Search

The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert benefial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. This was adressed by multimodal magnetic resonance imaging (MRI) before and after a three-week executive function training with prefrontal excitatory tDCS in 48 older adults. Results demonstrate that training combined with active tDCS enhanced prefrontal white matter microstructure which predicted individual performance gain. Training-plus-tDCS also resulted in microstructural grey matter reductions at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications.

BackgroundOscillatory rhythms during sleep such as slow oscillations (SO) and spindles, and most importantly their coupling, are thought to underlie processes of memory consolidation. External slow oscillatory transcranial direct current stimulation (so-tDCS) with a frequency of 0.75 Hz has been shown to improve this coupling and memory consolidation, however, effects varied quite markedly between individuals, studies, and species. Here, we aimed to determine how precisely the frequency of stimulation has to match the naturally occurring SO frequency in individuals to optimally improve SO-spindle coupling. Moreover, we systematically tested stimulation durations necessary to induce changes.MethodsWe addressed these questions by comparing so-tDCS with individualized frequency to standardized frequency of 0.75 Hz in a within-subject design with 28 older participants during napping while systematically varying stimulation train durations between 30 s, 2 min, and 5 min.ResultsStimulation trains as short as 30 s were sufficient to modulate the coupling between SOs and spindle activity. Contrary to our expectations, so-tDCS with standardized frequency indicated stronger aftereffects with regard to SO-spindle coupling compared to individualized frequency. Angle and variance of spindle maxima occurrence during the SO cycle were similarly modulated.ConclusionIn sum, short stimulation trains were sufficient to induce significant changes in sleep physiology allowing for more trains of stimulation, which provides methodological advantages and possibly even larger behavioral effects in future studies. With regard to individualized stimulation frequency, further options of optimization need to be investigated, such as closed-loop stimulation to calibrate stimulation frequency to the SO frequency at time of stimulation onset.Significance statementApplication of slow oscillatory transcranial direct current stimulation during sleep has been shown to enhance specific memory-relevant sleep parameters and memory performance after sleep, albeit with a high degree of variability. Here, we systematically explored two major stimulation parameters possibly accounting for this variability in humans: frequency and duration of stimulation. We found, contrary to our expectations, standardized frequency stimulation with 0.75 Hz being superior to individualized frequency stimulation in enhancing specific sleep parameters. Moreover short stimulation trains of 30 seconds were as effective as 5 min in modulating aftereffects. These are encouraging findings, implying methodological advantages as larger quantity of aftereffects data can be obtained within the same time window, which may also lead to enhanced behavioral stimulation effects.

Neural mechanisms of behavioral improvement induced by repeated transcranial direct current stimulation (tDCS) combined with cognitive training are yet unclear. Previously, we reported behavioral effects of a 3-day visuospatial memory training with concurrent anodal tDCS over the right temporoparietal cortex in older adults. To investigate intervention-induced neural alterations we here used functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) datasets available from 35 participants of this previous study, acquired before and after the intervention. To delineate changes in whole-brain functional network architecture, we employed eigenvector centrality mapping. Gray matter alterations were analyzed using DTI-derived mean diffusivity (MD). Network centrality in the bilateral posterior temporooccipital cortex was reduced after anodal compared to sham stimulation. This focal effect is indicative of decreased functional connectivity of the brain region underneath the anodal electrode and its left-hemispheric homolog with other "relevant" (i.e., highly connected) brain regions, thereby providing evidence for reorganizational processes within the brain's network architecture. Examining local MD changes in these clusters, an interaction between stimulation condition and training success indicated a decrease of MD in the right (stimulated) temporooccipital cluster in individuals who showed superior behavioral training benefits. Using a data-driven whole-brain network approach, we provide evidence for targeted neuromodulatory effects of a combined tDCS-and-training intervention. We show for the first time that gray matter alterations of microstructure (assessed by DTI-derived MD) may be involved in tDCS-enhanced cognitive training. Increased knowledge on how combined interventions modulate neural networks in older adults, will help the development of specific therapeutic interventions against age-associated cognitive decline.

Given rapid global population aging, developing interventions against age-associated cognitive decline is an important medical and societal goal. We evaluated a cognitive training protocol combined with transcranial direct current stimulation (tDCS) on trained and non-trained functions in non-demented older adults.Fifty-six older adults (65-80 years) were randomly assigned to one of two interventional groups, using age and baseline performance as strata. Both groups performed a nine-session cognitive training over 3 weeks with either concurrent anodal tDCS (atDCS, 1 mA, 20 minutes) over the left dorsolateral prefrontal cortex (target intervention) or sham stimulation (control intervention). Primary outcome was performance on the trained letter updating task immediately after training. Secondary outcomes included performance on other executive and memory (near and far transfer) tasks. All tasks were administered at baseline, post-intervention, and at 1- and 7-month follow-up assessments. Prespecified analyses to investigate treatment effects were conducted using mixed-model analyses.No between-group differences emerged in the trained letter updating and Markov decision-making tasks at post-intervention and at follow-up timepoints. Secondary analyses revealed group differences in one near-transfer task: Superior n-back task performance was observed in the tDCS group at post-intervention and at follow-up. No such effects were observed for the other transfer tasks. Improvements in working memory were associated with individually induced electric field strengths.Cognitive training with atDCS did not lead to superior improvement in trained task performance compared to cognitive training with sham stimulation. Thus, our results do not support the immediate benefit of tDCS-assisted multi-session cognitive training on the trained function. As the intervention enhanced performance in a near-transfer working memory task, we provide exploratory evidence for effects on non-trained working memory functions in non-demented older adults that persist over a period of 1 month.

Publisher Copyright: © 2022, The Author(s). Subjective cognitive decline (SCD), as expressed by older adults, is associated with negative affect, which, in turn, is a likely risk factor for Alzheimer’s Disease (AD). This study assessed the associations between negative affective burden, cognitive functioning, and functional connectivity in networks vulnerable to AD in the context of SCD. Older participants (60–90 years) with SCD (n = 51) and healthy controls (n = 50) were investigated in a cross-sectional study. Subclinical negative affective burden, quantified through a composite of self-reported negative affective factors, was related to cognitive functioning (self-perceived and objective) and functional connectivity. Seed-to-voxel analyses were carried out in default mode network (DMN) and salience network (SAL) nodes using resting-state functional magnetic resonance imaging. Greater negative affective burden was associated with lower self-perceived cognitive functioning and lower between-network functional connectivity of DMN and SAL nodes in the total sample. In addition, there was a significant moderation of SCD status. Greater negative affective burden related to higher functional connectivity within DMN (posterior cingulate-to-precuneus) and within SAL (anterior cingulate-to-insula) nodes in the SCD group, whereas in controls the inverse association was found. We show that negative affective burden is associated with functional brain alterations in older adults, regardless of SCD status. Specifically in the SCD phenotype, greater negative affective burden relates to higher functional connectivity within brain networks vulnerable to AD. Our findings imply that negative affective burden should be considered a potentially modifiable target for early intervention.

