The immediate effect of transcranial direct current stimulation combined with peripheral electrical stimulation in the control of temporomandibular pain in subjects with sickle cell disease: A protocol for one session randomized, crossover, double-blind clinical trial

Chronic pain in Sickle Cell Disease (SCD) is probably related to maladaptive plasticity of brain areas involved in nociceptive processing. Transcranial Direct Current Stimulation (tDCS) and Peripheral Electrical Stimulation (PES) can modulate cortical excitability and help to control chronic pain. Studies have shown that combined use of tDCS and PES has additive effects. However, to date, no study investigated additive effects of these neuromodulatory techniques on chronic pain in patients with SCD. This protocol describes a study aiming to assess whether combined use of tDCS and PES more effectively alleviate pain in patients with SCD compared to single use of each technique. The study consists of a one-session double blind, block-randomized clinical trial (NCT02813629) in which 128 participants with SCD and femoral osteonecrosis will be enrolled. Stepwise procedures will occur on two independent days. On day 1, participants will be screened for eligibility criteria. On day 2, data collection will occur in four stages: sample characterization, baseline assessment, intervention, and post-intervention assessment. These procedures will last ~5 h. Participants will be divided into two groups according to homozygous for S allele (HbSS) (n = 64) and heterozygous for S and C alleles (HbSC) (n = 64) genotypes. Participants in each group will be randomly assigned, equally, to one of the following interventions: (1) active tDCS + active PES; (2) active tDCS + sham PES; (3) sham tDCS + active PES; and (4) sham tDCS + sham PES. Active tDCS intervention will consist of 20 min 2 mA anodic stimulation over the primary motor cortex contralateral to the most painful hip. Active PES intervention will consist of 30 min sensory electrical stimulation at 100 Hz over the most painful hip. The main study outcome will be pain intensity, measured by a Visual Analogue Scale. In addition, electroencephalographic power density, cortical maps of the gluteus maximus muscle elicited by Transcranial Magnetic Stimulation (TMS), serum levels of Brain-derived Neurotrophic Factor (BDNF), and Tumor Necrosis Factor (TNF) will be assessed as secondary outcomes. Data will be analyzed using ANOVA of repeated measures, controlling for confounding variables.

Peripheral electrical stimulation (PES) is a common clinical technique known to induce changes in corticomotor excitability; PES applied to induce a tetanic motor contraction increases, and PES at sub-motor threshold (sensory) intensities decreases, corticomotor excitability. Understanding of the mechanisms underlying these opposite changes in corticomotor excitability remains elusive. Modulation of primary sensory cortex (S1) excitability could underlie altered corticomotor excitability with PES. Here we examined whether changes in primary sensory (S1) and motor (M1) cortex excitability follow the same time-course when PES is applied using identical stimulus parameters. Corticomotor excitability was measured using transcranial magnetic stimulation (TMS) and sensory cortex excitability using somatosensory evoked potentials (SEPs) before and after 30 min of PES to right abductor pollicis brevis (APB). Two PES paradigms were tested in separate sessions; PES sufficient to induce a tetanic motor contraction (30–50 Hz; strong motor intensity) and PES at sub motor-threshold intensity (100 Hz). PES applied to induce strong activation of APB increased the size of the N20-P25 component, thought to reflect sensory processing at cortical level, and increased corticomotor excitability. PES at sensory intensity decreased the size of the P25-N33 component and reduced corticomotor excitability. A positive correlation was observed between the changes in amplitude of the cortical SEP components and corticomotor excitability following sensory and motor PES. Sensory PES also increased the sub-cortical P14-N20 SEP component. These findings provide evidence that PES results in co-modulation of S1 and M1 excitability, possibly due to cortico-cortical projections between S1 and M1. This mechanism may underpin changes in corticomotor excitability in response to afferent input generated by PES.

