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Background: Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation method that can modulate many brain functions including learning and memory. Recent evidence suggests that tDCS memory effects may be caused by co-stimulation of scalp nerves such as the trigeminal nerve (TN), and not the electric field in the brain. The TN gives input to brainstem nuclei, including the locus coeruleus that controls noradrenaline release across brain regions, including hippocampus. However, the effects of TN direct current stimulation (TN-DCS) are currently not well understood. Hypothesis: In this study we tested the hypothesis that stimulation of the trigeminal nerve with direct current manipulates hippocampal activity via an LC pathway. Methods: We recorded neural activity in rat hippocampus using multichannel silicon probes. We applied 3 min of 0.25 mA or 1 mA TN-DCS, monitored hippocampal activity for up to 1 h and calculated spikes-rate and spike-field coherence metrics. Subcutaneous injections of xylocaine were used to block TN, while intraperitoneal and intracerebral injection of clonidine were used to block the LC pathway. Results: We found that 1 mA TN-DCS caused a significant increase in hippocampal spike-rate lasting 45 min in addition to significant changes in spike-field coherence, while 0.25 mA TN-DCS did not. TN blockage prevented spike-rate increases, confirming effects were not caused by the electric field in the brain. When 1 mA TN-DCS was delivered during clonidine blockage no increase in spike-rate was observed, suggesting an important role for the LC-noradrenergic pathway. Conclusion: These results support our hypothesis and provide a neural basis to understand the tDCS TN co-stimulation mechanism. TN-DCS emerges as an important tool to potentially modulate learning and memory.

Background: Pharmacological interventions for depression and anxiety in older adults often have significant side effects, presenting the need for more tolerable alternatives. Transcranial direct current stimulation (tDCS) is a promising non-pharmacological intervention for depression in clinical populations. However, its effects on depression and anxiety symptoms, particularly in older adults from the general public, are understudied. Objective: We conducted a secondary analysis of the Augmenting Cognitive Training in Older Adults (ACT) trial to assess tDCS efficacy in reducing psychological symptoms in older adults. We hypothesized that active stimulation would yield greater reductions in depression and state anxiety compared to sham post-intervention and at the one-year follow-up. We also explored tDCS effects in subgroups characterized by baseline symptom severity. Methods: A sample of 378 older adults recruited from the community completed a 12-week tDCS intervention with cognitive or education training. Electrodes were placed at F3/F4, and participants received active or sham tDCS during training sessions. We assessed the association between tDCS group and changes in depression, state anxiety, and trait anxiety from baseline to post-intervention and one-year controlling for covariates. Results: The active tDCS group demonstrated greater reductions in depression and state anxiety compared to sham post-intervention, particularly in individuals with mild depression and moderate/severe state anxiety at baseline. Furthermore, the active tDCS group with moderate/severe state anxiety maintained greater symptom reductions at one-year. Conclusions: tDCS effectively reduced depression and state anxiety symptoms in a large sample of older adults. These findings highlight the importance of considering symptom severity when identifying those who may benefit most from this intervention.

Objective: To observe the effects of combining targeted language training with transcranial direct current stimulation (tDCS) on speech rehabilitation in senile stroke patients with Wernicke's aphasia in the sequelae stage. Methods: A patient with Wernicke's aphasia caused by stroke, 15 months prior, was successively treated with regimen A (targeted language training), regimen B (L-Wernicke area tDCS + targeted language training), and regimen C (R-Wernicke area tDCS + targeted language training) for a total of 3 weeks, with a 2-day washout period between each regimen. The accuracy of spontaneous speech, auditory word-picture matching, visual word-picture matching, retelling, graph-reading writing, and graph-reading naming items was evaluated and compared before treatment and 3 weeks after treatment with regimens A, B, and C. Results: After 3 weeks of the regimen A treatment, there was no significant improvement in each evaluation item. After 3 weeks of treatment with regimen B, the patient's spontaneous speech slightly improved, but the expression remained meaningless. Visual word-graph matching was slightly improved, but auditory word-graph matching was not. After 3 weeks of treatment with regimen C, the spontaneous speech of the patient's increased significantly, and the correct rates of auditory word-graph matching, visual word-graph matching, retelling, and picture reading and writing were significantly improved compared with those before treatment and after 3 weeks of treatment with regimens A and B (P < 0.05). Conclusions: Targeted language training combined with tDCS stimulation of the non-dominant Wernicke's area can improve spontaneous speech, auditory word-picture matching, visual word-picture matching, retelling, and picture reading and writing ability in elderly patients with Wernicke's aphasia after stroke, thus promoting speech rehabilitation.

Background: Transcranial direct current stimulation (tDCS), via an electrical current being sent through the brains motor cortex, can elicit pain reduction and improved function in people with knee osteoarthritis (OA), compared to a sham. However, it is unknown whether tDCS-induced reductions in pain can be expected in hip OA given differences between hip and knee OA phenotypes. Methods: Two-armed (n ​= ​39 per arm), triple-blind, randomised controlled trial, with an 8-week intervention window and 8-week post-intervention follow-up assessing the efficacy of real anodal tDCS plus exercise versus sham tDCS plus exercise. Primary outcome measure is the International Hip Outcome Tool–33 (iHOT-33). Aims: The primary objective of this randomised controlled trial is to quantify the effect of tDCS and exercise on pain, disability and quality of life in people with hip OA. Our secondary objectives include: 1) quantifying the influence of motor cortex excitability and conditioned pain modulation on treatment effects, and 2) quantifying the economic cost/benefit of tDCS for improving health-related quality of life in people with hip OA. Analysis: Data distributions will be examined for each outcome and guide preliminary statistical between group test selections. Repeated mixed effects models will determine between-group differences for the primary outcome (iHOT-33), accounting for relevant confounders (i.e., age; sex; body mass index; radiographic severity) with relevant model assumptions examined. Secondary analysis will determine between-group differences for the other outcomes of interest (cortex excitability and conditioned pain modulation). Implications: This randomised controlled trial investigates a novel intervention to improve pain, function and quality of life in people with hip OA.

