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Introduction: Pain catastrophizing describes helplessness, rumination, and magnification of a pain experience. High pain catastrophizing is an independent risk factor for disability, pain severity, inadequate treatment response, chronicity, and opioid misuse. Interdisciplinary pain programs (IPPs) are beneficial and cost-effective for individuals with chronic pain, but their functional impact on individuals with high pain catastrophizing is not well established. The emerging field of placebo studies suggests that patient-provider relationships, positive treatment expectations, and sociobiologically informed care trigger physiological responses that may enhance therapeutic interventions., Methods: In this retrospective observational cohort study, we compared admission and discharge data for 428 adults with high-impact chronic pain (mean 8.5 years) who completed the Spaulding-Medford Functional Restoration Program (FRP). The interdisciplinary FRP team of physiatrists, behavioral health clinicians, physical therapists, and occupational therapists specializes in evidenced-based conventional rehabilitation, integrative health, and pain psychoeducation via enriched therapeutic encounters, fostering collaboration, validation, trust, self-efficacy, and positive expectations. Clinical outcome measures included the Canadian Occupational Performance Measure (COPM) assessing functional performance (COPM-PS) and satisfaction with function (COPM-SS), the Pain Numeric Rating Scale (NRS), the Pain Catastrophizing Scale (PCS), and the Patient Health Questionnaire-9 (PHQ-9)., Results: FRP participants with clinically elevated catastrophizing at baseline (PCS ≥30, mean PCS 39) achieved statistically significant improvements in function (mean delta -2.09, CHI2 = 15.56, p  < 0.001), satisfaction with function (COPM-SS mean delta -2.50, CHI2 = 7.42, p  = 0.007), pain (NRS mean delta 2.7), mood (PHQ-9 mean delta 1.87, p  = 0.002), and catastrophizing (PCS mean delta 4.16, p  < 0.001). Subgroup analysis revealed racial disparities in pain scores, and exploratory analysis showed a trend toward reducing opiate consumption., Discussion: Despite the known association of adverse outcomes with high catastrophizing, FRP participation was associated with increased productive engagement, reduced pain, reduced maladaptive thought processes, and improved mood. Although causation and efficacy cannot be established from a retrospective design, this is the first study to identify functional improvement in patients with high-impact chronic pain and clinically relevant high pain catastrophizing who participate in an IPP combining conventional and complementary rehabilitation with psychoeducation. These enriched therapeutic encounters may enhance the treatment process by promoting trust, empathy, collaboration, and beneficial reframing of patients' experiences, expectations, and goals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vora, Kennedy-Spaien, Gray, Estudillo-Guerra, Phillips, Mesia-Toledo, Glenn, Chin and Morales-Quezada.)

Neuropathic pain can be caused by multiple factors, and its prevalence can reach 10% of the global population. It is becoming increasingly evident that limited or short-lasting response to treatments for neuropathic pain is associated with psychological factors, which include psychiatric comorbidities known to affect quality of life. It is estimated that 60% of patients with neuropathic pain also experience depression, anxiety, and stress symptoms. Altered mood, including stress, can be a consequence of several painful conditions but can also favor pain chronicization when preexisting. Despite the apparent tight connection between clinical pain and mood/stress disorders, the exact physiological mechanisms remain unclear. This review aims to provide an overview of state-of-the-art research on the mechanisms of pain related to the pathophysiology of depression, anxiety, and stress disorders., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Type I Bipolar disorder (BD-I) is a neuropsychiatric disorder characterized by manic or mixed-featured episodes, impaired cognitive functioning, and persistent work and social functioning impairment. This study aimed to investigate within-subject; (i) differences in brain perfusion using Single-photon emission computed tomography (SPECT) between manic and euthymic states in BD-I patients; (ii) explore potential associations between altered brain perfusion and cognitive status; and (iii) examine the relationship between cerebral perfusion and mania symptom ratings. Seventeen adult patients diagnosed with BD-I in a manic episode were recruited, and clinical assessments, cognitive tests, and brain perfusion studies were conducted at baseline (mania state) and a follow-up visit 6 months later. The results showed cognitive impairment during the manic episode, which persisted during the euthymic state at follow-up. However, no significant changes in brain perfusion were observed between the manic and euthymic states. During mania, trends toward decreased perfusion in the left cerebellum and right superior parietal lobule were noted. Additionally, trends indicated a higher perfusion imbalance in the left superior and middle frontal gyrus during mania and the right superior and middle frontal gyrus during euthymia. No significant correlations existed between brain perfusion, mania symptom ratings, and cognitive performance, indicating that symptomatology might represent more than neural hemodynamics. These findings suggest that cognitive impairment may persist in BD-I patients and highlight the need for therapeutic interventions targeting cognitive deficits. More extensive studies with extended follow-up periods are warranted further to investigate brain perfusion and cognitive functioning in BD-I patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Estudillo-Guerra, Linnman, Galvez, Chapa-Koloffon, Pacheco-Barrios, Morales-Quezada and Flores Ramos.)

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES., Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided., Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity., Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases., Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials., (Copyright © 2022 International Federation of Clinical Neurophysiology. All rights reserved.)

Transcranial direct-current stimulation (tDCS) over the prefrontal cortex can improve signs of consciousness in patients in a minimally conscious state. Transcranial pulsed-current stimulation (tPCS) over the mastoids can modulate brain activity and connectivity in healthy controls. This study investigated the feasibility of tPCS as a therapeutic tool in patients with disorders of consciousness (DoC) and compared its neurophysiological and behavioral effects with prefrontal tDCS. This pilot study was a randomized, double-blind sham-controlled clinical trial with three sessions: bi-mastoid tPCS, prefrontal tDCS, and sham. Electroencephalography (EEG) and behavioral assessments were collected before and after each stimulation session. Post minus pre differences were compared using Kruskal-Wallis and Wilcoxon signed-rank tests. Twelve patients with DoC were included in the study (eight females, four traumatic brain injury, 50.3 ± 14 y.o., 8.8 ± 10.5 months post-injury). We did not observe any side-effects following tPCS, nor tDCS, and confirmed their feasibility and safety. We did not find a significant effect of the stimulation on EEG nor behavioral outcomes for tPCS. However, consistent with prior findings, our exploratory analyses suggest that tDCS induces behavioral improvements and an increase in theta frontal functional connectivity.

