significantly increased immediate memory indexed by Rey Auditory Verbal Learning Test score when compared to sham. This effect was dependent on basal BDNF levels. In addition, the model showed active stimulation increased orthographic and semantic verbal fluency scores (Controlled Oral Word Association Test) and short-term memory (Forward Digit Span). The combination of both techniques seemed to produce effects on specific cognitive functions related to short-term and long-term episodic memory and executive functions, which has clinical relevance for top-down treatment approaches in FM.

Anodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex modulates attention and pain in fibromyalgia: randomized clinical trial.

Cognitive dysfunction in fibromyalgia patients has been reported, especially when increased attentional demands are required. Transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) has been effective in modulating attention. We tested the effects of a single session of tDCS coupled with a Go/No-go task in modulating three distinct attentional networks: alertness, orienting and executive control. Secondarily, the effect on pain measures was evaluated. Forty females with fibromyalgia were randomized to receive active or sham tDCS. Anodal stimulation (1 mA, 20 min) was applied over the DLPFC. Attention indices were assessed using the Attention Network Test (ANT). Heat pain threshold (HPTh) and tolerance (HPTo) were measured. Active compared to sham tDCS led to increased performance in the orienting (mean difference [MD] = 14.63) and executive (MD = 21.00) attention networks. There was no effect on alertness. Active tDCS increased HPTh as compared to sham (MD = 1.93) and HPTo (MD = 1.52). Regression analysis showed the effect on executive attention is mostly independent of the effect on pain. DLPFC may be an important target for neurostimulation therapies in addition to the primary motor cortex for patients who do not respond adequately to neurostimulation therapies.

Preoperative transcranial direct current stimulation: Exploration of a novel strategy to enhance neuroplasticity before surgery to control postoperative pain. A randomized sham-controlled study.

BACKGROUND: An imbalance in the excitatory/inhibitory systems in the pain networks may explain the persistent chronic pain after hallux valgus surgery. Thus, to contra-regulate this dysfunction, the use of transcranial direct current stimulation (tDCS) becomes attractive. OBJECTIVE: We tested the hypothesis that two preoperative active(a)-tDCS sessions compared with sham(s)-tDCS could improve the postoperative pain [as indexed by Visual Analogue Scale (VAS) at rest and during walking (primary outcomes)]. To assess their effect on the change in the Numerical Pain Scale (NPS0-10) during Conditioned Pain Modulation (CPM-task), disability related to pain (DRP) and analgesic consumption (secondary outcomes). Also, we assessed if the brain derived neurotrophic factor (BDNF) in the cerebral spinal fluid (CSF) after tDCS could predict the intervention's effect on the DRP. METHODS: It is a prospective, double blind, sham-controlled, randomized single center, 40 women (18-70 years-old) who had undergone hallux valgus surgery were randomized to receive two sessions (20 minutes each) of anodal a-tDCS or s-tDCS on the primary motor cortex at night and in the morning before the surgery. To assess the DRP was used the Brazilian Profile of Chronic Pain: Screen (B-PCP:S). RESULTS: A-tDCS group showed lower scores on VAS at rest and during walking (P<0.001). At rest, the difference between groups was 2.13cm (95%CI = 1.59 to 2.68) while during walking was 1.67cm (95%CI = 1.05 to 2.28). A-tDCS, when compared to s-tDCS reduced analgesic doses in 73.25% (P<0.001), produced a greater reduction in B-PCP:S (mean difference of 9.41 points, 95%CI = 0.63 to 18.21) and higher function of descending pain modulatory system (DPMS) during CPM-task. CONCLUSION: A-tDCS improves postoperative pain, the DRP and the function of DPMS. Also, the CSF BDNF after a-tDCS predicted the improvement in the DRP. In overall, these findings suggest that a-tDCS effects may be mediated by top-down regulatory mechanisms associated with the inhibitory cortical control. TRIAL REGISTRATION: ClinicalTrials.gov NCT02360462.

Transcranial direct current stimulation did not revert the increased central and peripheral NGF levels induced by neuropathic pain in rats / Tratamento com estimulação transcraniana por corrente contínua não reverteu o aumento de NGF induzido por modelo de dor neuropática em ratos

ABSTRACT BACKGROUND AND OBJECTIVES: The expression of nerve growth factor (NGF) in the large-size neurons may represent a key role in the neuronal synaptic plasticity and re-organization of neuronal function after a nerve injury. Transcranial direct current stimulation (tDCS) is a non-invasive method of cerebral stimulation and represents a promising tool to pain management since it promotes neuroplasticity in the central system, and it can be combined with other interventions. The aim was to investigate the effects of tDCS in the NGF levels in central and peripheral nervous system structures of rats submitted to a neuropathic pain (NP) model. METHODS: The chronic constriction injury (CCI) of sciatic nerve was used for the induction of NP. For sham surgery, the sciatic nerve was exposed, but without any ligation. The control group did not undergo surgical procedure. After the establishment of NP, treated groups were subjected to tDCS treatment 0.5 mA/20min/day/8 days. NGF levels in cerebral cortex, spinal cord and sciatic nerve were determined by sandwich-ELISA at 48 hours and 7 days after the end of treatment. RESULTS: The CCI model increased NGF levels in all three structures analyzed at long-lasting time, evidencing the importance of this neurotrophin in neuropathic pain condition. On the other hand, there was no tDCS effect in the central and peripheral NGF levels discarding the participation of this neurotrophin in the analgesic tDCS effect. CONCLUSION: tDCS modulation effects of nociceptive pathways seem not to be linked to the NGF signaling in this chronic pain model.