INTRODUÇÃO: Recentes evidências têm demonstrado resultados bastante promissores para o uso de estratégias não invasivas de neuromodulação na melhora de habilidades físicas ou esportivas. A estimulação elétrica periférica (EEP) e a estimulação transcraniana por corrente contínua (ETCC) são técnicas não invasivas e não farmacológicas bastante utilizadas para modular a excitabilidade neuronal de áreas cortico-motoras e estimular a recuperação funcional. No entanto, poucos estudos têm investigado o efeito dessas técnicas na melhora do desempenho muscular. OBJETIVO: Investigar o efeito da estimulação elétrica periférica sensorial (EEPs) seguida de estimulação elétrica periférica motora (EEPm) ou estimulação transcraniana por corrente contínua (ETCC) na força isométrica máxima dos extensores do joelho em indivíduos saudáveis. MÉTODO: 20 universitários saudáveis foram distribuídos aleatoriamente em dois blocos distintos de 10 participantes cada: Bloco n°1 EEPs real + EEPm real ou EEPs simulada + EEPm real e bloco n°2 EEPs real + ETCC real ou EEPs simulada + ETCC real em uma única sessão. A contração voluntária isométrica máxima (CVIM) dos extensores do joelho foi avaliada por meio da dinamometria manual antes, durante e 10 min pós-estimulação. RESULTADOS: A CVIM dos extensores do joelho aumentou significativamente 10 minutos pós-ETCC isolada (diferença média = 0,23 N/Kg; IC 95% = 0,01 a 0,44 N/Kg; p = 0,04). A ETCC isolada também apresentou maior proporção cumulativa de respondedores seguido de EEPs+ETCC. CONCLUSÃO: A estimulação transcraniana por corrente contínua induz a aumentos significativos na CVIM em indivíduos saudáveis. No entanto, a aplicação prévia de estimulação elétrica periférica sensorial não impulsiona os efeitos da estimulação elétrica periférica motora ou cerebral na CVIM.

Targeting Chronic Recurrent Low Back Pain From the Top-down and the Bottom-up: A Combined Transcranial Direct Current Stimulation and Peripheral Electrical Stimulation Intervention

Recent evidence suggests that chronic low back pain is associated with plastic changes in the brain that can be modified by neuromodulation strategies. This study investigated the efficacy of transcranial direct current stimulation (tDCS) combined simultaneously with peripheral electrical stimulation (PES) for pain relief, disability and global perception in patients with chronic low back pain (CLBP). Ninety-two patients with CLBP were randomized to receive 12 sessions on nonconsecutive days of anodal tDCS (primary motor cortex, M1), 100Hz sensory PES (lumbar spine), tDCS+PES or sham tDCS+PES. Pain intensity (11-point numerical rating scale), disability and global perception were applied before treatment and four weeks, three months and six months post randomization. A two points reduction was achieved only by the tDCS+PES (mean reduction [MR]=-2.6, CI95%=-4.4 to -0.9) and PES alone (MR=-2.2, CI95%=-3.9 to -0.4) compared with the sham group, but not of tDCS alone (MR=-1.7, CI95%=-3.4 to -0.0). In addition to maintaining the analgesic effect for up to three months, tDCS+PES had a higher proportion of respondents in different cutoff points. Global perception was improved at four weeks and maintained three months after treatment only with tDCS+PES. None of the treatments improved disability and the affective aspect of pain consistently with pain reduction. The results suggest that tDCS+PES and PES alone are effective in relieving CLBP in the short term. However, only tDCS+PES induced a long-lasting analgesic effect. tDCS alone showed no clinical meaningful pain relief. Transcranial direct current stimulation combined simultaneously with PES leads to a significant and clinical pain relief that can last up to three months in chronic low back pain patients. For this article, a commentary is available at the Wiley Online Library.

