Andressa de Souza

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.

Reversal of chronic stress-induced pain by transcranial direct current stimulation (tDCS) in an animal model.

Transcranial direct current stimulation (tDCS) has been suggested as a therapeutic tool for pain syndromes. Although initial results in human subjects are encouraging, it still remains unclear whether the effects of tDCS can reverse maladaptive plasticity associated with chronic pain. To investigate this question, we tested whether tDCS can reverse the specific behavioral effects of chronic stress in the pain system, and also those indexed by corticosterone and interleukin-1β levels in serum and TNFα levels in the hippocampus, in a well-controlled rat model of chronic restraint stress (CRS). Forty-one adult male Wistar rats were divided into two groups control and stress. The stress group was exposed to CRS for 11 weeks for the establishment of hyperalgesia and mechanical allodynia as shown by the hot plate and von Frey tests, respectively. Rats were then divided into four groups control, stress, stress+sham tDCS and stress+tDCS. Anodal or sham tDCS was applied for 20min/day over 8 days and the tests were repeated. Then, the animals were killed, blood collected and hippocampus removed for ELISA testing. This model of CRS proved effective to induce chronic pain, as the animals exhibited hyperalgesia and mechanical allodynia. The hot plate test showed an analgesic effect, and the von Frey test, an anti-allodynic effect after the last tDCS session, and there was a significant decrease in hippocampal TNFα levels. These results support the notion that tDCS reverses the detrimental effects of chronic stress on the pain system and decreases TNFα levels in the hippocampus.

Cafeteria diet-induced obesity plus chronic stress alter serum leptin levels

Obesity is a disease that has become a serious public health issue worldwide, and chronic stressors, which are a problem for modern society, cause neuroendocrine changes with alterations in food intake. Obesity and chronic stress are associated with the development of cardiovascular diseases and metabolic disorders. In this study, a rat model was used to evaluate the effects of a hypercaloric diet plus chronic restraint stress on the serum leptin and lipids levels and on the weight of specific adipose tissue (mesenteric, MAT; subcutaneous, SAT and visceral, VAT). Wistar rats were divided into the following 4 groups: standard chow (C), hypercaloric diet (HD), stress plus standard chow (S), and stress plus hypercaloric diet (SHD). The animals in the stress groups were subjected to chronic stress (placed inside a 25 cm × 7 cm plastic tube for 1h per day, 5 days per week for 6 weeks). The following parameters were evaluated: the weight of the liver, adrenal glands and specific adipose tissue; the delta weight; the Lee index; and the serum levels of leptin, corticosterone, glucose, total cholesterol, and triglycerides. The hypercaloric diet induced obesity in rats, increasing the Lee index, weight, leptin, triglycerides, and cholesterol levels. The stress decreased weight gain even in animals fed a hypercaloric diet but did not prevent a significant increase in the Lee index. However, an interaction between the independent factors (hypercaloric diet and stress) was observed, which is demonstrated by the increased serum leptin levels in the animals exposed to both protocols.

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.

Obesity and chronic stress are able to desynchronize the temporal pattern of serum levels of leptin and triglycerides.

Disruption of the circadian system can lead to metabolic dysfunction as a response to environmental alterations. This study assessed the effects of the association between obesity and chronic stress on the temporal pattern of serum levels of adipogenic markers and corticosterone in rats. We evaluated weekly weight, delta weight, Lee index, and weight fractions of adipose tissue (mesenteric, MAT; subcutaneous, SAT; and pericardial, PAT) to control for hypercaloric diet-induced obesity model efficacy. Wistar rats were divided into four groups: standard chow (C), hypercaloric diet (HD), stress plus standard chow (S), and stress plus hypercaloric diet (SHD), and analyzed at three time points: ZT0, ZT12, and ZT18. Stressed animals were subjected to chronic stress for 1h per day, 5 days per week, during 80 days. The chronic exposure to a hypercaloric diet was an effective model for the induction of obesity and metabolic syndrome, increasing delta weight, Lee index, weight fractions of adipose tissue, and triglycerides and leptin levels. We confirmed the presence of a temporal pattern in the release of triglycerides, corticosterone, leptin, and adiponectin in naïve animals. Chronic stress reduced delta weight, MAT weight, and levels of triglycerides, total cholesterol, and leptin. There were interactions between chronic stress and obesity and serum total cholesterol levels, between time points and obesity and adiponectin and corticosterone levels, and between time points and chronic stress and serum leptin levels. In conclusion, both parameters were able to desynchronize the temporal pattern of leptin and triglyceride release, which could contribute to the development of metabolic diseases such as obesity and metabolic syndrome.

