Objective To compare the analgesic effects of stimulation of the anterior cingulate cortex (ACC) or the posterior superior insula (PSI) against sham deep (d) repetitive (r) transcranial magnetic stimulation (TMS) in patients with central neuropathic pain (CNP) after stroke or spinal cord injury in a randomized, double-blinded, sham-controlled, 3-arm parallel study. Methods Participants were randomly allocated into the active PSI-rTMS, ACC-rTMS, sham-PSI-rTMS, or sham-ACC-rTMS arms. Stimulations were performed for 12 weeks, and a comprehensive clinical and pain assessment, psychophysics, and cortical excitability measurements were performed at baseline and during treatment. The main outcome of the study was pain intensity (numeric rating scale [NRS]) after the last stimulation session. Results Ninety-eight patients (age 55.02 ± 12.13 years) completed the study. NRS score was not significantly different between groups at the end of the study. Active rTMS treatments had no significant effects on pain interference with daily activities, pain dimensions, neuropathic pain symptoms, mood, medication use, cortical excitability measurements, or quality of life. Heat pain threshold was significantly increased after treatment in the PSI-dTMS group from baseline (1.58, 95% confidence interval [CI] 0.09–3.06]) compared to sham-dTMS (−1.02, 95% CI −2.10 to 0.04, p = 0.014), and ACC-dTMS caused a significant decrease in anxiety scores (−2.96, 95% CI −4.1 to −1.7]) compared to sham-dTMS (−0.78, 95% CI −1.9 to 0.3; p = 0.018). Conclusions ACC- and PSI-dTMS were not different from sham-dTMS for pain relief in CNP despite a significant antinociceptive effect after insular stimulation and anxiolytic effects of ACC-dTMS. These results showed that the different dimensions of pain can be modulated in humans noninvasively by directly stimulating deeper SNC cortical structures without necessarily affecting clinical pain per se. ClinicalTrials.gov identifier: NCT01932905.

The pain that commonly occurs after brachial plexus avulsion poses an additional burden on the quality of life of patients already impaired by motor, sensory and autonomic deficits. Evidence-based treatments for the pain associated with brachial plexus avulsion are scarce, thus frequently leaving the condition refractory to treatment with the standard methods used to manage neuropathic pain. Unfortunately, little is known about the pathophysiology of brachial plexus avulsion. Available evidence indicates that besides primary nerve root injury, central lesions related to the abrupt disconnection of nerve roots from the spinal cord may play an important role in the genesis of neuropathic pain in these patients and may explain in part its refractoriness to treatment. The understanding of both central and peripheral mechanisms that contribute to the development of pain is of major importance in order to propose more effective treatments for brachial plexus avulsion-related pain. This review focuses on the current understanding about the occurrence of neuropathic pain in these patients and the role played by peripheral and central mechanisms that provides insights into its treatment. Pain after brachial plexus avulsion involves both peripheral and central components; thereby it is characterized as a mixed (central and peripheral) neuropathic pain syndrome.

Introduction: Chronic pain (CP) is highly prevalent and generally undertreated health condition. Noninvasive brain stimulation may contribute to decrease pain intensity and influence other aspects related to CP. Objective: To provide consensus-based recommendations for the use of noninvasive brain stimulation in clinical practice. Methods: Systematic review of the literature searching for randomized clinical trials followed by consensus panel. Recommendations also involved a cost-estimation study. Results: The systematic review wielded 24 transcranial direct current stimulation (tDCS) and 22 repetitive transcranial magnetic stimulation (rTMS) studies. The following recommendations were provided: (1) Level A for anodal tDCS over the primary motor cortex (M1) in fibromyalgia, and level B for peripheral neuropathic pain, abdominal pain, and migraine; bifrontal (F3/F4) tDCS and M1 high-definition (HD)-tDCS for fibromyalgia; Oz/Cz tDCS for migraine and for secondary benefits such as improvement in quality of life, decrease in anxiety, and increase in pressure pain threshold; (2) level A recommendation for high-frequency (HF) rTMS over M1 for fibromyalgia and neuropathic pain, and level B for myofascial or musculoskeletal pain, complex regional pain syndrome, and migraine; (3) level A recommendation against the use of anodal M1 tDCS for low back pain; and (4) level B recommendation against the use of HF rTMS over the left dorsolateral prefrontal cortex in the control of pain. Conclusion: Transcranial DCS and rTMS are recommended techniques to be used in the control of CP conditions, with low to moderate analgesic effects, and no severe adverse events. These recommendations are based on a systematic review of the literature and a consensus made by experts in the field. Readers should use it as part of the resources available to decision-making.

Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19.Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders.Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders.Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway.Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19.

Background: Central neuropathic pain (CNP) is often refractory to available therapeutic strategies and there are few evidence-based treatment options. Many patients with neuropathic pain are not diagnosed or treated properly. Thus, consensus-based recommendations, adapted to the available drugs in the country, are necessary to guide clinical decisions. Objective: To develop recommendations for the treatment of CNP in Brazil. Methods: Systematic review, meta-analysis, and specialists opinions considering efficacy, adverse events profile, cost, and drug availability in public health. Results: Forty-four studies on CNP treatment were found, 20 were included in the qualitative analysis, and 15 in the quantitative analysis. Medications were classified as first-, second-, and third-line treatment based on systematic review, meta-analysis, and expert opinion. As first-line treatment, gabapentin, duloxetine, and tricyclic antidepressants were included. As second-line, venlafaxine, pregabalin for CND secondary to spinal cord injury, lamotrigine for CNP after stroke, and, in association with first-line drugs, weak opioids, in particular tramadol. For refractory patients, strong opioids (methadone and oxycodone), cannabidiol/delta-9-tetrahydrocannabinol, were classified as third-line of treatment, in combination with first or second-line drugs and, for central nervous system (CNS) in multiple sclerosis, dronabinol. Conclusions: Studies that address the treatment of CNS are scarce and heterogeneous, and a significant part of the recommendations is based on experts opinions. The CNP approach must be individualized, taking into account the availability of medication, the profile of adverse effects, including addiction risk, and patients' comorbidities.

Transcranial direct current stimulation (tDCS) has been used aiming to boost exercise performance and inconsistent findings have been reported. One possible explanation is related to the limitations of the so-called “conventional” tDCS, which uses large rectangular electrodes, resulting in a diffuse electric field. A new tDCS technique called high-definition tDCS (HD-tDCS) has been recently developed. HD-tDCS uses small ring electrodes and produces improved focality and greater magnitude of its aftereffects. This study tested whether HD-tDCS would improve exercise performance to a greater extent than conventional tDCS. Twelve endurance athletes (29.4 ± 7.3 years; 60.15 ± 5.09 ml kg⁻¹ min⁻¹) were enrolled in this single-center, randomized, crossover, and sham-controlled trial. To test reliability, participants performed two time to exhaustion (TTE) tests (control conditions) on a cycle simulator with 80% of peak power until volitional exhaustion. Next, they randomly received HD-tDCS (2.4 mA), conventional (2.0 mA), or active sham tDCS (2.0 mA) over the motor cortex for 20-min before performing the TTE test. TTE, heart rate (HR), associative thoughts, peripheral (lower limbs), and whole-body ratings of perceived exertion (RPE) were recorded every minute. Outcome measures were reliable. There was no difference in TTE between HD-tDCS (853.1 ± 288.6 s), simulated conventional (827.8 ± 278.7 s), sham (794.3 ± 271.2 s), or control conditions (TTE1 = 751.1 ± 261.6 s or TTE2 = 770.8 ± 250.6 s) [F_{(1.95; 21.4)} = 1.537; P = 0.24; η²p = 0.123]. There was no effect on peripheral or whole-body RPE and associative thoughts (P > 0.05). No serious adverse effect was reported. A single session of neither HD-tDCS nor conventional tDCS changed exercise performance and psychophysiological responses in athletes, suggesting that a ceiling effect may exist.