Non-invasive brain stimulation for treatment-resistant schizophrenia: protocol of a systematic review and network meta-analysis.

BACKGROUND: Non-invasive brain stimulation (NIBS) is a promising intervention for treatment-resistant schizophrenia. However, there are multiple available techniques and a comprehensive synthesis of evidence is lacking. Thus, we will conduct a systematic review and network meta-analysis to investigate the comparative efficacy and safety of NIBS techniques as an add-on to antipsychotics for treatment-resistant schizophrenia. METHODS: We will include single- and double-blind randomized-controlled trials (RCT) comparing any NIBS technique with each other or with a control intervention as an add-on to antipsychotics in adult patients with treatment-resistant schizophrenia. We will exclude studies focusing on predominant negative symptoms, maintenance treatment, and single sessions. The primary outcome will be a change in overall symptoms, and secondary outcomes will be a change in symptom domains, cognitive performance, quality of life, functioning, response, dropouts, and side effects. We will search for eligible studies in previous reviews, multiple electronic databases and clinical trial registries from inception onwards. At least two independent reviewers will perform the study selection, data extraction, and risk of bias assessment. We will measure the treatment differences using standardized mean difference (SMD) and odds ratio (OR) for continuous and dichotomous outcomes, respectively. We will conduct pairwise and network meta-analysis within a frequentist framework using a random-effects model, except for rare event outcomes where we will use a fixed-effects Mantel-Haenszel method. We will investigate potential sources of heterogeneity in subgroup analyses. Reporting bias will be assessed with funnel plots and the Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) tool. The certainty in the evidence will be evaluated using the Confidence in Network Meta-analysis (CINeMA) approach. DISCUSSION: Our network meta-analysis would provide an up-to-date synthesis of the evidence from all available RCTs on the comparative efficacy and safety of NIBS for treatment-resistant schizophrenia. This information could guide evidence-based clinical practice and improve the outcomes of patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-ID CRD42023410645.

Transcranial electric stimulation modulates firing rate at clinically relevant intensities.

BACKGROUND: Notwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. OBJECTIVE: To measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow. METHODS: Current flow models were calibrated on electric field measures in the motor cortex (n = 2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 µA of applied skull currents). RESULTS: Electric fields of as low as 0.35 V/m (0.25-0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2-18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. CONCLUSION: In awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility.

Short-term effects of transcranial direct current stimulation on motor speech in Parkinson's disease: a pilot study.

INTRODUCTION: Hypokinetic dysarthria (HD) is a common motor speech symptom of Parkinson's disease (PD) which does not respond well to PD treatments. We investigated short-term effects of transcranial direct current stimulation (tDCS) on HD in PD using acoustic analysis of speech. Based on our previous studies we focused on stimulation of the right superior temporal gyrus (STG) - an auditory feedback area. METHODS: In 14 PD patients with HD, we applied anodal, cathodal and sham tDCS to the right STG using a cross-over design. A protocol consisting of speech tasks was performed prior to and immediately after each stimulation session. Linear mixed models were used for the evaluation of the effects of each stimulation condition on the relative change of acoustic parameters. We also performed a simulation of the mean electric field induced by tDCS. RESULTS: Linear mixed model showed a statistically significant effect of the stimulation condition on the relative change of median duration of silences longer than 50 ms (p = 0.015). The relative change after the anodal stimulation (mean = -5.9) was significantly lower as compared to the relative change after the sham stimulation (mean = 12.8), p = 0.014. We also found a correlation between the mean electric field magnitude in the right STG and improvement of articulation precision after anodal tDCS (R = 0.637; p = 0.019). CONCLUSIONS: The exploratory study showed that anodal tDCS applied over the auditory feedback area may lead to shorter pauses in a speech of PD patients.

Visualizing interferential stimulation of human brains.