Background : Based on our Phantom study on transcranial direct current stimulation (tDCS), we hypothesized that EEG band power and field confinement would be greater following left dorsolateral prefrontal cortex (DLPFC - F3) tDCS using circular vs. rectangular electrodes. Methods : Double-blind-randomized trial comparing tDCS with anode over left DLPFC (groups: rectangular electrodes, circular electrodes, sham) and 2 active subgroup references (right shoulder vs. right DLPFC). Results : Twenty-four randomized participants were assessed. We indeed found higher average EEG power spectral density (PSD) across bands for circular vs. rectangular electrodes, largely confined to F3 and there was a significant increase at AF3 for low alpha (p = 0.037). Significant differences included: increased PSD in low beta (p = 0.024) and theta bands (p = 0.021) at F3, and in theta (p = 0.036) at FC5 for the right DLPFC vs. shoulder with no coherence changes. We found PSD differences between active vs. sham tDCS at Fz for alpha (p = 0.043), delta (p = 0.036), high delta (p = 0.030); and at FC1 for alpha (p = 0.031), with coherence differences for F3-Fz in beta (p = 0.044), theta (p = 0.044), delta (p = 0.037) and high delta (p = 0.009). Conclusion : This pilot study despite low statistical power given its small sample size shows that active left DLPFC tDCS modulates EEG frontocentrally and suggests that electrode shapes/reference locations affect its neurophysiological effects, such as increased low alpha power at AF3 using circular vs. rectangular electrodes. Further research with more participants is warranted.

Active vision therapy using perceptual learning and/or dichoptic or binocular environments has shown its potential effectiveness in amblyopia, but some doubts remain about the type of stimuli and the mode and sequence of presentation that should be used. A search was performed in PubMed, obtaining 143 articles with information related to the stimuli used in amblyopia rehabilitation, as well as to the neural mechanisms implied in such therapeutic process. Visual deficits in amblyopia and their neural mechanisms associated are revised, including visual acuity loss, contrast sensitivity reduction and stereopsis impairment. Likewise, the most appropriate stimuli according to the literature that should be used for an efficient rehabilitation of the amblyopic eye are described in detail, including optotypes, Gabor's patches, random-dot stimuli and Vernier's stimuli. Finally, the properties of these stimuli that can be modified during the visual training are discussed, as well as the psychophysical method of their presentation and the type of environment used (perceptual learning, dichoptic stimulation or virtual reality). Vision therapy using all these revised concepts can be an effective option for treating amblyopia or accelerating the treatment period when combining with patching. It is essential to adapt the stimuli to the patient's individual features in both monocular and binocular training.

Primary Objective: This study evaluated whether a meditation practice incorporating mobile neurofeedback (mNF) offers any advantage over a more traditional form of focused attention (FA) meditation in managing persistent symptoms after traumatic brain injury (TBI) (clinicaltrials.gov NCT02615535)., Research Design: Pilot randomized clinical trial, exploring feasibility of mNF in TBI., Methods and Procedures: Participants included adults with chronic mood and/or cognitive complaints following mild-moderate TBI. Subjects practiced either FA (n = 10) or mNF (n = 10) meditation 12 minutes daily for 6 weeks. Pre-post intervention difference on the Neurobehavioral Symptom Inventory (NSI) was the primary outcome variable. Secondary outcomes included the Beck Anxiety Inventory (BAI), Beck Depression Inventory-II (BDI-II), amongst other scales and neurocognitive tests., Main Outcomes and Results: No significant pre-post between-group differences were found on the NSI ( p = .838) nor other assessments. In an exploratory analysis combining FA and mNF data, meditation was associated with significant improvements on the NSI ( p = .04), BAI ( p = .012) and BDI ( p = .037)., Conclusions: Meditating with neurofeedback does not appear to provide an advantage over meditating on one's own for chronic post-TBI symptoms. Further research on home-based meditation following TBI, whether self-directed or technologically facilitated, is warranted.