BackgroundKnee osteoarthritis (OA) has been linked to maladaptive plasticity in the brain, which may contribute to chronic pain. Neuromodulatory approaches, such as Transcranial Direct Current Stimulation (tDCS) and Peripheral Electrical Stimulation (PES), have been used therapeutically to counteract brain maladaptive plasticity. However, it is currently unclear whether these neuromodulatory techniques enhance the benefits of exercise when administered together. Therefore, this protocol aims to investigate whether the addition of tDCS combined or not with PES enhances the effects of a land-based strengthening exercise program in patients with knee OA.MethodsPatients with knee OA (n = 80) will undertake a structured exercise program for five consecutive days. In addition, they will be randomized into four subgroups receiving either active anodal tDCS and sham PES (group 1; n = 20), sham tDCS and active PES (group 2, n = 20), sham tDCS and PES (group 3, n = 20), or active tDCS and PES (group 4, n = 20) for 20 min/day for five consecutive days just prior to commencement of the exercise program. The primary outcomes will be subjective pain intensity (VAS) and related function (WOMAC). Secondary outcomes will include quality of life (SF-36), anxiety and depression symptoms (HAD), self-perception of improvement, pressure pain thresholds over the knee, quadriceps strength, and quadriceps electromyographic activity during maximum knee extension voluntary contraction. We will also investigate cortical excitability using transcranial magnetic stimulation. Outcome measures will be assessed at baseline, 1 month after, before any intervention, after 5 days of intervention, and at 1 month post exercise intervention.DiscussionThe motor cortex becomes less responsive in knee OA because of poorly adapted plastic changes, which can impede exercise therapy benefits. Adding tDCS and/or PES may help to counteract those maladaptive plastic changes and improve the benefits of exercises, and the combination of both neuromodulatory techniques must have a higher magnitude of effect. Trial registration: Brazilian Registry on Clinical Trials (ReBEC) – Effects of electrical stimulation over the skull and tight together with exercises for knee OA; protocol number RBR-9D7C7B.Trial registrationID: RBR-9D7C7B. Registered on 29 February 2016.

Somatosensory input plays a critical role in motor learning. Noise reduces the neural activation threshold and enhances the sensitivity of sensory neurons. While research has demonstrated that peripheral electrical stimulation with noise waveform improves motor performance and functions, the effects of noise electrical stimulation on motor learning remain unknown. This study aimed to investigate the immediate effects of peripheral noise electrical stimulation on motor learning and corresponding neural activities in the motor cortex. Eighteen healthy adults participated in 2 experimental sessions (i.e., noise and sham electrical stimulation conditions) on 2 separate days. Participants performed a grip force tracking task to follow a 0.5 Hz continuous sine wave with amplitudes of 10, 20, and 30% maximal voluntary isometric contraction while the electroencephalogram (EEG) of the sensorimotor cortex and the electromyography (EMG) of the right finger flexors were recorded. The differences (force error) between the actual and the targeted force were calculated, and motor learning was achieved by reducing the force error to a plateau. The efficiency of motor learning was defined as how fast the force error reached a plateau. Two-way (conditions [noise vs sham stimulation] by time [during vs post]) analysis of variance with repeated measures was used to compare the differences in force error, EEG power spectrum density (PSD), and EEG-EMG (corticomuscular) coherence (CMC). The significance level was set at 0.05. Noise electrical stimulation significantly reduced the force error both during and post motor learning (p <0.05) and required less time to reach a plateau of force error (p <0.05); however, for percipients who received sham stimulation first, the effect of noise on learning may not be optimal and thus not represent the net effect of stochastic resonance. For neural activities in the brain, noise electrical stimulation induced an immediate reduction in the EEG beta (15-30 Hz) band and gamma (>30 Hz) CMC. We also observed that motor learning resulted in a decrease in EEG PSD beta band and gamma CMC. This study demonstrated that noise electrical stimulation during motor learning significantly reduced the time required to learn a motor task. We also identified neurophysiological signatures that associate with motor learning, including desynchronization of EEG beta power and reduced functional connectivity between the brain and muscles. These findings could potentially help develop novel motor training strategies and precision interventions.

The effect of peripheral transcutaneous electrical nerve stimulation (TENS) on the reaction to experimental pain in human volunteers has been assessed. Placebo stimulation and electrical stimulation at moderate intensities failed to modify the response to the pain produced by conducted thermal stimuli. TENS at very high intensities did however elevate both the thermal pain threshold and the tolerance temperature. TENS at moderate intensities failed completely to alter the response to graded mechanical stimuli. The subjective pain assessment and the maximum pain tolerance produced by ischaemic pain after a submaximal effort tourniquet test were significantly modified by peripheral electrical stimulation at non-noxious intensities. The response to experimental pain can therefore be altered in man by peripheral electrical stimulation in a manner partly dependent on the sensory modality used for producing the experimental pain and on the intensity of the electrical stimulation.

