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Background: Opioid use disorder (OUD) is a chronic disorder with a considerable amount of morbidity and mortality. Despite remarkable improvement achieved by maintenance programs, an array of treatment goals were still unmet. Mounting evidence suggests that transcranial Direct Current Stimulation (tDCS) improves decision making and cognitive functions in addictive disorders. tDCS paired with a decision making task was depicted to diminish impulsivity as well. Objectives: The present study aimed to assess the effect of tDCS combined with cognitive training (CT) in OUD for the first time. Methods: In this triple-blind randomized sham-controlled pilot study, 38 individuals with OUD from the Buprenorphine-Naloxone Maintenance Therapy program were administered 20-minutes of 2 mA active/sham tDCS over the dorsolateral prefrontal cortex with concomitant cognitive training. A selected test battery evaluating decision making under risk and ambiguity as well as executive functions, verbal fluency and working memory was utilized before and after the intervention. Results: Greater improvements were observed in decision making under ambiguity (p = 0.016), set shifting ability and alternating fluency while no improvements were observed in decision making under risk in the active group, compared to sham. Conclusions: Deficits of decision making and executive functions have a pivotal role in the perpetuation and the relapse of the OUD. Alleviation of these impairments brought tDCS/CT forth as an expedient neuroscientifically-grounded treatment option that merits further exploration in OUD, Trial registration: NCT05568251.

The Onset fluency disorder is termed as stuttering or stammering, which is one of the most addressed disorder. There are numerous cause and stages of the stuttering, most of adolescent who run into this disorder will possesses either PWS or Dysfluency. These neuro cognitive disorders includes brain stimulation supported with significant research on brain and cognitive augmentation recommended and prescribed for the healthy adults and for the patients who suffered from neurological or psychiatric diseases. Number of sensing systems, for an instance functional near infrared spectroscopy (FNIRS) has been utilized in a significant manner to ascertain speech fluency and other related motor disabilities. In principle, FNIRS operated by quantifying hemoglobin-concentration changes in the brain based on optical intensity measurements, measuring the same hemodynamic changes. The said FNIRS provisioned to deliver as a neuro-imaging brain image interface (BCI) functioned to measure neuronal activities, significantly brain cortex considering neuro-vascular coupling through uniformly distributed opto-electronic devices. The dataset generated by the FNIRS confirmed the mapped reflection of the behavior of the brain depending upon the actions performed by the participants. Depending upon the disorder and severity, the placement of the optodes and sensitivity of the treatment or the module will vary. To boost it up a little bit, the simulation sessions will be conducted in a regular interval and the data which is being processed or collected through each sessions will be imparted onto the compute module as a prepossessed data to increase the scalability and reliability of the module.

Introduction: This study aimed to investigate the influence of neglect and the effect of prism adaptation (PA) combined with continuous Theta-burst transcranial magnetic stimulation (cTBS) on the art constructive errors in painting rehabilitation of stroke patients with neglect. Methods: Fourteen patients with neglect and art constructive errors in painting secondary to stroke were randomly assigned to the rehabilitation group and received PA combined with the inhibitory protocol of cTBS over the intact parietal cortex; the control group received PA combined with sham cTBS for two weeks in ten daily sessions. Patients were assessed for art constructive errors in painting in figure copying test (FCT), and coloring test (CT) before and after the intervention. Art constructive errors in painting were classified into omission, deformation, size, neglect of warm colors, and perseveration of errors. Neglect was evaluated using the line bisection task (LBT), figure copying test (FCT), and coloring test (CT). Results: All patients showed a significant improvement in art constructive errors in painting (measured using the pattern of painting’ errors in FCT and CT), and neglect (measured using LBT, FCT, and CT) (p

The majority of human activities show a trade-off between movement speed and accuracy. Here we tested 16 participants in a quick pointing action after 20 minutes (2 mA) of transcranial direct current stimulation (tDCS) delivered at the supplementary motor area in a single-blind crossover design study for testing the feedforward components in the control of action. tDCS stimuli were delivered in three randomized sessions of stimulations as anodal, cathodal and sham as a control. The task performed pre- and post-tDCS stimulation, was to point as fast and as precise as possible with the big toe to targets having different sizes (2 and 8 cm; Width) and positioned at different distances (20 and 60 cm; Distance). An optoelectronic motion capture system was used to collect the kinematics of movement. The result indicates that individuals after receiving anodal stimulation decreased their movement time and increased their movement speed, while the opposite happened after receiving a cathodal stimulation. The scarcity of studies in this area invites us to plan a research that aims at the trade-off especially in the clinical settings.

OBJECTIVE To synthesize and critically appraise literature exploring patient perceptions regarding the therapeutic use of noninvasive brain stimulation. MATERIAL AND METHODS A systematic search of CINHAL, PUBMED, Web of Science, and Medline was performed. Reference lists of relevant articles were also screened. Studies exploring participant perceptions regarding the therapeutic use of noninvasive brain stimulation were eligible for inclusion. Perceptions were divided into three domains: knowledge, experience, and attitudes. Noninvasive brain stimulation was defined as any neuromodulation technique that alters brain activity but does not require invasive methods such as surgery. No restrictions were placed upon study design or participant population. Two reviewers performed data extraction and risk of bias assessment. Data relating to methodological characteristics, participant demographics, type of noninvasive brain stimulation, and nature of perceptions (knowledge, experience, or attitudes) were extracted. RESULTS Four studies comprising data from 163 participants met the inclusion criteria. All studies investigated perceptions of repetitive transcranial magnetic stimulation (rTMS) in psychiatric populations. Most participants perceived rTMS to be safe and beneficial, demonstrated low-levels of fear, and were willing to recommend the intervention to others. No studies were found investigating patient perception of transcranial direct current stimulation (tDCS). CONCLUSION The findings from this review suggest that rTMS is well accepted as a therapeutic treatment among psychiatric populations, providing support for its clinical utility. Future work is needed to determine if similar findings exist for other conditions (e.g., chronic pain) and for other therapeutic forms of brain stimulation (e.g., tDCS).

Nonlinear dynamical systems describe neural activity at various scales and are frequently used to study brain functions and the impact of external perturbations. Here, we explore methods from optimal control theory (OCT) to study efficient, stimulating “control” signals designed to make the neural activity match desired targets. Efficiency is quantified by a cost functional, which trades control strength against closeness to the target activity. Pontryagin’s principle then enables to compute the cost-minimizing control signal. We then apply OCT to a Wilson–Cowan model of coupled excitatory and inhibitory neural populations. The model exhibits an oscillatory regime, low- and high-activity fixed points, and a bistable regime where low- and high-activity states coexist. We compute an optimal control for a state-switching (bistable regime) and a phase-shifting task (oscillatory regime) and allow for a finite transition period before penalizing the deviation from the target state. For the state-switching task, pulses of limited input strength push the activity minimally into the target basin of attraction. Pulse shapes do not change qualitatively when varying the duration of the transition period. For the phase-shifting task, periodic control signals cover the whole transition period. Amplitudes decrease when transition periods are extended, and their shapes are related to the phase sensitivity profile of the model to pulsed perturbations. Penalizing control strength via the integrated 1-norm yields control inputs targeting only one population for both tasks. Whether control inputs drive the excitatory or inhibitory population depends on the state-space location.