Opioid consumption for those in comprehensive inpatient rehabilitation units is high because of the complexity of their injuries. Notably, pain in rehabilitation leads to worsened clinical outcomes because of maladaptive behaviors and poor engagement during therapies. It is critical to developing evidence-based pharmacobehavioral interventions. Based on principles of classical conditioning, conditioning open-label placebo (COLP) is a promising approach for reducing opioid use in comprehensive inpatient rehabilitation, and this technique takes advantage of the possibility of association learning and opioid pharmacology to promote evoked placebo-driven analgesia., Objectives: In this brief report, we evaluate the feasibility of COLP as a pharmacobehavioral intervention to decrease total opioid consumption in patients with pain hospitalized at Spaulding Rehabilitation Hospital., Methods: Inpatients with spinal cord injury and polytrauma (n = 20) with moderate to severe pain were randomized to receive COLP (n = 10) or treatment-as-usual for 6 consecutive days. Opioid utilization was measured by morphine equivalents using the morphine equivalent dose conversion; pain severity was assessed using the numerical visual analog scale., Results: Conditioning open-label placebo significantly reduced total opioid consumption by the end of the intervention period ( P ≤ 0.001). Pain reduction was also significant for the COLP group ( P = 0.005), whereas the treatment-as-usual group demonstrated a trend towards pain reduction ( P = 0.05)., Conclusions: This study presents the first data in the use of a pharmacobehavioral intervention that capitalize on the benefits of open-label placebo and classical drug conditioning for opioid dose reduction in a population with moderate to severe pain exposed to intensive inpatient rehabilitation., Competing Interests: The authors have no conflicts of interest to declare. This research was supported by funding from the Spaulding Research Catalyst award and the Ellen R. and Melvin J. Gordon Center for the Cure and Treatment of Paralysis. L. Morales-Quezada was funded by the Institutional National Research Service Award from the National Center for Complementary and Integrative Health (NCCIH grant number T32AT000051) and the Foundation for the Science of the Therapeutic Encounter (F-STE).Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Patterns of altered cerebral perfusion and cognitive dysfunction have been described in Bipolar Disorder (BD) acute episodes and euthymia. Knowledge of the relationship between cognitive function and perfusion in a manic state and status when followed up is still limited., Objective: To describe brain perfusion alterations and its relationship with cognitive impairment in patients with BD during manic episodes and after 6 months., Methods: Observational-prospective study in 10 type I BD adults during moderate-severe manic episodes. We assessed sociodemographic data and clinical variables as well as cognitive function through Screening for Cognitive Impairment in Psychiatry (SCIP-S). Finally, we performed a Brain Perfusion SPECT using a Tc99m-ethyl cysteine dimer., Results: During manic episodes, patients showed cognitive impairment with a mean SCIP-S score of 63.8 ± 17.16. This was positively correlated with perfusion measured as relative reuptake index (RRI) at the right temporal pole (ρ = 0.65 p = .0435) and negatively correlated with right the orbitofrontal cortex (ρ = -0.70 p = .0077) and the right subgenual cingulate cortex (ρ = -0.70 p = .0256). Episode severity measured by the Young Mania Rating Scale (YMRS) positively correlated with RRI at the right temporal pole (ρ = 0.75, p = .01). At follow-up, six patients were taking treatment and were euthymic, we found a negative correlation with the YMRS and RRI at the bilateral orbitofrontal cortex (ρ = -0.8827, p = .019). They did not show significant improvement in cognitive performance at SCIP-S, and there was negative correlation with the following of the SCIP-S subscales; processing speed with the bilateral dorsolateral prefrontal, the bilateral medial prefrontal, the left temporal pole cortex RRI, and verbal fluency with the bilateral anterior cingulate cortex RRI., Conclusion: Cognitive impairment was correlated with brain perfusion patterns at baseline and follow-up. Large sample size studies with longer follow-up are needed to describe the changes in perfusion and cognitive functions in BD., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Nocebo effects refer to new or worsening symptoms that develop in response to negative health-related information, beliefs, and/or experiences. In recent years, research on concussion pathophysiology has significantly advanced. Through health campaigns and media coverage, emerging knowledge on the risks of this injury has been quickly disseminated to the public, and nowadays, the public perceives concussions as more hazardous to health than ever before. Although advancements in concussion-related research and care are of great importance and value, we ask in this article whether the increasing negative publicity regarding concussion also carries any latent costs. Are additional nocebo effects being fostered? To do so, we will review the literature on the psychological and neurobiological processes underlying nocebo effects, present a series of clinical studies demonstrating the ways in which nocebos may impact concussion outcomes both clinically and societally, then speculate on further potential mechanisms for nocebo effects in concussion. We conclude with an outline of the specific efforts one may take to minimize nocebo effects in concussion-related care.

Traumatic brain injury (TBI) results in a decrease in glutamate transporter-1 (GLT-1) expression, the major mechanism for glutamate removal from synapses. Coupled with an increase in glutamate release from dead and dying neurons, this causes an increase in extracellular glutamate. The ensuing glutamate excitotoxicity disproportionately damages vulnerable GABAergic parvalbumin-positive inhibitory interneurons, resulting in a progressively worsening cortical excitatory:inhibitory imbalance due to a loss of GABAergic inhibitory tone, as evidenced by chronic post-traumatic symptoms such as epilepsy, and supported by neuropathologic findings. This loss of intracortical inhibition can be measured and followed noninvasively using long-interval paired-pulse transcranial magnetic stimulation with mechanomyography (LI-ppTMS-MMG). Ceftriaxone, a β-lactam antibiotic, is a potent stimulator of the expression of rodent GLT-1 and would presumably decrease excitotoxic damage to GABAergic interneurons. It may thus be a viable antiepileptogenic intervention. Using a rat fluid percussion injury TBI model, we utilized LI-ppTMS-MMG, quantitative PCR, and immunohistochemistry to test whether ceftriaxone treatment preserves intracortical inhibition and cortical parvalbumin-positive inhibitory interneuron function after TBI in rat motor cortex. We show that neocortical GLT-1 gene and protein expression are significantly reduced 1 week after TBI, and this transient loss is mitigated by ceftriaxone. Importantly, whereas intracortical inhibition declines progressively after TBI, 1 week of post-TBI ceftriaxone treatment attenuates the loss of inhibition compared to saline-treated controls. This finding is accompanied by significantly higher parvalbumin gene and protein expression in ceftriaxone-treated injured rats. Our results highlight prospects for ceftriaxone as an intervention after TBI to prevent cortical inhibitory interneuron dysfunction, partly by preserving GLT-1 expression., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: Children with epilepsy experience cognitive deficits and well-being issues that have detrimental effects on their development. Pharmacotherapy is the standard of care in epilepsy; however, few interventions exist to promote cognitive development and to mitigate disease burden. We aimed to examine the impact of two different modalities of neurofeedback (NFB) on cognitive functioning and quality-of-life (QOL) measurements in children and adolescents with controlled focal epilepsy. The study also explored the effects of NFB on clinical outcomes and electroencephalography (EEG) quantitative analysis., Methods: Participants (n = 44) with controlled focal epilepsy were randomized to one of three arms: sensorimotor rhythm (SMR) NFB (n = 15), slow cortical potentials (SCP) NFB (n = 16), or sham NFB (n = 13). All participants received 25 sessions of intervention. The attention switching task (AST), Liverpool Seizure Severity Scale (LSSS), seizure frequency (SF), EEG power spectrum, and coherence were measured at baseline, postintervention, and at 3-month follow-up., Results: In children and adolescents with controlled focal epilepsy, SMR training significantly reduced reaction time in the AST (p = 0.006), and this was correlated with the difference of change for theta power on EEG (p = 0.03); only the SMR group showed a significant decrease in beta coherence (p = 0.03). All groups exhibited improvement in QOL (p = <0.05)., Conclusions: This study provides the first data on two NFB modalities (SMR and SCP) including cognitive, neurophysiological, and clinical outcomes in pediatric epilepsy. Sensorimotor rhythm NFB improved cognitive functioning, while all the interventions showed improvements in QOL, demonstrating a powerful placebo effect in the sham group., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) modulates neural networks. Computer simulations, while used to identify how currents behave within tissues of different conductivity properties, still need to be complemented by physical models., Objective/hypothesis: To better understand tDCS effects on biology-mimicking tissues by developing and testing the feasibility of a high-fidelity 3D head phantom model that has sensing capabilities at different compartmental levels., Methods: Models obtained from MRI images generated 3D printed molds. Agar phantoms were fabricated, and 18 monitoring electrodes were placed on specific phantom brain areas., Results: When using rectangular electrodes, the measured and simulated voltages at the monitoring electrodes agreed reasonably well, except at excitation locations. The electric field distribution in different phantom layers appeared better confined with circular electrodes compared to rectangular electrodes., Conclusion: The high-fidelity 3D head model was found to be feasible and comparable with computer-based electrical simulations, with high correlation between simulated and measured brain voltages. This feasibility study supports testing to further assess the reliability of this model., (Copyright © 2019 Morales-Quezada, El-Hagrassy, Costa, McKinley, Lv and Fregni.)

