Transcranial direct current stimulation (tDCS) is one of the most prominent non-invasive electrical brain stimulation method to alter neuronal activity as well as behavioral processes in cognitive and perceptual domains. However, the exact mode of action of tDCS-related cortical alterations is still unclear as the results of tDCS studies often do not comply with the somatic doctrine assuming that anodal tDCS enhances while cathodal tDCS decreases neuronal excitability. Changes in the regional cortical neurotransmitter balance within the stimulated cortex, measured by excitatory and inhibitory neurotransmitter levels, have the potential to provide direct neurochemical underpinnings of tDCS effects. Here we assessed tDCS-induced modulations of the neurotransmitter concentrations in the human auditory cortex (AC) by using magnetic resonance spectroscopy (MRS) at ultra-high-field (7 T). We quantified inhibitory gamma-amino butyric (GABA) concentration and excitatory glutamate (Glu) and compared changes in the relative concentration of GABA to Glu before and after tDCS application. We found that both, anodal and cathodal tDCS significantly increased the relative concentration of GABA to Glu with individual temporal specificity. Our results offer novel insights for a potential neurochemical mechanism that underlies tDCS-induced alterations of AC processing.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that allows the modulation of cortical excitability. TDCS effects can outlast the stimulation period presumably due to changes of GABA concentration which play a critical role in use-dependent plasticity. Consequently, tDCS and learning-related synaptic plasticity are assumed to share common mechanisms. Motor sequence learning has been related to activation changes within a cortico-subcortical network and findings from a meta-analysis point towards a core network comprising the cerebellum as well as the primary motor (M1) and the dorsolateral premotor cortex (dPMC). The latter has been particularly related to explicit motor learning by means of brain imaging techniques. We here test whether tDCS applied to the left dPMC affects the acquisition and reproduction of an explicitly learned motor sequence. To this end, 18 healthy volunteers received anodal, cathodal and sham tDCS to the left dPMC and were then trained on a serial reaction time task (SRTT) with their right hand. Immediately after the training and after overnight sleep, reproduction of the learned sequence was tested by means of reaction times as well as explicit recall. Regression analyses suggest that following cathodal tDCS reaction times at the end of the SRTT training-block explained a significant proportion of the number of correctly reported sequence items after overnight sleep. The present data suggest the left premotor cortex as one possible target for the application of non-invasive brain stimulation techniques in explicit motor sequence learning with the right hand.

Transcranial Direct Current Stimulation (tDCS) is a non‐invasive brain stimulation technique used to modulates cortical brain activity. However, its effects on brain metabolites within the dorsolateral prefrontal cortex (DLPFC), a crucial area targeted for brain stimulation in mental disorders, remain unclear. This study aimed to investigate whether prefrontal tDCS over the left and right DLPFC modulates levels of key metabolites, including gamma‐aminobutyric acid (GABA), glutamate (Glu), glutamine/glutamate (Glx), N‐acetylaspartate (NAA), near to the target region and to explore potential sex‐specific effects on these metabolite concentrations. A total of 41 healthy individuals (19 female, M_age = 25 years, SD = 3.15) underwent either bifrontal active (2 mA for 20 min) or sham tDCS targeting the left (anode: F3) and right (cathode: F4) DLPFC within a 3 Tesla MRI scanner. Magnetic resonance spectroscopy (MRS) was used to monitor neurometabolic changes before, during, and after 40 min of tDCS, with measurements of two 10‐min intervals during stimulation. A single voxel beneath F3 was used for metabolic quantification. Results showed a statistically significant increase in Glx levels under active tDCS compared to the sham condition, particularly during the second 10‐min window and persisting into the post‐stimulation phase. No significant changes were observed in other metabolites, but consistent sex differences were detected. Specifically, females showed lower levels of NAA and GABA under active tDCS compared to the sham condition, while no significant changes were observed in males. E‐field modeling showed no significant differences in field magnitudes between sexes, and the magnitude of the e‐fields did not correlate with changes in Glx levels between active and sham stimulation during the second interval or post‐stimulation. This study demonstrates that a single session of prefrontal tDCS significantly elevates Glx levels in the left DLPFC, with effects persisting post‐stimulation. However, the observed sex differences in the neurochemical response to tDCS were not linked to specific stimulation intervals or variations in e‐field magnitudes, highlighting the complexity of tDCS effects and the need for personalized neuromodulation strategies.