Background: Transcranial direct current stimulation (tDCS) is a frequently used brain stimulation method; however, studies on tactile perception using tDCS are inconsistent, which might be explained by the variations in endogenous and exogenous parameters that influence tDCS. Objectives: We aimed to investigate the effect of one of these endogenous parameters—the tDCS amplitude—on tactile perception. Methods: We conducted this experiment on 28 undergraduates/graduates aged 18–36 years. In separate sessions, participants received 20 min of 1 mA or 1.5 mA current tDCS in a counterbalanced order. Half of the participants received anodal tDCS of the left SI coupled with cathodal tDCS of the right SI, and this montage was reversed for the other half. Pre- and post-tDCS tactile discrimination performance was assessed using the Grating Orientation Task (GOT). In this task, plastic domes with gratings of different widths cut into their surfaces are placed on the fingertip, and participants have to rate the orientation of the gratings. Results: Linear modeling with amplitude, dome, and session as within factors and montage as between factors revealed the following: significant main effects of grating width, montage, and session and a marginally significant interaction effect of session and amplitude. Posthoc t-tests indicated that performance in GOT improved after 1 mA but not 1.5 mA tDCS independent of the montage pattern of the electrodes. Conclusion: Increasing the stimulation amplitude from 1 mA to 1.5 mA does not facilitate the tDCS effect on GOT performance. On the contrary, the effect seemed more robust for the lower-current amplitude.

Background: Few treatment options are available for targeting core symptoms of autism spectrum disorder (ASD). The development of treatments that target common neural circuit dysfunctions caused by known genetic defects, namely, disruption of the excitation/inhibition (E/I) balance, is promising. Transcranial direct current stimulation (tDCS) is capable of modulating the E/I balance in healthy individuals, yet its clinical and neurobiological effects in ASD remain elusive. Objective: This double-blind, randomized, sham-controlled trial investigated the effects of multisession cathodal prefrontal tDCS coupled with online cognitive remediation on social functioning, information processing efficiency and the E/I balance in ASD patients aged 14–21 years. Methods: Sixty individuals were randomly assigned to receive either active or sham tDCS (10 sessions in total, 20 min/session, stimulation intensity: 1.5 mA, cathode: F3, anode: Fp2, size of electrodes: 25 cm2) combined with 20 min of online cognitive remediation. Social functioning, information processing efficiency during cognitive tasks, and theta- and gamma-band E/I balance were measured one day before and after the treatment. Results: Compared to sham tDCS, active cathodal tDCS was effective in enhancing overall social functioning [F(1, 58) = 6.79, p = .012, ηp2 = 0.105, 90% CI: (0.013, 0.234)] and information processing efficiency during cognitive tasks [F(1, 58) = 10.07, p = .002, ηp2 = 0.148, 90% CI: (0.034, 0.284)] in these individuals. Electroencephalography data showed that this cathodal tDCS protocol was effective in reducing the theta-band E/I ratio of the cortical midline structures [F(1, 58) = 4.65, p = .035, ηp2 = 0.074, 90% CI: (0.010, 0.150)] and that this reduction significantly predicted information processing efficiency enhancement (b = −2.546, 95% BCa CI: [-4.979, −0.113], p = .041). Conclusion: Our results support the use of multisession cathodal tDCS over the left dorsolateral prefrontal cortex combined with online cognitive remediation for reducing the elevated theta-band E/I ratio in sociocognitive information processing circuits in ASD patients, resulting in more adaptive regulation of global brain dynamics that is associated with enhanced information processing efficiency after the intervention.

Background: Despite evidence regarding the benefits of transcranial direct current stimulation (tDCS) in patients with severe traumatic brain injury, few trials have examined the treatment safety. Therefore, we created a phase I trial in Japan to investigate the safety of tDCS after severe brain injury. Methods: We verified the safety of tDCS through constant left frontal anodal stimulation at 2 mA for 20 min for 5 consecutive days. Additionally, we added a variable stimuli period to explore the effects of stimulus intensity, location, and duration. We adapted a traditional 3 + 3 study design. We assessed the rate of adverse effects, including skin burns and clinical seizure. Changes in neurological symptoms were evaluated using the Glasgow Coma Scale, Coma Recovery Scale-Revised, and 4 states of consciousness (coma, unresponsive wakefulness syndrome, minimally conscious state, and severe disability). Results: Six patients completed the study. No obvious adverse events were observed during the constant stimulation period or the variable stimulation period (right frontal anodal stimulation, stimulation frequency 2–4 mA, 1 or 5 times per week for a period of 4 weeks). Regarding the Coma Recovery Scale-Revised, patients in 4 out of 6 instances (66.7 %) improved by more than 1 point. Conclusion: Our phase I safety study indicated that a single course of tDCS was safe in patients with severe traumatic brain injury. The next step is a phase II trial to investigate the preliminary efficacy and safety of tDCS at 2 mA (in comparison with sham stimulation).

Right hemisphere stroke patients frequently present with a combination of lateralised and non-lateralised attentional deficits characteristic of the neglect syndrome. Attentional deficits are associated with poor functional outcome and are challenging to treat, with non-lateralised deficits often persisting into the chronic stage and representing a common complaint among patients and families.In this study, we investigated the effects of non-invasive brain stimulation on non-lateralised attentional deficits in right-hemispheric stroke. In a randomised double-blind sham-controlled crossover study, twenty-two patients received real and sham transcranial Direct Current Stimulation (tDCS) whilst performing a non-lateralised attentional task. A high definition tDCS montage guided by stimulation modelling was employed to maximise current delivery over the right dorsolateral prefrontal cortex, a key node in the vigilance network. In a parallel study, we examined brain network response to this tDCS montage by carrying out concurrent fMRI during stimulation in healthy participants and patients.At the group level, stimulation improved target detection in patients, reducing overall error rate when compared with sham stimulation. TDCS boosted performance throughout the duration of the task, with its effects briefly outlasting stimulation cessation. Exploratory lesion analysis indicated that response to stimulation was related to lesion location rather than volume. In particular, reduced stimulation response was associated with damage to the thalamus and postcentral gyrus. Concurrent stimulation-fMRI revealed that tDCS did not affect local connectivity but influenced functional connectivity within large-scale networks in the contralesional hemisphere.This combined behavioural and functional imaging approach shows that brain stimulation targeted to surviving tissue in the ipsilesional hemisphere improves non-lateralised attentional deficits following stroke. This effect may be exerted via contralesional network effects.