This thesis investigated two cognitive approaches for improving the application of non-invasive brain stimulation in the treatment of depression. The goal of the first project was to test whether combining transcranial direct current stimulation (tDCS) with a reinforcement learning task can reduce negative biases in depression. Recent research suggests that negative biases might arise from overestimating the informativeness of negative vs. positive information which might lead to increased learning from negative information. Two samples were recruited to test whether bifrontal tDCS applied during reinforcement learning increases reward vs. punishment learning in healthy participants and individuals with low mood. For the experimental paradigm, we used the Information Bias Learning Task which manipulates the relative informativeness of reward and punishments. As hypothesised, real compared to sham tDCS selectively increased reward learning in healthy individuals. To investigate whether this effect might be helpful to normalise reinforcement learning in depression, we compared performance between individuals with low mood and healthy participants. We found that individuals with low mood adjusted their punishment learning rate less, and their reward learning rate more to changes in informativeness than healthy individuals. Bifrontal tDCS normalised learning rate adjustment in individuals with low mood, which might be beneficial in depression treatment. The reported findings were only observed in response to bifrontal tDCS applied during (as opposed to before) task performance. This suggests the hypothesis that tDCS combined with reinforcement learning might have larger antidepressant effects than tDCS alone, which can be tested in future clinical trials. The second project was motivated by the idea of investigating different cognitive phenotypes of depression to guide treatment selection for individual patients. Previous research indicates that the relative severity of anxiety vs. anhedonia might differentiate between phenotypes that differ in the TMS target region they best respond to. We therefore recruited participants with varying symptom levels on an online platform to test which parameters extracted from five cognitive tasks differentially relate to symptoms of anxiety and anhedonia. The cognitive process which seemed to best differentiate between anxiety and anhedonia was punishment learning with volatile and stable associations. Future clinical trials are needed to test whether these cognitive task parameters have any clinical value, for example for selecting the optimal TMS target region.

Brain stimulation is an increasingly popular neuromodulatory tool used in both clinical and research settings; however, the effects of brain stimulation, particularly those of non-invasive stimulation, are variable. This variability can be partially explained by an incomplete mechanistic understanding, coupled with a combinatorial explosion of possible stimulation parameters. Computational models constitute a useful tool to explore the vast sea of stimulation parameters and characterise their effects on brain activity. Yet the utility of modelling stimulation in-silico relies on its biophysical relevance, which needs to account for the dynamics of large and diverse neural populations and how underlying networks shape those collective dynamics. The large number of parameters to consider when constructing a model is no less than those needed to consider when planning empirical studies. This piece is centred on the application of phenomenological and biophysical models in non-invasive brain stimulation. We first introduce common forms of brain stimulation and computational models, and provide typical construction choices made when building phenomenological and biophysical models. Through the lens of four case studies, we provide an account of the questions these models can address, commonalities, and limitations across studies. We conclude by proposing future directions to fully realise the potential of computational models of brain stimulation for the design of personalized, efficient, and effective stimulation strategies.

Novel treatment modalities, such as non-invasive brain stimulation (NIBS), typically focus on patient groups that have failed multiple treatment interventions. Despite its promise, the clinical translation of NIBS in schizophrenia has been limited. One important obstacle to implementation is the inconsistent reporting of treatment resistance in the clinical trial literature contributing to heterogeneity in reported effects. In response, we develop a numerical approach to synthesize quality of assessment of Treatment-Resistant Schizophrenia (TRS) and apply this to studies investigating therapeutic response to NIBS in patients with schizophrenia. Literature search conducted through PubMed database identified 119 studies investigating Transcranial Magnetic Stimulation and Transcranial Electrical Stimulation in treating resistant schizophrenia symptoms. A quality score out of 11 was assigned to each study based on adherence to the international consensus guidelines for TRS developed by the Treatment Response and Resistance in Psychosis (TRRIP) group. Results revealed an overall paucity of studies with thorough assessment and/or reporting of TRS phenomenon, as evidenced by a mean quality score of 3.38/11 (SD: 1.01) for trials and 5.16/11 (SD: 1.57) for case reports, though this improved minimally since the publication of consensus criteria. Most studies considered treatment-resistance as a single dimensional construct by reporting resistance of a single symptom, and failed to establish treatment adherence, resistance time course and functional impairment. We conclude that the current NIBS literature in schizophrenia do not reflect its true effects on treatment-resistance. There is an urgent need to improve assessment and reporting standards of clinical trials that target TRS.

People with schizophrenia spectrum disorders (SSDs) often experience persistent social cognitive impairments, associated with poor functional outcome. There are currently no approved treatment options for these debilitating symptoms, highlighting the need for novel therapeutic strategies. Work to date has elucidated differential social processes and underlying neural circuitry affected in SSDs, which may be amenable to modulation using neurostimulation. Further, advances in functional connectivity mapping and electric field modeling may be used to identify individualized treatment targets to maximize the impact of brain stimulation on social cognitive networks. Here, we review literature supporting a roadmap for translating functional connectivity biomarker discovery to individualized treatment development for social cognitive impairments in SSDs. First, we outline the relevance of social cognitive impairments in SSDs. We review machine learning approaches for dimensional brain-behavior biomarker discovery, emphasizing the importance of individual differences. We synthesize research showing that brain stimulation techniques, such as repetitive transcranial magnetic stimulation, can be used to target relevant networks. Further, functional connectivity-based individualized targeting may enhance treatment response. We then outline recent approaches to account for neuroanatomical variability and optimize coil positioning to individually maximize target engagement. Overall, the synthesized literature provides support for the utility and feasibility of this translational approach to precision treatment. The proposed roadmap to translate biomarkers of social cognitive impairments to individualized treatment is currently under evaluation in precision-guided trials. Such a translational approach may also be applicable across conditions and generalizable for the development of individualized neurostimulation targeting other behavioral deficits.

Objectives Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression. Materials and methods Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS. Results VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS. Conclusions The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. 84 participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSION: Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD. NATIONAL CLINICAL TRIAL: NCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)” https://www.clinicaltrials.gov/ct2/show/NCT03449979

Noninvasive brain stimulation using focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2 – 0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.

