Understanding the Effects of Non-Invasive Transauricular Vagus Nerve Stimulation On EEG and HRV.

Several studies have demonstrated promising results of transcutaneous auricular vagus nerve stimulation (taVNS) in treating various disorders; however, no mechanistic studies have investigated this technique's neural network and autonomic nervous system effects. This study aims to describe how taVNS can affect EEG metrics, HRV, and pain levels. Healthy subjects were randomly allocated into two groups: the active taVNS group and the sham taVNS group. Electroencephalography (EEG) and Heart Rate Variability (HRV) were recorded at baseline, 30 min, and after 60 min of 30 Hz, 200-250 µs taVNS, or sham stimulation, and the differences between the metrics were calculated. Regarding vagal projections, some studies have demonstrated the role of the vagus nerve in modulating brain activity, the autonomic system, and pain pathways. However, more data is still needed to understand the mechanisms of taVNS on these systems. In this context, this study presents methods to provide data for a deeper discussion about the physiological impacts of this technique, which can help future therapeutic investigations in various conditions.

Electric Field Navigated 1-Hz rTMS for Poststroke Motor Recovery: The E-FIT Randomized Controlled Trial.

BACKGROUND: To determine if low-frequency repetitive transcranial magnetic stimulation targeting the primary motor cortex contralateral (M1CL) to the affected corticospinal tract in patients with hemiparetic stroke augments intensive training-related clinical improvement; an extension of the NICHE trial (Navigated Inhibitory rTMS to Contralesional Hemisphere Trial) using an alternative sham coil. METHODS: The present E-FIT trial (Electric Field Navigated 1Hz rTMS for Post-stroke Motor Recovery Trial) included 5 of 12 NICHE trial outpatient US rehabilitation centers. The stimulation protocol remained identical (1 Hz repetitive transcranial magnetic stimulation, M1CL, preceding 60-minute therapy, 18 sessions/6 wks; parallel arm randomized clinical trial). The sham coil appearance mimicked the active coil but without the weak electric field in the NICHE trial sham coil. Outcomes measured 1 week, and 1, 3, and 6 months after the end of treatment included the following: upper extremity Fugl-Meyer (primary, 6 months after end of treatment), Action Research Arm Test, National Institutes of Health Stroke Scale, quality of life (EQ-5D), and safety. RESULTS: Of 60 participants randomized, 58 completed treatment and were included for analysis. Bayesian analysis of combined data from the E-FIT and the NICHE trials indicated that active treatment was not superior to sham at the primary end point (posterior mean odds ratio of 1.94 [96% credible interval of 0.61-4.80]). For the E-FIT intent-to-treat population, upper extremity Fugl-Meyer improvement ≥5 pts occurred in 60% (18/30) active group and 50% (14/28) sham group. Participants enrolled 3 to 6 months following stroke had a 67% (31%-91% CI) response rate in the active group at the 6-month end point versus 50% in the sham group (21.5%-78.5% CI). There were significant improvements from baseline to 6 months for both active and sham groups in upper extremity Fugl-Meyer, Action Research Arm Test, and EQ-5D (P<0.05). Improvement in National Institutes of Health Stroke Scale was observed only in the active group (P=0.004). Ten serious unrelated adverse events occurred (4 active group, 6 sham group, P=0.72). CONCLUSIONS: Intensive motor rehabilitation 3 to 12 months after stroke improved clinical impairment, function, and quality of life; however, 1 Hz-repetitive transcranial magnetic stimulation was not an effective treatment adjuvant in the present sample population with mixed lesion location and extent. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03010462.

