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Transcranial direct current stimulation (tDCS) over prefrontal cortex (PFC) regions is currently proposed as therapeutic intervention for major depression and other psychiatric disorders. The in-depth mechanistic understanding of this bipolar and non-focal stimulation technique is still incomplete. In a pilot study, we investigated the effects of bifrontal stimulation on brain metabolite levels and resting state connectivity under the cathode using multiparametric MRI techniques and computational tDCS modeling. Within a double-blind cross-over design, 20 subjects (12 women, 23.7 ± 2 years) were randomized to active tDCS with standard bifrontal montage with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC. Magnetic resonance spectroscopy (MRS) was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma aminobutyric acid (GABA) concentration in these areas. Resting-state functional connectivity MRI (rsfcMRI) was acquired before and after the stimulation. The individual distribution of tDCS induced electric fields (efields) within the MRS voxel was computationally modelled using SimNIBS 2.0. There were no significant changes of Glu, Glx and GABA levels across conditions but marked differences in the course of Glu levels between female and male participants were observed. Further investigation yielded a significantly stronger Glu reduction after active compared to sham stimulation in female participants, but not in male participants. For rsfcMRI neither significant changes nor correlations with MRS data were observed. Exploratory analyses of the effect of efield intensity distribution on Glu changes showed distinct effects in different efield groups. Our findings are limited by the small sample size, but correspond to previously published results of cathodal tDCS. Future studies should address gender and efield intensity as moderators of tDCS induced effects.

Transcranial Current Stimulations (tCSs) are non-invasive brain stimulation techniques which modulate cortical excitability and spontaneous brain activity by the application of weak electric currents through the scalp, in a safe, economic, and well-tolerated manner. The direction of the cortical effects mainly depend on the polarity and the waveform of the applied current. The aim of the present work is to provide a broad overview of recent studies in which tCS has been applied to modulate sleepiness, sleep, and vigilance, evaluating the efficacy of different stimulation techniques and protocols. In recent years, there has been renewed interest in these stimulations and their ability to affect arousal and sleep dynamics. Furthermore, we critically review works that, by means of stimulating sleep/vigilance patterns, in the sense of enhancing or disrupting them, intended to ameliorate several clinical conditions. The examined literature shows the efficacy of tCSs in modulating sleep and arousal pattern, likely acting on the top-down pathway of sleep regulation. Finally, we discuss the potential application in clinical settings of this neuromodulatory technique as a therapeutic tool for pathological conditions characterized by alterations in sleep and arousal domains and for sleep disorders per se.

The brain has the innate ability to undergo neuronal plasticity, which refers to changes in its structure and functions in response to continued changes in the environment. Although these concepts are well established in animal slice preparation models, their application to a large number of human subjects could only be achieved using noninvasive brain stimulation (NIBS) techniques. In this review, we discuss the mechanisms of plasticity induction using NIBS techniques including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation (RNS), transcranial ultrasound stimulation (TUS), vagus nerve stimulation (VNS), and galvanic vestibular stimulation (GVS). We briefly introduce these techniques, explain the stimulation parameters and potential clinical implications. Although their mechanisms are different, all these NIBS techniques can be used to induce plasticity at the systems level, to examine the neurophysiology of brain circuits and have potential therapeutic use in psychiatric and neurological disorders. TMS is the most established technique for the treatment of brain disorders, and repetitive TMS is an approved treatment for medication-resistant depression. Although the data on the clinical utility of the other modes of stimulation are more limited, the electrical stimulation techniques (tDCS, tACS, RNS, VNS, GVS) have the advantage of lower cost, portability, applicability at home, and can readily be combined with training or rehabilitation. Further research is needed to expand the clinical utility of NIBS and test the combination of different modes of NIBS to optimize neuromodulation induced clinical benefits.

Transcranial Direct Current Stimulation (tDCS) is investigated for a broad range of neuropsychiatric indications, various rehabilitation applications, and to modulate cognitive performance in diverse tasks. Specificity of tDCS refers broadly to the ability of tDCS to produce precise, as opposed to diffuse, changes in brain function. Practically, specificity of tDCS implies application-specific customization of protocols to maximize desired outcomes and minimize undesired effects. Especially given the simplicity of tDCS and the complexity of brain function, understanding the mechanisms leading to specificity is fundamental to the rational advancement of tDCS. We define the origins of specificity based on anatomical and functional factors. Anatomical specificity derives from guiding current to targeted brain structures. Functional specificity may derive from either activity-selectivity, where active neuronal networks are preferentially modulated by tDCS, or input-selectivity, where bias is applied to different synaptic inputs. Rational advancement of tDCS may require leveraging all forms of specificity.