Introduction The physiological effects of transcranial direct current stimulation (tDCS) in non-motor cortex areas are not well understood. The dorsolateral prefrontal cortex (DLPFC) is a key tDCS target in several psychiatric disorders, and mechanisms of tDCS action are of particular interest. We therefore investigated the effects of tDCS over the DLPFC evaluating GABA, glutamate/glutamine (Glx) and glutamate (Glu) concentrations in healthy subjects. Methods Nineteen healthy subjects (11 women, mean age 23) were randomly assigned to active (20 min, 2 mA, 5 × 7 cm electrodes) and sham tDCS using a double-blind, cross-over design. The anode was positioned over F3 (left DLPFC), the cathode over F4 (right DLPFC). A MRS MEGA-PRESS sequence (TE = 68 ms, TR = 2000 ms) was acquired before, during, and after stimulation. Gannet 3.0 and LcModel were used to quantify GABA, Glx and Glu concentrations. Repeated-measures mixed effects models were conducted comparing pre, during and post measurements of active and sham tDCS. Mistakenly, the right and not the left DLPFC was targeted using MRS, therefore evaluating changes induced by cathodal tDCS in the right DLPFC. Results We found a significant reduction of right DLPFC glutamate concentrations during active stimulation (df = 133; P = .023; effect size d = 0.398) as well as a significant reduction of Glx concentration during active stimulation (df = 133; P = .007; effect size d = 0.477). No changes of GABA concentration in cortical regions in proximity to the cathode was observed during or after anodal tDCS stimulation. Conclusions Despite the methodological mistake on prefrontal data collection, the results are biologically plausible and contribute to unveil cathodal tDCS mechanisms of action over the right DLPFC. Confirming results of other trials by Stagg et al. (2009) [1] and Kim et al. (2014) [2] , cathodal stimulation exerts inhibitory effects on the brain. However, several methodological factors (e.g electrical field strengths and distribution, tDCS parameters and individual differences) may limit conclusive interpretation.

sary to give this speculation concrete support. Neuromodulators and tDCS tDCS can affect synaptic neuromodulator concentration. Conversely, the concentration of a neuromodulator, by affecting synaptic dynamics, can change the effect that tDCS has on that synapse (Figure 1A ). tDCS and serotonin enhance each other's function. For instance, atDCS reduced the symptoms of major depressive disorders (Murphy et al., 2009 ), in which the serotonergic system is compromised (Morrissette and Stahl, 2014 ). Moreover, the effects of tDCS on the serotonergic system seem to be mediated by specific variants of the serotonin transporter (5-HTTLPR) (Brunoni et al., 2013 ). We, therefore, speculate that genetic polymorphism contributes to the individual sensitivity toward tDCS. Plausibly, this is the reason for inter-subject variability in tDCS dependent MEP modulation (Wiethoff et al., 2014 ). Incremental increases in extracellular serotonin levels, using selective serotonin reuptake inhibitor (SSRI), boost anodal facilitation of MEP and caused ctDCS to have an excitatory effect (Nitsche et al., 2009 ). Moreover, atDCS of the temporal cortex improved memory formation when serotonergic neurotransmission was enhanced simultaneously (Prehn et al., 2016 ). Thus, tDCS magnifies the activity of serotonergic system. No existing models explain how serotonin might reverse the cathodal and enhance the anodal effects of tDCS. Nevertheless, the evidence does support a bidirectional relationship: atDCS promotes the function of the serotonergic system and serotonin facilitates atDCS effects. It is possible that tDCS modulates skill learning by altering brain-derived neurotrophic factor (BDNF) dependent cortical plasticity. This notion was validated by an in vitro M1 study in which the atDCS promoted BDNF-dependent LTP (Fritsch et al., 2010 ). It is plausible that tDCS: (i) enhances secretion of BDNF which influences the spike-time dependent plasticity (Tanaka et al., 2008 ) and, (ii) modulates th