RESUMO JUSTIFICATIVA E OBJETIVOS: A expressão do fator de crescimento neural (NGF) em neurônios de diâmetro largo pode representar um papel importante na plasticidade sináptica neuronal e na reorganização da função neuronal após lesão neural. A estimulação transcraniana por corrente contínua (ETCC) é um método não invasivo de estimulação cerebral e representa uma ferramenta promissora para o manejo da dor, pois promove neuroplasticidade no sistema central, podendo ser combinada com outras intervenções. O objetivo foi investigar os efeitos da ETCC nos níveis de NGF em estruturas do sistema nervoso central e periférico de ratos submetidos a um modelo de dor neuropática (DN). MÉTODOS: A constrição crônica (CCI) do nervo isquiático foi utilizada para indução do modelo de DN. Na cirurgia sham, o nervo foi exposto, no entanto não houve constrição do nervo. O grupo controle não foi submetido ao procedimento cirúrgico. Após estabelecimento da DN, os grupos tratados foram submetidos a ETCC 0,5 mA/20min/dia/8 dias. Os níveis de NGF no córtex cerebral, medula espinal e nervo isquiático foram mensurados pela técnica de ELISA 48 horas e 7 dias após o final do tratamento. RESULTADOS: O modelo de dor CCI aumentou os níveis de NGF nas três estruturas analisadas, evidenciando a importância desta neurotrofina na dor neuropática. Por outro lado, não houve efeito da ETCC nos níveis de NGF central e periférico, descartando o papel desta neurotrofina no efeito analgésico da ETCC. CONCLUSÃO: Efeitos da ETCC sobre vias nociceptivas não estão diretamente relacionados com a sinalização do NGF neste modelo de dor crônica.

Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology.

The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19-65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0-10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0-10)during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inter-hemispheric disinhibition as well as the dysfunction in the descending pain modulatory system is higher in chronic pain without tissue injury compared to a structural lesion. In addition, they suggest that a greater level of serum BDNF may be involved in the processes that mediate the disinhibition of motor cortex excitability, as well as the function of descending inhibitory pain modulation system, independently of the physiopathology mechanism of musculoskeletal pain syndromes.

Melatonin Alters the Mechanical and Thermal Hyperalgesia Induced by Orofacial Pain Model in Rats.

Melatonin is a neuroendocrine hormone that presents a wide range of physiological functions including regulating circadian rhythms and sleep, enhancing immune function, sleep improvement, and antioxidant effects. In addition, melatonin has received special attention in pain treatment since it is effective and presents few adverse effects. In this study, we evaluated the effect of acute dose of melatonin upon hyperalgesia induced by complete Freund's adjuvant in a chronic orofacial pain model in Sprague-Dawley rats. Nociceptive behavior was assessed by facial Von Frey and the hot plate tests at baseline and thereafter 30, 60, and 120 min, 24 h, and 7 days after melatonin treatment. We demonstrated that acute melatonin administration alters mechanical and thermal hyperalgesia induced by an orofacial pain model (TMD), highlighting that the melatonin effect upon mechanical hyperalgesia remained until 7 days after its administration. Besides, we observed specific tissue profiles of neuroimmunomodulators linked to pain conditions and/or melatonin effect (brain-derived neurotrophic factor, nerve growth factor, and interleukins 6 and 10) in the brainstem levels, and its effects were state-dependent of the baseline of these animals.

Obesity and Hyperlipidemia Modulate Alveolar Bone Loss in Wistar Rats.

BACKGROUND: A positive association between obesity-associated metabolic disorders (e.g., hyperlipidemia and diabetes) and periodontitis has been demonstrated in the literature. This study evaluates the role of cafeteria diet-induced obesity/hyperlipidemia (CAF) on alveolar bone loss (ABL) in rats. METHODS: Sixty male Wistar rats were randomly divided in four groups: control, periodontitis (PERIO), obesity/hyperlipidemia (CAF), and obesity/hyperlipidemia plus periodontitis (CAF+PERIO). Groups CAF and CAF+PERIO were exposed to a high-fat, hypercaloric diet. At week 12, periodontal disease was induced in groups PERIO and CAF+PERIO by ligatures in the upper second molar. The contralateral tooth was considered the intragroup control. Body weight and Lee index were evaluated weekly during the experiment. Serum glucose and cholesterol/triglycerides in the liver were evaluated, and percentage of ABL was measured by microcomputed tomography. Serum tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were evaluated by enzyme-linked immunosorbent assay at week 17. RESULTS: Body weight, Lee index, and cholesterol/triglycerides in the liver increased in groups exposed to the cafeteria diet. Groups PERIO and CAF+PERIO exhibited a significantly higher ABL compared to control and CAF groups. The presence of obesity and hyperlipidemia significantly increased ABL in the CAF+PERIO group compared to the PERIO group (53.60 ± 3.44 versus 42.78 ± 7.27, respectively) in the sides with ligature. Groups exposed to CAF exhibited higher ABL in the sides without ligature. No differences were observed among groups for IL-1ß and TNF-α. CONCLUSION: Obesity and hyperlipidemia modulate the host response to challenges in the periodontium, increasing the expression of periodontal breakdown.