Understanding the Neuroplastic Effects of Auricular Vagus Nerve Stimulation in Animal Models of Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Transauricular vagus nerve stimulation (taVNS) is being studied as a feasible intervention for stroke, but the mechanisms by which this non-invasive technique acts in the cortex are still broadly unknown. OBJECTIVES: This study aimed to systematically review the current pre-clinical evidence in the auricular vagus nerve stimulation (aVNS) neuroplastic effects in stroke. METHODS: We searched, in December of 2022, in Medline, Cochrane, Embase, and Lilacs databases. The authors executed the extraction of the data on Excel. The risk of bias was evaluated by adapted Cochrane Collaboration's tool for animal studies (SYRCLES's RoB tool). RESULTS: A total of 8 studies published between 2015 and 2022 were included in this review, including 391 animal models. In general, aVNS demonstrated a reduction in neurological deficits (SMD = -1.97, 95% CI -2.57 to -1.36, I2 = 44%), in time to perform the adhesive removal test (SMD = -2.26, 95% CI -4.45 to -0.08, I2 = 81%), and infarct size (SMD = -1.51, 95% CI -2.42 to -0.60, I2 = 58%). Regarding the neuroplasticity markers, aVNS showed to increase microcapillary density, CD31 proliferation, and BDNF protein levels and RNA expression. CONCLUSIONS: The studies analyzed show a trend of results that demonstrate a significant effect of the auricular vagal nerve stimulation in stroke animal models. Although the aggregated results show high heterogeneity and high risk of bias. More studies are needed to create solid conclusions.

Insights and Future Directions on the Combined Effects of Mind-Body Therapies with Transcranial Direct Current Stimulation: An Evidence-based Review.

Mind-body therapies (MBTs) use mental abilities to modify electrical neural activity across brain networks. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates neuronal membrane potentials to enhance neuroplasticity. A combination of these treatment strategies may generate synergistic or additive effects, and thus has been more commonly tested in clinical trials, fostering a novel yet promising field of research. We conducted a literature search in four different databases including only randomized clinical trials (RCTs) that tested the combination of MBTs with tDCS. Ten studies (n=461) were included. Combined protocols included meditation/mindfulness (8/10), biofeedback (1/10), and hypnosis (1/10). The RCTs were heterogeneous with regards to population, design, and types of outcomes. Based on the findings of this search, we provide here a content description, methodological and practical insights, and future directions for the field. We hope this review will provide future authors with information to facilitate the development of trials with improved protocols.

Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19. METHODS: A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment. RESULTS: After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes. CONCLUSIONS: taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19. TRIALS REGISTRY: The Brazilian Registry of Clinical Trials (RBR-399t4g5).

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.

Non-invasive neuromodulation effects on painful diabetic peripheral neuropathy: a systematic review and meta-analysis.

Diabetic Peripheral Neuropathy (DPN) typically is accompanied by painful symptoms. Several therapeutic agents have been tried for symptomatic relief, but with varying results. The use of non-invasive neuromodulation (NINM) is a potential treatment option for DPN. The objective of our study is to evaluate NINM effects on pain rating and nerve conduction velocity in DPN patients. The search was carried out in seven databases until Aug 30th, 2019. Finally, twenty studies met the inclusion criteria. We found a significant reduction of pain scores by central NINMs (effect size [ES] = - 0.75, 95% CI = - 1.35 to - 0.14), but not by the overall peripheral techniques (electrical and electromagnetic) (ES = - 0.58, 95% CI = - 1.23 to 0.07). However, the subgroup of peripheral electrical NINMs reported a significant higher effect (ES = - 0.84, 95% CI = - 1.57 to - 0.11) compared to electromagnetic techniques (ES = 0.21; 95% CI = - 1.00 to 1.42, I2 = 95.3%) . Other subgroup analysis results show that NINMs effects are higher with intensive protocols and in populations with resistant symptoms or intolerance to analgesic medications. Besides, NINMs can increase motor nerves velocity (ES = 1.82; 95% CI = 1.47 to 2.17), and there were no effects on sensory nerves velocity (ES = 0.01, 95% CI = - 0.79 to 0.80). The results suggest that central and peripheral electrical NINMs could reduce neuropathic pain among DPN patients, without reported adverse events. Well-powered studies are needed to confirm that NINM techniques as an alternative effective and safe treatment option.

Pain perception in chronic knee osteoarthritis with varying levels of pain inhibitory control: an exploratory study.