Certain neurophysiological characteristics of sleep, in particular slow oscillations (SO), sleep spindles, and their temporal coupling, have been well characterized and associated with human memory formation. Delta waves, which are somewhat higher in frequency and lower in amplitude compared to SO, have only recently been found to play a critical role in memory processing of rodents, through a competitive interplay between SO-spindle and delta-spindle coupling. However, human studies that comprehensively address delta waves, their interactions with spindles and SOs as well as their functional role for memory are still lacking.Electroencephalographic data were acquired across three naps of 33 healthy older human participants (17 female) to investigate delta-spindle coupling and the interplay between delta and SO-related activity. Additionally, we determined intra-individual stability of coupling measures and their potential link to the ability to form novel memories.Our results revealed weaker delta-spindle compared to SO-spindle coupling. Contrary to our initial hypothesis, we found that increased delta activity was accompanied by stronger SO-spindle coupling. Moreover, we identified the ratio between SO- and delta-nested spindles as the sleep parameter that predicted ability to form novel memories best.Our study suggests that SOs, delta waves and sleep spindles should be jointly considered when aiming to link sleep physiology and memory formation in aging.Significance statementInterrelations between delta waves, slow oscillations and sleep spindles have recently been causally linked to the balance between consolidation and forgetting in rats using optogenetics. In humans, SO-spindle coupling has been intensively investigated, but delta waves and their interaction with spindles were only studied jointly as SWA. Here we delineate the coupling of delta waves to spindles, investigate interactions of delta- and SO-related activity and investigate their role for the ability to form novel memories in healthy older individuals. Our results show differences as well as dependencies between SO- and delta-related activities including spindle coupling. Further, our results indicate that the ratio of SO- to delta-nested spindles might be the most informative sleep parameter for memory formation of older adults.

Transcranial direct current stimulation (tDCS) augments training-induced cognitive gains, an issue of particular relevance in the aging population. However, negative outcomes have been reported as well, and few studies so far have evaluated the impact of tDCS on episodic memory formation in elderly cohorts. The heterogeneity of previous findings highlights the importance of elucidating neuronal underpinnings of tDCS-induced modulations, and of determining individual predictors of a positive response. In the present study, we aimed to modulate episodic memory formation in 34 older adults with anodal tDCS (1 mA, 20 min) over left temporoparietal cortex. Participants were asked to learn novel associations between pictures and pseudowords, and episodic memory performance was subsequently assessed during immediate retrieval. Prior to experimental sessions, participants underwent resting-state functional magnetic resonance imaging. tDCS led to better retrieval performance and augmented learning curves. Hippocampo-temporoparietal functional connectivity was positively related to initial memory performance, and was positively associated with the magnitude of individual tDCS-induced enhancement. In sum, we provide evidence for brain stimulation-induced plasticity of episodic memory processes in older adults, corroborating and extending previous findings. Our results demonstrate that intrinsic network coupling may determine individual responsiveness to brain stimulation, and thus help to further explain variability of tDCS responsiveness in older adults.

IntroductionWith the worldwide increase of life expectancy leading to a higher proportion of older adults experiencing age-associated deterioration of cognitive abilities, the development of effective and widely accessible prevention and therapeutic measures has become a priority and challenge for modern medicine. Combined interventions of cognitive training and transcranial direct current stimulation (tDCS) have shown promising results for counteracting age-associated cognitive decline. However, access to clinical centres for repeated sessions is challenging, particularly in rural areas and for older adults with reduced mobility, and lack of clinical personnel and hospital space prevents extended interventions in larger cohorts. A home-based and remotely supervised application of tDCS would make the treatment more accessible for participants and relieve clinical resources. So far, studies assessing feasibility of combined interventions with a focus on cognition in a home-based setting are rare. With this study, we aim to provide evidence for the feasibility and the effects of a multisession home-based cognitive training in combination with tDCS on cognitive functions of healthy older adults.Methods and analysisThe TrainStim-Home trial is a monocentric, randomised, double-blind, placebo-controlled study. Thirty healthy participants, aged 60–80 years, will receive 2 weeks of combined cognitive training and anodal tDCS over left dorsolateral prefrontal cortex (target intervention), compared with cognitive training plus sham stimulation. The cognitive training will comprise a letter updating task, and the participants will be stimulated for 20 min with 1.5 mA. The intervention sessions will take place at the participants’ home, and primary outcome will be the feasibility, operationalised by two-thirds successfully completed sessions per participant. Additionally, performance in the training task and an untrained task will be analysed.Ethics and disseminationEthical approval was granted by the ethics committee of the University Medicine Greifswald. Results will be available through publications in peer-reviewed journals and presentations at national and international conferences.Trial registration numberNCT04817124.

Background Previous studies suggest that genetic polymorphisms and aging modulate inter-individual variability in brain stimulation-induced plasticity. However, the relationship between genetic polymorphisms and behavioral modulation through transcranial direct current stimulation (tDCS) in older adults remains poorly understood. Objective Link individual tDCS responsiveness, operationalized as performance difference between tDCS and sham condition, to common genetic polymorphisms in healthy older adults. Methods 106 healthy older participants from five tDCS-studies were re-invited to donate blood for genotyping of apoliproprotein E (APOE: e4 carriers and e4 non-carriers), catechol-O-methyltransferase (COMT: val/val, val/met, met/met), brain-derived neurotrophic factor (BDNF: val/val, val/met, met/met) and KIdney/BRAin encoding gene (KIBRA: C/C, C/T, T/T). Studies had assessed cognitive performance during tDCS and sham in cross-over designs. We now asked whether the tDCS responsiveness was related to the four genotypes using a linear regression models. Results We found that tDCS responsiveness was significantly associated with COMT polymorphism; i.e., COMT val carriers (compared to met/met) showed higher tDCS responsiveness. No other significant associations emerged. Conclusion Using data from five brain stimulation studies conducted in our group, we showed that only individual variation of COMT genotypes modulated behavioral response to tDCS. These findings contribute to the understanding of inherent factors that explain inter-individual variability in functional tDCS effects in older adults, and might help to better stratify participants for future clinical trials.