Background: Converging evidence points to impairments of the predictive function exerted by the cerebellum as one of the causes of the social cognition deficits observed in patients with cerebellar disorders. Objective: We tested the neurorestorative effects of cerebellar transcranial direct current stimulation (ctDCS) on the use of contextual expectations to interpret actions occurring in ambiguous sensory sceneries in a sample of adolescents and young adults with congenital, non-progressive cerebellar malformation (CM). Methods: We administered an action prediction task in which, in an implicit-learning phase, the probability of co-occurrence between actions and contextual elements was manipulated to form either strongly or moderately informative expectations. Subsequently, in a testing phase, we probed the use of these contextual expectations for predicting ambiguous (i.e., temporally occluded) actions. In a sham-controlled, within-subject design, participants received anodic or sham ctDCS during the task. Results: Anodic ctDCS, compared to sham, improved patients’ ability to use contextual expectations to predict the unfolding of actions embedded in moderately, but not strongly, informative contexts. Conclusions: These findings corroborate the role of the cerebellum in using previously learned contextual associations to predict social events and document the efficacy of ctDCS to boost social prediction in patients with congenital cerebellar malformation. The study encourages the further exploration of ctDCS as a neurorestorative tool for the neurorehabilitation of social cognition abilities in neurological, neuropsychiatric, and neurodevelopmental disorders featured by macro- or micro-structural alterations of the cerebellum.

Drug use causes significant social and financial problems and these are exacerbated by difficulties in stopping use and subsequent maintenance of abstinence. There is also difficulty in identifying the beneficial treatment for an individual, made more problematic given the high drop-out rates in treatment programs. Here, the effects of transcranial direct current stimulation (tDCS) on the amplitude of the P300 event-related potential component, previously suggested to be indicative of successful remission, was measured in recently abstinent amphetamine users. This component was collected during a Posner cuing task which was presented to this group and to control (non-user) participants, using task cues of neutral and drug-related images. The abstinent drug users were divided into two groups, one of which received tDCS daily for five days, with the cathode over the left dorsolateral prefrontal cortex (DLPFC) and the anode over the right DLPFC, and one receiving sham stimulation over the same time period. Behavioral performance and P300 amplitudes were measured before and after the period of tDCS delivery. Control participants were tested with the same time-schedule of task presentation but without administration of tDCS. Drug users initially showed a larger cost of invalid cues on task performance compared to control (non-drug user) participants and this was reduced following delivery of tDCS. Additionally, tDCS resulted in increased amplitude of the P300 component, significantly so for neutral cues, with the resulting pattern being more similar to that of the non-users. This provides a good basis for further investigation of both the utility of tDCS in modulation of cognition in addict groups, and to investigate the effects of modulating the P300 component on remission rates, a relationship that seems to be the case for this measure without use of tDCS modulation. Importantly, this study also provides a further addiction group showing P300 amplitude modulation as a result of tDCS administration.

Background: There is a need for effective interventions to stave off cognitive decline in older adults. Cognitive training has variably produced gains in untrained tasks and daily functioning. Combining cognitive training with transcranial direct current stimulation (tDCS) may augment cognitive training effects; however, this approach has yet to be tested on a large-scale. Objective: This paper will present the primary findings of the Augmenting Cognitive Training in Older Adults (ACT) clinical trial. We hypothesize that receiving active stimulation with cognitive training will result in greater improvements on an untrained fluid cognition composite compared to sham following intervention. Methods: 379 older adults were randomized, and 334 were included in intent-to-treat analyses for a 12-week multidomain cognitive training and tDCS intervention. Active or sham tDCS was administered at F3/F4 during cognitive training daily for two weeks then weekly for 10 weeks. To assess the tDCS effect, we fitted regression models for changes in NIH Toolbox Fluid Cognition Composite scores immediately following intervention and one year from baseline controlling for covariates and baseline scores. Results: Across the entire sample, there were improvements in NIH Toolbox Fluid Cognition Composite scores immediately post-intervention and one year following baseline; however, there were no significant tDCS group effects at either timepoint. Conclusions: The ACT study models rigorous, safe administration of a combined tDCS and cognitive training intervention in a large sample of older adults. Despite potential evidence of near-transfer effects, we failed to demonstrate an additive benefit of active stimulation. Future analyses will continue to assess the intervention's efficacy by examining additional measures of cognition, functioning, mood, and neural markers.

Racial and ethnic disparities exist for many nervous system disorders that are intervention targets for neuromodulation investigators. Yet, to date, there has been both a lack of racial and ethnic diversity and a lack of emphasis on diversity in neuromodulation research. In this paper, we suggest three potential reasons for the lack of racial and ethnic diversity in neuromodulation research: 1) the lack of diversity in the neuromodulation workforce, 2) incompatibility between the technologies employed and phenotypic traits (e.g., hair texture) commonly present in minoritized populations, and 3) minoritized populations’ reluctance to participate in clinical trials. We argue that increasing diversity in the neuromodulation workforce, in conjunction with mutual collaboration between current neuromodulation researchers and underrepresented communities in neuromodulation, can aid in removing barriers to diversity, equity, and inclusion in neuromodulation research. This is important, because greater diversity, equity, and inclusion in neuromodulation research brings with it the development of novel, yet safe and effective, treatment approaches for brain disorders and enhances the rigor and generalizability of discoveries in the field.

The extensive use of transcranial direct current stimulation (tDCS) in experimental and clinical settings does not correspond to an in-depth understanding of its underlying neurophysiological mechanisms. In previous studies, we employed an integrated system of Transcranial Magnetic Stimulation and Electroencephalography (TMS-EEG) to track the effect of tDCS on cortical excitability. At rest, anodal tDCS (a-tDCS) over the right Posterior Parietal Cortex (rPPC) elicits a widespread increase in cortical excitability. In contrast, cathodal tDCS (c-tDCS) fails to modulate cortical excitability, being indistinguishable from sham stimulation.Here we investigated whether an endogenous task-induced activation during stimulation might change this pattern, improving c-tDCS effectiveness in modulating cortical excitability.In Experiment 1, we tested whether performance in a Visuospatial Working Memory Task (VWMT) and a modified Posner Cueing Task (mPCT), involving rPPC, could be modulated by c-tDCS. Thirty-eight participants were involved in a two-session experiment receiving either c-tDCS or sham during tasks execution. In Experiment 2, we recruited sixteen novel participants who performed the same paradigm but underwent TMS-EEG recordings pre- and 10 min post- sham stimulation and c-tDCS.Behavioral results showed that c-tDCS significantly modulated mPCT performance compared to sham. At a neurophysiological level, c-tDCS significantly reduced cortical excitability in a frontoparietal network likely involved in task execution. Taken together, our results provide evidence of the state dependence of c-tDCS in modulating cortical excitability effectively. The conceptual and applicative implications are discussed.