Introduction: Transcranial electrical stimulation (TES) is limited in focally stimulating deep-brain regions, even with optimized stimulation montages. Recently, interferential stimulation (IFS), also known as transcranial temporal interference stimulation (TI, TIS, or tTIS), has drawn much attention in the TES community as both computational and experimental studies show that IFS can reach deep-brain areas. However, the underlying electrodynamics of IFS is complicated and difficult to visualize. Existing literature only shows static visualization of the interfered electric field induced by IFS. These could result in a simplified understanding that there is always one static focal spot between the two pairs of stimulation electrodes. This static visualization can be frequently found in the IFS literature. Here, we aimed to systematically visualize the entire dynamics of IFS. Methods and results: Following the previous study, the lead field was solved for the MNI-152 head, and optimal montages using either two pairs of electrodes or two arrays of electrodes were found to stimulate a deep-brain region close to the left striatum with the highest possible focality. We then visualized the two stimulating electrical currents injected with similar frequencies. We animated the instant electric field vector at the target and one exemplary off-target location both in 3D space and as a 2D Lissajous curve. We finally visualized the distribution of the interfered electric field and the amplitude modulation envelope at an axial slice going through the target location. These two quantities were visualized in two directions: radial-in and posterior-anterior. Discussion: We hope that with intuitive visualization, this study can contribute as an educational resource to the community's understanding of IFS as a powerful modality for non-invasive focal deep-brain stimulation.

A mini-review: recent advancements in temporal interference stimulation in modulating brain function and behavior.

Numerous studies have assessed the effect of Temporal Interference (TI) on human performance. However, a comprehensive literature review has not yet been conducted. Therefore, this review aimed to search PubMed and Web of Science databases for TI-related literature and analyze the findings. We analyzed studies involving preclinical, human, and computer simulations, and then discussed the mechanism and safety of TI. Finally, we identified the gaps and outlined potential future directions. We believe that TI is a promising technology for the treatment of neurological movement disorders, due to its superior focality, steerability, and tolerability compared to traditional electrical stimulation. However, human experiments have yielded fewer and inconsistent results, thus animal and simulation experiments are still required to perfect stimulation protocols for human trials.

[Research progress on transcranial electrical stimulation for deep brain stimulation].

Transcranial electric stimulation (TES) is a non-invasive, economical, and well-tolerated neuromodulation technique. However, traditional TES is a whole-brain stimulation with a small current, which cannot satisfy the need for effectively focused stimulation of deep brain areas in clinical treatment. With the deepening of the clinical application of TES, researchers have constantly investigated new methods for deeper, more intense, and more focused stimulation, especially multi-electrode stimulation represented by high-precision TES and temporal interference stimulation. This paper reviews the stimulation optimization schemes of TES in recent years and further analyzes the characteristics and limitations of existing stimulation methods, aiming to provide a reference for related clinical applications and guide the following research on TES. In addition, this paper proposes the viewpoint of the development direction of TES, especially the direction of optimizing TES for deep brain stimulation, aiming to provide new ideas for subsequent research and application.

Anatomical details affect electric field predictions for non-invasive brain stimulation in non-human primates.

Non-human primates (NHPs) have become key for translational research in noninvasive brain stimulation (NIBS). However, in order to create comparable stimulation conditions for humans it is vital to study the accuracy of current modeling practices across species. Numerical models to simulate electric fields are an important tool for experimental planning in NHPs and translation to human studies. It is thus essential whether and to what extent the anatomical details of NHP models agree with current modeling practices when calculating NIBS electric fields. Here, we create highly accurate head models of two non-human primates (NHP) MR data. We evaluate how muscle tissue and head field of view (depending on MRI parameters) affect simulation results in transcranial electric and magnetic stimulation (TES and TMS). Our findings indicate that the inclusion of anisotropic muscle can affect TES electric field strength up to 22% while TMS is largely unaffected. Additionally, comparing a full head model to a cropped head model illustrates the impact of head field of view on electric fields for both TES and TMS. We find opposing effects between TES and TMS with an increase up to 24.8% for TES and a decrease up to 24.6% for TMS for the cropped head model compared to the full head model. Our results provide important insights into the level of anatomical detail needed for NHP head models and can inform future translational efforts for NIBS studies.

Transcranial Electrical Stimulation for Associative Memory Enhancement: State-of-the-Art from Basic to Clinical Research.

