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Healthy aging often entails a decline in cognitive and motor functions, affecting independence and quality of life in older adults. Brain stimulation shows potential to enhance these functions, but studies show variable effects. Previous studies have tried to identify responders and non-responders through correlations between behavioral change and baseline parameters, but results lack generalization to independent cohorts. We propose a method to predict an individual's likelihood of benefiting from stimulation, based on baseline performance of a sequential motor task. Our results show that individuals with less efficient learning mechanisms benefit from stimulation, while those with optimal learning strategies experience none or even detrimental effects. This differential effect, first identified in a public dataset and replicated here in an independent cohort, was linked to one's ability to integrate task-relevant information and not age. This study constitutes a further step towards personalized clinical-translational interventions based on brain stimulation., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Because of the depth of the hippocampal-entorhinal complex (HC-EC) in the brain, understanding of its role in spatial navigation via neuromodulation was limited in humans. Here, we aimed to better elucidate this relationship in healthy volunteers, using transcranial temporal interference electric stimulation (tTIS), a noninvasive technique allowing to selectively neuromodulate deep brain structures. We applied tTIS to the right HC-EC in either continuous or intermittent theta-burst stimulation patterns (cTBS or iTBS), compared to a control condition, during a virtual reality-based spatial navigation task and concomitant functional magnetic resonance imaging. iTBS improved spatial navigation performance, correlated with hippocampal activity modulation, and decreased grid cell-like activity in EC. Collectively, these data provide the evidence that human HC-EC activity can be directly and noninvasively modulated leading to changes of spatial navigation behavior. These findings suggest promising perspectives for patients suffering from cognitive impairment such as following traumatic brain injury or dementia.

Aging populations face significant cognitive challenges, particularly in working memory (WM). Transcranial alternating current stimulation (tACS) offer promising avenues for cognitive enhancement, especially when inspired by brain physiology. This study (NCT04986787) explores the effect of multifocal tACS on WM performance in healthy older adults, focusing on fronto-parietal network modulation. Individualized physiology-inspired tACS applied to the fronto-parietal network was investigated in two blinded cross-over experiments. The first experiment involved monofocal/bifocal theta-tACS to the fronto-parietal network, while in the second experiment cross-frequency theta-gamma interactions between these regions were explored. Participants have done online WM tasks under the stimulation conditions. Network connectivity was assessed via rs-fMRI and multichannel electroencephalography. Prefrontal monofocal theta tACS modestly improved WM accuracy over sham (d = 0.30). Fronto-parietal stimulation enhanced WM task processing speed, with the strongest effects for bifocal in-phase theta tACS (d = 0.41). Cross-frequency stimulations modestly boosted processing speed with or without impairing task accuracy depending on the stimulation protocol. This research adds to the understanding of physiology-inspired brain stimulation for cognitive enhancement in older subjects., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Reinforcement feedback can improve motor learning, but the underlying brain mechanisms remain underexplored. In particular, the causal contribution of specific patterns of oscillatory activity within the human striatum is unknown. To address this question, we exploited a recently developed non-invasive deep brain stimulation technique called transcranial temporal interference stimulation (tTIS) during reinforcement motor learning with concurrent neuroimaging, in a randomized, sham-controlled, double-blind study. Striatal tTIS applied at 80 Hz, but not at 20 Hz, abolished the benefits of reinforcement on motor learning. This effect was related to a selective modulation of neural activity within the striatum. Moreover, 80 Hz, but not 20 Hz, tTIS increased the neuromodulatory influence of the striatum on frontal areas involved in reinforcement motor learning. These results show that tTIS can non-invasively and selectively modulate a striatal mechanism involved in reinforcement learning, expanding our tools for the study of causal relationships between deep brain structures and human behaviour., (© 2024. The Author(s).)

Background: Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke., Methods: Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation., Results: From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns ( P cluster <0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics., Conclusions: The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery., Competing Interests: Disclosures Dr Hummel serves as a board member for Novartis Foundation for Medical-Biological Research. Dr Blanke is a cofounder and a shareholder of Metaphysiks Engineering Société Anonyme, a company that develops immersive technologies, including applications of the robotic induction of presence hallucinations that are not related to the diagnosis, prognosis, or treatment in medicine. Dr Blanke is a member of the board and a shareholder of Mindmaze Société Anonyme.

Background: Phase synchronization over long distances underlies inter-areal communication and importantly, modulates the flow of information processing to adjust to cognitive demands., Objective: This study investigates the impact of single-session, cross-frequency (Alpha-Gamma) bifocal transcranial alternating current stimulation (cf-tACS) to the cortical visual motion network on inter-areal coupling between the primary visual cortex (V1) and the medio-temporal area (MT) and on motion direction discrimination., Methods: Based on the well-established phase-amplitude coupling (PAC) mechanism driving information processing in the visual system, we designed a novel directionally tuned cf-tACS protocol. Directionality of information flow was inferred from the area receiving low-frequency tACS (e.g., V1) projecting onto the area receiving high-frequency tACS (e.g., MT), in this case, promoting bottom-up information flow (Forward-tACS). The control condition promoted the opposite top-down connection (from MT to V1, called Backward-tACS), both compared to a Sham-tACS condition. Task performance and EEG activity were recorded from 45 young healthy subjects. An additional cohort of 16 stroke patients with occipital lesions and impairing visual processing was measured to assess the influence of a V1 lesion on the modulation of V1-MT coupling., Results: The results indicate that Forward cf-tACS successfully modulated bottom-up PAC (V1 α -phase -MT ɣ -amplitude ) in both cohorts, while producing opposite effects on the reverse MT-to-V1 connection. Backward-tACS did not change V1-MT PAC in either direction in healthy participants but induced a slight decrease in bottom-up PAC in stroke patients. However, these changes in inter-areal coupling did not translate into cf-tACS-specific behavioural improvements., Conclusions: Single session cf-tACS can alter inter-areal coupling in intact and lesioned brains but is probably not enough to induce longer-lasting behavioural effects in these cohorts. This might suggest that a longer daily visual training protocol paired with tACS is needed to unveil the relationship between externally applied oscillatory activity and behaviourally relevant brain processing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Swiss Federal School of Technology. Published by Elsevier Inc. All rights reserved.)