Transcranial direct current stimulation (tDCS) uses a weak electric current to modulate neuronal activity. A neurophysiologic outcome measure to demonstrate reliable tDCS modulation at the group level is transcranial magnetic stimulation engendered motor evoked potentials (MEPs). Here, we conduct a study testing the reliability of individual MEP response patterns following a common tDCS protocol. Fourteen participants (7m/7f) each underwent nine randomized sessions of 1 mA, 10 min tDCS (3 anode; 3 cathode; 3 sham) delivered using an M1/orbito-frontal electrode montage (sessions separated by an average of ~5.5 days). Fifteen MEPs were obtained prior to, immediately following and in 5 min intervals for 30 min following tDCS. TMS was delivered at 130 % resting motor threshold using neuronavigation to ensure consistent coil localization. A number of non-experimental variables were collected during each session. At the individual level, considerable variability was seen among different testing sessions. No participant demonstrated an excitatory response ≥20 % to all three anodal sessions, and no participant demonstrated an inhibitory response ≥20 % to all three cathodal sessions. Intra-class correlation revealed poor anodal and cathodal test–retest reliability [anode: ICC (2,1)  = 0.062; cathode: ICC (2,1)  = 0.055] and moderate sham test–retest reliability [ICC (2,1)  = 0.433]. Results also revealed no significant effect of tDCS at the group level. Using this common protocol, we found the effects of tDCS on MEP amplitudes to be highly variable at the individual level. In addition, no significant effects of tDCS on MEP amplitude were found at the group level. Future studies should consider utilizing a more strict experimental protocol to potentially account for intra-individual response variations.

Psychiatric disorders lead to disability, premature mortality and economic burden, highlighting the urgent need for more effective treatments. The understanding of psychiatric disorders as conditions of large-scale brain networks has created new opportunities for developing targeted, personalised, and mechanism-based therapeutic interventions. Non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can directly modulate dysfunctional neural networks, enabling treatments tailored to the individual’s unique functional network patterns. As NIBS techniques depend on our understanding of the neural networks involved in psychiatric disorders, this review offers a neural network-informed perspective on their applications. We focus on key disorders, including depression, schizophrenia, and obsessive-compulsive disorder, and examine the role of NIBS on cognitive impairment, a transdiagnostic feature that does not respond to conventional treatments. We discuss the advancements in identifying NIBS response biomarkers with the use of electrophysiology and neuroimaging, which can inform the development of optimised, mechanism-based, personalised NIBS treatment protocols. We address key challenges, including the need for more precise, individualised targeting of dysfunctional networks through integration of neurophysiological, neuroimaging and genetic data and the use of emerging techniques, such as low- intensity focused ultrasound, which has the potential to improve spatial precision and target access. We finally explore future directions to improve treatment protocols and promote widespread clinical use of NIBS as a safe, effective and patient-centred treatment for psychiatric disorders.

•This combined systematic review and modeling study identified 308 studies reporting tES or TMS E-Field values.•The effect of outcome measures on tES and TMS modeling results was quantified via over 1000,000 measurements.•Outcome measure choices critically affect the obtained E-field value and analyzed brain region.•Between-measure differences are E-field component-, person-, modality, and region specific.•We present four recommendations to enhance the quality, consistency, and rigor of E-field outcome reporting. Electric field (E-field) modeling is a potent tool to estimate the amount of transcranial magnetic and electrical stimulation (TMS and tES, respectively) that reaches the cortex and to address the variable behavioral effects observed in the field. However, outcome measures used to quantify E-fields vary considerably and a thorough comparison is missing. This two-part study aimed to examine the different outcome measures used to report on tES and TMS induced E-fields, including volume- and surface-level gray matter, region of interest (ROI), whole brain, geometrical, structural, and percentile-based approaches. The study aimed to guide future research in informed selection of appropriate outcome measures. Three electronic databases were searched for tES and/or TMS studies quantifying E-fields. The identified outcome measures were compared across volume- and surface-level E-field data in ten tES and TMS modalities targeting two common targets in 100 healthy individuals. In the systematic review, we extracted 308 outcome measures from 202 studies that adopted either a gray matter volume-level (n = 197) or surface-level (n = 111) approach. Volume-level results focused on E-field magnitude, while surface-level data encompassed E-field magnitude (n = 64) and normal/tangential E-field components (n = 47). E-fields were extracted in ROIs, such as brain structures and shapes (spheres, hexahedra and cylinders), or the whole brain. Percentiles or mean values were mostly used to quantify E-fields. Our modeling study, which involved 1,000 E-field models and > 1,000,000 extracted E-field values, revealed that different outcome measures yielded distinct E-field values, analyzed different brain regions, and did not always exhibit strong correlations in the same within-subject E-field model. Outcome measure selection significantly impacts the locations and intensities of extracted E-field data in both tES and TMS E-field models. The suitability of different outcome measures depends on the target region, TMS/tES modality, individual anatomy, the analyzed E-field component and the research question. To enhance the quality, rigor, and reproducibility in the E-field modeling domain, we suggest standard reporting practices across studies and provide four recommendations.