Background and aims Pain is a disabling symptom in knee osteoarthritis (KOA) and its underlying mechanism remains poorly understood. Dysfunction of descending pain modulatory pathways and reduced pain inhibition enhance pain facilitation in many chronic pain syndromes but do not fully explain pain levels in chronic musculoskeletal conditions. The objective of this study is to explore the association of clinical variables with pain intensity perception in KOA individuals with varying levels of Conditioned Pain Modulation (CPM) response. Methods This is a cross-sectional, exploratory analysis using baseline data of a randomized clinical trial investigating the effects of a non-invasive brain stimulation treatment on the perception of pain and functional limitations due to KOA. Sixty-three subjects with KOA were included in this study. Data on pain perception, mood perception, self-reported depression, physical function, quality of life, and quantitative sensory testing was collected. Multiple linear regression analysis was performed to explore the association between the clinical variables with pain perception for individuals with different levels of CPM response. Results For KOA patients with limited CPM response, perception of limitations at work/other activities due to emotional problems and stress scores were statistically significantly associated with pain scores, F(2, 37) = 7.02, p < 0.01. R-squared = 0.275. For KOA patients with normal CPM response, general health perception scores were statistically significantly associated with pain scores, F(1, 21) = 5.60, p < 0.05. R-squared = 0.2104. Limitations of this study include methodology details, small sample size and study design characteristics. Conclusions Pain intensity perception is associated differently with clinical variables according to the individual CPM response. Mechanistic models to explain pain perception in these two subgroups of KOA subjects are discussed.

Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: A randomized, double-blind, placebo-controlled trial.

This randomized, double-blinded, placebo-controlled trial tested the hypothesis that 20mg of melatonin before and during the first cycle of adjuvant chemotherapy for breast cancer (ACBC) reduced the side effects associated with cognitive impairment. We evaluated the effects of melatonin on cognition, depressive symptoms and sleep quality, and whether these effects were related to serum levels of Brain Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin kinase B (TrkB). Thirty-six women were randomly assigned to receive melatonin or placebo for 10 days. To evaluate cognitive performance, we used the Trail-Making-Test Parts A and B (A-B), Rey Auditory-Verbal Learning Test (RAVLT), Controlled Oral Word Association Test (COWAT) and an inhibitory task type Go / No-Go. Our results revealed that melatonin improved executive function on TMT scores, enhanced episodic memory (immediate and delayed) and recognition on RAVLT, and increased verbal fluency in the orthographic COWAT. The TMT-A-B(A-B) were negatively correlated with baseline levels of TrkB and BDNF, respectively. At the end of treatment, changes in TrkB and BDNF were inversely associated with depressive symptoms and sleep quality, but not with the TMT scores. These results suggest a neuroprotective effect of melatonin to counteract the adverse effects of ACBC on cognitive function, sleep quality and depressive symptoms.

Huperzine A for the treatment of cognitive, mood, and functional deficits after moderate and severe TBI (HUP-TBI): results of a Phase II randomized controlled pilot study: implications for understanding the placebo effect.

Objective: To investigate the effect of Huperzine A on memory and learning in individuals with moderate-severe traumatic brain injury (TBI).Design: Randomized, double-blind, placebo-controlled Phase II clinical trial.Methods: Subjects were randomly assigned to receive Huperzine A or placebo for 12 weeks and were assessed during in-person visits at screening/baseline, and 6, 12, 24, and 52 weeks post-injury. Changes in memory and learning scores on the California Verbal Learning Test - 2nd Edition (CVLT-II) from baseline to week 12 were assessed using permutation tests and regression analyses.Results: There was no difference between the Huperzine A and placebo groups in memory performance after 12 weeks of treatment. In the placebo group, significant improvements were noted in learning and memory scores. Both groups showed clinically important improvements in depression on the Beck Depression Index.Conclusions: The clinically important improvements in cognitive and emotional outcomes observed in both the placebo and active treatment arms of this clinical trial of Huperzine A are best understood in the context of a placebo effect. Future trials involving patients with moderate-severe TBI in the subacute to chronic phases of recovery should be designed to account for placebo effects as failure to do so may lead to spurious conclusions.

The Effects of Melatonin on the Descending Pain Inhibitory System and Neural Plasticity Markers in Breast Cancer Patients Receiving Chemotherapy: Randomized, Double-Blinded, Placebo-Controlled Trial.