Background: HD-tDCS is capable to increase the focality of neuromodulation and has been recently applied to improve endurance performance in healthy subjects. Objective/hypothesis: Whether these putative advantages could be exploited in active subjects with type 1 diabetes mellitus (T1D) remains questionable. Methods: In a double-blind, randomized crossover order, 11 high-level cyclists (27 ± 4.3 years; weight: 65.5 ± 8.6 kg; height: 180 ± 8 cm; VO2peak: 67.5 ± 2.9 mL min−1 kg−1) with T1D underwent either HD-tDCS (F3, F4) or control (SHAM) and completed a constant-load trial (CLT) at 75% of the 2nd ventilatory threshold plus a 15-km cycling time-trial (TT). Results: After HD-tDCS, the total time to cover the TT was 3.8% faster (P

Background and objective: Transcranial direct current stimulation (tDCS) has wide ranging applications in neuro-behavioural and physiological research, and in neurological rehabilitation. However, it is currently limited by substantial inter-subject variability in responses, which may be explained, at least in part, by anatomical differences that lead to variability in the electric field (E-field) induced in the cortex. Here, we tested whether the variability in the E-field in the stimulated cortex during anodal tDCS, estimated using computational simulations, explains the variability in tDCS induced changes in GABA, a neurophysiological marker of stimulation effect. Methods: Data from five previously conducted MRS studies were combined. The anode was placed over the left primary motor cortex (M1, 3 studies, N = 24) or right temporal cortex (2 studies, N = 32), with the cathode over the contralateral supraorbital ridge. Single voxel spectroscopy was performed in a 2x2x2cm voxel under the anode in all cases. MRS data were acquired before and either during or after 1 mA tDCS using either a sLASER sequence (7T) or a MEGA-PRESS sequence (3T). sLASER MRS data were analysed using LCModel, and MEGA-PRESS using FID-A and Gannet. E-fields were simulated in a finite element model of the head, based on individual structural MR images, using SimNIBS. Separate linear mixed effects models were run for each E-field variable (mean and 95th percentile; magnitude, and components normal and tangential to grey matter surface, within the MRS voxel). The model included effects of time (pre or post tDCS), E-field, grey matter volume in the MRS voxel, and a 3-way interaction between time, E-field and grey matter volume. Additionally, we ran a permutation analysis using PALM to determine whether E-field anywhere in the brain, not just in the MRS voxel, correlated with GABA change. Results: In M1, higher mean E-field magnitude was associated with greater anodal tDCS-induced decreases in GABA (t(24) = 3.24, p = 0.003). Further, the association between mean E-field magnitude and GABA change was moderated by the grey matter volume in the MRS voxel (t(24) = −3.55, p = 0.002). These relationships were consistent across all E-field variables except the mean of the normal component. No significant relationship was found between tDCS-induced GABA decrease and E-field in the temporal voxel. No significant clusters were found in the whole brain analysis. Conclusions: Our data suggest that the electric field induced by tDCS within the brain is variable, and is significantly related to anodal tDCS-induced decrease in GABA, a key neurophysiological marker of stimulation. These findings strongly support individualised dosing of tDCS, at least in M1. Further studies examining E-fields in relation to other outcome measures, including behaviour, will help determine the optimal E-fields required for any desired effects.

Background: Several studies on patients with Alzheimer's disease (AD) have used transcranial direct current stimulation (tDCS) to enhance neural excitability in the left dorsolateral prefrontal cortex (lDLPFC). Interindividual differences in brain anatomy in AD patients pose a challenge to efficiently target the lDLPFC using scalp-based coordinates, calling for new and more precise tDCS protocols. Objective: The purpose of this study was to explore how AD-related neuropathology affects the tDCS-induced electric field (EF) across different DLPFC montages using computational modeling. Method: Forty-eight realistic head models were created from structural magnetic resonance scans of AD patients and healthy controls collected from a publicly available database. We compared the tDCS-induced EF in different montages applied in the literature, in addition to a high definition (HD)-tDCS montage centered at electrode F3. Results: There was an overall global reduction in EF strength in the patient group, probably due to structural alterations that were also identified in the patient group. A widespread distribution of the EF was found across the frontal lobe for bipolar montages, while HD-tDCS yielded more focal stimulation, mainly restricted to the lDLPFC. Minor differences in the EF distribution were found when comparing the HD-tDCS montages. Conclusion: Neurodegenerative alterations present in patients with AD affect the magnitude, distribution and variability of the EF. HD-tDCS montages provide more focal stimulation of the target area, compared to bipolar montages with to pronounced group differences between AD patients and healthy matched controls. This finding poses substantial limitations to the comparison of cognitive effects of tDCS both between patients and controls and within patients at different stages of disease progression.

Mind wandering (MW) is a heterogeneous construct involving task-unrelated thoughts. Recently, the interest in modulating MW propensity via non-invasive brain stimulation techniques has increased. Single-session transcranial direct current stimulation (tDCS) in healthy controls has led to mixed results in modulating MW propensity, possibly due to methodological heterogeneity. Therefore, our aim was to conduct a systematic meta-analysis to examine the influence of left dorsolateral prefrontal cortex (lDLPFC) and right inferior parietal lobule (rIPL) targeted tDCS on MW propensity. Importantly, by computational modeling of tDCS-induced electric fields, we accounted for differences in tDCS-dose across studies that varied strongly in their applied methodology.Fifteen single-session, sham-controlled tDCS studies published until October 2021 were included. All studies involved healthy adult participants and used cognitive tasks combined with MW thought-probes. Heterogeneity in tDCS electrode placement, stimulation polarity and intensity were controlled for by means of electric field simulations, while overall methodological quality was assessed via an extended risk of bias (RoB) assessment.We found that RoB was the strongest predictor of study outcomes. Moreover, the rIPL was the most promising cortical area for influencing MW, with stronger anodal electric fields in this region being negatively associated with MW propensity. Electric field strength in the lDLPFC was not related to MW propensity.We identified several severe methodological problems that could have contributed to overestimated effect sizes in this literature, an issue that needs urgent attention in future research in this area. Overall, there is no reliable evidence for tDCS influencing MW in the healthy. However, the analysis also revealed that increasing neural excitability in the rIPL via tDCS might be associated with reduced MW propensity. In an exploratory approach, we also found some indication that targeting prefrontal regions outside the lDLPFC with tDCS could lead to increased MW propensity.