BACKGROUND. Older adults with late-life depression (LLD) often experience incomplete or lack of response to first-line pharmacotherapy. The treatment of LLD could be improved using objective biological measures to predict response. Transcranial magnetic stimulation (TMS) can be used to measure cortical excitability, inhibition, and plasticity, which have been implicated in LLD pathophysiology, and associated with brain stimulation treatment outcomes in younger adults with depression. TMS measures have not yet been investigated as predictors of treatment outcomes in LLD, or pharmacotherapy outcomes in adults of any age with depression. METHODS. We assessed whether pre-treatment single-pulse and paired-pulse TMS measures, combined with clinical and demographic measures, predict venlafaxine treatment response in 76 outpatients with LLD. We compared the predictive performance of machine learning models including or excluding TMS predictors. RESULTS. Two single-pulse TMS measures predicted venlafaxine response: cortical excitability (neuronal membrane excitability), and the variability of cortical excitability (dynamic fluctuations in excitability levels). In cross-validation, models using a combination of these TMS predictors, clinical markers of treatment resistance, and age, classified patients with 73±11% balanced accuracy (average correct classification rate of responders and non-responders; permutation testing, p

The role of the dorsolateral prefrontal cortex (DLPFC) in implicit sequence/statistical learning has received considerable attention in recent cognitive neuroscience research. Studies have used non-invasive brain stimulation methods to test whether the DLPFC plays a role in the incidental acquisition and expression of implicit sequence learning. In a recent study, Prutean et al. has concluded that stimulating the left or the right DLPFC might not affect the expression of implicit sequence learning measured by the Serial Reaction Time (SRT) task. The authors speculated that the previous results revealing improved implicit sequence learning following DLPFC stimulation might have been found because explicit awareness accumulated with the use of Alternating Serial Reaction Time (ASRT) task. Our response presents solid evidence that the ASRT task measures implicit sequence learning that remains unconscious both at the judgment and structural level. Therefore, contrary to the conclusion of Prutean et al., we argue that the DLPFC could have a crucial effect on implicit sequence learning that may be task-dependent. We suggest that future research should focus on the specific cognitive processes that may be differentially involved in the SRT versus ASRT tasks, and test what the role of the DLPFC is in those specific cognitive processes.

Drug-resistant epilepsy, characterized by ongoing seizures despite appropriate trials of anti-seizure medications, affects approximately one-third of people with epilepsy. Brain stimulation has recently become available as an alternative treatment option to reduce symptomatic seizures in short and long-term follow-up studies. Several questions remain on how to optimally develop patient-specific treatments and manage therapy over the long term. This review aims to discuss the clinical use and mechanisms of action of Responsive Neural Stimulation and Deep Brain Stimulation in the treatment of epilepsy and highlight recent advances that may both improve outcomes and present new challenges. Finally, a rational approach to device selection is presented based on current mechanistic understanding, clinical evidence, and device features.

Mental disorders are one of the health disorders that contribute to high rates of disability and mortality worldwide.The current therapeutic modalities used to treat mental disorders are medical and psychological approaches, but it becomes problematic in some conditions, such as drug-resistant mental disorders.Radio Electric Asymmetric Conveyer (REAC) technology can be used as an alternative to overcome this problem.This technology uses radio waves which are guaranteed to be non-invasive and do not cause side effects.This technology enables neuromodulation effects by maximizing cell polarity and optimizing endogenous bioelectric activity.Of course, the REAC's mechanism as a neuromodulator and being a non-invasive technology is safe to use. It allows REAC to be used as an adjuvant therapy to reduce symptoms of several mental disorders such as depression, anxiety, bipolar disorder, phobias, and stress.

Background Phase-amplitude coupling (PAC) in which the amplitude of a faster field potential oscillation is coupled to the phase of a slower rhythm, is one of the most well-studied interactions between oscillations at different frequency bands. In a healthy brain, PAC accompanies cognitive functions such as learning and memory, and changes in PAC have been associated with neurological diseases including Parkinson's disease (PD), schizophrenia, obsessive-compulsive disorder, Alzheimer's disease, and epilepsy. Objective /Hypothesis: In PD, normalization of PAC in the motor cortex has been reported in the context of effective treatments such as dopamine replacement therapy and deep brain stimulation (DBS), but the possibility of normalizing PAC through intervention at the cortex has not been shown in humans. Phase-targeted stimulation (PDS) has a strong potential to modulate PAC levels and potentially normalize it. Methods We applied stimulation pulses triggered by specific phases of the beta oscillations, the low frequency oscillations that define phase of gamma amplitude in beta-gamma PAC, to the motor cortex of seven PD patients at rest during DBS lead placement surgery We measured the effect on PAC modulation in the motor cortex relative to stimulation-free periods. Results We describe a system for phase-targeted stimulation locked to specific phases of a continuously updated slow local field potential oscillation (in this case, beta band oscillations) prediction. Stimulation locked to the phase of the peak of beta oscillations increased beta-gamma coupling both during and after stimulation in the motor cortex, and the opposite phase (trough) stimulation reduced the magnitude of coupling after stimulation. Conclusion These results demonstrate the capacity of cortical phase-targeted stimulation to modulate PAC without evoking motor activation, which could allow applications in the treatment of neurological disorders associated with abnormal PAC, such as PD.

Background Transcranial focused ultrasound (tFUS) is a noninvasive brain stimulation method that may modulate deep brain structures. This study investigates whether sonication of the right anterior thalamus would modulate thermal pain thresholds in healthy individuals. Methods We enrolled 19 healthy individuals in this three-visit, double-blind, sham-controlled, crossover trial. Participants first underwent a structural MRI scan used solely for tFUS targeting. They then attended two identical experimental tFUS visits (counterbalanced by condition) at least one week apart. Within the MRI scanner, participants received two, 10-min sessions of either active or sham tFUS spread 10 min apart targeting the right anterior thalamus [fundamental frequency: 650 kHz, Pulse repetition frequency: 10 Hz, Pulse Width: 5 ms, Duty Cycle: 5%, Sonication Duration: 30s, Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.0 995 mW/cm2, ISPTA.3 719 mW/cm2, Peak rarefactional pressure 0.72 MPa]. The primary outcome measure was quantitative sensory thresholding (QST), measuring sensory, pain, and tolerance thresholds to a thermal stimulus applied to the left forearm before and after right anterior thalamic tFUS. Results The right anterior thalamus was accurately sonicated in 17 of the 19 subjects. Thermal pain sensitivity was significantly attenuated after active tFUS. The pre-post x active-sham interaction was significant (F(1,245.95) = 4.03, p = .046). This interaction indicates that in the sham stimulation condition, thermal pain thresholds decreased 1.08 °C (SE = 0.28) pre-post session, but only decreased .51 °C (SE = 0.30) pre-post session in the active stimulation group. Conclusions Two 10-min sessions of anterior thalamic tFUS induces antinociceptive effects in healthy individuals. Future studies should optimize the parameter space, dose and duration of this effect which may lead to multi-session tFUS interventions for pain disorders.

Introduction: Numerous studies show the involvement of the cingulate gyrus in affective disorders, particularly in depression. With a preventive and curative aim, the authors raise questions leading to therapeutic applications such as focal brain stimulation. The cingulate gyrus is the primary target of these brain stimulation therapies for the treatment of depression. The objective of this work is to establish anatomoclinical correlations and to deduce the therapeutic implications. Methodology: Our work is a review of the literature. The inventory of the cingulate gyrus and depression was based on the development of a critical synthesis of bibliographic knowledge. Results: We found a bipartite Brodmann subdivision which evolved into a subdivision into four regions of the cingulate gyrus. Descriptions of the cingulate gyrus boundaries are imprecise and divergent. The anterior end of the anterior cingulate cortex is a confirmed target of stimulation in the treatment of major and resistant depression, thus requiring the authors, a consensus in its delineation. Brodmann’s area 25 has been described as the main target of brain stimulation therapies. Dysfunction by local lesion or by alteration of the connectivity of Brodmann’s area has repercussions on these different structures to which it is interconnected. These disturbances when they are in the direction of collapse paint a picture similar to major depression. Conclusion: The anterior cingulate cortex is involved in depression. The functional system organization of affectivity will allow new brain stimulation techniques to act on the entire functional system or on one of its components.