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.

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.

Transcranial direct current stimulation (tDCS) reverts behavioral alterations and brainstem BDNF level increase induced by neuropathic pain model: Long-lasting effect

INTRODUCTION Neuropathic pain (NP) is a chronic pain modality that usually results of damage in the somatosensory system. NP often shows insufficient response to classic analgesics and remains a challenge to medical treatment. The transcranial direct current stimulation (tDCS) is a non-invasive technique, which induces neuroplastic changes in central nervous system of animals and humans. The brain derived neurotrophic factor plays an important role in synaptic plasticity process. Behavior changes such as decreased locomotor and exploratory activities and anxiety disorders are common comorbidities associated with NP. OBJECTIVE Evaluate the effect of tDCS treatment on locomotor and exploratory activities, and anxiety-like behavior, and peripheral and central BDNF levels in rats submitted to neuropathic pain model. METHODS Rats were randomly divided: Ss, SsS, SsT, NP, NpS, and NpT. The neuropathic pain model was induced by partial sciatic nerve compression at 14 days after surgery; the tDCS treatment was initiated. The animals of treated groups were subjected to a 20 minute session of tDCS, for eight days. The Open Field and Elevated Pluz Maze tests were applied 24 h (phase I) and 7 days (phase II) after the end of tDCS treatment. The serum, spinal cord, brainstem and cerebral cortex BDNF levels were determined 48 h (phase I) and 8 days (phase II) after tDCS treatment by ELISA. RESULTS The chronic constriction injury (CCI) induces decrease in locomotor and exploratory activities, increases in the behavior-like anxiety, and increases in the brainstem BDNF levels, the last, in phase II (one-way ANOVA/SNK, P<0.05 for all). The tDCS treatment already reverted all these effects induced by CCI (one-way ANOVA/SNK, P<0.05 for all). Furthermore, the tDCS treatment decreased serum and cerebral cortex BDNF levels and it increased these levels in the spinal cord in phase II (one-way ANOVA/SNK, P<0.05). CONCLUSION tDCS reverts behavioral alterations associated to neuropathic pain, indicating possible analgesic and anxiolytic tDCS effects. tDCS treatment induces changes in the BDNF levels in different regions of the central nervous system (CNS), and this effect can be attributed to different cellular signaling activations.

Long-Lasting Effect of Transcranial Direct Current Stimulation in the Reversal of Hyperalgesia and Cytokine Alterations Induced by the Neuropathic Pain Model

BACKGROUND Neuropathic pain (NP) is caused by an insult or dysfunction in the peripheral or central nervous system (CNS), the main symptoms being mechanical allodynia and hyperalgesia. NP often shows insufficient response to classic analgesics and its management remains a challenge. Transcranial direct current stimulation (tDCS) is a non-invasive method of cerebral stimulation and represents a promising resource for pain management. OBJECTIVE/HYPOTHESIS We investigated the effects of tDCS on the nociceptive response and on IL-1β, IL-10, and TNF-α levels in CNS structures of rats with NP. METHODS After induction of NP by chronic constriction injury (CCI) of the sciatic nerve, the rats received 20 min of bicephalic tDCS for 8 days. Hyperalgesia was assessed by the hot plate and von Frey tests and evaluated at baseline, 7 days, and 14 days after CCI surgery, and also immediately, 24 hours, and 7 days following tDCS treatment. The levels of IL-1β, IL-10 and TNF-α in the cortex, spinal cord, and brainstem were determined by ELISA at 48 hours and 7 days post-tDCS. RESULTS The CCI model provoked thermal and mechanical hyperalgesia until at least 30 days post-CCI; however, bicephalic tDCS relieved the nociceptive behavior for up to 7 days after treatment completion. CONCLUSIONS Bicephalic tDCS is effective to promote antinociceptive behavior in neuropathic pain, which can be reflected by a spinal neuroimmunomodulation linked to pro- and anti-inflammatory cytokine levels observed in the long-term.