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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.

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).)

Objective: Neurofibromatosis type 1 (NF1) 1 is known to cause learning deficits in affected individuals. There has been evidence linking altered gamma-aminobutyric acid (GABA) 2 mediated inhibition to learning impairments in rodent models and humans with NF1. Still, evidence on the role of GABA in learning deficits associated with NF1 is inconclusive., Methods: We examined procedural learning and motor cortex excitability through intracortical facilitation and short interval intracortical inhibition and its activity dependent modulation while performing a procedural sequence learning task in 16 asymptomatic NF1 gene carriers. We aimed to analyze potential brain-behavior correlations in a carefully selected sample of gene carriers in order to minimize confounding factors., Results: Gene carriers did not differ from healthy controls when learning the task with their non-dominant hand over three days of training. Electrophysiological data did not reveal alterations in patients' inhibitory function of the motor cortex., Conclusions: In contrast with previous publications reporting various cognitive deficits in clinically asymptomatic individuals with NF1, here asymptomatic gene carriers did not show major neuropsychological or behavioral abnormalities., Significance: Our results support the concept that gene carriers may not always be impaired by the condition and the population of individuals with NF1 most likely comprises different subgroups according to patients' phenotype severity., Competing Interests: Declarations of Competing Interest None., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Transcranial direct current stimulation (tDCS)-based interventions for augmenting motor learning are gaining interest in systems neuroscience and clinical research. Current approaches focus largely on monofocal motorcortical stimulation. Innovative stimulation protocols, accounting for motor learning related brain network interactions also, may further enhance effect sizes. Here, we tested different stimulation approaches targeting the cerebro-cerebellar loop. Forty young, healthy participants trained a fine motor skill with concurrent tDCS in four sessions over two days, testing the following conditions: (1) monofocal motorcortical, (2) sham, (3) monofocal cerebellar, or (4) sequential multifocal motorcortico-cerebellar stimulation in a double-blind, parallel design. Skill retention was assessed after circa 10 and 20 days. Furthermore, potential underlying mechanisms were studied, applying paired-pulse transcranial magnetic stimulation and multimodal magnetic resonance imaging-based techniques. Multisession motorcortical stimulation facilitated skill acquisition, when compared with sham. The data failed to reveal beneficial effects of monofocal cerebellar or additive effects of sequential multifocal motorcortico-cerebellar stimulation. Multimodal multiple linear regression modelling identified baseline task performance and structural integrity of the bilateral superior cerebellar peduncle as the most influential predictors for training success. Multisession application of motorcortical tDCS in several daily sessions may further boost motor training efficiency. This has potential implications for future rehabilitation trials.

Brain imaging has recently evidenced that the structural state of distinct reciprocal cortico-cerebellar fiber tracts, the dentato-thalamo-cortical tract (DTCT), and the cortico-ponto-cerebellar tract (CPCeT), significantly influences residual motor output in chronic stroke patients, independent from the level of damage to the corticospinal tract (CST). Whether such structural information might also directly relate to measures of cortical excitability is an open question. Eighteen chronic stroke patients with supratentorial ischemic lesions and 17 healthy controls underwent transcranial magnetic stimulation to assess recruitment curves of motor evoked potentials of both hemispheres. Diffusion-weighted imaging and probabilistic tractography were applied to reconstruct reciprocal cortico-cerebellar motor tracts between the primary motor cortex and the cerebellum. Tract-related microstructure was estimated by means of fractional anisotropy, and linear regression modeling was used to relate it to cortical excitability. The main finding was a significant association between cortical excitability and the structural integrity of the DTCT, the main cerebellar outflow tract, independent from the level of damage to the CST. A comparable relationship was neither detectable for the CPCeT nor for the healthy controls. This finding contributes to a mechanistic understanding of the putative supportive role of the cerebellum for residual motor output by facilitating cortical excitability after stroke., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Hand motor function is often severely affected in stroke patients. Non-satisfying recovery limits reintegration into normal daily life. Understanding stroke-related network changes and identifying common principles that might underlie recovered motor function is a prerequisite for the development of interventional therapies to support recovery. Here, we combine the evaluation of functional activity (multichannel electroencephalography) and structural integrity (diffusion tensor imaging) in order to explain the degree of residual motor function in chronic stroke patients. By recording neural activity during a reaching and grasping task that mimics activities of daily living, the study focuses on deficit-related neural activation patterns. The study showed that the functional role of movement-related beta desynchronization in the supplementary motor area (SMA) for residual hand motor function in stroke patients depends on the microstructural integrity of the corticospinal tract (CST). In particular, in patients with damaged CST, stronger task-related activity in the SMA was associated with worse residual motor function. Neither CST damage nor functional brain activity alone sufficiently explained residual hand motor function. The findings suggest a central role of the SMA in the motor network during reaching and grasping in stroke patients, the degree of functional relevance of the SMA is depending on CST integrity., (© 2019 Wiley Periodicals, Inc.)