Background Brain stimulation is known to affect canonical pathways and proteins involved in memory. However, there are conflicting results on the ability of brain stimulation to improve to memory, which may be due to variations in timing of stimulation. Hypothesis We hypothesized that repetitive transcranial magnetic stimulation (rTMS) given following a learning task and within the time period before retrieval could help improve memory. Methods We implanted male B6129SF2/J mice (n = 32) with a cranial attachment to secure the rTMS coil so that the mice could be given consistent stimulation to the frontal area whilst freely moving. Mice then underwent the object recognition test sampling phase and given treatment +3, +24, +48 h following the test. Treatment consisted of 10 min 10 Hz rTMS stimulation (TMS, n = 10), sham treatment (SHAM, n = 11) or a control group which did not do the behavior test or receive rTMS (CONTROL n = 11). At +72 h mice were tested for their exploration of the novel vs familiar object. Results At 72-h's, only the mice which received rTMS had greater exploration of the novel object than the familiar object. We further show that promoting synaptic GluR2 and maintaining synaptic connections in the perirhinal cortex and hippocampal CA1 are important for this effect. In addition, we found evidence that these changes were linked to CAMKII and CREB pathways in hippocampal neurons. Conclusion By linking the known biological effects of rTMS to memory pathways we provide evidence that rTMS is effective in improving memory when given during the consolidation and maintenance phases.

Objective Noninvasive neural stimulation via temporally interferential (TI) electrical field is currently an area of interest as a noninvasive method of brain stimulation. The major limitation of TI stimulation is the difficulty of precise temporal control of the stimulation, due to the nature of the sinusoidal envelope generated by the interference. The purpose of this study was to investigate the possibility of improving interferential stimulation by introducing precise temporal control using phase modulation. Methods In conventional TI, a sinusoidal current is applied to two electrode pairs with slightly different frequencies, to cause interference. In this paper we describe phase modulation interference (PMI). Instead of shifting frequency, the phase of a sinusoidal wave was partially modulated, causing a transient increase or decrease of the envelope. The spatial distribution of envelope modulation amplitude by TI and PMI was visualized using both electromagnetic simulation and actual measurement using tissue phantom. Results The measured voltage transient in the tissue phantom produce a precise, temporally controlled pulse-like envelope using PMI. The spatial distributions of the amplitude of the envelope modulation by TI and PMI did not differ significantly, and were consistent with electromagnetic simulation. Conclusion PMI allows precise temporal control of interferential stimulation, thus increasing the practical utility of interferential stimulation. Significance PMI improves interferential stimulation, allowing more temporally precise stimulation to neural tissue located distantly from the stimulating electrodes.

IntroductionChronic pain and sleep disturbance are bi-directionally related. Cortical electrical activity in the alpha frequency band can be enhanced with sensory stimulation via the phenomenon of entrainment, and may reduce pain perception. A smartphone based programme which delivers 10 Hz stimulation through flickering light or binaural beats was developed for use at night, pre-sleep, with the aim of improving night time pain and sleep and thereby subsequent pain and related daytime symptoms. The aim of this study was to assess the feasibility and give an indication of effect of this programme for individuals with chronic pain and sleep disturbance.Materials and methodsIn a non-controlled feasibility study participants used audio or visual alpha entrainment for 30 min pre-sleep each night for 4 weeks, following a 1 week baseline period. The study was pre-registered at ClinicalTrials.gov with the ID NCT04176861.Results28 participants (79% female, mean age 45 years) completed the study with high levels of data completeness (86%) and intervention adherence (92%). Daily sleep diaries showed an increase compared to baseline in total sleep time of 29 min (p = 0.0033), reduction in sleep onset latency of 13 min (p = 0.0043), and increase in sleep efficiency of 4.7% (p = 0.0009). Daily 0–10 numerical rating scale of average pain at night improved by 0.5 points compared to baseline (p = 0.027). Standardised questionnaires showed significant within-participant improvements in sleep quality (change in median Global PSQI from 16 to 12.5), pain interference (change in median BPI Pain Interference from 7.5 to 6.8), fatigue (change in median MFI total score from 82.5 to 77), and depression and anxiety (change in median HADS depression score from 12 to 10.5 and anxiety from 13.5 to 11).DiscussionPre-sleep use of a smartphone programme for alpha entrainment by audio or visual stimulation was feasible for individuals with chronic pain and sleep disturbance. The effect on symptoms requires further exploration in controlled studies.

Transcranial magnetic stimulation (TMS) can be useful for therapeutic purposes for a variety of clinical conditions. Numerous studies have indicated the potential of this non-invasive brain stimulation technique to recover brain function and to study physiological mechanisms. Following this line, the articles contemplated in this Research Topic show that this field of knowledge is rapidly expanding and considerable advances have been made in the last few years. There are clinical protocols already approved for Depression (and anxiety comorbid with major depressive disorder), Obsessive compulsive Disorder (OCD), migraine headache with aura, and smoking cessation treatment but many studies are concentrating their efforts on extending its application to other diseases, e.g., as a treatment adjuvant. In this Research Topic we have the example of using TMS for pain, post-stroke depression, or smoking cessation, but other diseases/injuries of the central nervous system need attention (e.g., tinnitus or the surprising epilepsy). Further, the potential of TMS in health is being explored, in particular regarding memory enhancement or the mapping of motor control regions, which might also have implications for several diseases. published

Response inhibition—our ability to suppress actions—is achieved through coordinated reactive and proactive processes that may recruit different neurophysiological mechanisms. Here we adapted a two-step continuous performance task in which the decision to respond depends on a combination of an initial context cue and a subsequent target probe. Using transcranial magnetic stimulation (TMS), we mapped changes in corticospinal excitability and inhibition, providing indices of reactive and proactive processes that influence the state of the motor system in the lead-up to initiating or suppressing a response. We found distinct changes in corticospinal excitability at critical timepoints when participants were preparing in advance to inhibit a response (during the cue) and while inhibiting a response (during the probe). Motor system activity during early timepoints correlated with behavioural indices of proactive capacity and predicted whether participants would later successfully inhibit their response. Implications for theories of inhibitory control will be discussed.