Background Head and brain anatomy have been related to e-field strength induced by transcranial electrical stimulation (tES). Individualization based on anatomic factors require high-quality structural magnetic resonance images, which are not always available. Head circumference (HC) can serve as an alternative means, but its linkage to electric field strength has not yet been established. Methods We simulated electric fields induced by tES based on individual T1w- and T2w-images of 47 healthy adults, for four conventional (“standard”) and four corresponding focal (”4x1”) electrode montages. Associations of electric field strength with individual HC were calculated using linear mixed models. Results Larger HC was associated with lower electric field strength across montages. We provide mathematical equations to estimate individual electric field strength based on the HC. Conclusion HC can be used as an alternative to estimate interindividual differences of the tES-induced electric field strength and to prospectively individualize stimulation dose, e.g., in the clinical context.

Variations in head and brain anatomy determine the strength and distribution of electrical fields in humans and may account for inconsistent behavioral and neurophysiological results in transcranial electrical stimulation (tES) studies. However, it is insufficiently understood which anatomical features contribute to the variability of the modelled electric fields, and if their impact varies across age groups. In the present study, we tested the associations of global head anatomy, indexed by extra- and intra-cranial volumes, with electric field measures, comparing young and older adults. We modelled six “conventional” electrode montages typically used in tES studies using SimNIBS software in 40 individuals (20 young, 20 older adults; 20-35, 64-79 years). We extracted individual electric field strengths and focality values for each montage to identify tissue volumes that account for variability of the induced electric fields in both groups. Linear mixed models explained most of the inter-individual variability of the overall induced field strength in the brain, but not of field focality. Higher absolute head volume and relative volume of skin, skull and cerebrospinal fluid (CSF) were associated with lower overall electric field strengths. Additionally, we found interactions of age group with head volume and CSF, indicating that this relationship was mitigated in the older group. Our results demonstrate the importance to adjust brain stimulation not only according to brain atrophy, but also to additional parameters of head anatomy. Future studies need to elucidate the mechanisms underlying individual variability of tES effects in young and older adults, and verify the usefulness of the proposed models in terms of neurophysiology and behavior in empirical studies.

BackgroundLow intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation (tACS or tDCS), applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional magnetic resonance imaging (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies.ObjectiveTo develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency, and reproducibility (ContES Checklist).MethodsA two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists (EP) through the International Network of the tES-fMRI (INTF) Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC based on a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed using the checklist.ResultsExperts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (1) technological factors, (2) safety and noise tests, and (3) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article.ConclusionsUse of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies, and increase methodological transparency and reproducibility.

Non-invasive transcranial stimulation of cerebellum and primary motor cortex (M1) has been shown to enhance motor learning. However, the mechanisms by which stimulation improves learning remain largely unknown. Here, we sought to shed light on the neural correlates of transcranial direct current stimulation (tDCS) during motor learning by simultaneously recording functional magnetic resonance imaging (fMRI). We found that right cerebellar tDCS, but not left M1 tDCS, led to enhanced sequence learning in the serial reaction time task. Performance was also improved following cerebellar tDCS compared to sham in a sequence production task, reflecting superior training effects persisting into the post-training period. These behavioral effects were accompanied by increased learning-specific activity in right M1, left cerebellum lobule VI, left inferior frontal gyrus and right inferior parietal lobule during cerebellar tDCS compared to sham. Despite the lack of group-level changes comparing left M1 tDCS to sham, activity increase in right M1, supplementary motor area, and bilateral superior frontal cortex, under M1 tDCS, was associated with better sequence performance. This suggests that lack of group effects in M1 tDCS relate to inter-individual variability in learning-related activation patterns. We further investigated how tDCS modulates effective connectivity in the cortico-striato-cerebellar learning network. Using dynamic causal modelling, we found altered connectivity patterns during both M1 and cerebellar tDCS when compared to sham. Specifically, during cerebellar tDCS, negative modulation of a connection from putamen to cerebellum was decreased for sequence learning only, effectively leading to decreased inhibition of the cerebellum. These results show specific effects of cerebellar tDCS on functional activity and connectivity in the motor learning network and may facilitate the optimization of motor rehabilitation involving cerebellar non-invasive stimulation.

IntroductionA substantial number of patients diagnosed with COVID-19 experience long-term persistent symptoms. First evidence suggests that long-term symptoms develop largely independently of disease severity and include, among others, cognitive impairment. For these symptoms, there are currently no validated therapeutic approaches available. Cognitive training interventions are a promising approach to counteract cognitive impairment. Combining training with concurrent transcranial direct current stimulation (tDCS) may further increase and sustain behavioural training effects. Here, we aim to examine the effects of cognitive training alone or in combination with tDCS on cognitive performance, quality of life and mental health in patients with post-COVID-19 subjective or objective cognitive impairments.Methods and analysisThis study protocol describes a prospective randomised open endpoint-blinded trial. Patients with post-COVID-19 cognitive impairment will either participate in a 3-week cognitive training or in a defined muscle relaxation training (open-label interventions). Irrespective of their primary intervention, half of the cognitive training group will additionally receive anodal tDCS, all other patients will receive sham tDCS (double-blinded, secondary intervention). The primary outcome will be improvement of working memory performance, operationalised by an n-back task, at the postintervention assessment. Secondary outcomes will include performance on trained and untrained tasks and measures of health-related quality of life at postassessment and follow-up assessments (1 month after the end of the trainings).Ethics and disseminationEthical approval was granted by the Ethics Committee of the University Medicine Greifswald (number: BB 066/21). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences.Trial registration numberNCT04944147.