One of the major questions in high-density transcranial electrical stimulation (TES) is: given a region of interest (ROI) and electric current limits for safety, how much current should be delivered by each electrode for optimal targeting of the ROI? Several solutions, apparently unrelated, have been independently proposed depending on how “optimality” is defined and on how this optimization problem is stated mathematically. The least squares (LS), weighted LS (WLS), or reciprocity-based approaches are the simplest ones and have closed-form solutions. An extended optimization problem can be stated as follows: maximize the directional intensity at the ROI, limit the electric fields at the non-ROI, and constrain total injected current and current per electrode for safety. This problem requires iterative convex or linear optimization solvers. We theoretically prove in this work that the LS, WLS and reciprocity-based closed-form solutions are specific solutions to the extended directional maximization optimization problem. Moreover, the LS/WLS and reciprocity-based solutions are the two extreme cases of the intensity-focality trade-off, emerging under variation of a unique parameter of the extended directional maximization problem, the imposed constraint to the electric fields at the non-ROI. We validate and illustrate these findings with simulations on an atlas head model. The unified approach we present here allows a better understanding of the nature of the TES optimization problem and helps in the development of advanced and more effective targeting strategies. [Display omitted] •Most optimization approaches used in TES/tDCS are linked together.•We analytically link LS/WLS and constrained directional maximization methods.•We analytically link reciprocity and constrained directional maximization methods.•LS/WLS and reciprocity are two opposite solutions of the same optimization problem.

Transcranial electric stimulation (tES) is a promising tool to non-invasively manipulate neuronal activity in the human brain. Several studies have shown behavioral effects of tES, but stimulation artifacts complicate the simultaneous investigation of neural activity with EEG or MEG. Here, we first show for EEG and MEG, that contrary to previous assumptions, artifacts do not simply reflect stimulation currents, but that heartbeat and respiration non-linearly modulate stimulation artifacts. These modulations occur irrespective of the stimulation frequency, i.e. during both transcranial alternating and direct current stimulations (tACS and tDCS). Second, we show that, although at first sight previously employed artifact rejection methods may seem to remove artifacts, data are still contaminated by non-linear stimulation artifacts. Because of their complex nature and dependence on the subjects' physiological state, these artifacts are prone to be mistaken as neural entrainment. In sum, our results uncover non-linear tES artifacts, show that current techniques fail to fully remove them, and pave the way for new artifact rejection methods. •Systematic characterization of tES artifacts on simultaneously recorded EEG and MEG.•tES artifacts are non-linearly modulated by heartbeat and respiration for EEG and MEG.•Current artifact rejection methods fail to fully remove tES artifacts.

In vivo effects of transcranial direct current stimulation (tDCS) have attracted much attention nowadays as this area of research spreads to both the motor and cognitive domains. The common assumption is that the anode electrode causes an enhancement of cortical excitability during stimulation, which then lasts for a few minutes thereafter, while the cathode electrode generates the opposite effect, i.e., anodal-excitation and cathodal-inhibition effects (AeCi). Yet, this dual-polarity effect has not been observed in all tDCS studies. Here, we conducted a meta-analytical review aimed to investigate the homogeneity/heterogeneity of the effect sizes of the AeCi dichotomy in both motor and cognitive functions. The AeCi effect was found to occur quite commonly with motor investigations and rarely in cognitive studies. When the anode electrode is applied over a non-motor area, in most cases, it will cause an excitation as measured by a relevant cognitive or perceptual task; however, the cathode electrode rarely causes an inhibition. We found homogeneity in motor studies and heterogeneity in cognitive studies with the electrode’s polarity serving as a moderator that can explain the source of heterogeneity in cognitive studies. The lack of inhibitory cathodal effects might reflect compensation processes as cognitive functions are typically supported by rich brain networks. Further insights as to the polarity and domain interaction are offered, including subdivision to different classes of cognitive functions according to their likelihood of being affected by stimulation.