The overarching aim of the study is to investigate the possibility to enhance neuroplasticity of the hypothalamus network to improve metabolism and dopamine-dependent cognitive functions. Specific objectives * Specifically, it is the first aim to study the predictive value of white matter microstructure (fiber tracts structurally connecting the target network) for tDCS-intervention response and to investigate tDCS-induced neuroplasticity changes of the hypothalamus brain network using functional magnetic resonance imaging (fMRI). * It is the second aim of this study to deepen our understanding of brain structure and function of the target network, which is known to rely on the neurotransmitter dopamine for its communication. Hence, we will use dopamine-dependent cognitive and eating behavior assessments. Participants will receive a thorough screening to obtain body composition by MRI, anthropometric measures, fasting glucose and insulin, indirect calorimetry, and general cognitive functions. Thereafter, participants will participate in three measurement days (separated by approx.

<h4>Objective</h4>This study investigated whether combining exercise with transcranial direct current stimulation (tDCS) improves overall cognition, memory, and executive function in older adults.<h4>Methods</h4>Following PRISMA guidelines, we systematically searched databases including PubMed, Web of Science, CNKI, and Wan Fang for randomized controlled trials (RCTs) examining the combined effect of exercise and tDCS on cognitive function in older adults. Used RStudio (version 4.2.0) to merge effect sizes and represent them as SMD with a 95% confidence interval (CI). The main effects are synthesized using a random effects model, and heterogeneity sources are explored through subgroup regression and sensitivity analysis.<h4>Results</h4>The combined exercise and tDCS intervention significantly improved global cognitive function in older adults (SMD = 0.62, 95% CI: 0.36 to 0.89, <i>p</i> < 0.0001). Significant enhancements were observed in executive function (SMD = 0.54, 95% CI: 0.16 to 0.92, <i>p</i> = 0.005) and general cognitive ability (SMD = 0.75, 95% CI: 0.21 to 1.30, <i>p</i> = 0.006), while memory showed a non-significant improvement (SMD = 0.58, 95% CI: -0.03 to 1.19, <i>p</i> = 0.063). Both interventions lasting less than 6 weeks (SMD = 0.94, 95% CI: 0.60 to 1.27, <i>p</i> < 0.0001) and those lasting 6 weeks or longer (SMD = 0.24, 95% CI: 0.10 to 0.37, <i>p</i> = 0.0006) positively impacted cognitive function. However, the effect size was larger for cognitively healthy older adults (SMD = 0.69, 95% CI: 0.20 to 1.18, <i>p</i> = 0.006) compared to those with cognitive impairment (SMD = 0.60, 95% CI: 0.29 to 0.92, <i>p</i> = 0.0002). The combination of tDCS and integrated exercise produced the largest effect size (SMD = 1.74), despite high heterogeneity, while the combination of tDCS and Tai Chi produced the smallest but most robust effect (SMD = 0.25, I ² = 0%), indicating that exercise type significantly regulates the intervention effect of tDCS (<i>p</i> = 0.0015). Regression analysis shows that tDCS stimulation time has a significant positive regulatory effect on cognitive function in elderly people (<i>p</i> = 0.0002), while the combined intervention period (<i>p</i> = 0.030) and single exercise time (<i>p</i> = 0.034) both have a significant negative regulatory effect.<h4>Conclusion</h4>Based on limited evidence, we found that a combined intervention of exercise and tDCS is a potentially effective means of improving cognitive function in older adults. However, the extent of improvement varies with the cognitive domain, baseline performance level, and intervention plan.