The exact mechanisms behind the effects of transcranial direct current stimulation (tDCS) at a network level are still poorly understood, with most studies to date focusing on local (cortical) effects and changes in motor-evoked potentials or BOLD signal. Here, we explored stationary and dynamic effective connectivity across the motor network at rest in two experiments where we applied tDCS over the primary motor cortex (M1-tDCS) or the cerebellum (cb-tDCS) respectively. Two cohorts of healthy volunteers (n = 21 and n = 22) received anodal, cathodal, and sham tDCS sessions (counterbalanced) during 20 min of resting-state functional magnetic resonance imaging (fMRI). We used spectral Dynamic Causal Modelling (DCM) and hierarchical Parametrical Empirical Bayes (PEB) to analyze data after (compared to a pre-tDCS baseline) and during stimulation. We also implemented a novel dynamic (sliding windows) DCM/PEB approach to model the nature of network reorganisation across time. In both experiments we found widespread effects of tDCS that extended beyond the targeted area and modulated effective connectivity between cortex, thalamus, and cerebellum. These changes were characterised by unique nonlinear temporal fingerprints across connections and polarities. Our results support growing research challenging the classic notion of anodal and cathodal tDCS as excitatory and inhibitory respectively, as well as the idea of a cumulative effect of tDCS over time. Instead, they described a rich set of changes with specific spatial and temporal patterns. Our work provides a starting point for advancing our understanding of network-level tDCS effects and may guide future work to optimise its cognitive and clinical applications.

Background: Transcranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect. Methods: FEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to treatment, comprising three courses of clinic-based tDCS (SMA, L-OFC, Sham), randomly allocated and delivered in counterbalanced order. Each course comprised four 20-min 2 mA stimulations, delivered over two consecutive days, separated by a ‘washout’ period of at least four weeks. Assessments were carried out by raters who were blind to stimulation-type. Clinical outcomes were assessed before, during, and up to four weeks after stimulation. Patient representatives with lived experience of OCD were actively involved at all stages. Results: Clinicians showed willingness to recruit participants and recruitment to target was achieved. Adherence to treatment and study interventions was generally good, with only two dropouts. There were no serious adverse events, and adverse effects which did occur were transient and mostly mild in intensity. Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores were numerically improved from baseline to 24 h after the final stimulation across all intervention groups but tended to worsen thereafter. The greatest effect size was seen in the L-OFC arm, (Cohen's d = −0.5 [95% CI −1.2 to 0.2] versus Sham), suggesting this stimulation site should be pursued in further studies. Additional significant sham referenced improvements in secondary outcomes occurred in the L-OFC arm, and to a lesser extent with SMA stimulation. Conclusions: tDCS was acceptable, practicable to apply, well-tolerated and appears a promising potential treatment for OCD. The L-OFC represents the most promising target based on clinical changes, though the effects on OCD symptoms were not statistically significant compared to sham. SMA stimulation showed lesser signs of promise. Further investigation of tDCS in OCD is warranted, to determine the optimal stimulation protocol (current, frequency, duration), longer-term effectiveness and brain-based mechanisms of effect. If efficacy is substantiated, consideration of home-based approaches represents a rational next step.Trial registration: ISRCTN17937049. https://doi.org/10.1186/ISRCTN17937049

Transcranial direct current stimulation (tDCS) is a possible alternative to psychostimulants in Attention-Deficit/Hyperactivity Disorder (ADHD), but its mechanisms of action in children and adolescents with ADHD are poorly understood. We conducted the first 15-session, sham-controlled study of anodal tDCS over right inferior frontal cortex (rIFC) combined with cognitive training (CT) in 50 children/adolescents with ADHD. We investigated the mechanisms of action on resting and Go/No-Go Task-based QEEG measures in a subgroup of 23 participants with ADHD (n, sham = 10; anodal tDCS = 13). We failed to find a significant sham versus anodal tDCS group differences in QEEG spectral power during rest and Go/No-Go Task performance, a correlation between QEEG and Go/No-Go Task performance, and changes in clinical and cognitive measures. These findings extend the non-significant clinical and cognitive effects in our sample of 50 children/adolescents with ADHD. Given that the subgroup of 23 participants would have been underpowered, the interpretation of our findings is limited and should be used as a foundation for future investigations. Larger, adequately powered randomized controlled trials should explore different protocols titrated to the individual and using comprehensive measures to assess cognitive, clinical, and neural effects of tDCS and its underlying mechanisms of action in ADHD.

Introduction: The ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS. Objective: To report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials. Methods: We analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18–78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs). Results: No serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity. Conclusions: At-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs.

Background: Transcranial direct current stimulation (tDCS) is a non-invasive sub-threshold stimulation, widely accepted for its amelioration of distinct neuropsychiatric disorders. The weak electric field of tDCS modulates the activity of cortical neurons, which in turn modifies brain functioning. However, the underlying mechanisms for that are not fully understood.Objective/Hypothesis: Previous studies demonstrated that the axons are the most sensitive subcellular compartment for tDCS-induced polarization. Moreover, it was posited that DCS-induced axonal polarization is amplified by modifying the conductance of ionic channels. We posit that voltage-gated potassium-channels that are highly expressed in axons play a crucial role in DCS-induced modulation of cortical neurons functioning. Methods: We examined the involvement of voltage-gated potassium-channels in the active modulation of spontaneous vesicle release by DCS. For that, we measured spontaneous excitatory postsynaptic currents (sEPSCs) from layer-V motor cortex during DCS application, while co-applying distinct voltage-gated potassium-channels blockers. Moreover, we examined the role of Kv1 potassium channels in DCS-induced modulation of action potential waveform at axon terminals by recording action potentials at terminal axon blebs during DCS application while locally inhibiting the Kv1 potassium-channels. Results: We demonstrated that inhibiting voltage-gated potassium-channels occluded the DCS-induced modulation of subthreshold presynaptic vesicle release. Moreover, we showed that inhibiting Kv1 voltage-gated potassium-channels also occluded the DCS-induced modulation of action potential waveform at axon terminals. Conclusion: We suggest that DCS-induced depolarization inactivates the Kv1 potassium channels thus reducing potassium conductance, which amplifies axonal depolarization, subsequently enhancing the presynaptic component of synaptic transmission. Whereas DCS-induced hyperpolarization induces opposite effects.

Background: There is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution. Objective: Here we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task. Methods: Participants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (

The ability to regulate the intake of unhealthy foods is critical in modern, calorie dense food environments. Frontal areas of the brain, such as the dorsolateral prefrontal cortex (DLPFC), are thought to play a central role in cognitive control and emotional regulation. Therefore, increasing activity in the DLPFC may enhance these functions which could improve the ability to reappraise and resist consuming highly palatable but unhealthy foods. One technique for modifying brain activity is transcranial direct current stimulation (tDCS), a non-invasive technique for modulating neuronal excitability that can influence performance on a range of cognitive tasks. We tested whether anodal tDCS targeting the right DLPFC would influence how people perceived highly palatable foods. In the present study, 98 participants were randomly assigned to receive a single session of active tDCS (2.0 mA) or sham stimulation. While receiving active or sham stimulation, participants viewed images of highly palatable foods and reported how pleasant it would be to eat each food (liking) and how strong their urge was to eat each food (wanting). We found that participants who received active versus sham tDCS stimulation perceived food as less pleasant, but there was no difference in how strong their urge was to eat the foods. Our findings suggest that modulating excitability in the DLPFC influences “liking” but not “wanting” of highly palatable foods. Non-invasive brain stimulation might be a useful technique for influencing the hedonic experience of eating but more work is needed to understand when and how it influences food cravings.