Background . Although recent evidence has shown a new role of fluoxetine in motor rehabilitation, results are mixed. We conducted a randomized clinical trial to evaluate whether combining repetitive transcranial magnetic stimulation (rTMS) with fluoxetine increases upper limb motor function in stroke. Methods . Twenty-seven hemiparetic patients within 2 years of ischemic stroke were randomized into 3 groups: Combined (active rTMS + fluoxetine), Fluoxetine (sham rTMS + fluoxetine), or Placebo (sham rTMS + placebo fluoxetine). Participants received 18 sessions of 1-Hz rTMS in the unaffected primary motor cortex and 90 days of fluoxetine (20 mg/d). Motor function was assessed using Jebsen-Taylor Hand Function (JTHF) and Fugl-Meyer Assessment (FMA) scales. Corticospinal excitability was assessed with TMS. Results . After adjusting for time since stroke, there was significantly greater improvement in JTHF in the combined rTMS + fluoxetine group (mean improvement: -214.33 seconds) than in the placebo (-177.98 seconds, P = 0.005) and fluoxetine (-50.16 seconds, P < 0.001) groups. The fluoxetine group had less improvement than placebo on both scales (respectively, JTHF: -50.16 vs -117.98 seconds, P = 0.038; and FMA: 6.72 vs 15.55 points, P = 0.039), suggesting that fluoxetine possibly had detrimental effects. The unaffected hemisphere showed decreased intracortical inhibition in the combined and fluoxetine groups, and increased intracortical facilitation in the fluoxetine group. This facilitation was negatively correlated with motor function improvement (FMA, r 2 = -0.398, P = 0.0395). Conclusion . Combined fluoxetine and rTMS treatment leads to better motor function in stroke than fluoxetine alone and placebo. Moreover, fluoxetine leads to smaller improvements than placebo, and fluoxetine's effects on intracortical facilitation suggest a potential diffuse mechanism that may hinder beneficial plasticity on motor recovery.

It is still unclear whether chronic neuropathic pain and itch share similar neural mechanisms. They are two of the most commonly reported challenges following a burn injury and can be some of the most difficult to treat. Transcranial direct current stimulation (tDCS) has previously been studied as a method to modulate pain related neural circuits. Therefore, we aimed to test the effects of tDCS on post-burn neuropathic pain and itch as to understand whether this would induce a simultaneous modulation of these two sensory manifestations. We conducted a pilot randomized controlled clinical trial comprised of two phases of active or sham M1 tDCS (Phase I: 10 sessions followed by a follow-up period of 8 weeks; Phase II: additional 5 sessions followed by a follow-up period of 8 weeks, and a final visit 12 months from baseline). Pain levels were assessed with the Brief Pain Inventory (BPI) and levels of itch severity were assessed with the Visual Analogue Scale (VAS). Measurements were collected at baseline, after the stimulation periods, at 2, 4 and 8-week follow up both for Phase I and II, and at the final visit. Sixteen patients were assigned to the active group and 15 to the sham group. Ten sessions of active tDCS did not reduce the level of pain or itch. We identified that itch levels were reduced at 2-week follow-up after the sham tDCS session, while no placebo effect was found for the active group. No difference between active and sham groups was observed for pain. We did not find any treatment effects during Phase II. Based on these findings, it seems that an important placebo effect occurred during sham tDCS for itch, while active M1 tDCS seems to disrupt sensory compensatory mechanisms. We hypothesize that pain and itch are complementary but distinct mechanisms of adaptation after peripheral sensory injury following a burn injury and need to be treated differently., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In recent years, several randomized controlled trials evaluating pharmaceutical treatments for traumatic brain injury (TBI) have failed to demonstrate efficacy over placebo, with both active and placebo arms improving at comparable rates. These findings could be viewed in opposing ways, suggesting on the one hand failure of the tested outcome, but on the other, representing evidence of robust placebo effects in TBI. In this article, we examine several of the primary psychological processes driving placebo effects (verbal suggestion, cognitive re-framing, interpersonal interactions, conditioning, therapeutic alliance, anxiety reduction) as well as placebo neurobiology (top-down cortical regulation, reward system activation, dopaminergic and serotonergic neurotransmission). We then extrapolate from the literature to explore whether something inherent in TBI makes it particularly responsive to placebos. Viewed as such here, placebos may indeed represent a powerful and effective treatment for a variety of post-TBI complaints.