Background Given the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer’s disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stimulation (tDCS) to be an effective method to boost cognitive performance, especially when applied in combination with cognitive training in healthy older adults. So far, no studies combining tDCS concurrent with an intense multi-session cognitive training in prodromal AD populations have been conducted. Methods The AD-Stim trial is a monocentric, randomized, double-blind, placebo-controlled study, including a 3-week tDCS-assisted cognitive training with anodal tDCS over left DLPFC (target intervention), compared to cognitive training plus sham (control intervention). The cognitive training encompasses a letter updating task and a three-stage Markov decision-making task. Forty-six participants with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) will be randomized block-wise to either target or control intervention group and participate in nine interventional visits with additional pre- and post-intervention assessments. Performance in the letter updating task after training and anodal tDCS compared to sham stimulation will be analyzed as primary outcome. Further, performance on the second training task and transfer tasks will be investigated. Two follow-up visits (at 1 and 7 months post-training) will be performed to assess possible maintenance effects. Structural and functional magnetic resonance imaging (MRI) will be applied before the intervention and at the 7-month follow-up to identify possible neural predictors for successful intervention. Significance With this trial, we aim to provide evidence for tDCS-induced improvements of multi-session cognitive training in participants with SCD and MCI. An improved understanding of tDCS effects on cognitive training performance and neural predictors may help to develop novel approaches to counteract cognitive decline in participants with prodromal AD. Trial registration ClinicalTrials.gov, NCT04265378. Registered on 07 February 2020. Retrospectively registered. Protocol version: Based on BB 004/18 version 1.2 (May 17, 2019). Sponsor: University Medicine Greifswald.

Ageing involves significant neurophysiological changes that are both systematic while at the same time exhibiting divergent trajectories across individuals. These changes underlie cognitive impairments in elderly while also affecting the response of aged brains to interventions like transcranial direct current stimulation (tDCS). While the cognitive benefits of tDCS are more variable in elderly, older adults also respond differently to stimulation protocols compared to young adults. The age-related neurophysiological changes influencing the responsiveness to tDCS remain to be addressed in-depth. We review and discuss the premise that, in comparison to the better calibrated brain networks present in young adults, aged systems perform further away from a homoeostatic set-point. We argue that this age-related neurophysiological deviation from the homoeostatic optimum extends the leeway for tDCS to modulate the aged brain. This promotes the potency of immediate tDCS effects to induce directional plastic changes towards the homoeostatic equilibrium despite the impaired plasticity induction in elderly. We also consider how age-related neurophysiological changes pose specific challenges for tDCS that necessitate proper adaptations of stimulation protocols. Appreciating the distinctive properties of aged brains and the accompanying adjustment of stimulation parameters can increase the potency and reliability of tDCS as a treatment avenue in older adults. Special Issue:SI

Executive functioning of two simultaneous component tasks in dual-task situations is primarily associated with activation of the lateral prefrontal cortex (PFC), as demonstrated in functional imaging studies. However, the precise role of the lateral PFC and the causal relation between this area's activity and executive functioning in dual tasks has exclusively been demonstrated for the left lateral PFC so far. To investigate this relation for the right lateral PFC, we used anodal transcranial direct current stimulation (atDCS; 1 mA, 20 min) in contrast to sham stimulation (1 mA, 30 s) in Experiment 1 (N = 30) as well as cathodal transcranial direct current stimulation (ctDCS; 1 mA, 20 min) in contrast to sham stimulation (1 mA, 30 s) in Experiment 2 (N = 25) over the right inferior frontal junction under conditions of random task order in dual tasks; random dual tasks require decisions on task order and thus high demands on executive functioning. Across these experiments, our results showed different tDCS-related effects: while atDCS improved performance evident from reduced error rates (Experiment 1), ctDCS impaired dual-task performance and increased these rates (Experiment 2). Moreover, baseline performance correlated with tDCS-induced performance changes, indicating that baseline performance was associated with atDCS-induced improvement. Our findings suggest that dual-task performance is causally related to right lateral PFC activation under conditions that require executive functioning as well as cognitive control of task sets and task order.

Executive functions define a set of general-purpose control mechanisms that modulate the operation of cognitive subprocesses and regulate the dynamics of human cognition. Core components of executive functioning are shifting (i.e., task switching, dual tasking), updating, and inhibition. These components are associated with activation in the prefrontal cortex in brain imaging studies. The present review investigates whether different levels of prefrontal activation are related with performance modulations in executive functions. Therefore, we summarize studies that have used a noninvasive brain stimulation technique, namely transcranial direct current stimulation (tDCS), during performance in executive tasks. This summary demonstrates that tDCS leads to modulations of all core components of executive functioning. Furthermore, the present review makes assumptions about the cognitive mechanisms underlying these tDCS-related modulations. The current state of the literature allows generating such assumptions at least for the components dual tasking and updating.

Background: With increasing aging populations worldwide, developing interventions against age-associated cognitive decline is particularly important. Evidence suggests that combination of brain stimulation with cognitive training intervention may enhance training effects in terms of performance gain or transfer to untrained domains. This protocol describes a Phase IIb clinical trial that investigates the intervention effects of training combined with brain stimulation in older adults. Methods: The TrainStim study is a monocentric, randomized, single-blind, placebo-controlled intervention. The study will investigate cognitive training with concurrent anodal tDCS (transcranial direct current stimulation) over the left dorsolateral prefrontal cortex (target intervention) compared to cognitive training with sham stimulation (control intervention) over nine sessions in three weeks, consisting of a letter updating task and a three-stage Markov decision-making task. Fifty-six older adults will be recruited from the general population. Baseline assessment will be performed including neuropsychological screening and performance on training tasks. Participants will be allocated to one of the two study arms using block-wise randomization stratified by age and baseline performance with a 1:1 allocation ratio. Primary outcome is performance in the letter updating task after training under anodal tDCS compared to sham stimulation. Secondary outcomes include performance changes in the decision-making task and transfer tasks, as well as brain structure and functional networks assessed by structural and functional magnetic resonance imaging that are acquired pre- and post-intervention. Significance: The main aim of the TrainStim study is to provide evidence for behavioral and neuronal effects of tDCS-accompanied cognitive training and to elucidate the underlying mechanisms in older adults. Our findings will contribute towards developing efficient interventions for age-associated cognitive decline. Trial registration: This trial was retrospectively registered at ClinicalTrials.gov with the Identifier: NCT03838211 at February 12, 2019. https://clinicaltrials.gov/ct2/show/NCT03838211 Protocol version: Based on BB 004/18 version 1.2 (May, 17, 2019).