Background: Adjuvant chemotherapy for breast cancer (ACBC) has been associated with fatigue, pain, depressive symptoms, and disturbed sleep. And, previous studies in non-cancer patients showed that melatonin could improve the descending pain modulatory system (DPMS). We tested the hypothesis that melatonin use before and during the first cycle of ACBC is better than placebo at improving the DPMS function assessed by changes in the 0-10 Numerical Pain Scale (NPS) during the conditioned pain modulating task (CPM-task) (primary outcome). The effects of melatonin were evaluated in the following secondary endpoints: heat pain threshold (HPT), heat pain tolerance (HPTo), and neuroplasticity state assessed by serum brain-derived neurotrophic factor (BDNF), tropomyosin kinase receptor B, and S100B-protein and whether melatonin's effects on pain and neuroplasticity state are due more so to its impact on sleep quality. Methods: Thirty-six women, ages 18 to 75 years old, scheduled for their first cycle of ACBC were randomized to receive 20mg of oral melatonin (n = 18) or placebo (n = 18). The effect of treatment on the outcomes was analyzed by delta (Δ)-values (from pre to treatment end). Results: Multivariate analyses of covariance revealed that melatonin improved the function of the DPMS. The Δ-mean (SD) on the NPS (0-10) during the CPM-task in the placebo group was -1.91 [-1.81 (1.67) vs. -0.1 (1.61)], and in the melatonin group was -3.5 [-0.94 (1.61) vs. -2.29 (1.61)], and the mean difference (md) between treatment groups was 1.59 [(95% CI, 0.50 to 2.68). Melatonin's effect increased the HPTo and HPT while reducing the (Δ)-means of the serum neuroplasticity marker in placebo vs. melatonin. The Δ-BDNF is 1.87 (7.17) vs. -20.44 (17.17), respectively, and the md = 22.31 [(95% CI = 13.40 to 31.22)]; TrKB md = 0.61 [0.46 (0.17) vs. -0.15 (0.18); 95% CI = 0.49 to 0.73)] and S00B-protein md = -8.27[(2.89 (11.18) vs. -11.16 (9.75); 95% CI = -15.38 to -1.16)]. However, melatonin's effect on pain and the neuroplastic state are not due to its effect on sleep quality. Conclusions: These results suggest that oral melatonin, together with the first ACBC counteracts the dysfunction in the inhibitory DPMS and improves pain perception measures. Also, it shows that changes in the neuroplasticity state mediate the impact of melatonin on pain. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03205033.

Emerging targets and uses of neuromodulation for pain.

INTRODUCTION: There has been great development in the testing of invasive and non-invasive neuromodulation for chronic pain. To date, it is known that central and peripheral stimulation targets, combined or not, may influence chronic pain sensation. Although most of the significant results of chronic pain studies come from motor cortex stimulation, novel targets are being explored to increase effect sizes and to induce pain relief in non-responders. Areas covered: In this article, we discuss three emerging targets of non-invasive neuromodulation for chronic pain: (i) a central target: prefrontal cortex stimulation; (ii) a peripheral target: vagal nerve stimulation (VNS); and (iii) a combined peripheral-central target: combination of central and peripheral neural stimulation. Expert commentary: Clinical trials' results on novel targets for chronic pain are at an earlier stage and the mechanisms involved with their combination remain unclear. An important challenge to validate new targets is to determine whether they may be equivalent or even more effective than traditional ones. In spite of the significant advance in this field, especially in refractory chronic pain, mechanistic elements are yet to be comprehended. Thus, exploring multifactorial aspects of novel brain stimulation approaches is fundamental to achieve meaningful results and further augment clinical practice.

Neurostimulation in dry eye disease-past, present, and future.

Neuromodulation is a novel approach that utilizes electrical signals, pharmaceutical agents, or other forms of energy to modulate abnormal neural function through neurostimulation. Neurostimulation is a novel technique that uses electrical currents to stimulate the nervous system. During the recent few decades, neuromodulation has gained significant attention, in particular for the treatment of chronic neurological diseases, due to its success in treating patients unresponsive to conventional pharmacological therapies. Dry eye disease (DED) is a chronic, multifactorial disease that affects millions of people worldwide. Recent data have demonstrated that neurosensory abnormalities contribute to the pathogenesis of DED. Current mainstays of dry eye therapy include lubrication, tear retention, and anti-inflammatory therapies, among others. The recent development of intranasal neurostimulation therapy for DED utilizes the nasolacrimal reflex as an alternative pathway, not only to increase tear production via increased lacrimation, but also to target other tear film components, such as mucin and meibum secretion, promoting tear film homeostasis. This review aims to describe the different types of neuromodulation devices available and their application for non-ocular diseases, as well as to review recent advances and literature on ocular neurostimulation.

Effects of 8-week sensory electrical stimulation combined with motor training on EEG-EMG coherence and motor function in individuals with stroke.

The peripheral sensory system is critical to regulating motor plasticity and motor recovery. Peripheral electrical stimulation (ES) can generate constant and adequate sensory input to influence the excitability of the motor cortex. The aim of this proof of concept study was to assess whether ES prior to each hand function training session for eight weeks can better improve neuromuscular control and hand function in chronic stroke individuals and change electroencephalography-electromyography (EEG-EMG) coherence, as compared to the control (sham ES). We recruited twelve subjects and randomly assigned them into ES and control groups. Both groups received 20-minute hand function training twice a week, and the ES group received 40-minute ES on the median nerve of the affected side before each training session. The control group received sham ES. EEG, EMG and Fugl-Meyer Assessment (FMA) were collected at four different time points. The corticomuscular coherence (CMC) in the ES group at fourth weeks was significantly higher (p = 0.004) as compared to the control group. The notable increment of FMA at eight weeks and follow-up was found only in the ES group. The eight-week rehabilitation program that implemented peripheral ES sessions prior to function training has a potential to improve neuromuscular control and hand function in chronic stroke individuals.

Strategies for replacing non-invasive brain stimulation sessions: recommendations for designing neurostimulation clinical trials.

INTRODUCTION: Despite the potential impact of missed visits on the outcomes of neuromodulation treatments, it is not clear how this issue has been addressed in clinical trials. Given this gap in the literature, we reviewed articles on non-invasive brain stimulation in participants with depression or chronic pain, and investigated how missed visits were handled. Areas covered: We performed a search on PUBMED/MEDLINE using the keywords: 'tDCS', 'transcranial direct current stimulation', 'transcranial magnetic stimulation', 'depression', and 'pain'. We included studies with a minimum of five participants who were diagnosed with depression or chronic pain, who underwent a minimum of five tDCS or TMS sessions. A total of 181 studies matched our inclusion criteria, 112 on depression and 69 on chronic pain. Of these, only fifteen (8%) articles reported or had a protocol addressing missed visits. This review demonstrates that, in most of the trials, there is no reported plan to handle missed visits. Expert commentary: Based on our findings and previous studies, we developed suggestions on how to handle missed visits in neuromodulation protocols. A maximum of 20% of missing sessions should be allowed before excluding a patient and these sessions should be replaced at the end of the stimulation period.

Transcranial direct current stimulation combined with integrative speech therapy in a child with cerebral palsy: A case report.

The aim of this study was to describe the results of the first case combining integrative speech therapy with anodal transcranial direct current stimulation (tDCS) over Broca's area in a child with cerebral palsy. The ABFW phonology test was used to analyze speech based on the Percentage of Correct Consonants (PCC) and Percentage of Correct Consonants - Revised (PCC-R). After treatment, increases were found in both PCC (Imitation: 53.63%-78.10%; Nomination: 53.19%-70.21%) and PPC-R (Imitation: 64.54%-83.63%; Nomination: 61.70%-77.65%). Moreover, reductions occurred in distortions, substitutions and improvement was found in oral performance, especially tongue mobility (AMIOFE-mobility before = 4 after = 7). The child demonstrated a clinically important improvement in speech fluency as shown in results of imitation number of correct consonants and phonemes acquire. Based on these promising findings, continuing research in this field should be conducted with controlled clinical trials.

Noninvasive brain stimulation for addiction medicine: From monitoring to modulation.