Conventional transcranial direct current stimulation (tDCS) protocols rely on applying electrical current at a fixed intensity and duration without using surrogate markers to direct the interventions. This has led to some mixed results; especially because tDCS induced effects may vary depending on the ongoing level of brain activity. Therefore, the objective of this preliminary study was to assess the feasibility of an EEG-triggered tDCS system based on EEG online analysis of its frequency bands. Six healthy volunteers were randomized to participate in a double-blind sham-controlled crossover design to receive a single session of 10[Formula: see text]min 2[Formula: see text]mA cathodal and sham tDCS. tDCS trigger controller was based upon an algorithm designed to detect an increase in the relative beta power of more than 200%, accompanied by a decrease of 50% or more in the relative alpha power, based on baseline EEG recordings. EEG-tDCS closed-loop-system was able to detect the predefined EEG magnitude deviation and successfully triggered the stimulation in all participants. This preliminary study represents a proof-of-concept for the development of an EEG-tDCS closed-loop system in humans. We discuss and review here different methods of closed loop system that can be considered and potential clinical applications of such system.

Introduction: Phantom limb pain (PLP) is a common and poorly understood pathology of difficult medical control that progressively takes place after amputation occurs. Objective: This article discusses the multifactorial bases of PLP. These bases involve local changes at the stump level, spinal modifications of excitability, deafferentation, and central sensitization, leading to the development of maladaptive plasticity, and consequentially, defective processing of sensory information by associative neural networks. These changes can be traced by neurophysiology and imaging topographical studies, indicating a degree of cortical reorganization that perpetuates pain and discomfort. Intervention: Noninvasive brain stimulation can be an alternative way to manage PLP. This article discusses two techniques-transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS)-that have shown promising results for controlling PLP. The modulation that both techniques rely on is based on synaptic mechanisms linked to long-term potentiation and long-term depression phenomena. By applying tDCS or rTMS, clinicians can target processes associated with central sensitization and maladaptive plasticity, while promoting adequate sensory information processing by integrative cognitive behavioral techniques in a comprehensive rehabilitation program. Conclusions: Understanding PLP from a dynamic neurocomputational perspective will help to develop better treatments. Furthermore, Bayesian analysis of sensory information can help guide and monitor therapeutic interventions directed toward PLP resolution., Competing Interests: The author has no conflicts of interest to declare.

Objective: To explore and determine the reorganizational changes in the cortical neural circuits associated with pruritis, this study was undertaken to compare the electroencephalography (EEG) changes in burn patients having primary symptoms of chronic itching (pruritis) and their paired healthy subjects., Methods: Eight subjects were recruited for this exploratory pilot study: 4 patients with pruritus after burn injury matched by gender and age with 4 healthy subjects. EEG recordings were analyzed for absolute alpha, low beta, high beta, and theta power for both groups., Results: The mean age of the burn patients was 41.75 years; while the mean age for the matched healthy subjects was 41.5 years. All subjects were male. A decreased alpha activity was observed in the occipital channels (0.82 vs. 1.4; p=0.01) and a decreased low beta activity in the frontal area (0.22 vs. 0.4; p=0.049) in eyes closed conditions. An overall decreased theta trend was observed in both the eyes open and eyes closed conditions in burn patients, compared to healthy individuals., Conclusion: This preliminary study presents initial evidence that chronic pruritus in burn subjects may be associated with brain reorganizational changes at the cortical level characterized by an EEG pattern., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Transcranial pulsed current stimulation (tPCS) is a neuromodulatory technique that has been studied in the last decade. Several parameters have been assessed independently to optimize the effects. Our aim was to explore the effects of tPCS using different montages on cortical brain oscillations indexed by power spectrum and interhemispheric coherence in different electroencephalography frequency bands. Twenty healthy individuals were randomized to receive either active tPCS or sham intervention using the following bilateral montages: ear clip (conventional), ear hook, or mastoid placement. Electroencephalography was recorded before and after the electroencephalography intervention to assess tPCS-induced after effects. Our results showed that active tPCS with bimastoid montage increased significantly alpha absolute power (P=0.0166) and low alpha (P=0.0014) in the frontal region, as well as in the low alpha power spectrum in the central (P=0.0001) and parieto-occipital regions (P=0.0068) compared with the other montages. For interhemispheric coherence analysis, the Kruskal-Wallis test showed a significant main effect of group for theta (P=0.0012) in the frontal region, mainly for ear-clip montage. Our findings evidenced that tPCS delivered through different electrode montages exert different effects on cortical brain oscillations and thus have a different neural signature. We discuss the implications of these findings as well as potential clinical explorations of this technique.