Numerical simulation of the electric fields induced by non-invasive brain stimulation (NIBS), using realistic anatomical head models has gained interest in recent years for understanding the NIBS effects in individual subjects. Although automated tools for generating the head models and performing the electric field simulations have become available, individualized modelling is still not a standard practice in NIBS studies. This is likely partly explained by the lack of robustness and usability of the previously available software tools, and partly by the still developing understanding of the link between physiological effects and electric field distributions in the brain. To facilitate individualized modelling in NIBS, we have introduced the SimNIBS (Simulation of NIBS) software package, providing easy-to-use automated tools for electric field modelling. In this chapter, we give an overview of the modelling pipeline in SimNIBS 2.1, with step-by-step examples of how to run a simulation. Furthermore, we demonstrate a set of scripts for extracting average electric fields for a group of subjects, and finally demonstrate the accuracy of automated placement of standard electrode montages on the head model. SimNIBS 2.1 is freely available at www.simnibs.org .

As we age, the brain not only undergoes structural changes, but also a cascade of neurophysiological and neurochemical changes. These age-related changes result in declines in cognition, motor, and sensory function, even in the absence of neurological or neurodegenerative disease. Transcranial direct current stimulation-based effects on neuronal activity, neuroplastic response of tissue, and modulation of hyper vs. hypo active brain systems may have significant benefit for ameliorating symptoms of advanced aging in the brain. However, there are significant practical, technical and methodological considerations necessary for appropriately designing and implementing tDCS in aging populations. In this chapter, we will discuss the impact of brain atrophy and comorbid age-related conditions on tDCS, as well as potential modifying effects of medications commonly used in older adults. This chapter will describe appropriate considerations for selection of functional outcomes for tDCS studies in older adults. This will include discussion of relevant changes in motor and cortical excitability with age that can impact tDCS outcomes. We then review evidence for effects of tDCS on age-related cognitive, physical and motor function, and sensory processing while paying special attention to methodological challenges in these domains. This chapter will also cover special considerations for the adjunctive use of tDCS with electrophysiology and functional magnetic resonance imaging in older adults, and specific ethical consideration of tDCS use in this population. Finally, the chapter will examine additional considerations for the application of tDCS for purposes of enhancing function in healthy seniors in the absence of disease states.

Action comprehension that is related to language or gestural integration has been shown to engage the motor system in the brain, thus providing preliminary evidence for the gestural-verbal embodiment concept. Based on the involvement of the sensorimotor cortex (M1) in language processing, we aimed to further explore its role in the cognitive embodiment necessary for gestural-verbal integration. As such, we applied anodal (excitatory) and sham transcranial direct current stimulation (tDCS) over the left M1 (with reference electrode over the contralateral supraorbital region) during a gestural-verbal integration task where subjects had to make a decision about the semantic congruency of the gesture (prime) and the word (target). We used a cross-over within-subject design in young subjects. Attentional load and simple reaction time (RT) tasks served as control conditions, applied during stimulation (order of three tasks was counterbalanced). Our results showed that anodal (atDCS) compared to sham tDCS (stDCS) reduced RTs in the gestural-verbal integration task, specifically for incongruent pairs of gestures and verbal expressions, with no effect on control task performance. Our findings provide evidence for the involvement of the sensorimotor system in gestural-verbal integration performance. Further, our results suggest that functional modulation induced by sensorimotor tDCS may be specific to gestural-verbal integration. Future studies should now evaluate the modulatory effect of tDCS on semantic congruency by using tDCS over additional brain regions and include assessments of neural connectivity.

Background Recent research on neural and behavioral consequences of transcranial direct current stimulation (tDCS) has highlighted the impact of individual factors, such as brain anatomy which determines current field distribution and may thus significantly impact stimulation effects. Computational modeling approaches may significantly advance our understanding of such factors, but the association of simulation-based tDCS-induced fields and neurophysiological outcomes has not been investigated. Objectives To provide empirical evidence for the relationship between tDCS-induced neurophysiological outcomes and individually induced electric fields. Methods We applied tDCS during eyes-closed resting-state functional resonance imaging (rsfMRI) and assessed pre-post magnetic resonance spectroscopy (MRS) in 24 participants. We aimed to quantify effects of 15-min tDCS using the “classical” left SM1-right supraorbital area montage on sensorimotor network (SMN) strength and gamma-aminobutyric acid (GABA) and glutamate concentrations, implementing a cross-over counterbalanced design with three stimulation conditions. Additional structural anatomical MRI sequences and recordings of individual electrode configurations allowed individual electric field simulations based on realistic head models of all participants for both conditions. Results On a neurophysiological level, we observed the expected reduction of GABA concentrations and increase in SMN strength, both during anodal and cathodal compared to sham tDCS, replicating previous results. The magnitudes of neurophysiological modulations induced by tDCS were significantly associated with simulation-based electric field strengths within the targeted left precentral gyrus. Conclusion Our findings corroborate previous reports on tDCS-induced neurophysiological modulations and further advance the understanding of underlying mechanisms by providing first empirical evidence for the association of the injected electric field and neuromodulatory effects.

Background Previous studies have demonstrated an enhancement of hippocampal-dependent declarative memory consolidation, associated slow wave sleep (SWS) and slow wave activity (SWA) after weak slow oscillatory stimulation (so-tDCS) during early non-rapid eye movement sleep (NREM) in young adults. Recent studies in older individuals could not confirm these findings. However, it remained unclear if this difference was due to variations in study protocol or to the age group under study. Objective/Hypothesis Here, we asked if so-tDCS promotes neurophysiological events and associated sleep-dependent memory in the visuo-spatial domain in older adults, using a stimulation protocol that closely resembled the one employed in young adults. Methods In a randomized, placebo-controlled single-blind (participant) crossover study so-tDCS (0.75 Hz; max. current density 0.522 mA/cm 2 ) vs. sham stimulation was applied over the frontal cortex of 21 healthy older subjects. Impact of stimulation on frequency band activity (linear mixed models), two declarative and one procedural memory tasks (repeated measures ANOVA) and percentage of sleep stages (comparison of means) was assessed. Results so-tDCS, as compared to sham, increased SWA and spindle activity immediately following stimulation, accompanied by significantly impaired visuo-spatial memory consolidation. Furthermore, verbal and procedural memory remained unchanged, while percentage of NREM sleep stage 4 was decreased over the entire night (uncorrected). Conclusion so-tDCS increased SWA and spindle activity in older adults, events previously associated with stimulation-induced improved consolidation of declarative memories in young subjects. However, consolidation of visuo-spatial (primary outcome) and verbal memories was not beneficially modulated, possibly due to decline in SWS over the entire night that may have prevented and even reversed immediate beneficial effects of so-tDCS on SWA.