Antinociceptive effect of peripheral segmental electrical stimulation in the rat

Backgroud: Low back pain (LBP) has been associated with severe impairments, primarily related to activities of daily living, functional ability and quality of life. A multimodal approach to pain management, such as transcranial direct current stimulation (tDCS) and peripheral electrical stimulation (PES), may improve outcomes in chronic LBP. However, the optimal cerebral target for stimulation still remains controversial. This pilot trial aims to investigate whether active stimulation could promote additional gains to the PES results in LBP patients. Our secondary objective is to investigate whether the stimulation of primary motor cortex and dorsolateral prefrontal cortex results in distinct clinical effects for the patients involved. Methods: Sixty patients with chronic low back pain will be randomized into one of three tDCS groups associated with PES: motor primary cortex, dorsolateral prefrontal cortex and sham stimulation. Each group will receive transcranial direct current stimulation at an intensity of 2 mA for 30 minutes daily for 10 consecutive days. Patients will be assessed with a Brief Pain Inventory (BPI), Roland Morris Disability Questionnaire (RMDQ), Medical Outcomes Study 36-item Short - Form Health Survey (SF-36) and electromyography at baseline, endpoint (after 10 sessions) and 1-month follow up. Discussion: This study will help to clarify the additive effects of tDCS combined with peripheral electrical stimulation on pain relief, muscle function and improvement in quality of life. Additionally, we will provide data to identify optimal targets for management of chronic low back pain.

Endogenous pain modulation (EPM) reflects the brain's ability to modulate incoming nociceptive inputs, and deficient EPM was implicated as a chronic pain mechanism. EPM status has been investigated in temporomandibular disorders (TMD) patients with conflicting results, and its relationship with clinical characteristics in this population is not well known. (a) Determine EPM responses in chronic TMD cases and pain-free controls; (b) Derive pain modulation profiles (PMP) based on individual EPM responses; and (c) Categorise clinical characteristics of TMD cases and pain-free controls based on their individual PMP. Twenty-two chronic TMD cases and 17 age-matched pain-free controls, all females, were comprehensively characterised regarding clinical characteristics and underwent EPM testing using temporal summation of pain (TSP) and conditioned pain modulation (CPM) protocols over the face and hand. Individuals were categorised into PMPs (I-IV) based on predetermined cut-off points for TSP and CPM responses. Between-group comparisons showed similar TSP and CPM responses (P>0.23) in the face, while TMD cases showed significantly increased TSP (P=0.04) but similar CPM responses (P>0.17) in the hand relative to controls. Similar distribution across PMPs and clinical characteristics when categorised into PMPs was found for both groups. Body mass index was associated with increased TSP and reduced CPM in the face in TMD cases. Endogenous pain modulation responses over the face were similar between groups. TMD cases showed increased hand TSP compared to controls while both groups showed no significant hand CPM. PMP classification showed similar results between groups, and further refinement of PMP determination is warranted.

Opposite modulations of corticospinal excitability by intermittent and continuous peripheral electrical stimulation in healthy subjects