Associative memory (AM) is the ability to bind new information into complex memory representations. Noninvasive brain stimulation (NIBS), especially transcranial electric stimulation (tES), has gained increased interest in research of associative memory (AM) and its impairments. To provide an overview of the current state of knowledge, we conducted a systematic review following PRISMA guidelines covering basic and clinical research. Out of 374 identified records, 41 studies were analyzed-twenty-nine in healthy young adults, six in the aging population, three comparing older and younger adults, as well as two studies on people with MCI, and one in people with Alzheimer's dementia. Studies using transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS) as well as oscillatory (otDCS) and high-definition protocols (HD-tDCS, HD-tACS) have been included. The results showed methodological heterogeneity in terms of study design, stimulation type, and parameters, as well as outcome measures. Overall, the results show that tES is a promising method for AM enhancement, especially if the stimulation is applied over the parietal cortex and the effects are assessed in cued recall paradigms.

Effects on Corticospinal Tract Homology of Faremus Personalized Neuromodulation Relieving Fatigue in Multiple Sclerosis: A Proof-of-Concept Study.

OBJECTIVES: Fatigue in multiple sclerosis (MS) is a frequent and invalidating symptom, which can be relieved by non-invasive neuromodulation, which presents only negligible side effects. A 5-day transcranial direct-current stimulation, 15 min per day, anodically targeting the somatosensory representation of the whole body against a larger occipital cathode was efficacious against MS fatigue (fatigue relief in multiple sclerosis, Faremus treatment). The present proof-of-concept study tested the working hypothesis that Faremus S1 neuromodulation modifies the homology of the dominant and non-dominant corticospinal (CST) circuit recruitment. METHODS: CST homology was assessed via the Fréchet distance between the morphologies of motor potentials (MEPs) evoked by transcranial magnetic stimulation in the homologous left- and right-hand muscles of 10 fatigued MS patients before and after Faremus. RESULTS: In the absence of any change in MEP features either as differences between the two body sides or as an effect of the treatment, Faremus changed in physiological direction the CST's homology. Faremus effects on homology were more evident than recruitment changes within the dominant and non-dominant sides. CONCLUSIONS: The Faremus-related CST changes extend the relevance of the balance between hemispheric homologs to the homology between body sides. With this work, we contribute to the development of new network-sensitive measures that can provide new insights into the mechanisms of neuronal functional patterning underlying relevant symptoms.

Towards causal mechanisms of consciousness through focused transcranial brain stimulation.

Conscious experience represents one of the most elusive problems of empirical science, namely neuroscience. The main objective of empirical studies of consciousness has been to describe the minimal sets of neural events necessary for a specific neuronal state to become consciously experienced. The current state of the art still does not meet this objective but rather consists of highly speculative theories based on correlates of consciousness and an ever-growing list of knowledge gaps. The current state of the art is defined by the limitations of past stimulation techniques and the emphasis on the observational approach. However, looking at the current stimulation technologies that are becoming more accurate, it is time to consider an alternative approach to studying consciousness, which builds on the methodology of causal explanations via causal alterations. The aim of this methodology is to move beyond the correlates of consciousness and focus directly on the mechanisms of consciousness with the help of the currently focused brain stimulation techniques, such as geodesic transcranial electric neuromodulation. This approach not only overcomes the limitations of the correlational methodology but will also become another firm step in the following science of consciousness.

Mind matters: A narrative review on affective state-dependency in non-invasive brain stimulation.

Variability in findings related to non-invasive brain stimulation (NIBS) have increasingly been described as a result of differences in neurophysiological state. Additionally, there is some evidence suggesting that individual differences in psychological states may correlate with the magnitude and directionality of effects of NIBS on the neural and behavioural level. In this narrative review, it is proposed that the assessment of baseline affective states can quantify non-reductive properties which are not readily accessible to neuroscientific methods. Particularly, affective-related states are theorized to correlate with physiological, behavioural and phenomenological effects of NIBS. While further systematic research is needed, baseline psychological states are suggested to provide a complementary cost-effective source of information for understanding variability in NIBS outcomes. Implementing measures of psychological state may potentially contribute to increasing the sensitivity and specificity of results in experimental and clinical NIBS studies.

Dynamic sensitivity analysis: Defining personalised strategies to drive brain state transitions via whole brain modelling.