Physiological and psychological stressors can exert wide-ranging effects on the human brain and behavior. Research has improved understanding of how the sympatho-adreno-medullary (SAM) and hypothalamic-pituitary-adrenocortical (HPA) axes respond to stressors and the differential responses that occur depending on stressor type. Although the physiological function of SAM and HPA responses is to promote survival and safety, exaggerated psychobiological reactivity can occur in psychiatric disorders. Exaggerated reactivity may occur more for certain types of stressors, specifically, psychosocial stressors. Understanding stressor effects and how the body regulates these responses can provide insight into ways that psychobiological reactivity can be modulated. Non-invasive neuromodulation is one way that responding to stressors may be altered; research into these interventions may provide further insights into the brain circuits that modulate stress reactivity. This review focuses on the effects of acute psychosocial stressors and how neuromodulation might be effective in altering stress reactivity. Although considerable research into stress interventions focuses on treating pathology, it is imperative to first understand these mechanisms in non-clinical populations; therefore, this review will emphasize populations with no known pathology and consider how these results may translate to those with psychiatric pathologies.

Background: Neuromodulatory effects of transcranial direct current stimulation (tDCS) in older humans have shown heterogeneous results, possibly due to sub-optimal stimulation protocols associated with limited knowledge about optimized stimulation parameters in this age group. We systematically explored the association between the stimulation dosage of cathodal tDCS and induced after-effects on motor cortex excitability in the elderly. Method: Thirty-nine healthy volunteers in two age groups, namely Pre-Elderly (50–65 years) and Elderly (66–80 years), participated in the study. Ten sessions of cathodal tDCS, with a combination of four intensities (1, 2, 3 mA and sham) and three durations (15, 20, 30 min) were conducted over the M1 in each participant. Cortical excitability changes were monitored with TMS-induced motor evoked potentials (MEPs) for up to 2 h after stimulation. Results: Motor cortex excitability was reduced by cathodal stimulation intensities of 1 and 3 mA in both age groups, in accordance with results observed in the younger age groups of previous studies. For the 2 mA stimulation condition, an age-dependent conversion of plasticity into a stimulation duration-dependent excitability enhancement was observed in the Pre-Elderly group, whereas in the Elderly group, LTD-like plasticity was preserved, or abolished, depending on stimulation duration. Conclusion: The LTD-like plasticity effects induced by cathodal tDCS originally described in young adults are also observable in older humans, but non-linearities of the resulting plasticity were partially preserved only in the Pre-Elderly, but not the Elderly group. These results aid in understanding age-dependent plasticity dynamics in humans, and to define more efficient tDCS protocols in the aging brain.

Background: The clinical effects and neurophysiological mechanisms of prefrontal tDCS and concurrent cognitive remediation training in individuals with autism spectrum disorder (ASD) remain unclear. Objective: This two-armed, double-blind, randomized, sham-controlled trial aimed to investigate the beneficial effects of tDCS combined with concurrent cognitive remediation training on adolescents and young adults with ASD. Methods: Participants were randomly assigned to either active or sham tDCS groups and received 1.5 mA prefrontal tDCS with left dorsolateral prefrontal cortex (dlPFC) cathode placement and right supraorbital region anode placement for 20 minutes over two consecutive weeks. tDCS was delivered concurrently with a computerized cognitive remediation training program. Social functioning and its underlying cognitive processes, as well as prefrontal resting-state functional connectivity (rsFC), were measured. Results: The results from 41 participants indicated that multisession prefrontal tDCS, compared to sham tDCS, significantly enhanced the social functioning of ASD individuals [F(1,39) = 4.75, p = .035, ηp2 = 0.11]. This improvement was associated with enhanced emotion recognition [F(1,39) = 8.34, p = .006, ηp2 = 0.18] and cognitive flexibility [F(1,39) = 4.91, p = .033, ηp2 = 0.11]. Specifically, this tDCS protocol optimized information processing efficiency [F(1,39) = 4.43, p = .042, ηp2 = 0.10], and the optimization showed a trend to be associated with enhanced rsFC in the right medial prefrontal cortex (ρ = 0.339, pFDR = .083). Conclusion: Multisession tDCS with left dlPFC cathode placement and right supraorbital region anode placement paired with concurrent cognitive remediation training promoted social functioning in individuals with ASD. This appeared to be associated with the enhancement of the functional connectivity of the right medial PFC, a major hub for flexible social information processing, allowing these individuals to process information more efficiently in response to different social situations. Trial registration: ClinicalTrials.gov (ID: NCT03814083)