Transkranielle Gleichstromstimulation (tDCS) ist mittlerweile ein gangiges Verfahren in den Neurowissenschaften, mit dem sich kognitive Funktionen modulieren lassen. Aktuelle Studien legen nahe, dass uber die Modulation neuronaler Aktivitat und Konnektivitat eine Verbesserung der behavioralen Leistung erzielt werden kann. Demnach stellt die tDCS auch im klinischen Kontext ein vielversprechendes Verfahren zur Restitution beeintrachtigter Funktionen des Gedachtnisses infolge der Alzheimer-Krankheit oder der Aphasie nach einem Schlaganfall dar. Jedoch gibt es bisher nur wenige Befunde aus randomisierten, placebokontrollierten klinischen Studien. Die Ergebnisse der tDCS-induzierten Leistungsverbesserung bei Patienten mit (Pra-)Demenz deuten darauf hin, dass eine mit einem Gedachtnistraining kombinierte Stimulation zu Verbesserungen fuhren konnte. Die fruhe Intervention bereits im Stadium der leichten kognitiven Beeintrachtigung konnte dabei entscheidend sein, bedarf aber weiterer Studien. Bei Patienten mit schlaganfallbedingter Aphasie zeigten sich unterschiedliche Erfolge links- oder rechtshemispharischer tDCS je nach Polaritat und Schwere der Symptomatik. Patienten mit leichter Aphasie konnten hierbei besonders von der Stimulation der sprachdominanten Hirnhalfte profitieren, wahrend bei schwerer Aphasie ein Ausweichen auf rechtshemispharische homologe Areale Erfolg versprechend ist. Auch hier konnte die Applikation der tDCS bereits im subakuten Stadium besonders vielversprechend sein. Insgesamt eroffnet die tDCS also die Moglichkeit der Funktionsrestitution bei neurologischen Patienten. Ob die Stimulation in der Praxis eingesetzt werden kann, um weiteren Funktionsverlust bei neurodegenerativen Prozessen zu verhindern, und ob die in experimentellen Studien gezeigten Verbesserungen auch langfristig die Alltagsaktivitaten verbessern, muss in kunftigen Studien geklart werden.

Abstract. Executive processing in the task switching paradigm is primarily associated with activation of the lateral prefrontal cortex (lPFC), demonstrated in numerous functional imaging studies (e.g., Brass & von Cramon, 2002 ). However, there are only very few attempts to modulate neural activation related with executive functions and to investigate the effects of this modulation on the performance in this paradigm. To modulate lPFC activity here, we used the non-invasive transcranial Direct Current Stimulation (tDCS; atDCS [1 mA, 20 min] vs. ctDCS [1 mA, 20 min] vs. sham stimulation [1 mA, 30 s]) over the left inferior frontal junction under conditions of single tasks, task repetitions, and task switches in the task switching paradigm. We assessed the performance effects of online tDCS on mixing costs (single tasks vs. task repetitions) as well as on switching costs (task repetitions vs. task switches). In a within-subjects design across three sessions, there was no evidence of stimulation on the magnitude of these cost types. However, when taking a between-subjects perspective in the first session (i.e., after excluding dominant effects of task experience), atDCS showed an increase in mixing costs in contrast to ctDCS and sham. We interpreted this finding in the context of task switching theories on task activation and task inhibition and their neural localizations.

Functional magnetic resonance imaging (fMRI) studies have suggested that advanced age may mediate the effects of transcranial direct current stimulation (tDCS) on brain function. However, studies directly comparing neural tDCS effects between young and older adults are scarce and limited to task-related imaging paradigms. Resting-state (rs-) fMRI, that is independent of age-related differences in performance, is well suited to investigate ageassociated differential neural tDCS effects. Three “online” tDCS conditions (anodal, cathodal, sham) were compared in a cross-over, within-subject design, in 30 young and 30 older adults. Active stimulation targeted the left sensorimotor network (active electrode over left sensorimotor cortex with right supraorbital reference electrode). A graph-based rs-fMRI data analysis approach (eigenvector centrality mapping) and complementary seed-based analyses characterized neural tDCS effects. An interaction between anodal tDCS and age group was observed. Specifically, centrality in bilateral paracentral and posterior regions (precuneus, superior parietal cortex) was increased in young, but decreased in older adults. Seed-based analyses revealed that these opposing patterns of tDCS-induced centrality modulation were explained from differential effects of tDCS on functional coupling of the stimulated left paracentral lobule. Cathodal tDCS did not show significant effects. Our study provides first evidence for differential tDCS effects on neural network organization in young and older adults. Anodal stimulation mainly affected coupling of sensorimotor with ventromedial prefrontal areas in young and decoupling with posteromedial areas in older adults.

Transcranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults, in whom the majority of studies have been conducted, cannot be easily transferred to older populations. Here, we investigated tDCS-induced effects in older adults (N= 48; age range, 50–79 years) using magnetic resonance spectroscopy to quantify GABA levels as well as resting-state functional magnetic resonance imaging to assess sensorimotor network strength and interhemispheric connectivity. In a randomized, counterbalanced, crossover design, we applied anodal tDCS (atDCS), cathodal tDCS (ctDCS), and sham tDCS (stDCS) over the left sensorimotor region. We observed a significant reduction of GABA levels after atDCS compared with stDCS, reflecting the preserved neuromodulatory effect of atDCS in older adults. Moreover, resting-state functional coupling was decreased during atDCS compared with stDCS, most likely indicating augmented efficiency in brain network functioning. Increased levels of interhemispheric connectivity with age were diminished by atDCS, suggesting stimulation-induced functional decoupling. Further, the magnitude of atDCS-induced local plasticity was related to baseline functional network strength. Our findings provide novel insight into the neuronal correlates underlying tDCS-induced neuronal plasticity in older adults and thus might help to develop tDCS interventions tailored to the aging brain.SIGNIFICANCE STATEMENTTranscranial direct current stimulation (tDCS) modulates human behavior, neuronal patterns, and metabolite concentrations, with exciting potential for neurorehabilitation. However, the understanding of tDCS-induced alterations on the neuronal level is incomplete, and conclusions from young adults cannot be easily transferred to older populations. We used a systematic multimodal imaging approach to investigate the neurophysiological effects of tDCS in older adults and found stimulation-induced effects on GABA levels, reflecting augmented local plasticity and functional connectivity, suggesting modulation of network efficiency. Our findings may help to reconcile some of the recent reports on the variability of tDCS-induced effects, not only implicating age as a crucial modulating factor, but detailing its specific impact on the functionality of neural networks.