Impairment of hand motor function is a frequent consequence after a stroke and strongly determines the ability to regain a self-determined life. An influential research strategy for improving motor deficits is the combined application of behavioral training and non-invasive brain stimulation of the motor cortex (M1). However, a convincing clinical translation of the present stimulation strategies has not been achieved yet. One alternative and innovative approach is to target the functionally relevant brain network-based architecture, e.g., the dynamic interactions within the cortico-cerebellar system during learning. Here, we tested a sequential multifocal stimulation strategy targeting the cortico-cerebellar loop. Anodal transcranial direct current stimulation (tDCS) was applied simultaneously to a hand-based motor training in N = 11 chronic stroke survivors during four training sessions on two consecutive days. The tested conditions were: sequential multifocal (M1-cerebellum (CB)-M1-CB) vs. monofocal control stimulation (M1-sham-M1-sham). Additionally, skill retention was assessed 1 and 10 days after the training phase. Paired-pulse transcranial magnetic stimulation data were recorded to characterize stimulation response determining features. The application of CB-tDCS boosted motor behavior in the early training phase in comparison to the control condition. No faciliatory effects on the late training phase or skill retention were detected. Stimulation response variability was related to the magnitude of baseline motor ability and short intracortical inhibition (SICI). The present findings suggest a learning phase-specific role of the cerebellar cortex during the acquisition of a motor skill in stroke and that personalized stimulation strategies encompassing several nodes of the underlying brain network should be considered., (© 2023. The Author(s).)

Objective . Selective neuromodulation of deep brain regions has for a long time only been possible through invasive approaches, because of the steep depth-focality trade-off of conventional non-invasive brain stimulation (NIBS) techniques. Approach . An approach that has recently emerged for deep NIBS in humans is transcranial Temporal Interference Stimulation (tTIS). However, a crucial aspect for its potential wide use is to ensure that it is tolerable, compatible with efficient blinding and safe. Main results . Here, we show the favorable tolerability and safety profiles and the robust blinding efficiency of deep tTIS targeting the striatum or hippocampus by leveraging a large dataset (119 participants, 257 sessions), including young and older adults and patients with traumatic brain injury. tTIS-evoked sensations were generally rated as 'mild', were equivalent in active and placebo tTIS conditions and did not enable participants to discern stimulation type. Significance . Overall, tTIS emerges as a promising tool for deep NIBS for robust double-blind, placebo-controlled designs., (Creative Commons Attribution license.)

The motor learning process entails plastic changes in the brain, especially in brain network reconfigurations. In the current study, we sought to characterize motor learning by determining changes in the coupling behaviour between the brain functional and structural connectomes on a short timescale. 39 older subjects (age: mean (SD) = 69.7 (4.7) years, men:women = 15:24) were trained on a visually guided sequential hand grip learning task. The brain structural and functional connectomes were constructed from diffusion-weighted MRI and resting-state functional MRI, respectively. The association of motor learning ability with changes in network topology of the brain functional connectome and changes in the correspondence between the brain structural and functional connectomes were assessed. Motor learning ability was related to decreased efficiency and increased modularity in the visual, somatomotor, and frontoparietal networks of the brain functional connectome. Between the brain structural and functional connectomes, reduced correspondence in the visual, ventral attention, and frontoparietal networks as well as the whole-brain network was related to motor learning ability. In addition, structure-function correspondence in the dorsal attention, ventral attention, and frontoparietal networks before motor learning was predictive of motor learning ability. These findings indicate that, in the view of brain connectome changes, short-term motor learning is represented by a detachment of the brain functional from the brain structural connectome. The structure-function uncoupling accompanied by the enhanced segregation into modular structures over the core functional networks involved in the learning process may suggest that facilitation of functional flexibility is associated with successful motor learning., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective. The literature investigating the effects of alpha oscillations on corticospinal excitability is divergent. We believe inconsistency in the findings may arise, among others, from the electroencephalography (EEG) processing for brain-state determination. Here, we provide further insights in the effects of the brain-state on cortical and corticospinal excitability and quantify the impact of different EEG processing. Approach. Corticospinal excitability was measured using motor evoked potential (MEP) peak-to-peak amplitudes elicited with transcranial magnetic stimulation (TMS); cortical responses were studied through TMS-evoked potentials' TEPs features. A TMS-EEG-electromyography (EMG) dataset of 18 young healthy subjects who received 180 single-pulse (SP) and 180 paired pulses (PP) to determine short-intracortical inhibition (SICI) was investigated. To study the effect of different EEG processing, we compared the brain-state estimation deriving from three published methods. The influence of presence of neural oscillations was also investigated. To evaluate the effect of the brain-state on MEP and TEP features variability, we defined the brain-state based on specific EEG phase and power combinations, only in trials where neural oscillations were present. The relationship between TEPs and MEPs was further evaluated. Main results. The presence of neural oscillations resulted in more consistent results regardless of the EEG processing approach. Nonetheless, the latter still critically affected the outcomes, making conclusive claims complex. With our approach, the MEP amplitude was positively modulated by the alpha power and phase, with stronger responses during the trough phase and high power. Power and phase also affected TEP features. Importantly, similar effects were observed in both TMS conditions. Significance. These findings support the view that the brain state of alpha oscillations is associated with the variability observed in cortical and corticospinal responses to TMS, with a tight correlation between the two. The results further highlight the importance of closed-loop stimulation approaches while underlining that care is needed in designing experiments and choosing the analytical approaches, which should be based on knowledge from offline studies to control for the heterogeneity originating from different EEG processing strategies., (Creative Commons Attribution license.)