To examine the effects of photobiomodulation (PBM) in healthy volunteers using photonic stimulation of acupuncture points on conditioned pain modulation (CPM), temporal summation of pain (TSP), and offset analgesia (OA), which reflect some aspects of endogenous pain modulation. We included 15 men and 15 women (age, 31.5 [27.3–37.0], body mass index, 25.7 [24.4–27.1], Fitzpatrick skin typing, II: 20, III: 8, IV: 2). CPM, TSP, and OA were evaluated after a sham procedure (control session) and after acupuncture point stimulation (LI4 and LI10 on the non-dominant forearm) using linear polarized near-infrared light irradiation (LPNILI; wavelengths peaked at approximately 1000 nm, output: 1.4 W/cm2, spot diameter: 10 mm, spot size: 1.02 cm2, maximum temperature: 40.5 °C, pulse width: 1 s, frequency: 0.2 Hz) (PBM session). Differences in CPM, TSP, and OA between the two sessions were evaluated by the paired t-test and Fisher’s exact test (statistical significance: p < 0.05). Values indicate median [interquartile range]. LPNILI significantly increased CPM in all participants (control session: 12.1 [−4.5–37.4], PBM session: 23.9 [8.3–44.8], p < 0.05) and women (control session: 16.7 [−3.4–36.6], PBM session: 38.7 [24.6–52.1], p < 0.05). The CPM effect increment was significantly higher in women than in men (p = 0.0253). LPNILI decreased TSP in participants with higher TSP ratios (p = 0.0219) and increased OA in participants with lower OA scores (p = 0.0021). LPNILI enhanced endogenous pain modulation in healthy volunteers, particularly in women, as evaluated using CPM. CPM, TSP, and OA evaluations are potentially useful for discriminating PBM responders from non-responders.

Aims: To test the effect of repetitive active transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) associated with a hypocaloric diet (HD) on glucose homeostasis in overweight or obese adults. Method: We selected in a RCT double-blind study, overweight or obese adults with different degrees of glucose tolerance to complete a 4-week (20 sessions; five consecutive weekdays) of fixed-dose tDCS (2mA, 20min) delivered over the right DLPFC associated with a standard HD. Subjects were randomly assigned (1:1) and stratified by sex to active tDCS group (AG) or sham tDCS group (SG). Changes on the glycemic and insulinemic response were assessed in a 4h liquid meal tolerance test (LMTT), performed before (t0) and after (t20) the 4-week intervention. Plasma glucose and insulin concentrations were used to determine glucose and insulin AUCs, indices of insulin sensitivity (MISI, Matsuda Insulin Sensitivity Index), insulin secretion (ISI, Insulin Secretion Index), and pancreatic β-cell function (DI, Disposition Index). Data were analyzed with generalized estimating equations adjusted for age, carbohydrate intake, and weight loss (%). Results: Twenty-eight participants were randomized (79% obese; 29% IGT, 4% T2D; 37.6 [5.8] years). Changes over the time (mean [95% CI]) for FPG was higher in AG than in SG (∆t20-t0 = −7.8 [−14.0, −1.6] vs. ∆t20-t0 = −0.9 [−4.0, 2.1] mg/dL; p = 0.043) after the intervention. Likewise, the MISI was improved in AG compared with SG (∆t20-t0 = 3.2 [1.5 to 4.9] vs. ∆t20-t0 = 0.5 [−1.5, 2.5] pmol-1x mmol-1; p = 0.044). There were no significant differences between groups in fasting insulin, glucose and insulin AUCs, ISI, or DI over the study. Conclusions: Repetitive active tDCS over the right DLPFC may be a promising non-invasive technique that could be used to improve glucose homeostasis in overweight or obese individuals on a low-calorie diet. ClinicalTrials.org: NCT02683902. Disclosure C. de Araujo: None. R.C. Fitz: None. G.R. Natividade: None. A.F. Osório: None. P.N. Merello: None. P. Schestatsky: None. F. Gerchman: Speaker's Bureau; Self; Novo Nordisk Inc. Other Relationship; Self; Sanofi-Aventis. Funding Hospital de Clínicas de Porto Alegre (FIPE15-0119, 16-0417)

Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that non-painful PES of accessory spinal nerve (ASN) can promote cortical activation of sensorimotor cortex (SMC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a crossover study. The hemodynamic cortical response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40-channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest (CAI) was observed through the activation of right-DLPFC (p = 0.025) and left-SMC (p = 0.042) in the active group but not in sham group. Regarding left-DLPFC (p = 0.610) and right-SMC (p = 0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) top-down modulation, bottom-up electrical stimulation to the ASN seems to activate the same critical cortical areas on pain pathways related to sensory-discriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the use of peripheral nerve electrical stimulation as a neuromodulatory tool (NCT 03295370— www.clinicaltrials.gov).