Transcranial Ultrasonic Stimulation (TUS) is a non-invasive brain stimulation method that allows stimulation of even subcortical brain tissue with unprecedented focality. Although it has been firmly proven successful in animal studies (Folloni et al., 2019; Kamimura et al., 2016; Khalighinejad et al., 2020; Kubanek et al., 2020; Verhagen et al., 2019), there is currently limited evidence of its effectiveness in online neuromodulation in humans. Here, we seek to develop an effective online TUS protocol in humans by translating a well-established protocol in non-human primates (Kubanek et al., 2020) that showed biased eye movement following stimulation of the primate frontal eye fields (FEFs). We specifically chose this paradigm and protocol to increase the likelihood of success in this translational effort. The conventional relationship between neural activation/inhibition and the behavioral read-out of the FEFs in relation to eye movements ensures that any modulation of behavior can be interpreted unambiguously in terms of corresponding neuromodulatory effects of this TUS protocol. In short, the FEFs control voluntary eye movements to the contralateral side (Beurze et al., 2009; Curtis & Connolly, 2008; Gutteling et al., 2010; Ikkai & Curtis, 2008; Kastner et al., 2007; Vernet et al., 2014), such that excitation of the FEF drives contralateral eye movements, whereas inhibition drives ipsilateral eye movements. Our a-priori hypothesis is this online protocol will bias saccades contralaterally, i.e. have an excitatory effect, similar to the previous primate study (Kubanek et al., 2020). However, our design allows us to differentiate between excitatory, inhibitory, and perturbatory effects of TUS.

The prefrontal cortex is appreciated as a key neurobiological player in human eating behavior. A special focus is herein dedicated to the dorsolateral prefrontal cortex (DLPFC), which is critically involved in executive function such as cognitive control over eating. Persons with obesity display hypoactivity in this brain area, which is linked to overconsumption and food craving. Contrary to that, higher activity in the DLPFC is associated with successful weight-loss and weight-maintenance. Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation tool used to enhance self-control and inhibitory control. The number of studies using tDCS to influence eating behavior rapidly increased in the last years. However, the effectiveness of tDCS is still unclear, as studies show mixed results and individual differences were shown to be an important factor in the effectiveness of non-invasive brain stimulation. Here, we describe the current state of research of human studies using tDCS to influence food intake, food craving, subjective feeling of hunger and body weight. Excitatory stimulation of the right DLPFC seems most promising to reduce food cravings to highly palatable food, while other studies provide evidence that stimulating the left DLPFC shows promising effects on weight loss and weight maintenance, especially in multisession approaches. Overall, the reported findings are heterogeneous pointing to large interindividual differences in tDCS responsiveness.

The aim of this study was to evaluate the effects of transcranial direct current stimulation (tDCS) on anxiety-like behavior and neural parameters in rats with chronic pain exposed to alcohol. Thirty-six adult male Wistar rats were randomly assigned to control (CT), neuropathic pain (NP), NPtDCS, NP + alcohol (NPAL), or NPALtDCS groups, subjected to sciatic nerve chronic constriction injury (CCI) and exposed to alcohol (20% v/v solution, 4 g/kg) or vehicle by gavage for 15 days. Afterward, rats were treated using bimodal tDCS (0.5 mA/20 min/8 days) and tested in the open field. Rats were killed 24 h after the last behavioral assessment, and brain and spinal cord tissue samples were collected and processed for NPY immunohistochemistry, expression of Il1a and Il1b in the spinal cord, cerebellum, and hippocampus, and levels of IL-1α and IL-1β in the same brain structures and the striatum. tDCS reverted the anxiety-like behavior induced by CCI and alcohol, and the increased expression of Il1a in the spinal cord induced by alcohol, which increased the expression of Il1b in the cerebellum. In addition, tDCS modulated the hypothalamic NPY-immunoreactivity, increased the levels of IL-1α in the hippocampus (like NP and AL), and increased the expression of Il1b in the spinal cord (like AL). Thus, this study shows that tDCS changes NP and alcohol-induced anxiety-like behavior, possibly through its central modulatory effect of NPY and spinal cord expression of Il1a and Il1b, being considered a treatment option for alcohol and NP-induced anxiety symptoms.

Purpose of review Chronic pain is debilitating and difficult to treat with pharmacotherapeutics alone. Consequently, exploring alternative treatment methods for chronic pain is essential. Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are increasingly being investigated for their neuropharmacological effects in the treatment of chronic pain. This review aims to examine and evaluate the present state of evidence regarding the use of tDCS and TMS in the treatment of chronic pain. Recent findings Despite conflicting evidence in the early literature, evidence from recent rigorous research supports the use of tDCS and TMS in treating chronic pain conditions. For both tDCS and TMS, standardized stimulation parameters have been identified with the recommendation for repeated maintenance stimulation to ensure that the analgesic effect is sustained beyond discontinuation of therapy. Summary Due to a lack of defined stimulation protocols, early findings on the efficacy of tDCS and TMS are mixed. Although the application of tDCS and TMS as pain relief approaches is still in its early stages, the introduction of standardized stimulation protocols is paving the way for more robust and informed research.

BACKGROUND: Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by cardinal motor symptoms in addition to cognitive impairment. New insights concerning multisite non-invasive brain stimulation effects have been gained, which can now be used to develop innovative treatment approaches. OBJECTIVE: Map the researchs involving multisite non-invasive brain stimulation in PD, synthesize the available evidence and discuss future directions. METHODS: The databases PubMed, PsycINFO, CINAHL, LILACS and The Cochrane Library were searched from inception until April 2020, without restrictions on the date of publication or the language in which it was published. The reviewers worked in pairs and sequentially evaluated the titles, abstracts and then the full text of all publications identified as potentially relevant. RESULTS: Twelve articles met the inclusion criteria. The target brain regions included mainly the combination of a motor and a frontal area, such as stimulation of the primary motor córtex associated with the dorsolateral prefrontal cortex. Most of the trials showed that this modality was only more effective for the motor component, or for the cognitive and/or non-motor, separately. CONCLUSIONS: Despite the results being encouraging for the use of the multisite aproach, the indication for PD management should be carried out with caution and deserves scientific deepening.

This is the second chapter of the series on the use of clinical neurophysiology for the study of movement disorders. It focusses on methods that can be used to probe neural circuits in brain and spinal cord. These include use of spinal and supraspinal reflexes to probe the integrity of transmission in specific pathways; transcranial methods of brain stimulation such as transcranial magnetic stimulation and transcranial direct current stimulation, which activate or modulate (respectively) the activity of populations of central neurones; EEG methods, both in conjunction with brain stimulation or with behavioural measures that record the activity of populations of central neurones; and pure behavioural measures that allow us to build conceptual models of motor control. The methods are discussed mainly in relation to work on healthy individuals. Later chapters will focus specifically on changes caused by pathology.

Conceptual knowledge is central to human cognition. The left posterior inferior parietal lobe (pIPL) is implicated by neuroimaging studies as a multimodal hub representing conceptual knowledge related to various perceptual-motor modalities. However, the causal role of left pIPL in conceptual processing remains unclear. Here, we transiently disrupted left pIPL function with transcranial magnetic stimulation (TMS) to probe its causal relevance for the retrieval of action and sound knowledge. We compared effective TMS over left pIPL with sham TMS, while healthy participants performed three different tasks-lexical decision, action judgment, and sound judgment-on words with a high or low association to actions and sounds. We found that pIPL-TMS selectively impaired action judgments on low sound-low action words. For the first time, we directly related computational simulations of the TMS-induced electrical field to behavioral performance, which revealed that stronger stimulation of left pIPL is associated with worse performance for action but not sound judgments. These results indicate that left pIPL causally supports conceptual processing when action knowledge is task-relevant and cannot be compensated by sound knowledge. Our findings suggest that left pIPL is specialized for the retrieval of action knowledge, challenging the view of left pIPL as a multimodal conceptual hub.