Degradation of brain white matter components is partly responsible for memory loss in the course of healthy aging. However, the exact tract parameters responsible for this deterioration need more investigation. From young adults, evidence suggests a relationship of white matter microstructure and memory components. However, studies with older adults are still scarce. In the present study, three main memory networks were reconstructed individually using probabilistic tractography: the parahippocampal cingulum, the uncinate fasciculus and the fornix. A sample of 30 older adults between the age of 50 and 79 years were administered an implicit learning and memory paradigm and diffusion tensor imaging (DTI) was performed to extract the fractional anisotropy (FA) and the mean diffusivity (MD) of each tract. Memory performance was assessed after the acquisition of the novel vocabulary. Association of tract parameters (adjusted for age) with memory performance were investigated. Consistent with previous evidence, FA was negatively and MD was positively related to higher age. In addition, lower memory performance was associated with fornix microstructure degradation, but not with other structural parameters such as parahippocampal, uncinate microstructure or volume. Our findings suggest that particularly fornix degradation is a predictor of age-related cognitive decline.

Cognitive neuroscience of the healthy aging human brain has thus far addressed age-related changes of local functional and structural properties of gray and white matter and their association with declining or preserved cognitive functions. In addition to these localized changes, recent neuroimaging research has attributed an important role to neural networks with a stronger focus on interacting rather than isolated brain regions. The analysis of functional connectivity encompasses task-dependent and -independent synchronous activity in the brain, and thus reflects the organization of the brain in distinct performance-relevant networks. Structural connectivity in white matter pathways, representing the integrity of anatomical connections, underlies the communication between the nodes of these functional networks. Both functional and structural connectivity within these networks have been demonstrated to change with aging, and to have different predictive values for cognitive abilities in older compared to young adults. Structural degeneration has been found in the entire cerebral white matter with greatest deterioration in frontal areas, affecting whole brain structural network efficiency. With regard to functional connectivity, both higher and lower functional coupling has been observed in the aging compared to the young brain. Here, high connectivity within the nodes of specific functional networks on the one hand, and low connectivity to regions outside this network on the other hand, were associated with preserved cognitive functions in aging in most cases. For example, in the language domain, connections between left-hemisphere language-related prefrontal, posterior temporal and parietal areas were described as beneficial, whereas connections between the left and right hemisphere were detrimental for language task performance. Of note, interactions between structural and functional network properties may change in the course of aging and differentially impact behavioral performance in older versus young adults. Finally, studies using noninvasive brain stimulation techniques like transcranial direct current stimulation (tDCS) to simultaneously modulate behavior and functional connectivity support the importance of ‘selective connectivity' of aging brain networks for preserved cognitive functions. These studies demonstrate that enhancing task performance by tDCS is paralleled by increased connectivity within functional networks. In this review, we outline the network perspective on healthy brain aging and discuss recent developments in this field.

The rising proportion of elderly people worldwide will yield an increased incidence of age-associated cognitive impairments, imposing major burdens on societies. Consequently, growing interest emerged to evaluate new strategies to delay or counteract cognitive decline in aging. Here, we assessed immediate effects of anodal transcranial direct current stimulation (atDCS) on cognition and previously described detrimental changes in brain activity attributable to aging. Twenty healthy elderly adults were assessed in a crossover sham-controlled design using functional magnetic resonance imaging (fMRI) and concurrent transcranial DCS administered to the left inferior frontal gyrus. Effects on performance and task-related brain activity were evaluated during overt semantic word generation, a task that is negatively affected by advanced age. Task-absent resting-state fMRI (RS-fMRI) assessed atDCS-induced changes at the network level independent of performance. Twenty matched younger adults served as controls. During sham stimulation, task-related fMRI demonstrated that enhanced bilateral prefrontal activity in older adults was associated with reduced performance. RS-fMRI revealed enhanced anterior and reduced posterior functional brain connectivity. atDCS significantly improved performance in older adults up to the level of younger controls; significantly reduced task-related hyperactivity in bilateral prefrontal cortices, the anterior cingulate gyrus, and the precuneus; and induced a more “youth-like” connectivity pattern during RS-fMRI. Our results provide converging evidence from behavioral analysis and two independent functional imaging paradigms that a single session of atDCS can temporarily reverse nonbeneficial effects of aging on cognition and brain activity and connectivity. These findings may translate into novel treatments to ameliorate cognitive decline in normal aging in the future.

Anodale transkranielle Gleichstromstimulation (anodal transcranial direct current stimulation, atDCS) kann kognitive Funktionen bei Menschen verbessern. Die neuronalen Grundlagen ihrer Funktionsweise wurden allerdings bisher noch unzureichend untersucht. In einer Plazebo-kon­trollierten Studie untersuchten wir daher die neuronalen Korrelate der Leistungsverbesserung in einer semantischen Wortfindungsaufgabe mittels funktioneller Magnetresonanztomografie (fMRT) bei gleichzeitiger Stimulation des linken Gyrus frontalis inferior (IFG), einem zentralen sprachrelevanten Gehirnareal. atDCS wurde dabei im MRT wahrend der Aufgabendurchfuhrung appliziert. Simultan gemessene aufgaben-spezifische sowie aufgaben-unabhangige Ruhe-fMRT (sog. resting-state) Messungen dienten zur Charakterisierung der Auswirkung von atDCS auf Hirnfunktionen. Der durch atDCS signifikant verbesserte Wortabruf ging mit einer selektiven Aktivitatsreduktion im linken ventralen IFG einher, welcher speziell fur semantische Abrufprozesse eine Rolle spielt. Des Weiteren erhohte atDCS die funktionelle Konnektivitat des linken IFG und anderer sprachrelevanter Hirnareale im Rahmen der Ruhe-fMRT Untersuchung. Zusammenfassend konnte gezeigt werden, dass atDCS bedingte Leistungsverbesserungen mit charakteristischen Veranderungen von Hirnaktivitat- und Konnektivitat assoziiert sind, die u. U. erhohte Verarbeitungseffizienz widerspiegeln.