Transcranial pulsed current stimulation (tPCS) and transcranial direct current stimulation (tDCS) are two noninvasive neuromodulatory brain stimulation techniques whose effects on human brain and behavior have been studied individually. In the present study we aimed to quantify the effects of tDCS and tPCS, individually and in combination, on cortical activity, sensitivity and pain-related assessments in healthy individuals in order to understand their neurophysiological mechanisms and potential applications in clinical populations. A total of 48 healthy individuals participated in this randomized double blind sham controlled study. Participants were randomized to receive a single stimulation session of either: active or sham tPCS and active or sham tDCS. Quantitative electroencephalography (qEEG), sensitivity and pain assessments were used before and after each stimulation session. We observed that tPCS had a higher effect on power, as compared to tDCS, in several bandwidths on various cortical regions: the theta band in the parietal region (p=0.021), the alpha band in the temporal (p=0.009), parietal (p=0.0063), and occipital (p<0.0001) regions. We found that the combination of tPCS and tDCS significantly decreased power in the low beta bandwidth of the frontal (p=0.0006), central (p=0.0001), and occipital (p=0.0003) regions, when compared to sham stimulation. Additionally, tDCS significantly increased power in high beta over the temporal (p=0.0015) and parietal (p=0.0007) regions, as compared to sham. We found no effect on sensitivity or pain-related assessments. We concluded that tPCS and tDCS have different neurophysiological mechanisms, elicit distinct signatures, and that the combination of the two leads to no effect or a decrease on qEEG power. Further studies are required to examine the effects of these techniques on clinical populations in which EEG signatures have been found altered., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Transcranial direct current stimulation (tDCS) has been evaluated in medication refractory epilepsy patients. The results have been inconclusive and protocols have varied between studies., Objective: To evaluate the safety and efficacy of two protocols of tDCS in adult patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS)., Methods: This is a randomized placebo-controlled, double-blinded clinical trial, with 3 arms, 3 sessions, 5 sessions and placebo stimulation. Frequency of seizures (SZs), interictal epileptiform discharges (IEDs) and adverse effects (AEs) were registered before and after treatment, and at 30 and 60 days follow-up. Descriptive statistics, k-related samples, Friedman's test, and relative risk (RR) estimation were used for analysis., Results: We included twenty-eight subjects (3d n = 12, 5d n = 8, placebo n = 8), 16/28 (57%) men, age 37.8(±10.9) years old. There was a significant reduction of the frequency of SZs at one (p = 0.001) and two (p = 0.0001) months following cathodal tDCS compared to baseline in the 3 arms (p = 0.0001). The mean reduction of SZ frequency at two months in both active groups was significantly higher than placebo (-48% vs. -6.25%, p < 0.008). At 3 days (-43.4% vs. -6.25%, p < 0.007) and 5 days (-54.6% vs. -6.25%, p < 0.010) individual groups showed a greater reduction of SZs. A significant IED reduction effect was found between baseline and immediately after interventions (p = 0.041) in all groups. Side effects were minor., Conclusions: Cathodal tDCS technique of 3 and 5 sessions decreased the frequency of SZs and IEDs (between baseline and immediately post-tDCS) in adult patients with MTLE-HS compared to placebo tDCS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To explore the duration of tPCS after effects given different durations of stimulation on power and interhemispheric coherence of the EEG frequency bands. Our hypothesis was that longer tPCS duration would induce a differential effect on the EEG analysis and a longer duration of after effects on the EEG frequency bands., Materials and Methods: We conducted a double blind, sham controlled study in which forty healthy subjects were randomized to receive a single session of either 10, 20, 30 min of active (2 mA, random frequency between 6 and 10 Hz, ear clip montage) or sham tPCS. EEG was recorded before and after the intervention to assess tPCS induced after effects., Results: We found that 10 and 20 min of active tPCS induced a significant increase in alpha (p = 0.004) and theta (p = 0.006) coherence in the frontal region as compared with the sham stimulation. No significant changes were found with 30 min of stimulation (p < 0.05). The Kaplan Meier analysis showed that 10 and 20 min of tPCS induced after effects that lasted 50 min., Conclusions: These results evidence the nonlinear relationship between the stimulation duration and the tPCS after effects, suggesting the presence of homeostatic mechanisms., (© 2016 International Neuromodulation Society.)

Objective: Emotional disturbance is a common complication of stroke significantly affecting functional recovery and quality of life. Identifying relevant neurophysiologic markers associated with post-stroke emotional disturbance may lead to a better understanding of this disabling condition, guiding the diagnosis, development of new interventions and the assessments of treatment response., Methods: Thirty-five subjects with chronic stroke were enrolled in this study. The emotion sub-domain of Stroke Impact Scale (SIS-Emotion) was used to assess post-stroke mood and emotional control. The relation between SIS-Emotion and neurophysiologic measures was assessed by using covariance mapping and univariate linear regression. Multivariate analyses were conducted to identify and adjust for potential confounders. Neurophysiologic measures included power asymmetry and coherence assessed by electroencephalography (EEG); and motor threshold, intracortical inhibition (ICI) and intracortical facilitation (ICF) measured by transcranial magnetic stimulation (TMS)., Results: Lower scores on SIS-Emotion was associated with (1) frontal EEG power asymmetry in alpha and beta bands, (2) central EEG power asymmetry in alpha and theta bands, and (3) lower inter-hemispheric coherence over frontal and central areas in alpha band. SIS-Emotion also correlated with higher ICF and MT in the unlesioned hemisphere as measured by TMS., Conclusions: To our knowledge, this is the first study using EEG and TMS to index neurophysiologic changes associated with post-stroke mood and emotional control. Our results suggest that inter-hemispheric imbalance measured by EEG power and coherence, as well as an increased ICF in the unlesioned hemisphere measured by TMS might be relevant markers associated with post-stroke mood and emotional control which can guide future studies investigating new diagnostic and treatment modalities in stroke rehabilitation.

Transcranial pulsed current stimulation (tPCS) has been shown to increase inter-hemispheric coherence of brain oscillatory activity, mainly in fronto-temporal regions, leading to enhancement of functional connectivity across neural networks. The question is whether tPCS can modulate behavior significantly. Our aim was to identify the effects of tPCS on paired associative learning task (PALT) and attention switching task (AST), and to further categorize physiological autonomic responses by heart rate variability and electrodermal activity measurements before and after task performance. Thirty healthy volunteers were randomized to receive a single session of sham or active 2mA tPCS stimulation with a random frequency between 1 and 5Hz. We show that active tPCS significantly improved response time in the AST compared to sham stimulation, so that subjects who received active tPCS significantly exhibit decreased switching cost between repeat and switch trials. No differences were found in response accuracy on AST and PALT. No significant changes were observed in physiological parameters. Based on our results, we suggest that tPCS has a more pronounced effect on tasks that require the increase of functional connectivity across pre-existent neural circuitry, rather than on tasks that require the development of new learning circuits or the creation of new connections., (Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)