Transcranial magnetic stimulation (TMS) is a widely used non-invasive tool to study and modulate human brain functions. However, our knowledge of TMS neurophysiology is largely limited due to various difficulties in studying neural activities in vivo in real-time under the strong electromagnetic interference generated by TMS. In this work, the author first reviews the state-of-the-art knowledge in the neurophysiology of TMS and highlights the need to conduct further studies at the level of individual neurons and their neural networks. The second chapter is dedicated to the technical development of a research platform that allows faithful concurrent TMS and EEP recording in laboratory rodents. Building on this methodology, the third chapter focuses on characterizing the dynamics of neuronal activities in M1 evoked by a monophasic single-pulse TMS (mspTMS) that triggers unilateral MEPs in the forearm. Bringing the investigation further, the fourth chapter explores the mechanism of TMS-evoked intermediate excitation, a period of synaptic-mediated excitatory neuronal activities in M1 triggered by TMS, in the cortico-basal ganglia-thalamo-cortical (CBGTC) and the cortico-cerebello-thalamo-cortical (CCTC) loop. Finally, the fifth chapter summarizes the results from this work, discusses their limitations and implications, and proposes future research.

Persons with autism spectrum disorder (ASD) have impaired mentalizing skills. In this study, a group of persons with ASD traits (high-AQ scores) initially received sham tDCS before completing a pre-test in two mentalizing tasks: false belief and self-other judgments. Over the next week, on four consecutive days, they received sessions of anodal electrical stimulation (a-tDCS) over the right temporo-parietal junction (rTPJ), a region frequently associated with the theory of mind. On the last day, after the stimulation session, they completed a new set of mentalizing tasks. A control group (with low-AQ scores) matched in age, education and intelligence received just sham stimulation and completed the same pre-test and post-test. The results showed that the high-AQ group improved their performance (faster responses), after a-tDCS, in the false belief and in the self-other judgments of mental features, whereas they did not change performance in the false photographs or the self-other judgments of physical features. These selective improvements cannot be attributed to increased familiarity with the tasks, because the performance of the low-AQ control group remained stable about one week later. Therefore, our study provides initial proof that tDCS could be used to improve mentalizing skills in persons with ASD traits.

Neurodegenerative disorders (NDs) are highly prevalent among the aging population. It affects primarily the central nervous system (CNS) but the effects are also observed in the peripheral nervous system. Neural degeneration is a progressive loss of structure and function of neurons, which may ultimately involve cell death. Such patients suffer from debilitating memory loss and altered motor coordination which bring up non-affordable and unavoidable socio-economic burdens. Due to the unavailability of specific therapeutics and diagnostics, the necessity to control or manage NDs raised the demand to investigate and develop efficient alternative approaches. Keeping trends and advancements in view, this report describes both state-of-the-art and challenges in nano-biotechnology-based approaches to manage NDs, toward personalized healthcare management. Sincere efforts are being made to customize nano-theragnostics to control: therapeutic cargo packaging, delivery to the brain, nanomedicine of higher efficacy, deep brain stimulation, implanted stimulation, and managing brain cell functioning. These advancements are useful to design future therapy based on the severity of the patient's neurodegenerative disease. However, we observe a lack of knowledge shared among scientists of a variety of expertise to explore this multi-disciplinary research field for NDs management. Consequently, this review will provide a guideline platform that will be useful in developing novel smart nano-therapies by considering the aspects and advantages of nano-biotechnology to manage NDs in a personalized manner. Nano-biotechnology-based approaches have been proposed as effective and affordable alternatives at the clinical level due to recent advancements in nanotechnology-assisted theragnostics, targeted delivery, higher efficacy, and minimal side effects.

Aim Cognitive deficits are recognized features of depressive disorders in youth aged 12-25. These deficits are distressing, predict functional impairment and limit the effectiveness of psychological therapies. Cognitive enhancement using behavioural, biochemical or physical treatments may be useful in young people with depression, but studies have not been synthesized. The aim was to systematically review the evidence for treatments for objective and subjective cognitive functioning, and their acceptability and functional outcomes in people aged 12-25 with depression. Method Three electronic databases were searched for articles using pre-specified criteria. Pharmacological treatments were not eligible. Risk of bias was rated using the Cochrane Collaboration's revised risk-of-bias tool. Dual full-text article screening, data extraction and quality ratings were completed. Results Twelve studies were included for review (median participant age: 20.39 years), five of which were randomized-controlled trials (RCTs). Sample sizes were generally small (median = 23; range: 9-46). Eight studies investigated behavioural treatments including aerobic exercise, cognitive training and education or strategy-based methods. Four studies examined repetitive transcranial magnetic brain stimulation (rTMS). Most behavioural treatments revealed preliminary evidence of improved cognitive function in youth depression. Consent rates were greatest for exercise- and education-based approaches, which may indicate higher acceptability levels. Findings from rTMS trials were mixed, with only half showing cognitive improvement. Functional outcomes were reported by three behavioural treatment trials and one rTMS trial, with functional improvement reported only in the former. Some concern of risk of bias was found in each RCT. Conclusion Behavioural treatments, such as exercise, cognitive training and education/strategy-focused techniques, show encouraging results and appear to be acceptable methods of addressing cognitive deficits in youth depression based on participation rates. Brain stimulation and biochemical treatments (e.g., nutrient-based treatment) require further investigation.

Background and Study Aims Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a highly effective therapy for primary generalized and focal dystonias, but therapeutic success is compromised by a nonresponder rate of up to 20%. Variability in electrode placement and in tissue stimulated inside the GPi may explain in part different outcomes among patients. Refinement of the target within the pallidal area could be helpful for surgery planning and clinical outcomes. The objective of this study was to discuss current and potential methodological (somatotopy, neuroimaging, and neurophysiology) aspects that might assist neurosurgical targeting of the GPi, aiming to treat generalized or focal dystonia. Methods We selected published studies by searching electronic databases and scanning the reference lists for articles that examined the anatomical and electrophysiologic aspects of the GPi in patients with idiopathic/inherited dystonia who underwent functional neurosurgical procedures. Results The sensorimotor sector of the GPi was the best target to treat dystonic symptoms, and was localized at its lateral posteroventral portion. The effective volume of tissue activated (VTA) to treat dystonia had a mean volume of 153 mm3 in the posterior GPi area. Initial tractography studies evaluated the close relation between the electrode localization and pallidothalamic tract to control dystonic symptoms.Regarding the somatotopy, the more ventral, lateral, and posterior areas of the GPi are associated with orofacial and cervical representation. In contrast, the more dorsal, medial, and anterior areas are associated with the lower limbs; between those areas, there is the representation of the upper limb. Excessive pallidal synchronization has a peak at the theta band of 3 to 8 Hz, which might be responsible for generating dystonic symptoms. Conclusions Somatotopy assessment of posteroventral GPi contributes to target-specific GPi sectors related to segmental body symptoms. Tractography delineates GPi output pathways that might guide electrode implants, and electrophysiology might assist in pointing out areas of excessive theta synchronization. Finally, the identification of oscillatory electrophysiologic features that correlate with symptoms might enable closed-loop approaches in the future.