Traditionally, in neuroimaging, model-free analyses are used to find significant differences between brain states via signal detection theory. Depending on the a priori assumptions about the underlying data, different spatio-temporal features can be analysed. Alternatively, model-based techniques infer features from the data and compare significance from model parameters. However, to assess transitions from one brain state to another remains a challenge in current paradigms. Here, we introduce a "Dynamic Sensitivity Analysis" framework that quantifies transitions between brain states in terms of stimulation ability to rebalance spatio-temporal brain activity towards a target state such as healthy brain dynamics. In practice, it means building a whole-brain model fitted to the spatio-temporal description of brain dynamics, and applying systematic stimulations in-silico to assess the optimal strategy to drive brain dynamics towards a target state. Further, we show how Dynamic Sensitivity Analysis extends to various brain stimulation paradigms, ultimately contributing to improving the efficacy of personalised clinical interventions.

A map of evidence using transcranial direct current stimulation (tDCS) to improve cognition in adults with traumatic brain injury (TBI).

Introduction: Cognition impairments often occur after a traumatic brain injury and occur at higher rates in military members. Cognitive symptoms impair daily function, including balance and life quality, years after the TBI. Current treatments to regain cognitive function after TBI, including medications and cognitive rehabilitation, have shown limited effectiveness. Transcranial direct current stimulation (tDCS) is a low-cost, non-invasive brain stimulation intervention that improves cognitive function in healthy adults and people with neuropsychologic diagnoses beyond current interventions. Despite the available evidence of the effectiveness of tDCS in improving cognition generally, only two small TBI trials have been conducted based on the most recent systematic review of tDCS effectiveness for cognition following neurological impairment. We found no tDCS studies that addressed TBI-related balance impairments. Methods: A scoping review using a peer-reviewed search of eight databases was completed in July 2022. Two assessors completed a multi-step review and completed data extraction on included studies using a priori items recommended in tDCS and TBI research guidelines. Results: A total of 399 results were reviewed for inclusion and 12 met the criteria and had data extracted from them by two assessors using Google Forms. Consensus on combined data results included a third assessor when needed. No studies using tDCS for cognition-related balance were found. Discussion: Guidelines and technology measures increase the identification of brain differences that alter tDCS effects on cognition. People with mild-severe and acute-chronic TBI tolerated and benefited from tDCS. TBI-related cognition is understudied, and systematic research that incorporates recommended data elements is needed to advance tDCS interventions to improve cognition after TBI weeks to years after injury.

Research progress on transcranial electrical stimulation for deep brain stimulation / 生物医学工程学杂志

Transcranial electric stimulation (TES) is a non-invasive, economical, and well-tolerated neuromodulation technique. However, traditional TES is a whole-brain stimulation with a small current, which cannot satisfy the need for effectively focused stimulation of deep brain areas in clinical treatment. With the deepening of the clinical application of TES, researchers have constantly investigated new methods for deeper, more intense, and more focused stimulation, especially multi-electrode stimulation represented by high-precision TES and temporal interference stimulation. This paper reviews the stimulation optimization schemes of TES in recent years and further analyzes the characteristics and limitations of existing stimulation methods, aiming to provide a reference for related clinical applications and guide the following research on TES. In addition, this paper proposes the viewpoint of the development direction of TES, especially the direction of optimizing TES for deep brain stimulation, aiming to provide new ideas for subsequent research and application.

A novel tDCS control condition using optimized anesthetic gel to block peripheral nerve input.

Background: Recent studies indicate that some transcranial direct current stimulation (tDCS) effects may be caused by indirect stimulation of peripheral nerves in the scalp rather than the electric field in the brain. To address this, we developed a novel tDCS control condition in which peripheral input is blocked using topical anesthetics. We developed a compounded anesthetic gel containing benzocaine and lidocaine (BL10) that blocks peripheral input during tDCS. Methods: In a blinded randomized cross-over study of 18 healthy volunteers (M/F), we compared the gel's efficacy to EMLA and an inert placebo gel. Subjects used a visual analog scale (VAS) to rate the stimulation sensation in the scalp produced by 10 s of 2 mA tDCS every 2 min during 1 h. In an additional in-vitro experiment, the effect of a DC current on gel resistivity and temperature was investigated. Results: Both the BL10 and EMLA gel, lowered the stimulation sensations compared to the placebo gel. The BL10 gel showed a tendency to work faster than the EMLA gel with reported sensations for the BL10 gel being lower than for EMLA for the first 30 min. The DC current caused a drastic increase in gel resistivity for the EMLA gel, while it did not affect gel resistivity for the BL10 and placebo gel, nor did it affect gel temperature. Conclusions: Topical anesthetics reduce stimulation sensations by blocking peripheral nerve input during tDCS. The BL10 gel tends to work faster and is more electrically stable than EMLA gel. Clinical trial registration: The study is registered at ClinicalTrials.gov with name "Understanding the Neural Mechanisms Behind tDCS" and number NCT04577677.