Myofascial pain syndrome (MPS) is a leading cause of chronic musculoskeletal pain. However, its neurobiological mechanisms are not entirely elucidated. Given the complex interaction between the networks involved in pain process, our approach, to providing insights into the neural mechanisms of pain, was to investigate the relationship between neurophysiological, neurochemical and clinical outcomes such as corticospinal excitability. Recent evidence has demonstrated that three neural systems are affected in chronic pain: (i) motor corticospinal system; (ii) internal descending pain modulation system; and (iii) the system regulating neuroplasticity. In this cross-sectional study, we aimed to examine the relationship between these three central systems in patients with chronic MPS of whom do/do not respond to the Conditioned Pain Modulation Task (CPM-task). The CPM-task was to immerse her non-dominant hand in cold water (0-1°C) to produce a heterotopic nociceptive stimulus. Corticospinal excitability was the primary outcome; specifically, the motor evoked potential (MEP) and intracortical facilitation (ICF) as assessed by transcranial magnetic stimulation (TMS). Secondary outcomes were the cortical excitability parameters [current silent period (CSP) and short intracortical inhibition (SICI)], serum brain-derived neurotrophic factor (BDNF), heat pain threshold (HPT), and the disability related to pain (DRP). We included 33 women, (18-65 years old). The MANCOVA model using Bonferroni's Multiple Comparison Test revealed that non-responders (n = 10) compared to responders (n = 23) presented increased intracortical facilitation (ICF; mean ± SD) 1.43 (0.3) vs. 1.11 (0.12), greater motor-evoked potential amplitude (μV) 1.93 (0.54) vs. 1.40 (0.27), as well a higher serum BDNF (pg/Ml) 32.56 (9.95) vs. 25.59 (10.24), (P < 0.05 for all). Also, non-responders presented a higher level of DRP and decreased HPT (P < 0.05 for all). These findings suggest that the loss of net descending pain inhibition was associated with an increase in ICF, serum BDNF levels, and DRP. We propose a framework to explain the relationship and potential directionality of these factors. In this framework we hypothesize that increased central sensitization leads to a loss of descending pain inhibition that triggers compensatory mechanisms as shown by increased motor cortical excitability.

Unlabelled: In this large, sham-controlled, randomized trial, we examined the efficacy of the combination of standard treatment and paraspinous lidocaine injection compared with standard therapy alone in subjects with chronic low back pain. There is little research-based evidence for the routine clinical use of paraspinous lidocaine injection for low back pain. A total of 378 subjects with nonspecific chronic low back pain were randomized to 3 groups: paraspinous lidocaine injection, analgesics, and exercises (group 1, LID-INJ); sham paraspinous lidocaine injection, analgesics, and exercises (group 2, SH-INJ); and analgesics and exercises (group 3, STD-TTR). A blinded rater assessed the study outcomes at 3 time points: baseline, after treatment, and after 3 months of follow-up. There were increased frequency of pain responses and better low back functional scores in the LID-INJ group compared with the SH-INJ and STD-TTR groups. These effects remained at the 3-month follow-up but differed between all 3 groups. There were significant changes in pain threshold immediately after treatment, supporting the effects of this intervention in reducing central sensitization. Paraspinous lidocaine injection therapy is not associated with a higher risk of adverse effects compared with conventional treatment and sham injection. Its effects on hyperalgesia might correlate with changes in central sensitization., Clinical Trial Registration: NCT02387567., Perspective: There are few data to support paraspinous lidocaine injection use in patients with nonspecific chronic low back pain. Our results show that this therapy when combined with standard therapy significantly increases the number of responders versus standard treatment alone. Its effects on hyperalgesia might correlate with a change in central sensitization., (Copyright © 2016. Published by Elsevier Inc.)

The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar-motor cortex connectivity, likely via cerebellar-thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions., (© The Author(s) 2014.)

Purpose: Understanding the neural mechanisms of stroke recovery is of paramount importance for neurorehabilitation., Methods: For this purpose, we analyzed several TMS and EEG variables and their association with motor recovery. Thirty-five subjects with chronic stroke were recruited. The neurophysiological examination included assessments by transcranial magnetic stimulation (TMS), intra- and inter-hemispheric EEG coherence in different frequency bands (e.g. alpha (8-13 Hz)) as determined by quantitative electroencephalography (qEEG). Motor function was measured by Fugl-Meyer (FM). Multiple univariate and multivariate linear regression analyses were performed to identify the predictors for FM., Results: Multivariate analyses, showed a significant interaction effect of motor threshold (MT) in the lesioned hemisphere and beta coherence in the unlesioned hemisphere. This interaction suggests that higher beta activity in the unlesioned hemisphere strengthens the negative association between MT and FM scores., Conclusions: Our results suggest that MT in the lesioned hemisphere is the strongest predictors of motor recovery after stroke. Moreover, cortical activity in the unlesioned hemisphere measured by qEEG provides additional information, specifying the association between MT and FM scores. Therefore, complementary application of EEG and TMS can help constitute a better model of the lesioned and the unlesioned hemispheres that supports the importance of bihemispheric activity in recovery.

Given the recent results provided by previous investigations on transcranial pulsed current stimulation (tPCS) demonstrating its modulatory effects on cortical connectivity; we aimed to explore the application of different random pulsed frequencies. The utility of tPCS as a neuromodulatory technique for cognition performance will come as additional frequency ranges are tested with the purpose to find optimal operational parameters for tPCS. This study was designed to analyze the effects of tPCS using the following random frequencies; 1-5, 6-10, and 11-15 Hz compared with sham on quantitative electroencephalographic changes in the spectral power and interhemispheric coherence of each electroencephalographic frequency band. This was a parallel, randomized, double-blinded, sham-controlled trial. Forty healthy individuals older than 18 years were eligible to participate. The main outcomes were differences in the spectral power analysis and interhemispheric coherence as measured by quantitative electroencephalography. Participants were randomly allocated to four groups of random frequency stimulation and received a single session of stimulation for 20 min with a current intensity of 2 mA delivered by bilateral periauricular electrode clips. We found that a random pulsed frequency between 6-10 Hz significantly increased the power and coherence in frontal and central areas for the alpha band compared with sham stimulation, while 11-15 Hz tPCS decreased the power for the alpha and theta bandwidth. Our findings corroborate the hypothesis that a random frequency ranging into the boundaries of 6-10 Hz induces changes in the naturally occurring alpha oscillatory activity, providing additional data for further studies with tPCS.