As well as consolidating memory, sleep has been proposed to serve a second important function for memory, i.e. to free capacities for the learning of new information during succeeding wakefulness. The slow wave activity (SWA) that is a hallmark of slow wave sleep could be involved in both functions. Here, we aimed to demonstrate a causative role for SWA in enhancing the capacity for encoding of information during subsequent wakefulness, using transcranial slow oscillation stimulation (tSOS) oscillating at 0.75 Hz to induce SWA in healthy humans during an afternoon nap. Encoding following the nap was tested for hippocampus-dependent declarative materials (pictures, word pairs, and word lists) and procedural skills (finger sequence tapping). As compared with a sham stimulation control condition, tSOS during the nap enhanced SWA and significantly improved subsequent encoding on all three declarative tasks (picture recognition, cued recall of word pairs, and free recall of word lists), whereas procedural finger sequence tapping skill was not affected. Our results indicate that sleep SWA enhances the capacity for encoding of declarative materials, possibly by down-scaling hippocampal synaptic networks that were potentiated towards saturation during the preceding period of wakefulness.

Sleep-related consolidation of declarative memories, as well as associated neurophysiological events such as slow oscillatory and spindle activity, deteriorate in the course of aging. This process is accelerated in neurodegenerative disease. Transcranial slow oscillatory stimulation (so-tDCS) during sleep has been shown to enhance slow oscillatory brain activity and thereby improve memory consolidation in young subjects. Here, we investigated whether so-tDCS applied to older adults during an afternoon nap exerts similar effects. Eighteen older human subjects were assessed using visuo-spatial (picture memory, primary, and location memory) and verbal memory tasks before and after a 90-min nap either comprising weak so-tDCS at 0.75Hz over fronto-central location or sham (no) stimulation in a within-subject design. Electroencephalographic activity was recorded throughout the naps and immediate effects of stimulation on brain activity were evaluated. Here, spectral power within three frequency bands of interest were computed, i.e., slow oscillatory activity, slow spindle and fast spindle activity; in 1-min stimulation-free intervals following 5 stimulation blocks. So-tDCS significantly increased frontal slow oscillatory activity as well as fast spindle activity, and significantly improved picture memory retention after sleep. Retention in the location memory subtask and in the verbal memory task was not affected. These findings may indicate a novel strategy to counteract cognitive decline in aging in a convenient manner during brief daytime naps.

Recently, transcranial alternating current stimulation (tACS) has emerged as a tool to enhance human cognitive processes. Here, we provide a brief summary of the rationale behind tACS-induced effects on task-relevant brain oscillations and associated cognitive functions and review previous studies in young subjects that have applied tACS in cognitive paradigms. Additionally, we present pilot data where we administered theta-tACS (6 Hz) over the temporoparietal cortex and a supraorbital reference for 20 min during implicit language learning in healthy young (mean/SD age: 22/2) and older (mean/SD age: 66/4) adults, in a sham-controlled crossover design. Linear mixed models revealed significantly increased retrieval accuracy following tACS-accompanied associative learning, after controlling for session order and learning success. These data provide the first implementation of tACS during cognitive performance in older adults and support recent studies suggesting that tACS in the theta frequency range may serve as a tool to enhance cognition, possibly through direct modulation of task-relevant brain oscillations. So far, studies have been heterogeneous in their designs, leaving a number of issues to be addressed in future research, including the setup of electrodes and optimal stimulation frequencies to be employed, as well as the interaction with age and underlying brain pathologies in specific patient populations.

Excitatory anodal transcranial direct current stimulation (atDCS) can improve human cognitive functions, but neural underpinnings of its mode of action remain elusive. In a cross-over placebo (“sham”) controlled study we used functional magnetic resonance imaging (fMRI) to investigate neurofunctional correlates of improved language functions induced by atDCS over a core language area, the left inferior frontal gyrus (IFG). Intrascanner transcranial direct current stimulation-induced changes in overt semantic word generation assessed behavioral modulation; task-related and task-independent (resting-state) fMRI characterized language network changes. Improved word-retrieval during atDCS was paralleled by selectively reduced task-related activation in the left ventral IFG, an area specifically implicated in semantic retrieval processes. Under atDCS, resting-state fMRI revealed increased connectivity of the left IFG and additional major hubs overlapping with the language network. In conclusion, atDCS modulates endogenous low-frequency oscillations in a distributed set of functionally connected brain areas, possibly inducing more efficient processing in critical task-relevant areas and improved behavioral performance.

Introduction Transcranial direct current stimulation (tDCS) has emerged as an efficient tool to enhance cognitive functioning in young as well as older adults. The underlying neuronal mechanisms, however, are still insufficiently understood. Especially studies investigating neuronal correlates of tDCS-induced plasticity in healthy older adults are rare. Objectives The objective of the study was to investigate the mechanisms underlying tDCS-induced neuronal modulation in a group of healthy older adults. In particular, alterations in resting state functional connectivity within the motor network as well as GABA concentration within the primary motor cortex were examined. Materials and methods In this study, we assessed the effects of anodal, cathodal, and sham tDCS over the left primary motor cortex on functional connectivity of the motor network and GABA concentration in a group of healthy older adults. Stimulation of 1 mA was applied for 15 min with anodal or cathodal polarity; for 30 s in sham stimulation. The three stimulation conditions were separated by at least one week and their order was counterbalanced across the group. GABA concentration was assessed by MRS using MEGA-PRESS at 3 T before and after the stimulation interval. Resting-state fMRI scans were obtained twice during stimulation, separated by a break of 3 min. Results In line with previous studies with young adults, GABA concentration change was lower in the anodal tDCS condition as compared to the sham tDCS condition. Resting state motor networks showed a reduced inter-hemispheric functional connectivity between left and right primary motor cortices during anodal tDCS compared to cathodal and sham tDCS. This observation is consistent with results in young and older adults that have assessed tDCS-induced alterations of inter-hemispheric functional connectivity during resting-state fMRI. Conclusion Our study demonstrates tDCS-induced neuronal plasticity in healthy older adults. This observed reorganization of the functional architecture of the motor cortex is in line with recent tDCS studies in young adults, however, research results are still heterogeneous. In sum, our data suggests that anodal tDCS induced a functional decoupling of motor cortices, indicating a reversal of age-related effects on inter-hemispheric connectivity.