Addiction is a chronic relapsing brain disease with significant economical and medical burden on the societies but with limited effectiveness in the available treatment options. Better understanding of the chemical, neuronal, regional, and network alterations of the brain due to drug abuse can ultimately lead to tailoring individualized and more effective interventions. To this end, employing new assessment and intervention procedures seems crucial. Noninvasive brain stimulation (NIBS) techniques including transcranial electrical and magnetic stimulations (tES and TMS) have provided promising opportunities for the addiction medicine in two main domains: (1) providing new insights into neurochemical and neural circuit changes in the human brain cortex and (2) understanding the role of different brain regions by using NIBS and modulating cognitive functions, such as drug craving, risky decision making, inhibitory control and executive functions to obtain specific treatment outcomes. In spite of preliminary positive results, there are several open questions, which need to be addressed before routine clinical utilization of NIBS techniques in addiction to medicine, such as how to account for interindividual differences, define optimal cognitive and neural targets, optimize stimulation protocols, and integrate NIBS with other therapeutic methods. Therefore, in this chapter we revise the available literature on the use of NIBS (TMS and tES) in the diagnostic, prognostic, and therapeutic aspects of the addiction medicine.

Contribution of Corticospinal Modulation and Total Electrical Energy for Peripheral-Nerve-Stimulation-Induced Neuroplasticity as Indexed by Additional Muscular Force.

BACKGROUND: Protocols to induce motor related neuroplasticity are usually directed to central neural structures such as the motor cortex or the spinal cord. OBJECTIVE: Herein, we aimed to evaluate the effects of peripheral nerve stimulation using a current intensity (stimulation intensity) approach to understand the contribution of the corticospinal system and total energy to electrically-induced neuroplasticity. METHODS: Electrical stimulation trains of lower intensity, interlaced with 2-s bursts of higher intensity, were applied to anesthetized rabbits. Nerve blocks were applied to the proximal side of the stimulation site with identical stimulation trains in a different session to block the contribution of corticospinal volleys during intensity-modulated electrical stimulation. RESULTS: Additional force corresponding to additional recruitment of motoneurons was observed when a 2-s burst of high intensity was present (burst/constant: 24.7 ± 3.6%/2.09 ± 4.8%; p < .001). Additional force was absent in sessions when the neural pathway to the spinal cord was blocked (unblocked/blocked: 29.3 ± 3.8%/-2.49 ± 4.8%; p < .001). CONCLUSIONS: The results suggest that induced neuroplasticity indexed by the additional force is dependent on the total energy applied and connectivity to central structures. These results give additional evidence for the contribution of two factors for induced neuroplasticity: (i) modulation by corticospinal structures and (ii) total energy of stimulation. Further protocols should explore simultaneous peripheral and central stimulation.

Electroacupuncture analgesia is associated with increased serum brain-derived neurotrophic factor in chronic tension-type headache: a randomized, sham controlled, crossover trial.

BACKGROUND: Chronic tension-type headache (CTTH) is characterized by almost daily headaches and central sensitization, for which electroacupuncture (EA) might be effective. The central nervous system (CNS) plasticity can be tracked in serum using the brain-derived neurotrophic factor (BDNF), a neuroplasticity mediator. Thus, we tested the hypothesis that EA analgesia in CTTH is related to neuroplasticity indexed by serum BDNF. METHODS: We enrolled females aged 18-60 years with CTTH in a randomized, blinded, placebo-controlled crossover trial, comparing ten EA sessions applied for 30 minutes (2-10 Hz, intensity by tolerance) in cervical areas twice per week vs. a sham intervention. Treatment periods were separated by two washout weeks. Pain on the 10-cm visual analog scale (VAS) and serum BDNF were assessed as primary outcomes. RESULTS: Thirty-four subjects underwent randomization, and twenty-nine completed the protocol. EA was superior to sham to alleviate pain (VAS scores 2.38 ± 1.77 and 3.02 ± 2.49, respectively, P = 0.005). The VAS scores differed according to the intervention sequence, demonstrating a carryover effect (P < 0.05). Using multiple regression, serum BDNF was adjusted for the Hamilton depression rating scale (HDRS) and the VAS scores (r-squared = 0.07, standard ß coefficients = -0.2 and -0.14, respectively, P < 0.001). At the end of the first intervention period, the adjusted BDNF was higher in the EA phase (29.31 ± 3.24, 27.53 ± 2.94 ng/mL, Cohen's d = 0.55). CONCLUSION: EA analgesia is related to neuroplasticity indexed by the adjusted BDNF. EA modulation of pain and BDNF occurs according to the CNS situation at the moment of its administration, as it was related to depression and the timing of its administration.