Dataset of middle cerebral artery blood flow stability in response to high-definition transcranial electrical stimulation.

This supplementary dataset is supportive of the randomized sham-controlled, double-blind, crossover clinical trial investigating polarity- and intensity-dependent effects of high-definition transcranial electrical stimulation (HD-tDCS) applied over the right temporo-parietal junction on mean middle cerebral artery blood flow velocity (MCA-BFv) bilaterally. Data of eleven healthy right-handed adults (6 women, 5 men; mean age 31 ± 5.6 years old) were analyzed for MCA-BFv, assessed using transcranial doppler ultrasound on the stimulated and the contralateral hemisphere concomitantly, during and after 3 blocks of 2 min HD-tDCS at 1, 2, and 3 mA. Participants received three electrical stimulation conditions (anode center, cathode center, and sham) randomly ordered across different days. The collected data is publicly available at Mendeley Data. This article and the data will inform future related investigations and safety analysis of transcranial non-invasive brain stimulation.

Electric Fields Induced in the Brain by Transcranial Electric Stimulation: A Review of In Vivo Recordings.

Transcranial electrical stimulation (tES) techniques, such as direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), cause neurophysiological and behavioral modifications as responses to the electric field are induced in the brain. Estimations of such electric fields are based mainly on computational studies, and in vivo measurements have been used to expand the current knowledge. Here, we review the current tDCS- and tACS-induced electric fields estimations as they are recorded in humans and non-human primates using intracerebral electrodes. Direct currents and alternating currents were applied with heterogeneous protocols, and the recording procedures were characterized by a tentative methodology. However, for the clinical stimulation protocols, an injected current seems to reach the brain, even at deep structures. The stimulation parameters (e.g., intensity, frequency and phase), the electrodes' positions and personal anatomy determine whether the intensities might be high enough to affect both neuronal and non-neuronal cell activity, also deep brain structures.

Can Transcranial Electrical Stimulation Facilitate Post-stroke Cognitive Rehabilitation? A Systematic Review and Meta-Analysis.

Background: Non-invasive brain stimulation methods have been widely utilized in research settings to manipulate and understand the functioning of the human brain. In the last two decades, transcranial electrical stimulation (tES) has opened new doors for treating impairments caused by various neurological disorders. However, tES studies have shown inconsistent results in post-stroke cognitive rehabilitation, and there is no consensus on the effectiveness of tES devices in improving cognitive skills after the onset of stroke. Objectives: We aim to systematically investigate the efficacy of tES in improving post-stroke global cognition, attention, working memory, executive functions, visual neglect, and verbal fluency. Furthermore, we aim to provide a pathway to an effective use of stimulation paradigms in future studies. Methods: Preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were followed. Randomized controlled trials (RCTs) were systematically searched in four different databases, including Medline, Embase, Pubmed, and PsychInfo. Studies utilizing any tES methods published in English were considered for inclusion. Standardized mean difference (SMD) for each cognitive domain was used as the primary outcome measure. Results: The meta-analysis includes 19 studies assessing at least one of the six cognitive domains. Five RCTs studying global cognition, three assessing visual neglect, five evaluating working memory, three assessing attention, and nine studies focusing on aphasia were included for meta-analysis. As informed by the quantitative analysis of the included studies, the results favor the efficacy of tES in acute improvement in aphasic deficits (SMD = 0.34, CI = 0.02-0.67, p = 0.04) and attention deficits (SMD = 0.59, CI = -0.05-1.22, p = 0.07), however, no improvement was observed in any other cognitive domains. Conclusion: The results favor the efficacy of tES in an improvement in aphasia and attentive deficits in stroke patients in acute, subacute, and chronic stages. However, the outcome of tES cannot be generalized across cognitive domains. The difference in the stimulation montages and parameters, diverse cognitive batteries, and variable number of training sessions may have contributed to the inconsistency in the outcome. We suggest that in future studies, experimental designs should be further refined, and standardized stimulation protocols should be utilized to better understand the therapeutic effect of stimulation.