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.

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.

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BackgroundNeuroplastic changes in nociceptive pathways contribute to severity of symptoms in knee osteoarthritis (KOA). A new look at neuroplastic changes management includes modulation of the primary motor cortex by transcranial direct current stimulation (tDCS).ObjectivesWe investigated whether tDCS combined with intramuscular electrical stimulation (EIMS) would be more efficacious than a sham (s) intervention (s-tDCS/s-EIMS) or a single active(a)-tDCS/s-EIMS intervention and/or s-tDCS/a-EIMS in the following domains: pain measures (visual analog scale [VAS] score and descending pain modulatory system [DPMS], and outcomes, and analgesic use, disability, and pain pressure threshold (PPT) for secondary outcomes.RegistrationThe trial is registered in Clinicaltrials.gov: NCT01747070.MethodsSixty women with KOA, aged 50–75 years old, randomly received five sessions of one of the four interventions (a-tDCS/a-EIMS, s-tDCS/s-EIMS, a-tDCS/s-EIMS, and s-tDCS/a-EIMS). tDCS was applied over the primary motor cortex (M1), for 30 minutes at 2 mA and the EIMS paraspinal of L1–S2.ResultsA generalized estimating equation model revealed the main effect of the a-tDCS/a-EIMS in the VAS pain scores at end treatment compared with the other three groups (P<0.0001). There existed a significant effect of time and a significant interaction between group and time (P<0.01 for both). The delta-(Δ) pain score on VAS in the a-tDCS/a-EIMS group was −3.59, 95% CI: −4.10 to −2.63. The (Δ) pain scores on VAS in the other three groups were: a-tDCS/s-EIMS=−2.13, 95% CI: −2.48 to −1.64; s-tDCS/a-EIMS=−2.25, 95% CI: −2.59 to −1.68; s-tDCS/s-EIMS MR =–1.77, 95% CI: −2.08 to −1.38. The a-tDCS/a-EIMS led to better effect in DPMS, PPT, analgesic use, and disability related to pain.ConclusionThis study provides additional evidence regarding additive clinical effects to improve pain measures and descending pain inhibitory controls when the neuromodulation of the primary motor cortex with tDCS is combined with a bottom-up modulation with EIMS in KOA. Also, it improved the ability to walk due to reduced pain and reduced analgesic use.

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 serum BDNF revealed an inverse relationship with PPT independent of the treatment group. These results suggest that a-EIMS enhanced the corticospinal inhibitory systems in cortical and infracortical pain processing sites most likely by bottom-up regulation mechanisms.

Neuroplasticity mediators could play a role as screening tools for pain clinicians, and as validation of the complex and diffuse symptoms of these patients.

BackgroundCentral disinhibition is a mechanism involved in the physiopathology of fibromyalgia. Melatonin can improve sleep quality, pain and pain threshold. We hypothesized that treatment with melatonin alone or in combination with amitriptyline would be superior to amitriptyline alone in modifying the endogenous pain-modulating system (PMS) as quantified by conditional pain modulation (CPM), and this change in CPM could be associated with serum brain-derived neurotrophic factor (BDNF). We also tested whether melatonin improves the clinical symptoms of pain, pain threshold and sleep quality.MethodsSixty-three females, aged 18 to 65, were randomized to receive bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for a period of six weeks. The descending PMS was assessed with the CPM-TASK. It was assessed the pain score on the Visual Analog Scale (VAS 0-100 mm), the score on Fibromyalgia Impact Questionnaire (FIQ), heat pain threshold (HPT), sleep quality and BDNF serum. Delta values (post- minus pre-treatment) were used to compare the treatment effect. The outcomes variables were collected before, one and six weeks after initiating treatment.ResultsMelatonin alone or in combination with amitriptyline reduced significantly pain on the VAS compared with amitriptyline alone (P < 0.01). The delta values on the VAS scores were-12.85 (19.93),-17.37 (18.69) and-20.93 (12.23) in the amitriptyline, melatonin and melatonin+amitriptyline groups, respectively. Melatonin alone and in combination increased the inhibitory PMS as assessed by the Numerical Pain Scale [NPS(0-10)] reduction during the CPM-TASK:-2.4 (2.04) melatonin + amitriptyline,-2.65 (1.68) melatonin, and-1.04 (2.06) amitriptyline, (P < 0.05). Melatonin + amitriptyline treated displayed better results than melatonin and amitriptyline alone in terms of FIQ and PPT improvement (P < 0.05, fort both).ConclusionMelatonin increased the inhibitory endogenous pain-modulating system as assessed by the reduction on NPS(0-10) during the CPM-TASK. Melatonin alone or associated with amitriptyline was better than amitriptyline alone in improving pain on the VAS, whereas its association with amitriptyline produced only marginal additional clinical effects on FIQ and PPT.Trial registrationCurrent controlled trail is registered at clinical trials.gov upon under number NCT02041455. Registered January 16, 2014.