Background: Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation therapy in epilepsy with conflicting results in terms of efficacy and safety., Objective: Review the literature about the efficacy and safety of tDCS in epilepsy in humans and animals., Methods: We searched studies in PubMed, MedLine, Scopus, Web of Science and Google Scholar (January 1969 to October 2013) using the keywords 'transcranial direct current stimulation' or 'tDCS' or 'brain polarization' or 'galvanic stimulation' and 'epilepsy' in animals and humans. Original articles that reported tDCS safety and efficacy in epileptic animals or humans were included. Four review authors independently selected the studies, extracted data and assessed the methodological quality of the studies using the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions, PRISMA guidelines and Jadad Scale. A meta-analysis was not possible due to methodological, clinical and statistical heterogeneity of included studies., Results: We analyzed 9 articles with different methodologies (3 animals/6 humans) with a total of 174 stimulated individuals; 109 animals and 65 humans. In vivo and in vitro animal studies showed that direct current stimulation can successfully induce suppression of epileptiform activity without neurological injury and 4/6 (67%) clinical studies showed an effective decrease in epileptic seizures and 5/6 (83%) reduction of inter-ictal epileptiform activity. All patients tolerated tDCS well., Conclusions: tDCS trials have demonstrated preliminary safety and efficacy in animals and patients with epilepsy. Further larger studies are needed to define the best stimulation protocols and long-term follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Transcranial pulsed current stimulation (tPCS) is emerging as an option in the field of neuromodulation; however, little is known about its effects on cognition and behavior and its neurophysiological correlates as indexed by autonomic responses. Our aim was to identify the effects of tPCS on arithmetic processing and risk-taking behavior, and to further categorize physiological autonomic responses by heart rate variability (HRV) and electrodermal activity measurements before, during, and after exposure to task performance and stimulation. Thirty healthy volunteers were randomized to receive a single session of sham or active stimulation with a current intensity of 2 mA and a random frequency between 1 and 5 Hz. Our results showed that tPCS has a modest and specific effect on cognitive performance as indexed by the cognitive tasks chosen in this study. There was a modest effect of active tPCS only on performance facilitation on a complex-level mathematical task as compared to sham stimulation. On autonomic responses, we observed that HRV total power increased while LF/HF ratio decreased in the tPCS active group compared to sham. There were no group differences for adverse effects. Based on our results, we conclude that tPCS, in healthy subjects, has a modest and specific cognitive effect as shown by the facilitation of arithmetical processing on complex mathematical task. These effects are accompanied by modulation of the central autonomic network providing sympathetic-vagal balance during stressful conditions. Although behavioral results were modest, they contribute to the understanding of tPCS effects and cognitive enhancement.

Stroke is a leading cause of disability in the United States. Available treatments for stroke have only a modest effect on motor rehabilitation and about 50-60% of stroke patients remain with some degree of motor impairment after standard treatment. Non-invasive brain stimulation (NIBS) techniques have been proposed as adjuvant treatments to physical therapy for motor recovery after stroke. High frequency rTMS and anodal tDCS can be delivered over the affected motor cortex in order to increase cortical excitability and induce brain plasticity with the intention to enhance motor learning and achieve functional goals in stroke patients. Similarly, low frequency rTMS and cathodal tDCS can be delivered to the unaffected motor cortex to reduce interhemispheric inhibition and hinder maladaptive plasticity. The use of several drugs such as amphetamines, selective serotonin reuptake inhibitors (SSRIs), levodopa and cholinergic agents have been also proposed to enhance the motor function. Given that both NIBS and pharmacotherapy might provide some treatment effect independently for motor rehabilitation in stroke and with the rationale that they could work in a synergistic fashion, we believe that a combined therapy- NIBS plus pharmacotherapy- canlead to better outcomes than one or the other alone. In this paper we review the literature that support the potential use of a combined approach in stroke recovery and present the studies that have already investigated this idea.

Defining optimal parameters for stimulation is a critical step in the development of noninvasive neuromodulation techniques. Transcranial pulsed current stimulation (tPCS) is emerging as another option in the field of neuromodulation; however, little is known about its mechanistic effects on electrical brain activity and how it can modulate its oscillatory patterns. The aim of this study was to identify the current intensity needed to exert an effect on quantitative electroencephalogram (qEEG) measurements. Forty healthy volunteers were randomized to receive a single session of sham or active stimulation at 0.2, 1, or 2 mA current intensity with a random frequency with an oscillatory pulsed range between 1 and 5 Hz. We conducted an exploratory frequency domain analysis to detect changes in absolute power for theta, alpha, and beta frequency bands and also interhemispheric coherence for alpha, theta, and four different sub-bands. Cognitive and nonspecific adverse effects were also recorded. Our results showed that both 1 and 2 mA can modulate interhemispheric coherence at the fronto-temporal areas for the theta band as compared with sham, while 2 mA also increased the low-beta and high-beta interhemispheric coherence at the same anatomical location. There were no group differences for adverse effects and participants could not guess correctly whether they received active versus sham stimulation. On the basis of our results, we conclude that tPCS is associated with an intensity-dependent facilitatory effect on interhemispheric connectivity. These results can guide future tPCS applications and will define its role as a neuromodulatory technique in the field.

Transcranial pulsed current stimulation (tPCS) is a non-invasive brain stimulation technique that employs weak, pulsed current at different frequency ranges, inducing electrical currents that reach cortical and subcortical structures. Very little is known about its effects on brain oscillations and functional connectivity and whether these effects are dependent on the frequency of stimulation. Our aim was to evaluate the effects of tPCS with different frequency ranges in cortical oscillations indexed by high-resolution qEEG changes for power and interhemispheric coherence. Thirty-eight healthy subjects were enrolled and received a single 20-min session of either sham or active stimulation with 1 Hz, 100 Hz or random frequency (1-5 Hz). We conducted an exploratory analysis to detect changes in mean power for theta, alpha and beta, and interhemispheric coherence for alpha and theta and four different sub-bands cognitive and non-specific adverse effects were recorded. We found that active stimulation with a random frequency ranging between 1 and 5 Hz is able to significantly increase functional connectivity for the theta and low-alpha band as compared to sham and active stimulation with either 1 or 100 Hz. Based on these findings, we discuss the possible effects of tPCS on resting functional connectivity for low-frequency bands in fronto-temporal areas. Future studies should be conducted to investigate the potential benefit of these induced changes in pathologic states., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)