Background and purpose Multiple sclerosis (MS) is a chronic inflammatory disease causing a wide range of symptoms including motor and cognitive impairment, fatigue and pain. Over the last two decades, non-invasive brain stimulation, especially transcranial direct current stimulation (tDCS), has increasingly been used to modulate brain function in various physiological and pathological conditions. However, its experimental applications for people with MS were noted only as recently as 2010 and have been growing since then. The efficacy for use in people with MS remains questionable with the results of existing studies being largely conflicting. Hence, the aim of this review is to paint a picture of the current state of tDCS in MS research grounded on studies applying tDCS that have been done to date. Methods A keyword search was performed to retrieve articles from the earliest article identified until 14 February 2021 using a combination of the groups (1) ‘multiple sclerosis’, ‘MS’ and ‘encephalomyelitis’ and (2) ‘tDCS’ and ‘transcranial direct current stimulation’. Results The analysis of the 30 articles included in this review underlined inconsistent effects of tDCS on the motor symptoms of MS based on small sample sizes. However, tDCS showed promising benefits in ameliorating fatigue, pain and cognitive symptoms. Conclusion Transcranial direct current stimulation is attractive as a non-drug approach in ameliorating MS symptoms, where other treatment options remain limited. The development of protocols tailored to the individual's own neuroanatomy using high definition tDCS and the introduction of network mapping in the experimental designs might help to overcome the variability between studies.

The therapeutic approaches currently applied in Alzheimer's disease (AD) and similar neurodegenerative diseases are essentially based on pharmacological strategies. However, despite intensive research, the effectiveness of these treatments is limited to transient symptomatic effects, and they are still far from exhibiting a true therapeutic effect capable of altering prognosis. The lack of success of such pharmacotherapy-based protocols may be derived from the cases in the majority of trials being too advanced to benefit significantly in therapeutic terms at the clinical level. For neurodegenerative diseases, mild cognitive impairment (MCI) may be an early stage of the disease continuum, including Alzheimer's. Noninvasive brain stimulation (NIBS) techniques have been developed to modulate plasticity in the human cortex in the last few decades. NIBS techniques have made it possible to obtain unique findings concerning brain functions, and design novel approaches to treat various neurological and psychiatric conditions. In addition, its synaptic and cellular neurobiological effects, NIBS is an attractive treatment option in the early phases of neurodegenerative diseases, such as MCI, with its beneficial modifying effects on cellular neuroplasticity. However, there is still insufficient evidence about the potential positive clinical effects of NIBS on MCI. Furthermore, the huge variability of the clinical effects of NIBS limits its use. In this article, we reviewed the combined approach of NIBS with various neuroimaging and electrophysiological methods. Such methodologies may provide a new horizon to the path for personalized treatment, including a more individualized pathophysiology approach which might even define new specific targets for specific symptoms of neurodegenerations.

OBJECTIVE Chronic pain results in an enormous societal and financial burden. Opioids are the mainstay of treatment, but opioid abuse has led to an epidemic in the United States. Nonpharmacological treatment strategies like deep brain stimulation could be applied to refractory chronic pain if safe and effective brain targets are identified. The anterior insula is a putative mediator of pain-related affective-motivational and cognitive-evaluative cerebral processing. However, the effect of anterior insula stimulation on pain perception is still unknown. Here, the authors provide behavioral and neurophysiological evidence for stimulating the anterior insula as a means of potential therapeutic intervention for patients with chronic pain. METHODS Six patients with epilepsy in whom intracerebral electrodes had been implanted for seizure localization were recruited to the study. The direct anterior insula stimulations were performed in the inpatient epilepsy monitoring unit while subjects were fully awake, comfortable, and without sedating medications. The effects of anterior insula stimulation were assessed with quantitative sensory testing for heat pain threshold, nociceptive-specific cutaneous laser-evoked potentials, and intracranial electroencephalogram (EEG) recordings. Control stimulation of noninsular brain regions was performed to test stimulation specificity. Sham stimulations, in which no current was delivered, were also performed to control for potential placebo effects. The safety of these stimulations was evaluated by bedside physicians, real-time intracranial EEG monitoring, and electrocardiogram recordings. RESULTS Following anterior insula stimulations, the heat pain threshold of each patient significantly increased from baseline (p < 0.001) and correlated with stimulation intensity (regression analysis: β = 0.5712, standard error 0.070, p < 0.001). Significant changes in ongoing intracranial EEG frequency band powers (p < 0.001), reduction in laser pain intensity, and attenuated laser-evoked potentials were also observed following stimulations. Furthermore, the observed behavioral and neurophysiological effects persisted beyond the stimulations. Subjects were not aware of the stimulations, and there were no cardiovascular or untoward effects. CONCLUSIONS Additional, nonpharmacological therapies are imperative for the future management of chronic pain conditions and to mitigate the ongoing opioid crisis. This study suggests that direct stimulation of the anterior insula can safely alter cerebral pain processing in humans. Further investigation of the anterior insula as a potential target for therapeutic neuromodulation is underway.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 Tesla), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear.ObjectiveTo assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice.MethodsLongitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF).ResultsWe found strong evidence (BF>10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice.ConclusionThese findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity.

Background: Alcohol dependence is a significant public health problem, contributing to the global health burden. Due to its immense socio-economic burden, various psychosocial, psychological, and pharmacological approaches have attempted to alter the behaviour of the patient misusing or abusing alcohol, but their efficacy is modest at best. Therefore, there is a search for newer treatment approaches, including non-invasive brain stimulation in the management of alcohol dependence. We plan to study the efficacy of Prefrontal Cortex Transcranial direct current stimulation Treatment in Alcohol dependence syndrome (PreCoTTA). Methods: Two hundred twenty-five male patients with alcohol dependence syndrome will be randomized into the three study arms (2 active, left dorsolateral prefrontal cortex and left orbitofrontal cortex, and 1 sham) to receive a total of 14 tDCS sessions (10 continuous and 4 booster sessions). Data will be collected from these sessions at five different time points on clinical, neuropsychological and biochemical parameters. In addition, 225 healthy age and education matched controls will be administered the neuropsychological test battery at baseline for comparison with the patient group. Discussion: The proposed study aims to explore the use of non-invasive brain stimulation; tDCS as a treatment alternative. We also aim to overcome the methodological gaps of limited sample sizes, fewer tDCS intervention sessions, lack of long-term follow-ups to measure the sustainability of gains, and lack of comprehensive measures to track changes in functioning and abstinence after tDCS intervention. The main outcomes include clinical (reduction in cue-induced craving, time to first drink, and QFI); neuropsychological (risk-taking, impulsivity, and other neuropsychological domains), and biochemical markers (BDNF, leptin and adiponectin). The findings of the study will have translational value as they may help to improve the clinician’s ability to effectively manage craving in patients with alcohol dependence syndrome. Furthermore, we will have a better understanding of the neuropsychological and biochemical effects of non-invasive brain stimulation techniques which are of interest in the comprehensive treatment of addiction disorders. Trial registration: The study has been registered with the Clinical Trials Registry-India (CTRI/ 2020/09/027582) on September 03rd 2020.