Successful adaptation to complex environments depends on the balance of at least two systems: a flexible but slow goal-directed system encoding action-outcome associations and an efficient but rigid habitual system linking responses to preceding stimuli. Recent evidence suggests that the inferolateral prefrontal cortex (ilPFC), a region well known to contribute to cognitive control processes, may play a crucial role in the balance of goal-directed and habitual responding. This evidence, however, comes mainly from correlational data and whether the ilPFC is indeed causally involved in the goal-directed vs. habitual control of behavior is unclear. Here, we used neuro-navigated theta-burst stimulation (TBS) to either inhibit or enhance right ilPFC functionality before participants completed an instrumental learning task designed to probe goal-directed vs. habitual behavioral control. TBS did not affect overall learning performance. However, participants that had received inhibitory TBS were less able to adapt their behavior to altered task demands, indicating a shift from goal-directed towards more habitual control of behavior. Sham or excitatory TMS groups showed no such effect and were comparable in their performance to an unstimulated control group. Our findings indicate a causal role of the ilPFC in the balance of goal-directed vs. habitual control of behavior.

Functional imaging studies have argued that interactions between cortical motor areas and the cerebellum are relevant for motor output and recovery processes after stroke. However, the impact of the underlying structural connections is poorly understood. To investigate this, diffusion-weighted brain imaging was conducted in 26 well-characterized chronic stroke patients (aged 63 ± 1.9 years, 18 males) with supratentorial ischemic lesions and 26 healthy participants. Probabilistic tractography was used to reconstruct reciprocal cortico-cerebellar tracts and to relate their microstructural integrity to residual motor functioning applying linear regression modeling. The main finding was a significant association between cortico-cerebellar structural connectivity and residual motor function, independent from the level of damage to the cortico-spinal tract. Specifically, white matter integrity of the cerebellar outflow tract, the dentato-thalamo-cortical tract, was positively related to both general motor output and fine motor skills. Additionally, the integrity of the descending cortico-ponto-cerebellar tract contributed to rather fine motor skills. A comparable structure-function relationship was not evident in the controls. The present study provides first tract-related structural data demonstrating a critical importance of distinct cortico-cerebellar connections for motor output after stroke., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Physiological aging is paralleled by a decline of fine motor skills accompanied by structural and functional alterations of the underlying brain network. Here, we aim to investigate age-related changes in the spectral distribution of neuronal oscillations during fine skilled motor function. We employ the concept of spectral entropy in order to describe the flatness and peaked-ness of a frequency spectrum to quantify changes in the spectral distribution of the oscillatory motor response in the aged brain. Electroencephalogram was recorded in elderly ( n = 32) and young ( n = 34) participants who performed either a cued finger movement or a pinch or a whole hand grip task with their dominant right hand. Whereas young participant showed distinct, well-defined movement-related power decreases in the alpha and upper beta band, elderly participants exhibited a flat broadband, frequency-unspecific power desynchronization. This broadband response was reflected by an increase of spectral entropy over sensorimotor and frontal areas in the aged brain. Neuronal activation patterns differed between motor tasks in the young brain, while the aged brain showed a similar activation pattern in all tasks. Moreover, we found a wider recruitment of the cortical motor network in the aged brain. The present study adds to the understanding of age-related changes of neural coding during skilled motor behavior, revealing a less predictable signal with great variability across frequencies in a wide cortical motor network in the aged brain. The increase in entropy in the aged brain could be a reflection of random noise-like activity or could represent a compensatory mechanism that serves a functional role.