Background: The indication for mechanical thrombectomy (MT) in stroke patients with large vessel occlusion has been constantly expanded over the past years. Despite remarkable treatment effects at the group level in clinical trials, many patients remain severely disabled even after successful recanalization. A better understanding of this outcome variability will help to improve clinical decision-making on MT in the acute stage. Here, we test whether current outcome models can be refined by integrating information on the preservation of the corticospinal tract as a functionally crucial white matter tract derived from acute perfusion imaging., Methods: We retrospectively analyzed 162 patients with stroke and large vessel occlusion of the anterior circulation who were admitted to the University Medical Center Lübeck between 2014 and 2020 and underwent MT. The ischemic core was defined as fully automatized based on the acute computed tomography perfusion with cerebral blood volume data using outlier detection and clustering algorithms. Normative whole-brain structural connectivity data were used to infer whether the corticospinal tract was affected by the ischemic core or preserved. Ordinal logistic regression models were used to correlate this information with the modified Rankin Scale after 90 days., Results: The preservation of the corticospinal tract was associated with a reduced risk of a worse functional outcome in large vessel occlusion-stroke patients undergoing MT, with an odds ratio of 0.28 (95% CI, 0.15-0.53). This association was still significant after adjusting for multiple confounding covariables, such as age, lesion load, initial symptom severity, sex, stroke side, and recanalization status., Conclusions: A preinterventional computed tomography perfusion-based surrogate of corticospinal tract preservation or disconnectivity is strongly associated with functional outcomes after MT. If validated in independent samples this concept could serve as a novel tool to improve current outcome models to better understand intersubject variability after MT in large vessel occlusion stroke., Competing Interests: Disclosures Dr Fiehler reports compensation from Acandis, MicroVention, Inc, Roche, Medtronic USA, Inc, Stryker Corporation, Tonbridge, Cerenovus, Penumbra, Inc, and Phenox for consultant services. He reports stock holdings in Eppdata and Tegus Medical and employment by Eppdata. Dr Thomalla reports compensation from Boehringer Ingelheim, Alexion Pharmaceuticals, Inc, Daiichi Sankyo Europe GmbH, Bristol Myers Squibb, and Amarin Pharma, Inc, for other services and Bayer, Boehringer Ingelheim, Acandis, Portola Pharmaceuticals LLC, and Stryker for consultant services. He reports grants from FP7 Health. Dr Royl reports compensation from Cardinal Health 200 LLC, AstraZeneca, Boehringer Ingelheim, Ipsen Pharma SAS, and Bristol Myers Squibb for consultant services and Novartis Pharma AG for other services. He reports travel support from Boehringer Ingelheim. The other authors report no conflicts.

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here we show successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, functional magnetic resonance imaging studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as an exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional role. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles., (© 2023. The Author(s).)

Background: Around 25% of patients who have had a stroke suffer from severe upper-limb impairment and lack effective rehabilitation strategies. The AVANCER proof-of-concept clinical trial (NCT04448483) tackles this issue through an intensive and personalized-dosage cumulative intervention that combines multiple non-invasive neurotechnologies., Methods: The therapy consists of two sequential interventions, lasting until the patient shows no further motor improvement, for a minimum of 11 sessions each. The first phase involves a brain-computer interface governing an exoskeleton and multi-channel functional electrical stimulation enabling full upper-limb movements. The second phase adds anodal transcranial direct current stimulation of the motor cortex of the lesioned hemisphere. Clinical, electrophysiological, and neuroimaging examinations are performed before, between, and after the two interventions (T0, T1, and T2). This case report presents the results from the first patient of the study., Findings: The primary outcome (i.e., 4-point improvement in the Fugl-Meyer assessment of the upper extremity) was met in the first patient, with an increase from 6 to 11 points between T0 and T2. This improvement was paralleled by changes in motor-network structure and function. Resting-state and transcranial magnetic stimulation-evoked electroencephalography revealed brain functional changes, and magnetic resonance imaging (MRI) measures detected structural and task-related functional changes., Conclusions: These first results are promising, pointing to feasibility, safety, and potential efficacy of this personalized approach acting synergistically on the nervous and musculoskeletal systems. Integrating multi-modal data may provide valuable insights into underlying mechanisms driving the improvements and providing predictive information regarding treatment response and outcomes., Funding: This work was funded by the Wyss-Center for Bio and Neuro Engineering (WCP-030), the Defitech Foundation, PHRT-#2017-205, ERA-NET-NEURON (Discover), and SNSF (320030L&#95;197899, NiBS-iCog)., Competing Interests: Declaration of interests A.E. works for the Wyss Center for Bio and Neuroengineering, sponsor of the clinical trial., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Home-based non-invasive brain stimulation (NIBS) has been suggested as an adjunct treatment strategy for neuro-psychiatric disorders. There are currently no available solutions to direct and monitor correct placement of the stimulation electrodes. To address this issue, we propose an easy-to-use digital tool to support patients for self-application., Methods: We recruited 36 healthy participants and compared their cap placement performance with the one of a NIBS-expert investigator. We tested participants' placement accuracy with instructions before (Pre) and after the investigator's placement (Post), as well as participants using the support tool (CURRENT). User experience (UX) and confidence were further evaluated., Results: Permutation tests demonstrated a smaller deviation within the CURRENT compared with Pre cap placement (p = 0.02). Subjective evaluation of ease of use and usefulness of the tool were vastly positive (8.04 out of 10). CURRENT decreased the variability of performance, ensured placement within the suggested maximum of deviation (10 mm) and supported confidence of correct placement., Conclusions: This study supports the usability of this novel technology for correct electrode placement during self-application in home-based settings., Significance: CURRENT provides an exciting opportunity to promote home-based, self-applied NIBS as a safe, high-frequency treatment strategy that can be well integrated in patients' daily lives., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Motor skill learning is a crucial process at all ages. However, healthy aging is often accompanied by a reduction in motor learning capabilities. This study characterized the brain dynamics of healthy older adults during motor skill acquisition and identified brain regions associated with changes in different components of performance. Forty-three subjects participated in a functional magnetic resonance imaging study during which they learned a sequential grip force modulation task. We evaluated the continuous changes in brain activation during practice as well as the continuous performance-related changes in brain activation. Practice of the motor skill was accompanied by increased activation in secondary motor and associative areas. In contrast, visual and frontal areas were less recruited as task execution progressed. Subjects showed significant improvements on the motor skill. While faster execution relied on parietal areas and was inversely associated with frontal activation, accuracy was related to activation in primary and secondary motor areas. Better performance was achieved by the contribution of parietal regions responsible for efficient visuomotor processing and cortical motor regions involved in the correct action selection. The results add to the understanding of online motor learning in healthy older adults, showing complementary roles of specific networks for implementing changes in precision and speed., (© The Author(s) 2023. Published by Oxford University Press.)

Cortico-cortical paired associative stimulation (ccPAS), which repeatedly pairs single-pulse transcranial magnetic stimulation (TMS) over two distant brain regions, is thought to modulate synaptic plasticity. We explored its spatial selectivity (pathway and direction specificity) and its nature (oscillatory signature and perceptual consequences) when applied along the ascending ( Forward ) and descending ( Backward ) motion discrimination pathway. We found unspecific connectivity increases in bottom-up inputs in the low gamma band, probably reflecting visual task exposure. A clear distinction in information transfer occurred in the re-entrant alpha signals, which were only modulated by Backward-ccPAS, and predictive of visual improvements in healthy participants. These results suggest a causal involvement of the re-entrant MT-to-V1 low-frequency inputs in motion discrimination and integration in healthy participants. Modulating re-entrant input activity could provide single-subject prediction scenarios for visual recovery. Visual recovery might indeed partly rely on these residual inputs projecting to spared V1 neurons., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

The analysis of motor evoked potentials (MEPs) generated by transcranial magnetic stimulation (TMS) is crucial in research and clinical medical practice. MEPs are characterized by their latency and the treatment of a single patient may require the characterization of thousands of MEPs. Given the difficulty of developing reliable and accurate algorithms, currently the assessment of MEPs is performed with visual inspection and manual annotation by a medical expert; making it a time-consuming, inaccurate, and error-prone process. In this study, we developed DELMEP, a deep learning-based algorithm to automate the estimation of MEP latency. Our algorithm resulted in a mean absolute error of about 0.5 ms and an accuracy that was practically independent of the MEP amplitude. The low computational cost of the DELMEP algorithm allows employing it in on-the-fly characterization of MEPs for brain-state-dependent and closed-loop brain stimulation protocols. Moreover, its learning ability makes it a particularly promising option for artificial-intelligence-based personalized clinical applications., (© 2023. The Author(s).)

Stroke as the leading cause of adult long-term disability and has a significant impact on patients, society and socio-economics. Non-invasive brain stimulation (NIBS) approaches such as transcranial magnetic stimulation (TMS) or transcranial electrical stimulation (tES) are considered as potential therapeutic options to enhance functional reorganization and augment the effects of neurorehabilitation. However, non-invasive electrical and magnetic stimulation paradigms are limited by their depth focality trade-off function that does not allow to target deep key brain structures critically important for recovery processes. Transcranial ultrasound stimulation (TUS) is an emerging approach for non-invasive deep brain neuromodulation. Using non-ionizing, ultrasonic waves with millimeter-accuracy spatial resolution, excellent steering capacity and long penetration depth, TUS has the potential to serve as a novel non-invasive deep brain stimulation method to establish unprecedented neuromodulation and novel neurorehabilitation protocols. The purpose of the present review is to provide an overview on the current knowledge about the neuromodulatory effects of TUS while discussing the potential of TUS in the field of stroke recovery, with respect to existing NIBS methods. We will address and discuss critically crucial open questions and remaining challenges that need to be addressed before establishing TUS as a new clinical neurorehabilitation approach for motor stroke recovery., (© 2023 The Authors.)

Background: Most studies on stroke have been designed to examine one deficit in isolation; yet, survivors often have multiple deficits in different domains. While the mechanisms underlying multiple-domain deficits remain poorly understood, network-theoretical methods may open new avenues of understanding., Methods: Fifty subacute stroke patients (7±3days poststroke) underwent diffusion-weighted magnetic resonance imaging and a battery of clinical tests of motor and cognitive functions. We defined indices of impairment in strength, dexterity, and attention. We also computed imaging-based probabilistic tractography and whole-brain connectomes. To efficiently integrate inputs from different sources, brain networks rely on a rich-club of a few hub nodes. Lesions harm efficiency, particularly when they target the rich-club. Overlaying individual lesion masks onto the tractograms enabled us to split the connectomes into their affected and unaffected parts and associate them to impairment., Results: We computed efficiency of the unaffected connectome and found it was more strongly correlated to impairment in strength, dexterity, and attention than efficiency of the total connectome. The magnitude of the correlation between efficiency and impairment followed the order attention>dexterity ≈ strength (strength: | r |=.03, P =0.02, dexterity: | r |=.30, P =0.05, attention: | r |=.55, P <0.001). Network weights associated with the rich-club were more strongly correlated to efficiency than non-rich-club weights., Conclusions: Attentional impairment is more sensitive to disruption of coordinated networks between brain regions than motor impairment, which is sensitive to disruption of localized networks. Providing more accurate reflections of actually functioning parts of the network enables the incorporation of information about the impact of brain lesions on connectomics contributing to a better understanding of underlying stroke mechanisms.

Enhanced behavioral interventions are gaining increasing interest as innovative treatment strategies for major depressive disorder (MDD). In this study protocol, we propose to examine the synergistic effects of a self-administered home-treatment, encompassing transcranial direct current stimulation (tDCS) along with a video game based training of attentional control. The study is designed as a two-arm, double-blind, randomized and placebo-controlled multi-center trial (ClinicalTrials.gov: NCT04953208). At three study sites (Israel, Latvia, and Germany), 114 patients with a primary diagnosis of MDD undergo 6 weeks of intervention (30 × 30 min sessions). Patients assigned to the intervention group receive active tDCS (anode F3 and cathode F4; 2 mA intensity) and an action-like video game, while those assigned to the control group receive sham tDCS along with a control video game. An electrode-positioning algorithm is used to standardize tDCS electrode positioning. Participants perform their designated treatment at the clinical center (sessions 1-5) and continue treatment at home under remote supervision (sessions 6-30). The endpoints are feasibility (primary) and safety, treatment efficacy (secondary, i.e., change of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week six from baseline, clinical response and remission, measures of social, occupational, and psychological functioning, quality of life, and cognitive control (tertiary). Demonstrating the feasibility, safety, and efficacy of this novel combined intervention could expand the range of available treatments for MDD to neuromodulation enhanced interventions providing cost-effective, easily accessible, and low-risk treatment options.ClinicalTrials.gov: NCT04953208., (© 2022. The Author(s).)

Oscillatory activity in the cerebellum and linked networks is an important aspect of neuronal processing and functional implementation of behavior. So far, it was challenging to quantify and study cerebellar oscillatory signatures in human neuroscience due to the constraints of non-invasive cerebellar electrophysiological recording and interventional techniques. The emerging cerebellar transcranial alternating current stimulation technique (CB-tACS) is a promising tool, which may partially overcome this challenge and provides an exciting non-invasive opportunity to better understand cerebellar physiology.Several studies have successfully demonstrated that CB-tACS can modulate the cerebellar outflow and cerebellum-linked behavior. In the present narrative review, we summarize current studies employing the CB-tACS approach and discuss open research questions. Hereby, we aim to provide an overview on this emerging electrophysiological technique and strive to promote future research in the field. CB-tACS will contribute in the further deciphering of cerebellar oscillatory signatures and its role for motor, cognitive, or affective functions. In long term, CB-tACS could develop into a therapeutic tool for retuning disturbed oscillatory activity in cerebellar networks underlying brain disorders., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective. Sources of heterogeneity in non-invasive brain stimulation literature can be numerous, with underlying brain states and protocol differences at the top of the list. Yet, incoherent results from brain-state-dependent stimulation experiments suggest that there are further factors adding to the variance. Hypothesizing that different signal processing pipelines might be partly responsible for heterogeneity; we investigated their effects on brain-state forecasting approaches. Approach. A grid-search was used to determine the fastest and most-accurate combination of preprocessing parameters and phase-forecasting algorithms. The grid-search was applied on a synthetic dataset and validated on electroencephalographic (EEG) data from a healthy ( n = 18) and stroke ( n = 31) cohort. Main results. Differences in processing pipelines led to different results; the grid-search chosen pipelines significantly increased the accuracy of published forecasting methods. The accuracy achieved in healthy was comparably high in stroke patients. Significance. This systematic offline analysis highlights the importance of the specific EEG processing and forecasting pipelines used for online state-dependent setups where precision in phase prediction is critical. Moreover, successful results in the stroke cohort pave the way to test state-dependent interventional treatment approaches., (Creative Commons Attribution license.)

Task-specific training constitutes a core element for evidence-based rehabilitation strategies targeted at improving upper extremity activity after stroke. Its combination with additional treatment strategies and neurotechnology-based solutions could further improve patients' outcomes. Here, we studied the effect of gamified robot-assisted upper limb motor training on motor performance, skill learning, and transfer with respect to a non-gamified control condition with a group of chronic stroke survivors. The results suggest that a gamified training strategy results in more controlled motor performance during the training phase, which is characterized by a higher accuracy (lower deviance), higher smoothness (lower jerk), but slower speed. The responder analyses indicated that mildly impaired patients benefited most from the gamification approach. In conclusion, gamified robot-assisted motor training, which is personalized to the individual capabilities of a patient, constitutes a promising investigational strategy for further improving motor performance after a stroke., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Despite recent improvements, complete motor recovery occurs in <15% of stroke patients. To improve the therapeutic outcomes, there is a strong need to tailor treatments to each individual patient. However, there is a lack of knowledge concerning the precise neuronal mechanisms underlying the degree and course of motor recovery and its individual differences, especially in the view of brain network properties despite the fact that it became more and more clear that stroke is a network disorder. The TiMeS project is a longitudinal exploratory study aiming at characterizing stroke phenotypes of a large, representative stroke cohort through an extensive, multi-modal and multi-domain evaluation. The ultimate goal of the study is to identify prognostic biomarkers allowing to predict the individual degree and course of motor recovery and its underlying neuronal mechanisms paving the way for novel interventions and treatment stratification for the individual patients. A total of up to 100 patients will be assessed at 4 timepoints over the first year after the stroke: during the first (T1) and third (T2) week, then three (T3) and twelve (T4) months after stroke onset. To assess underlying mechanisms of recovery with a focus on network analyses and brain connectivity, we will apply synergistic state-of-the-art systems neuroscience methods including functional, diffusion, and structural magnetic resonance imaging (MRI), and electrophysiological evaluation based on transcranial magnetic stimulation (TMS) coupled with electroencephalography (EEG) and electromyography (EMG). In addition, an extensive, multi-domain neuropsychological evaluation will be performed at each timepoint, covering all sensorimotor and cognitive domains. This project will significantly add to the understanding of underlying mechanisms of motor recovery with a strong focus on the interactions between the motor and other cognitive domains and multimodal network analyses. The population-based, multi-dimensional dataset will serve as a basis to develop biomarkers to predict outcome and promote personalized stratification toward individually tailored treatment concepts using neuro-technologies, thus paving the way toward personalized precision medicine approaches in stroke rehabilitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fleury, Koch, Wessel, Bonvin, San Millan, Constantin, Vuadens, Adolphsen, Cadic Melchior, Brügger, Beanato, Ceroni, Menoud, De Leon Rodriguez, Zufferey, Meyer, Egger, Harquel, Popa, Raffin, Girard, Thiran, Vaney, Alvarez, Turlan, Mühl, Léger, Morishita, Micera, Blanke, Van De Ville and Hummel.)

Objectives: (i) to create a shortened version of the Action Research Arm Test scale, (ii) to investigate its psychometric properties compared to the original scale and (iii) to externally validate it within an independent cohort., Design: Prospective longitudinal cohort study., Settings: Two University Hospitals (France, Switzerland)., Participants: 47 patients with poststroke motor deficits of the upper limb coming from two different sites were included and divided into two cohorts (n = 22 for the construction cohort; n = 25 for the validation cohort)., Main Measures: We used the first cohort to build the Mini-ARAT by shortening the Action Research Arm Test scale on the basis of ceiling/floor effects and collinearity of the subscales. We studied its reliability, validity, and responsiveness and performed an external validation with the second cohort., Results: The Mini-ARAT consisted of 2 subscales from the original Action Research Arm Test scale (Grip and Pinch). Internal consistency (α = 87) and inter-rater reliability (0.99, 95% CI: 0.98-0.99, p  < 0.01) were good and similar to those of the Action Research Arm Test scale. The Minimal Clinically Important Difference of the Mini-ARAT was 9 points. The predictive validity in the construction and validation cohorts showed good correlation between the Mini-ARAT at baseline and the Fugl Meyer at 3 months (rho, 95% CI: 0.77, 0.49-0.90, p  < 0.01, and 0.58, 0.19-0.96, p  < 0.01)., Conclusion: The Mini-ARAT is a time-effective tool able to capture the dynamics of motor deficits with high reliability and consistency, providing excellent information about residual motor functions, which is critically important for clinical and research purposes.

Tractography enables identifying and evaluating the healthy and diseased brain's white matter pathways from diffusion-weighted magnetic resonance imaging data. As previous evaluation studies have reported significant false-positive estimation biases, recent microstructure-informed tractography algorithms have been introduced to improve the trade-off between specificity and sensitivity. However, a major limitation for characterizing the performance of these techniques is the lack of ground truth brain data. In this study, we compared the performance of two relevant microstructure-informed tractography methods, SIFT2 and COMMIT, by assessing the subject specificity and reproducibility of their derived white matter pathways. Specifically, twenty healthy young subjects were scanned at eight different time points at two different sites. Subject specificity and reproducibility were evaluated using the whole-brain connectomes and a subset of 29 white matter bundles. Our results indicate that although the raw tractograms are more vulnerable to the presence of false-positive connections, they are highly reproducible, suggesting that the estimation bias is subject-specific. This high reproducibility was preserved when microstructure-informed tractography algorithms were used to filter the raw tractograms. Moreover, the resulting track-density images depicted a more uniform coverage of streamlines throughout the white matter, suggesting that these techniques could increase the biological meaning of the estimated fascicles. Notably, we observed an increased subject specificity by employing connectivity pre-processing techniques to reduce the underlaying noise and the data dimensionality (using principal component analysis), highlighting the importance of these tools for future studies. Finally, no strong bias from the scanner site or time between measurements was found. The largest intraindividual variance originated from the sole repetition of data measurements (inter-run)., Competing Interests: Conflict of interest G.F.P., T.H., and T.K. are employees of Siemens Healthcare AG, Switzerland., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mitochondrial health is based on a delicate balance of specific mitochondrial functions (e.g. metabolism, signaling, dynamics) that are impaired in neurodegenerative diseases. Rescuing mitochondrial function by selectively targeting mitochondrial stressors, such as reactive oxygen species, inflammation or proteotoxic insults ("bottom-up" approaches) thus is a widely investigated therapeutic strategy. While successful in preclinical studies, these approaches have largely failed to show clear clinical benefits. Promoting the capacity of mitochondria - and other cellular components - to restore a healthy cellular environment is a promising complementary or alternative approach. Herein, we provide a non-technical overview for neurologists and scientists interested in brain metabolism on neuroprotective strategies targeting mitochondria and focus on top-down interventions such as metabolic modulators, exercise, dietary restriction, brain stimulation and conditioning. We highlight general conceptual differences to bottom-up approaches and provide hypotheses on how these mechanistically comparatively poorly characterized top-down therapies may work, discussing notably mitochondrial stress responses and mitohormesis., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Quantitative magnetic resonance imaging (qMRI) can increase the specificity and sensitivity of conventional weighted MRI to underlying pathology by comparing meaningful physical or chemical parameters, measured in physical units, with normative values acquired in a healthy population. This study focuses on multi-echo T 2 relaxometry, a qMRI technique that probes the complex tissue microstructure by differentiating compartment-specific T 2 relaxation times. However, estimation methods are still limited by their sensitivity to the underlying noise. Moreover, estimating the model's parameters is challenging because the resulting inverse problem is ill-posed, requiring advanced numerical regularization techniques. As a result, the estimates from distinct regularization strategies are different. In this work, we aimed to investigate the variability and reproducibility of different techniques for estimating the transverse relaxation time of the intra- and extra-cellular space ( T 2 I E ) in gray (GM) and white matter (WM) tissue in a clinical setting, using a multi-site, multi-session, and multi-run T 2 relaxometry dataset. To this end, we evaluated three different techniques for estimating the T 2 spectra (two regularized non-negative least squares methods and a machine learning approach). Two independent analyses were performed to study the effect of using raw and denoised data. For both the GM and WM regions, and the raw and denoised data, our results suggest that the principal source of variance is the inter-subject variability, showing a higher coefficient of variation (CoV) than those estimated for the inter-site, inter-session, and inter-run, respectively. For all reconstruction methods studied, the CoV ranged between 0.32 and 1.64%. Interestingly, the inter-session variability was close to the inter-scanner variability with no statistical differences, suggesting that T 2 I E is a robust parameter that could be employed in multi-site neuroimaging studies. Furthermore, the three tested methods showed consistent results and similar intra-class correlation (ICC), with values superior to 0.7 for most regions. Results from raw data were slightly more reproducible than those from denoised data. The regularized non-negative least squares method based on the L-curve technique produced the best results, with ICC values ranging from 0.72 to 0.92., Competing Interests: Authors GP, TH, TY, and TK are employees of Siemens Healthineers International AG, Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fischi-Gomez, Girard, Koch, Yu, Pizzolato, Brügger, Piredda, Hilbert, Cadic-Melchior, Beanato, Park, Morishita, Wessel, Schiavi, Daducci, Kober, Canales-Rodríguez, Hummel and Thiran.)

Practicing a previously unknown motor sequence often leads to the consolidation of motor chunks, which enable its accurate execution at increasing speeds. Recent imaging studies suggest the function of these structures to be more related to the encoding, storage, and retrieval of sequences rather than their sole execution. We found that optimal motor skill acquisition prioritizes the storage of the spatial features of the sequence in memory over its rapid execution early in training, as proposed by Hikosaka in 1999. This process, seemingly diminished in older adults, was partially restored by anodal transcranial direct current stimulation over the motor cortex, as shown by a sharp improvement in accuracy and an earlier yet gradual emergence of motor chunks. These results suggest that the emergence of motor chunks is preceded by the storage of the sequence in memory but is not its direct consequence; rather, these structures depend on, and result from, motor practice.

Discrimination and integration of motion direction requires the interplay of multiple brain areas. Theoretical accounts of perception suggest that stimulus-related (i.e., exogenous) and decision-related (i.e., endogenous) factors affect distributed neuronal processing at different levels of the visual hierarchy. To test these predictions, we measured brain activity of healthy participants during a motion discrimination task, using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We independently modeled the impact of exogenous factors (task demand) and endogenous factors (perceptual decision-making) on the activity of the motion discrimination network and applied Dynamic Causal Modeling (DCM) to both modalities. DCM for event-related potentials (DCM-ERP) revealed that task demand impacted the reciprocal connections between the primary visual cortex (V1) and medial temporal areas (V5). With practice, higher visual areas were increasingly involved, as revealed by DCM-fMRI. Perceptual decision-making modulated higher levels (e.g., V5-to-Frontal Eye Fields, FEF), in a manner predictive of performance. Our data suggest that lower levels of the visual network support early, feature-based selection of responses, especially when learning strategies have not been implemented. In contrast, perceptual decision-making operates at higher levels of the visual hierarchy by integrating sensory information with the internal state of the subject., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Effective, patient-tailored rehabilitation to restore upper-limb motor function in severely impaired stroke patients is still missing. If suitably combined and administered in a personalized fashion, neurotechnologies offer a large potential to assist rehabilitative therapies to enhance individual treatment effects. AVANCER (clinicaltrials.gov NCT04448483) is a two-center proof-of-concept trial with an individual based cumulative longitudinal intervention design aiming at reducing upper-limb motor impairment in severely affected stroke patients with the help of multiple neurotechnologies. AVANCER will determine feasibility, safety, and effectivity of this innovative intervention. Thirty chronic stroke patients with a Fugl-Meyer assessment of the upper limb (FM-UE) <20 will be recruited at two centers. All patients will undergo the cumulative personalized intervention within two phases: the first uses an EEG-based brain-computer interface to trigger a variety of patient-tailored movements supported by multi-channel functional electrical stimulation in combination with a hand exoskeleton. This phase will be continued until patients do not improve anymore according to a quantitative threshold based on the FM-UE. The second interventional phase will add non-invasive brain stimulation by means of anodal transcranial direct current stimulation to the motor cortex to the initial approach. Each phase will last for a minimum of 11 sessions. Clinical and multimodal assessments are longitudinally acquired, before the first interventional phase, at the switch to the second interventional phase and at the end of the second interventional phase. The primary outcome measure is the 66-point FM-UE, a significant improvement of at least four points is hypothesized and considered clinically relevant. Several clinical and system neuroscience secondary outcome measures are additionally evaluated. AVANCER aims to provide evidence for a safe, effective, personalized, adjuvant treatment for patients with severe upper-extremity impairment for whom to date there is no efficient treatment available., Competing Interests: MC and AE is employed by the Wyss Center acting as the sponsor of this study. MC is employed by confinis AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bigoni, Zandvliet, Beanato, Crema, Coscia, Espinosa, Henneken, Hervé, Oflar, Evangelista, Morishita, Wessel, Bonvin, Turlan, Birbaumer and Hummel.)

Background: Healthy older adults show a decrease in motor performance and motor learning capacity as well as in working memory (WM) performance. WM has been suggested to be involved in motor learning processes, such as sequence learning. Correlational evidence has shown the involvement of the frontoparietal network (FPN), a network underlying WM processes, in motor sequence learning. However, causal evidence is currently lacking. Non-invasive brain stimulation (NIBS) studies have focused so far predominantly on motor-related areas to enhance motor sequence learning while areas associated with more cognitive aspects of motor learning have not yet been addressed., Hypothesis: In this study, we aim to provide causal evidence for the involvement of WM processes and the underlying FPN in the successful performance of a motor sequence learning task by using theta transcranial alternating current stimulation (tACS) targeting the FPN during a motor sequence learning task., Methods: In a cohort of 20 healthy older adults, we applied bifocal tACS in the theta range to the FPN during a sequence learning task. With the use of a double-blind, cross-over design, we tested the efficacy of active compared to sham stimulation. Two versions of the motor task were used: one with high and one with low WM load, to explore the efficacy of stimulation on tasks differing in WM demand. Additionally, the effects of stimulation on WM performance were addressed using an N-back task. The tACS frequency was personalized by means of EEG measuring the individual theta peak frequency during the N-back task., Results: The application of personalized theta tACS to the FPN improved performance during the motor sequence learning task with high WM load (p < .001), but not with low WM load. Active stimulation significantly improved both speed (p < .001), and accuracy (p = .03) during the task with high WM load. In addition, the stimulation paradigm improved performance on the N-back task for the 2-back task (p = .013), but not for 1-back and 3-back., Conclusion: The performance during a motor sequence learning task can be enhanced by means of personalized bifocal theta tACS to the FPN when WM load is high, indicating that the efficacy of this stimulation paradigm is dependent on the cognitive demand during the learning task. These data provide further causal evidence for the critical involvement of WM processes and the FPN during the execution of a motor sequence learning task in healthy older. These findings open new exciting possibilities to counteract the age-related decline in motor performance, learning capacity and WM performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background. Latencies of motor evoked potentials (MEPs) can provide insights into the motor neuronal pathways activated by transcranial magnetic stimulation. Notwithstanding its clinical relevance, accurate, unbiased methods to automatize latency detection are still missing. Objective. We present a novel open-source algorithm suitable for MEP onset/latency detection during resting state that only requires the post-stimulus electromyography signal and exploits the approximation of the first derivative of this signal to find the time point of initial deflection of the MEP. Approach. The algorithm has been benchmarked, using intra-class coefficient (ICC) and effect sizes, to manual detection of latencies done by three researchers independently on a dataset comprising almost 6500 MEP trials from healthy participants ( n = 18) and stroke patients ( n = 31) acquired during rest. The performance was further compared to currently available automatized methods, some of which created for active contraction protocols. Main results. The unstandardized effect size between the human raters and the present method is smaller than the sampling period for both healthy and pathological MEPs. Moreover, the ICC increases when the algorithm is added as a rater. Significance. The present algorithm is comparable to human expert decision and outperforms currently available methods. It provides a promising method for automated MEP latency detection under physiological and pathophysiological conditions., (Creative Commons Attribution license.)

Interhemispheric interactions demonstrate a crucial role for directing bimanual movement control. In humans, a well-established paired-pulse transcranial magnetic stimulation paradigm enables to assess these interactions by means of interhemispheric inhibition (IHI). Previous studies have examined changes in IHI from the active to the resting primary motor cortex during unilateral muscle contractions; however, behavioral relevance of such changes is still inconclusive. In the present study, we evaluated two bimanual tasks, i.e., mirror activity and bimanual anti-phase tapping, to examine behavioral relevance of IHI for bimanual movement control within this behavioral framework. Two age groups (young and older) were evaluated as bimanual movement control demonstrates evident behavioral decline in older adults. Two types of IHI with differential underlying mechanisms were measured; IHI was tested at rest and during a motor task from the active to the resting primary motor cortex. Results demonstrate an association between behavior and short-latency IHI in the young group: larger short-latency IHI correlated with better bimanual movement control (i.e., less mirror activity and better bimanual anti-phase tapping). These results support the view that short-latency IHI represents a neurophysiological marker for the ability to suppress activity of the contralateral side, likely contributing to efficient bimanual movement control. This association was not observed in the older group, suggesting age-related functional changes of IHI. To determine underlying mechanisms of impaired bimanual movement control due to neurological disorders, it is crucial to have an in-depth understanding of age-related mechanisms to disentangle disorder-related mechanisms of impaired bimanual movement control from age-related ones., (© 2021. The Author(s).)

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., (Copyright © 2021. Published by Elsevier Inc.)

Visual motion discrimination involves reciprocal interactions in the alpha band between the primary visual cortex (V1) and mediotemporal areas (V5/MT). We investigated whether modulating alpha phase synchronization using individualized multisite transcranial alternating current stimulation (tACS) over V5 and V1 regions would improve motion discrimination. We tested 3 groups of healthy subjects with the following conditions: (1) individualized In-Phase V1 alpha -V5 alpha tACS (0° lag), (2) individualized Anti-Phase V1 alpha -V5 alpha tACS (180° lag) and (3) sham tACS. Motion discrimination and EEG activity were recorded before, during and after tACS. Performance significantly improved in the Anti-Phase group compared to the In-Phase group 10 and 30 min after stimulation. This result was explained by decreases in bottom-up alpha-V1 gamma-V5 phase-amplitude coupling. One possible explanation of these results is that Anti-Phase V1 alpha -V5 alpha tACS might impose an optimal phase lag between stimulation sites due to the inherent speed of wave propagation, hereby supporting optimized neuronal communication., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)