Transcranial direct current stimulation (tDCS) is a form of novel brain stimulating method that has attracted interest owing to its relative inexpensiveness and ease of administration. It has been evaluated in many studies for its effectiveness in improving cognitive symptoms in Alzheimer's disease (AD). However, our understanding regarding its efficacy and the most effective way of administering tDCS (in terms of lead placement to achieve response and prevent harmful consequences) is still evolving. The current meta-analysis was conducted to resolve the above issues. A search using appropriate keywords and medical subject headings was conducted on PubMed, Scopus and DOAJ database. Studies were analysed on pre-defined inclusion and exclusion criteria. Finally 11 studies were included for quantitative analysis from 1,021 obtained from initial search. All the studies included were methodologically of high quality, though an asymmetrical funnel plot raised the possibility of publication bias. tDCS was found to significantly improve the scores on cognition as compared to sham. Anodal tDCS was found to be significantly beneficial in this regards, whereas cathodal and dual stimulation were not. There were no significant difference in the number of drop-outs and adverse reaction in tDCS and sham group. The quality of evidence that we have reviewed in this study is robust. tDCS, particularly anodal tDCS is an effective treatment modality in AD. It is well tolerated in patients with AD. However, further studies are warranted to probe the role of tDCS in other domains of AD.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation therapy that has become a method of choice for the treatment of several neuropsychiatric disorders such as depression and OCD. It is considered to be a safe and well-tolerated treatment, with only few side effects. The most serious adverse event during any rTMS treatment is the potential induction of a seizure. rTMS has shown very encouraging results for treatment-resistant OCD, although the optimal target area and the stimulation frequency are still matters of controversy. Here, we present a 19-year-old female patient with OCD who experienced seizure during the 7th session of her rTMS treatment using the FDA-approved 20-Hz protocol for OCD applied bilaterally over the left and right DMPFC using a double-cone coil. Nonetheless, it still unknown whether the seizure occurred as a consequence of rTMS, as the patient was also in a specific seizure risk group. Future reviews are needed to further clarify the mechanisms that may trigger seizures during rTMS treatments in order to reduce the likelihood of rTMS-induced seizures.

Aim Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that shows potential for treating psychiatric disorders. Although several studies have sought to investigate new TMS modalities for the treatment of various psychiatric disorders, no study has yet examined publication trends in research on TMS modalities for psychiatric disorders. This study investigated publication trends in TMS research for 13 psychiatric disorders, including addiction, dementia, major depressive disorder (MDD), and obsessive‐compulsive disorder (OCD), and schizophrenia, as well as 9 TMS modalities, including bilateral stimulation, deep TMS, high‐frequency stimulation, low‐frequency stimulation, and theta burst stimulation. Methods Articles published in PubMed from 1985 to 2019 were searched to determine the number of published articles for each year in each category using the “Results by year” tool from the PubMed database. Results Over the past 30 years, an increasing number of articles were published regarding TMS research for the treatment of MDD, addiction, and dementia, which were among those most commonly investigated psychiatric disorders, whereas the number of articles addressing schizophrenia and OCD treated via TMS remained steady since 2015. Regarding TMS modalities, previous high‐frequency stimulation, low‐frequency stimulation, and bilateral stimulation were the most common topics, with research regarding deep TMS and theta burst stimulation having increased since 2000 and 2005, respectively. Conclusion TMS applications are rapidly developing and becoming increasingly ubiquitous in various psychiatric disorders. Determining publication trends in TMS research can be a useful method for monitoring TMS research interests and applications of new TMS modalities for psychiatric disorders.

Background. The relationship between the levodopa challenge test (LDCT) and postoperative subthalamic nucleus-deep brain stimulation (STN-DBS) benefits is controversial in patients with Parkinson’s disease (PD). We aim to evaluate the value of total levodopa response (TLR) and symptom levodopa response (SLR) in predicting postoperative improvement in different PD motor subtypes. Methods. Studies were split into a training set (147 patients) and a validation set (304 patients). We retrospectively collected data from 147 patients who received the Unified Parkinson’s Disease Rating Scale- (UPDRS-) III and the Parkinson’s Disease Questionnaire- (PDQ-) 39 evaluation. Patients were classified into tremor-dominant (TD), akinetic-rigid-dominant (AR), and mixed (MX) groups. Clinically important difference (CID) was employed to dichotomize DBS effects. For patients in each subtype group from the training set, we used the correlation and receiver operator characteristic (ROC) curve analyses to explore the strength of their relations. Areas under the curve (AUCs) were calculated and compared through the DeLong test. Results developed from the training set were applied into the validation set to predict postoperative improvement in different PD motor subtypes. Results. In the validation cohort, TLR significantly correlated with postoperative motor ( p < 0.001 ) and quality of life (QOL) ( p < 0.001 ) improvement in the MX group. The AUC between TLR and UPDRS-III (TU) is 0.800. The AUC between TLR and PDQ-39 (TP) is 0.770. An associated criterion in both TU and TP is around 50%. In the AR group, strong correlation was only found in SLR and PDQ-39 (SP) ( p < 0.001 ). And the AUC of SP is significantly larger than that in TLR and PDQ-39 (TP) ( p = 0.034 ). An associated criterion in SP is around 37%. No significant correlation was found in the TD group. Conclusions. We provide a more accurate judgment for LDCT. TLR strongly correlated with postoperative UPDRS-III and PDQ-39 improvement in MX patients. A TLR > 50 % may indicate a higher possibility of clinically meaningful benefits from STN-DBS comparing to medication only. SLR can well predict QOL improvement in AR patients. Similarly, a SLR > 37 % may indicate a higher possibility of clinically significant benefits from STN-DBS. LDCT provides limited information for TD patients.

In this paper, a closed-loop brain stimulation control problem is investigated using the nonsingular integral terminal sliding mode (NITSM) control approach. First, the thalamocortical model of epilepsy seizure is given, which is composed of the cortical PY-IN subnetwork and the subcortical RE-TC subsystem. Then, a nonsingular integral terminal sliding mode surface is designed utilizing the derived output tracking error, and the stability of the sliding mode dynamics is proved by Lyapunov approach. Furthermore, a disturbance observer (DOB) based NITSM controller design approach is proposed for the established thalamocortical model, and the reachability of the closed-loop control system under the designed controller is analyzed using Lyapunov theory. Finally, simulation results are given to illustrate the effectiveness and superiority of the designed control scheme.