Background: Transcranial direct current stimulation (tDCS) is a subthreshold neurostimulation therapeutic method that ameliorate neuropsychiatric impairments. The most sensitive subcellular compartment for tDCS are the axons that polarize. However, how these relatively small polarizations significantly alter synaptic dynamics is still unknown.Objective/Hypothesis: We hypothesized that tDCS-induced axonal polarization modulates calcium channel activity at the presynaptic compartment, thus playing a crucial role in synaptic vesicle release. Methods: For this aim, we examined how different DCS conditions and orientations affect the spontaneous excitatory post synaptic currents (sEPSCs) recorded from hippocampal CA1 pyramidal neurons. Since P/Q-type calcium-channels are the main presynaptic voltage-dependent calcium-channels in the hippocampus, we further examined the DCS effects while applying a P/Q-type calcium channels blocker, ω-agatoxin. Additionally, to explain the DCS-induced calcium channel-regulated vesicle release dynamics, we developed a simplified model to complement our experimental results. Results: We demonstrated that anodal-DCS application in a dorso-ventral orientation, similar to that of in-vivo experiments, enhanced the sEPSCs frequency, while cathodal-DCS was ineffective. Moreover, DCS application in parallel to the Schaffer collaterals (medio-lateral orientation), showed both anodal and cathodal significant effects. Furthermore, the ω-agatoxin application occluded the DCS-induced modulation of sEPSC frequencies in any orientation. The model showed the interaction between DCS-induced membrane polarization, calcium channel activation and presynaptic vesicle release. Conclusion: Using experiments and modeling we show that DCS induces a small variation in terminal membrane potential sufficient to activate P/Q type voltage-gated calcium channels, and that this is sufficient to modify presynaptic calcium concentration, subsequently altering spontaneous vesicle release.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans.Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject’s age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be “safe” where they are applying stimulation beyond that examined in published studies that also investigated potential side effects.Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Background: Noninvasive brain stimulation has been successfully applied to improve stroke-related impairments in different behavioral domains. Yet, clinical translation is limited by heterogenous outcomes within and across studies. It has been proposed to develop and apply noninvasive brain stimulation in a patient-tailored, precision medicine-guided fashion to maximize response rates and effect magnitude. An important prerequisite for this task is the ability to accurately predict the expected response of the individual patient. Objective: This review aims to discuss current approaches studying noninvasive brain stimulation in stroke and challenges associated with the development of predictive models of responsiveness to noninvasive brain stimulation. Methods: Narrative review. Results: Currently, the field largely relies on in-sample associational studies to assess the impact of different influencing factors. However, the associational approach is not valid for making claims of prediction, which generalize out-of-sample. We will discuss crucial requirements for valid predictive modeling in particular the presence of sufficiently large sample sizes. Conclusion: Modern predictive models are powerful tools that must be wielded with great care. Open science, including data sharing across research units to obtain sufficiently large and unbiased samples, could provide a solid framework for addressing the task of building robust predictive models for noninvasive brain stimulation responsiveness.

Background: Approximately half of all people with alcohol use disorder (AUD) relapse into alcohol reuse in the next few weeks after a withdrawal treatment. Brain stimulation and cognitive training represent recent forms of complementary interventions in the context of AUD. Objective: To evaluate the clinical efficacy of five sessions of 2 mA bilateral transcranial direct current stimulation (tDCS) for 20 min over the dorsolateral prefrontal cortex (DLPFC) (left cathodal/right anodal) combined with alcohol cue inhibitory control training (ICT) as part of rehabilitation. The secondary outcomes were executive functioning (e.g. response inhibition) and craving intensity, two mechanisms strongly related to abstinence. Methods: A randomized clinical trial with patients (n = 125) with severe AUD at a withdrawal treatment unit. Each patient was randomly assigned to one of four conditions, in a 2 [verum vs. sham tDCS] x 2 [alcohol cue vs. neutral ICT] factorial design. The main outcome of treatment was the abstinence rate after two weeks or more (up to one year). Results: Verum tDCS improved the abstinence rate at the 2-week follow-up compared to the sham condition, independently of the training condition (79.7% [95% CI = 69.8–89.6] vs. 60.7% [95% CI = 48.3–73.1]; p = .02). A priori contrasts analyses revealed higher abstinence rates for the verum tDCS associated with alcohol cue ICT (86.1% [31/36; 95% CI = 74.6–97.6]) than for the other three conditions (64% [57/89; 95% CI = 54–74]). These positive clinical effects on abstinence did not persist beyond two weeks after the intervention. Neither the reduction of craving nor the improvement in executive control resulted specifically from prefrontal-tDCS and ICT. Conclusions: AUD patients who received tDCS applied to DLPFC showed a significantly higher abstinence rate during the weeks following rehabilitation. When combined with alcohol specific ICT, brain stimulation may provide better clinical outcomes. Trial Registration: ClinicalTrials.gov number NCT03447054 https://clinicaltrials.gov/ct2/show/NCT03447054.

The ability to keep track of time is one of the fundamental human behaviours that enhance survival in the wild. It is still an essential skill that enables an individual to function well in modern society. In the present study, we tested the attentional gate model, one of the most common conceptual frameworks in studies of subjective time perception. Its utility has been well established, but it has been criticised for its lack of neurophysiological support; few studies attempted to systematically identify its components and their neural correlates. Previous studies established that the dorsolateral prefrontal cortex (DLPFC) was associated with working memory tasks and a correlation between activity in the cerebellum and the timing of tasks. An fMRI study was conducted to confirm that these two cortical regions were activated during the execution of a new time discrimination task that considers individual variations in subjective time perception. Simulations were conducted to optimize the electrode placement in order to maximize the electric fields of tDCS perturbation to these two areas. According to the attentional gate model, hypotheses about tDCS perturbation to subjective time perception, attention and working memory were formulated and tested. Attention and working memory were measured by the attention network and N-back tasks. There are weak effects to the perceived subjective equivalent and the reaction time in the attention network task, but both are not statistically significant after correction for multiple comparisons. Exploration analyses show a link between attention and subjective time perception after tDCS perturbation. To conclude, the results do not support the attentional gate model, but show a linkage between attention and subjective time perception in terms of similar neural circuits and their relationships under certain circumstances.

Background: Working memory decline has been associated with normal aging. The frontal brain structure responsible for this decline is primarily located in the prefrontal cortex (PFC). Our previous neuroimaging study demonstrated a significant change in functional connectivity between the left dorsolateral PFC (DLPFC) and left ventrolateral PFC (VLPFC) when applying 2 mA tDCS in MRI scanner during an N-Back task. These regions were part of the working memory network. The present study is the first study that utilizes individualized finite element models derived from older adults’ MRI to predict significant changes of functional connectivity observed from an acute tDCS application. Methods: Individualized head models from 15 healthy older adults (mean age = 71.3 years) were constructed to create current density maps. Each head model was segmented into 11 tissue types: white matter, gray matter, CSF, muscle, blood vessels, fat, eyes, air, skin, cancellous, and cortical bone. Electrodes were segmented from T1-weighted images and added to the models. Computed median and maximum current density values in the left DLPFC and left VLPFC regions of interest (ROIs) were correlated with beta values as functional connectivity metrics measured in different timepoint (baseline, during stimulation) and stimulation condition (active and sham). Main results: Positive significant correlations (R2 = 0.523 for max J, R2 = 0.367 for median J, p

Background: Transcranial direct current stimulation (DCS) has lasting effects that may be explained by a boost in synaptic long-term potentiation (LTP). We hypothesized that this boost is the result of a modulation of somatic spiking in the postsynaptic neuron, as opposed to indirect network effects. To test this directly we record somatic spiking in a postsynaptic neuron during LTP induction with concurrent DCS. Methods: We performed rodent in-vitro patch-clamp recordings at the soma of individual CA1 pyramidal neurons. LTP was induced with theta-burst stimulation (TBS) applied concurrently with DCS. To test the causal role of somatic polarization, we manipulated polarization via current injections. We also used a computational multi-compartment neuron model that captures the effect of electric fields on membrane polarization and activity-dependent synaptic plasticity. Results: TBS-induced LTP was enhanced when paired with anodal DCS as well as depolarizing current injections. In both cases, somatic spiking during the TBS was increased, suggesting that evoked somatic activity is the primary factor affecting LTP modulation. However, the boost of LTP with DCS was less than expected given the increase in spiking activity alone. In some cells, we also observed DCS-induced spiking, suggesting DCS also modulates LTP via induced network activity. The computational model reproduces these results and suggests that they are driven by both direct changes in postsynaptic spiking and indirect changes due to network activity. Conclusion: DCS enhances synaptic plasticity by increasing postsynaptic somatic spiking, but we also find that an increase in network activity may boost but also limit this enhancement.

