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Neurobiological Effects of Transcranial Direct Current Stimulation: A Review

Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique that is affordable and easy to operate compared to other neuromodulation techniques. Anodal stimulation increases cortical excitability, while the cathodal stimulation decreases it. Although tDCS is a promising treatment approach for chronic pain as well as for neuropsychiatric diseases and other neurological disorders, several complex neurobiological mechanisms that are not well understood are involved in its effect. The purpose of this systematic review is to summarize the current knowledge regarding the neurobiological mechanisms involved in the effects of tDCS. The initial search resulted in 171 articles. After applying inclusion and exclusion criteria, we screened 32 full-text articles to extract findings about the neurobiology of tDCS effects including investigation of cortical excitability parameters. Overall, these findings show that tDCS involves a cascade of events at the cellular and molecular levels. Moreover, tDCS is associated with glutamatergic, GABAergic, dopaminergic, serotonergic, and cholinergic activity modulation. Though these studies provide important advancements toward the understanding of mechanisms underlying tDCS effects, further studies are needed to integrate these mechanisms as to optimize clinical development of tDCS.

Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial.

&NA; Melatonin reduced pain scores and analgesic use, and improved sleep quality in endometriosis‐associated chronic pelvic pain. Melatonin modulates the secretion of brain‐derived neurotrophic factor independently of its analgesic effect in endometriosis. &NA; Endometriosis‐associated chronic pelvic pain (EACPP) presents with an intense inflammatory reaction. Melatonin has emerged as an important analgesic, antioxidant, and antiinflammatory agent. This trial investigates the effects of melatonin compared with a placebo on EACPP, brain‐derived neurotrophic factor (BDNF) level, and sleep quality. Forty females, aged 18 to 45 years, were randomized into the placebo (n = 20) or melatonin (10 mg) (n = 20) treatment groups for a period of 8 weeks. There was a significant interaction (time vs group) regarding the main outcomes of the pain scores as indexed by the visual analogue scale on daily pain, dysmenorrhea, dysuria, and dyschezia (analysis of variance, P < 0.01 for all analyses). Post hoc analysis showed that compared with placebo, the treatment reduced daily pain scores by 39.80% (95% confidence interval [CI] 12.88–43.01%) and dysmenorrhea by 38.01% (95% CI 15.96–49.15%). Melatonin improved sleep quality, reduced the risk of using an analgesic by 80%, and reduced BNDF levels independently of its effect on pain. This study provides additional evidence regarding the analgesic effects of melatonin on EACPP and melatonin’s ability to improve sleep quality. Additionally, the study revealed that melatonin modulates the secretion of BDNF and pain through distinct mechanisms.

Repetitive Transcranial Magnetic Stimulation Increases the Corticospinal Inhibition and the Brain-Derived Neurotrophic Factor in Chronic Myofascial Pain Syndrome: An Explanatory Double-Blinded, Randomized, Sham-Controlled Trial

UNLABELLED Chronic myofascial pain syndrome has been related to defective descending inhibitory systems. Twenty-four females aged 19 to 65 years with chronic myofascial pain syndrome were randomized to receive 10 sessions of repetitive transcranial magnetic stimulation (rTMS) (n = 12) at 10 Hz or a sham intervention (n = 12). We tested if pain (quantitative sensory testing), descending inhibitory systems (conditioned pain modulation [quantitative sensory testing + conditioned pain modulation]), cortical excitability (TMS parameters), and the brain-derived neurotrophic factor (BDNF) would be modified. There was a significant interaction (time vs group) regarding the main outcomes of the pain scores as indexed by the visual analog scale on pain (analysis of variance, P < .01). Post hoc analysis showed that compared with placebo-sham, the treatment reduced daily pain scores by -30.21% (95% confidence interval = -39.23 to -21.20) and analgesic use by -44.56 (-57.46 to -31.67). Compared to sham, rTMS enhanced the corticospinal inhibitory system (41.74% reduction in quantitative sensory testing + conditioned pain modulation, P < .05), reduced the intracortical facilitation in 23.94% (P = .03), increased the motor evoked potential in 52.02% (P = .02), and presented 12.38 ng/mL higher serum BDNF (95% confidence interval = 2.32-22.38). No adverse events were observed. rTMS analgesic effects in chronic myofascial pain syndrome were mediated by top-down regulation mechanisms, enhancing the corticospinal inhibitory system possibly via BDNF secretion modulation. PERSPECTIVE High-frequency rTMS analgesic effects were mediated by top-down regulation mechanisms enhancing the corticospinal inhibitory, and this effect involved an increase in BDNF secretion.

Higher serum S100B and BDNF levels are correlated with a lower pressure-pain threshold in fibromyalgia

BackgroundFibromyalgia (FM) is conceptualized as a central sensitization (CS) condition, that presents high serum brain-derived neurotrophic factor (BDNF) and neuroglia activation. Although the S100B protein regulates neuroglia functions, it has been traditionally used as a proxy of central nervous system damage. However, neither BDNF nor S100B association with the clinical picture of FM has been elucidated. To explore their association with the pressure-pain threshold (PPT) in FM, we performed a cross-sectional study, including 56 females with confirmed FM aged 18–65 years. Linear regression models were used to adjust for potential confounding factors between serum BDNF, S100B and PPT.ResultsSerum BDNF and S100B were correlated (Spearman’s Rho = 0.29). Serum BDNF (log) and S100B (log) were correlated with the PPT (log) (Partial η2 = 0.129, P = 0.012 for the BDNF (log), and Partial η2 = 0.105, P = 0.025 for the S100B (log)). Serum BDNF (log) was inversely associated with PPT (log) (β = -1.01, SE = 0.41), age (β = -0.02, SE = 0.15) and obsessive compulsive disorder (β = -0.36, SE = 0.15), while serum S100B (log) was inversely associated with PPT (log) (β = -1.38, SE = 0.50), only.ConclusionsBoth neuroglia key mediators in the CS process were inversely correlated with the PPT. Serum assessment of BDNF and S100B deserve further study to determine its potential as a proxy for the CS spectrum in FM.

Neuroplastic Effects of Transcranial Direct Current Stimulation on Painful Symptoms Reduction in Chronic Hepatitis C: A Phase II Randomized, Double Blind, Sham Controlled Trial

Introduction: Pegylated Interferon Alpha (Peg-IFN) in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV) and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS) in controlling the painful symptoms related to Peg-IFN side effects. Materials and Methods: In this phase II double-blind trial, twenty eight (n = 28) HCV subjects were randomized to receive either 5 consecutive days of active tDCS (n = 14) or sham (n = 14) during 5 consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 min. The primary outcomes were visual analogue scale (VAS) pain and brain-derived neurotrophic factor (BDNF) serum levels. Secondary outcomes were the pressure-pain threshold (PPT), the Brazilian Profile of Chronic Pain: Screen (B-PCP:S), and drug analgesics use. Results: tDCS reduced the VAS scores (P < 0.003), with a mean pain drop of 56% (p < 0.001). Furthermore, tDCS was able to enhance BDNF levels (p < 0.01). The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p < 0.001) and reduced the B-PCP:S scores and analgesic use (p < 0.05). Conclusions: Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials) are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition. Trial registration: Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327.

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.

The Relationship Between Cortical Excitability and Pain Catastrophizing in Myofascial Pain

UNLABELLED Pain catastrophizing regularly occurs in chronic pain patients. It has been suggested that pain catastrophizing is a stable, person-based construct. These findings highlight the importance of investigating catastrophizing in conceptualizing specific approaches for pain management. One important area of investigation is the mechanism underlying pain catastrophizing. Therefore, this study explored the relationship between a neurophysiological marker of cortical excitability, as assessed by transcranial magnetic stimulation, and catastrophizing, as assessed by the Brazilian Portuguese Pain Catastrophizing Scale, in patients with chronic myofascial pain syndrome. The Pain Catastrophizing Scale is a robust questionnaire used to examine rumination, magnification and helplessness that are associated with the experience of pain. We include 24 women with myofascial pain syndrome. The Brazilian Portuguese Pain Catastrophizing Scale and cortical excitability were assessed. Functional and behavioral aspects of pain were evaluated with a version of the Profile of Chronic Pain scale and by multiple pain measurements (eg, pain intensity, pressure pain threshold, and other quantitative sensory measurements). Intracortical facilitation was found to be significantly associated with pain catastrophizing (β = .63, P = .001). Our results did not suggest that these findings were influenced by other factors, such as age or medication use. Furthermore, short intracortical inhibition showed a significant association with pressure pain threshold (β = .44, P = .04). This study elaborates on previous findings indicating a relationship between cortical excitability and catastrophizing. The present findings suggest that glutamatergic activity may be associated with mechanisms underlying pain catastrophizing; thus, the results highlight the need to further investigate the neurophysiological mechanisms associated with pain and catastrophizing. PERSPECTIVE This study highlights the relationship between cortical excitability and catastrophizing. Cortical measures may illuminate how catastrophizing responses may be related to neurophysiological mechanisms associated with chronic pain.

Clinical Value of Serum Neuroplasticity Mediators in Identifying the Central Sensitivity Syndrome in Patients With Chronic Pain With and Without Structural Pathology.

Background and Objectives:Central sensitivity syndrome (CSS) encompasses disorders with overlapping symptoms in a spectrum of structural pathology from persistent somatic nociception (eg, osteoarthritis) to absence of tissue injury such as in fibromyalgia, chronic tension-type headache, and myofascial pain syndrome. Likewise, the spectrum of the neuroplasticity mediators associated with CSS might present a pattern of clinical utility. Methods:We studied the brain-derived neurotrophic factor (BDNF), tumor necrosis factor-&agr; (TNF-&agr;), and interleukins 6 (IL-6) and IL-10 in female patients with CSS absent of structural pathology (chronic tension-type headache [n=30], myofascial pain syndrome [n=29], fibromyalgia [n=22]); with CSS due to persistent somatic/visceral nociception (osteoarthritis [n=27] and endometriosis [n=32]); and in pain-free controls (n=37). Results:Patients with CSS absent of structural pathology presented higher serum TNF-&agr; (28.61±12.74 pg/mL) and BDNF (49.87±31.86 ng/mL) than those with persistent somatic/visceral nociception (TNF-&agr;=17.35±7.38 pg/mL; BDNF=20.44±8.30 ng/mL) and controls (TNF-&agr;=21.41±5.74 pg/mL, BDNF=14.09±11.80 ng/mL). Moreover, CSS patients absent of structural pathology presented lower IL levels. Receiver operator characteristics analysis showed the ability of BDNF to screen CSS (irrespective of the presence of structural pathology) from controls (cutoff=13.31 ng/mL, area under the curve [AUC]=0.86, sensitivity=95.06%, specificity=56.76%); and its ability to identify persistent nociception in CSS patients when experiencing moderate-severe depressive symptoms (AUC=0.81; cutoff=42.83 ng/mL, sensitivity=56.80%, specificity=100%). When the level of pain measured on the visual analog scale was <5 and moderate-severe depressive symptoms were observed TNF-&agr; discriminated structural pathology in the chronic pain conditions (AUC=0.97; cutoff=22.11 pg/mL, sensitivity=90%, specificity=91.3%). Conclusion:Neuroplasticity mediators could play a role as screening tools for pain clinicians, and as validation of the complex and diffuse symptoms of these patients.

Fatores associados à hipertensão arterial sistêmica e ao estado nutricional de hipertensos inscritos no programa Hiperdia

OBJECTIVE: To analyze factors associated with hypertension and its relation with nutritional status of hypertensive subjects enrolled in the program Hiperdia in a municipality of Rio Grande do Sul. METHODS: We evaluated patients with hypertension enrolled in Hiperdia. The data related with risk factors for hypertension were collected through a semi structured questionnaire composed of the following variables: age, education, exercise, smoking, drugs consumed, genetics, chronic diseases, weight, height and waist circumference. RESULTS: Among the 402 hypertensive patients studied, 138 (34.3%) were adults and 264 (65.7%) were elderly, and the majority were female. The prevalence of overweight was 76.8% in adults, while 35% of them were normal weight. When compared the ages, 11% of the elderly were significantly associated with illiteracy. The adults and the elderly presented waist circumference and BMI classification above desired levels. CONCLUSION: In this study, hypertension was associated with increase of age, excess of weight, waist circumference, low education, smoking and alcohol consumption. Excess of weight was configured as one of the most aggravating factors in this population.

Neural signature of tDCS, tPCS and their combination: Comparing the effects on neural plasticity

Transcranial pulsed current stimulation (tPCS) and transcranial direct current stimulation (tDCS) are two noninvasive neuromodulatory brain stimulation techniques whose effects on human brain and behavior have been studied individually. In the present study we aimed to quantify the effects of tDCS and tPCS, individually and in combination, on cortical activity, sensitivity and pain-related assessments in healthy individuals in order to understand their neurophysiological mechanisms and potential applications in clinical populations. A total of 48 healthy individuals participated in this randomized double blind sham controlled study. Participants were randomized to receive a single stimulation session of either: active or sham tPCS and active or sham tDCS. Quantitative electroencephalography (qEEG), sensitivity and pain assessments were used before and after each stimulation session. We observed that tPCS had a higher effect on power, as compared to tDCS, in several bandwidths on various cortical regions: the theta band in the parietal region (p=0.021), the alpha band in the temporal (p=0.009), parietal (p=0.0063), and occipital (p<0.0001) regions. We found that the combination of tPCS and tDCS significantly decreased power in the low beta bandwidth of the frontal (p=0.0006), central (p=0.0001), and occipital (p=0.0003) regions, when compared to sham stimulation. Additionally, tDCS significantly increased power in high beta over the temporal (p=0.0015) and parietal (p=0.0007) regions, as compared to sham. We found no effect on sensitivity or pain-related assessments. We concluded that tPCS and tDCS have different neurophysiological mechanisms, elicit distinct signatures, and that the combination of the two leads to no effect or a decrease on qEEG power. Further studies are required to examine the effects of these techniques on clinical populations in which EEG signatures have been found altered.