Cerebellar transcranial direct current stimulation (tDCS) has the potential to modulate cerebellar outputs and visuomotor adaptation. The cerebellum plays a pivotal role in the acquisition and control of skilled hand movements, especially its temporal aspects. We applied cerebellar anodal tDCS concurrently with training of a synchronization-continuation motor task. We hypothesized that anodal cerebellar tDCS will enhance motor skill acquisition. Cerebellar tDCS was applied to the right cerebellum in 31 healthy subjects in a double-blind, sham-controlled, parallel design. During synchronization, the subjects tapped the sequence in line with auditory cues. Subsequently, in continuation, the learned sequence was reproduced without auditory cuing. Motor task performance was evaluated before, during, 90 min, and 24 h after training. Anodal cerebellar tDCS, compared with sham, improved the task performance in the follow-up tests (F1,28 = 5.107, P = 0.032) of the synchronization part. This effect on retention of the skill was most likely mediated by enhanced motor consolidation. We provided first evidence that cerebellar tDCS can enhance the retention of a fine motor skill. This finding supports the promising approach of using noninvasive brain stimulation techniques to restore impaired motor functions in neurological patients, such after a stroke., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Cognitive difficulties are the most common neurological complications in neurofibromatosis type 1 (NF1) patients. Recent animal models proposed increased GABA-mediated inhibition as one underlying mechanism directly affecting the induction of long-term potentiation (LTP) and learning. In most adult NF1 patients, apparent cognitive and attentional deficits, tumors affecting the nervous system and other confounding factors for neuroscientific studies are difficult to control for. Here we used a highly specific group of adult NF1 patients without cognitive or nervous system impairments. Such selected NF1 patients allowed us to address the following open questions: Is the learning process of acquiring a challenging motor skill impaired in NF1 patients? And is such an impairment in relation to differences in intracortical inhibition?, Methods: We used an established non-invasive, double-pulse transcranial magnetic stimulation (dp-TMS) paradigm to assess practice-related modulation of intracortical inhibition, possibly mediated by gamma-minobutyric acid (GABA)ergic-neurotransmission. This was done during an extended learning paradigm in a group of NF1 patients without any neuropsychological deficits, functioning normally in daily life and compared them to healthy age-matched controls., Findings: NF1 patients experienced substantial decline in motor skill acquisition (F = 9.2, p = 0.008) over five-consecutives training days mediated through a selective reduction in the early acquisition (online) and the consolidation (offline) phase. Furthermore, there was a consistent decrease in task-related intracortical inhibition as a function of the magnitude of learning (T = 2.8, p = 0.014), especially evident after the early acquisition phase., Interpretations: Collectively, the present results provide evidence that learning of a motor skill is impaired even in clinically intact NF1 patients based, at least partially, on a GABAergic-cortical dysfunctioning as suggested in previous animal work.

The dentato-thalamo-cortical tract (DTCT) connects the lateral cerebellum with contralateral motor and nonmotor areas, such as the primary motor cortex (M1), the ventral premotor cortex (PMv), and the dorsolateral prefrontal cortex (DLPFC). As the acquisition of precisely timed finger movements requires the interplay between these brain regions, the structural integrity of the underlying connections might explain variance in behavior. Diffusion tensor imaging was used to 1) reconstruct the DTCT connecting the dentate nucleus with M1, PMv, and DLPFC and 2) examine to which extent their microstructural integrity (tract-related fractional anisotropy) relates to learning gains in a motor-sequence learning paradigm consisting of a synchronization and continuation part. Continuous DTCT were reconstructed from the dentate nucleus to all cortical target areas. We found that the microstructural integrity of the DTCT connecting the left dentate nucleus with the right DLPFC was associated with better early consolidation in rhythm continuation (R = -0.69, P = 0.02). The present data further advances the knowledge about a right-hemispheric timing network in the human brain with the DLPFC as an important node contributing to learning gains in precise movement timing., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Impaired motor skill acquisition is a feature of older age. Acquisition of new motor skills requires the interplay between different cortical motor areas. Using diffusion tensor imaging we reconstructed cortico-cortical connections between the primary motor cortex (M1) and secondary motor areas in 11 older and 11 young participants who took part in a motor skill acquisition paradigm with the nondominant left hand. Examining the extent to which tract-related integrity correlated with training gains we found that white matter integrity of fibers connecting contralateral M1 with both contralateral (r = 0.85) and ipsilateral supplementary motor areas (r = 0.92) were positively associated in old participants. Also, fibers connecting contralateral M1 with ipsilateral dorsal premotor (r = 0.82) and fibers connecting ipsilateral dorsal premotor and supplementary motor area (r = 0.88) were positively related to skill acquisition (all p < 0.05). A similar structure-behavior relationship was not present in the young control subjects suggesting a critical role of brain structural integrity for motor learning in healthy aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)