Background: tDCS modulates cortical plasticity and has shown potential to improve cognitive/motor functions in healthy young humans. However, age-related alterations of brain structure and functions might require an adaptation of tDCS-parameters to achieve a targeted plasticity effect in older humans and conclusions obtained from young adults might not be directly transferable to older adults. Thus, our study aimed to systematically explore the association between tDCS-parameters and induced aftereffects on motor cortical excitability to determine optimal stimulation protocols for older individuals, as well as to investigate age-related differences of motor cortex plasticity in two different age groups of older adults. Methods: 32 healthy, volunteers from two different age groups of Young-Old (50–65 years, n = 16) and Old-Old (66–80 years, n = 16) participated in this study. Anodal tDCS was applied over the primary motor cortex, with respective combinations of three intensities (1, 2, and 3 mA) and durations (15, 20, and 30 min), in a sham-controlled cross-over design. Cortical excitability alterations were monitored by single-pulse TMS-induced MEPs until the next day morning after stimulation. Results: All active stimulation conditions resulted in a significant enhancement of motor cortical excitability in both age groups. The facilitatory aftereffects of anodal tDCS did not significantly differ between age groups. We observed prolonged plasticity in the late-phase range for two protocols with the highest stimulation intensity (i.e., 3 mA-20 min, 3 mA-30 min). Conclusions: Our study highlights the role of stimulation dosage in tDCS-induced neuroplastic aftereffects in the motor cortex of healthy older adults and delivers crucial information about optimized tDCS protocols in the domain of the primary motor cortex. Our findings might set the grounds for the development of optimal stimulation protocols to reinstate neuroplasticity in different cortical areas and induce long-lasting, functionally relevant plasticity in normal aging and in pathological conditions, which would require however systematic tDCS titration studies over respective target areas.

Background: Skin sensation is the primary factor limiting the intensity of transcranial electrical stimulation (tES). It is well established that different waveforms generate different sensations, yet transcranial stimulation has been limited to a relatively small number of prototypical waveforms. Objective: We explore whether alternative stimulation waveforms could substantially reduce skin sensation and thus allow for stronger intensities in tES. Methods: We systematically tested a range of waveforms in a series of 6 exploratory experiments stimulating human adults on the forearm and in one instance on the head. Subjects were asked to rate skin sensation level on a numerical scale from “none” to “extreme”. Results: High frequency (>1 kHz) monophasic square wave stimulation was found to decrease in sensation with increasing duty cycle, baseline, and frequency, but the sensation was never lower than for constant current stimulation. For the purpose of injecting a net direct current (DC), a constant current is optimal. For stimulation with alternating current (AC), sensation decreased with increasing frequency, consistent with previous reports. Amplitude modulation did not reduce sensation below stimulation with constant AC amplitude, and biphasic square waveforms produced higher sensation levels than biphasic sinusoidal waveforms. Furthermore, for DC stimulation, sensation levels on the arm were similar to those reported on the head. Conclusion: Our comparisons of various waveforms for monophasic and biphasic stimulation indicate that conventional DC and AC waveforms may provide the lowest skin sensations levels for transcutaneous electrical stimulation. These results are likely generalizable to tES applications.

A primary goal of translational neuroscience is to identify the neural mechanisms of age-related cognitive decline and develop protocols to maximally improve cognition. Here, we demonstrate how interventions that apply noninvasive neurostimulation to older adults improve working memory (WM). We found that one session of sham-controlled transcranial direct current stimulation (tDCS) selectively improved WM in older adults with more education, extending earlier work and underscoring the importance of identifying individual predictors of tDCS responsivity. Improvements in WM were associated with two distinct electrophysiological signatures. First, a broad enhancement of theta network synchrony tracked improvements in behavioral accuracy, with tDCS effects moderated by education level. Further analysis revealed that accuracy dynamics reflected an anterior-posterior network distribution regardless of cathode placement. Second, specific enhancements of theta-gamma phase-amplitude coupling (PAC) reflecting tDCS current flow tracked improvements in reaction time (RT). RT dynamics further explained inter-individual variability in WM improvement independent of education. These findings illuminate theta network synchrony and theta-gamma PAC as distinct but complementary mechanisms supporting WM in aging. Both mechanisms are amenable to intervention, the effectiveness of which can be predicted by individual demographic factors.

Background: Transcranial direct current stimulation (tDCS) has been demonstrated in randomized clinical trials (RCTs) to be an effective treatment option for major depressive disorder (MDD). The aim of this study was to characterize the real-life effectiveness and tolerability of tDCS and to identify predictors of treatment outcome in patients with MDD. Methods: A total of 462 patients with depressive symptoms, who were treated with tDCS as a part of routine clinical practice, were enrolled in the study. Depressive symptoms were evaluated using validated depression scales before and after the tDCS treatment in 410 patients who completed the treatment and for whom all the necessary treatment information was available. Results: Complete clinical response (CCR) was achieved by 54.9% (n = 225), remission by 19.5% (n = 80), and minimal clinically important difference (MCID) by 94.6% (n = 388) of the study patients after the tDCS treatment completion. At least half of the patients achieved CCR in all severity classes and in patients with and without concomitant use of psychotropics. No serious adverse effects were reported during the treatment. Limitations: As a non-interventional study based on retrospective data collection from routine clinical practice, the study did not include a control group. Medical history data was available from the tDCS treatment initiation. Conclusions: This real-world study showed good tolerability and a reduction of depressive symptoms in patients with MDD after tDCS treatment. The results suggest that tDCS is a well-suited treatment alternative for MDD, either as a stand-alone treatment or in combination with antidepressant medication.

Background: Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. Objective: We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. Methods: We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. Results: We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear conditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. Conclusions: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD.