Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills.

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.

Single session cross-frequency bifocal tACS modulates visual motion network activity in young healthy population and stroke patients.

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 É£-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.

Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

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 (Pcluster<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.

Safety, tolerability and blinding efficiency of non-invasive deep transcranial temporal interference stimulation: first experience from more than 250 sessions.

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.

MEP and TEP features variability: is it just the brain-state?

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.

Brain connectome correlates of short-term motor learning in healthy older subjects.

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.

Preserved Corticospinal Tract Revealed by Acute Perfusion Imaging Relates to Better Outcome After Thrombectomy in Stroke.

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.

Noninvasive theta-burst stimulation of the human striatum enhances striatal activity and motor skill learning.

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.

Novel personalized treatment strategy for patients with chronic stroke with severe upper-extremity impairment: The first patient of the AVANCER trial.

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_197899, NiBS-iCog).

Pathway and directional specificity of Hebbian plasticity in the cortical visual motion processing network.

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.

DELMEP: a deep learning algorithm for automated annotation of motor evoked potential latencies.

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.

Early motor skill acquisition in healthy older adults: brain correlates of the learning process.

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.

Differential Impact of Brain Network Efficiency on Poststroke Motor and Attentional Deficits.

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.

Optimization of phase prediction for brain-state dependent stimulation: a grid-search approach.

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.

Mini-review: Transcranial Alternating Current Stimulation and the Cerebellum.

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.

The effect of gamified robot-enhanced training on motor performance in chronic stroke survivors.

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.

Toward individualized medicine in stroke-The TiMeS project: Protocol of longitudinal, multi-modal, multi-domain study in stroke.

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.

A Novel Patient-Tailored, Cumulative Neurotechnology-Based Therapy for Upper-Limb Rehabilitation in Severely Impaired Chronic Stroke Patients: The AVANCER Study Protocol.

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.

Dissecting motor skill acquisition: Spatial coordinates take precedence.

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.