IntroductionPrecise motor timing including the ability to adjust movements after changes in the environment is fundamental to many daily activities. Sensorimotor timing in the sub-and supra-second range might rely on at least partially distinct brain networks, with the latter including the basal ganglia (BG) and the prefrontal cortex (PFC). Since both structures are particularly vulnerable to age-related decline, the present study investigated whether age might distinctively affect sensorimotor timing and error correction in the supra-second range.MethodsA total of 50 healthy right-handed volunteers with 22 older (age range: 50–60 years) and 28 younger (age range: 20–36 years) participants synchronized the tap-onsets of their right index finger with an isochronous auditory pacing signal. Stimulus onset asynchronies were either 900 or 1,600 ms. Positive or negative step-changes that were perceivable or non-perceivable were occasionally interspersed to the fixed intervals to induce error correction. A simple reaction time task served as control condition.Results and DiscussionIn line with our hypothesis, synchronization variability in trials with supra-second intervals was larger in the older group. While reaction times were not affected by age, the mean negative asynchrony was significantly smaller in the elderly in trials with positive step-changes, suggesting more pronounced tolerance of positive deviations at older age. The analysis of error correction by means of the phase correction response (PCR) suggests reduced error correction in the older group. This effect emerged in trials with supra-second intervals and large positive step-changes, only. Overall, these results support the hypothesis that sensorimotor synchronization in the sub-second range is maintained but synchronization accuracy and error correction in the supra-second range is reduced in the elderly as early as in the fifth decade of life suggesting that these measures are suitable for the early detection of age-related changes of the motor system.

Precise motor timing requires the ability to flexibly adapt one's own movements with respect to changes in the environment. Previous studies suggest that the correction of perceived as compared to non-perceived timing errors involves at least partially distinct brain networks. The dorsolateral prefrontal cortex (dPFC) has been linked to the correction of perceived timing errors and evidence for a contribution of the ventrolateral PFC (vPFC) specifically to the correction of non-perceived errors exists. The present study aimed at clarifying the functional contribution of the left vPFC for the correction of timing errors by adopting high-definition transcranial direct current stimulation (HD-tDCS). Twenty-one young healthy volunteers synchronized their right index finger taps with respect to an isochronous auditory pacing signal. Perceivable and non-perceivable step-changes of the metronome were interspersed, and error correction was analyzed by means of the phase-correction response (PCR). In subsequent sessions anodal and cathodal HD-tDCS was applied to the left vPFC to establish a brain-behavior relationship. Sham stimulation served as control condition. Synchronization accuracy as well as error correction were determined immediately prior to and after HD-tDCS. The analysis suggests a detrimental effect of cathodal HD-tDCS distinctively on error correction in trials with perceived timing errors. The data support the significance of the left vPFC for error correction in the temporal domain but contradicts the view of a role in the correction of non-perceived errors.

Accurate motor timing requires the temporally precise coupling between sensory input and motor output including the adjustment of movements with respect to changes in the environment. Such error correction has been related to a cerebello-thalamo-cortical network. At least partially distinct networks for the correction of perceived (i.e., conscious) as compared to nonperceived (i.e., nonconscious) errors have been suggested. While the cerebellum, the premotor, and the prefrontal cortex seem to be involved in conscious error correction, the network subserving nonconscious error correction is less clear. The present study is aimed at investigating the functional contribution of the primary motor cortex (M1) for both types of error correction in the temporal domain. To this end, anodal transcranial direct current stimulation (atDCS) was applied to the left M1 in a group of 18 healthy young volunteers during a resting period of 10 minutes. Sensorimotor synchronization as well as error correction of the right index finger was tested immediately prior to and after atDCS. Sham stimulation served as control condition. To induce error correction, nonconscious and conscious temporal step-changes were interspersed in a sequence of an isochronous auditory pacing signal in either direction (i.e., negative or positive) yielding either shorter or longer intervals. Prior to atDCS, faster error correction in conscious as compared to nonconscious trials was observed replicating previous findings. atDCS facilitated nonconscious error correction, but only in trials with negative step-changes yielding shorter intervals. In contrast to this, neither tapping speed nor synchronization performance with respect to the isochronous pacing signal was significantly modulated by atDCS. The data suggest M1 as part of a network distinctively contributing to the correction of nonconscious negative step-changes going beyond sensorimotor synchronization.

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

The study investigates how transcranial direct current stimulation (tDCS) over the auditory cortex (AC) modulates memory for melodies under different noise conditions, whilst also considering cumulative disruptive interference effects. Forty-one participants completed a continuous recognition melody task, as well as a visual control task, which included four noise conditions for which noise was either present only during encoding (N-C), only during retrieval (C-N), during both (N-N) or not at all (C-C) and completed the tasks after receiving anodal or sham tDCS over the right AC. The results of the sham session replicate previous findings by revealing that memory for melodies is worse when noise in added to the encoding phase (N-C) whereas the N-N condition shows good performance, highlighting a context effect, and that cumulative disruptive interference is not present in memory for melodies except in the N-C condition. After anodal stimulation the memory pattern differs such as that memory performance is best in the C-C condition and furthermore the cumulative disruptive interference effect in the N-C condition is diminished. In sum, the study highlights the involvement of the right AC for memory for melodies and the results indicate an association of the AC for creating context effects.

Learning of new motor skills occurs particularly during training on a task (i.e. online) but has been observed between training-blocks lasting up to days after the end of the training (i.e. offline). Offline-learning occurs as further improvement in task performance indicated by increased accuracy and/or faster responses as well as less interference with respect to a distracting condition. Successful motor learning requires the functional interplay between cortical as well as subcortical brain areas. While the involvement of the primary motor cortex in online as well as early offline-learning is well established, the functional significance of the posterior parietal cortex (PPC) is less clear. Since the PPC may act as sensory-motor interface, a causal involvement in motor learning is conceivable. In order to characterize the functional significance of the left PPC for motor sequence learning, transcranial direct current stimulation (tDCS) was applied either immediately prior to, during or immediately after training on a serial reaction time task (SRTT) in a total of 54 healthy volunteers. While the analysis did not provide evidence for a significant modulation of reaction times during SRTT training (i.e. online-learning), cathodal tDCS decelerated reaction times of the learned sequences as compared to anodal and sham stimulation 30 min after the end of training. The findings suggest that cathodal tDCS over the left parietal cortex interferes with the reproduction of learned sequences.

Beta oscillations within motor-cortical areas have been linked to sensorimotor function. In line with this, pathologically altered beta activity in cortico-basal ganglia pathways has been suggested to contribute to the pathophysiology of Parkinson's disease (PD), a neurodegenerative disorder primarily characterized by motor impairment. Although its precise function is still discussed, beta activity might subserve an anticipatory role in preparation of future actions. By reanalyzing previously published data, we aimed at investigating the role of pre-stimulus motor-cortical beta power modulation in motor sequence learning and its alteration in PD. 20 PD patients and 20 healthy controls (HC) performed a serial reaction time task (SRTT) in which reaction time gain presumably reflects the ability to anticipate subsequent sequence items. Randomly varying patterns served as control trials. Neuromagnetic activity was recorded using magnetoencephalography (MEG) and data was reanalyzed with respect to task stimuli onset. Assuming that pre-stimulus beta power modulation is functionally related to motor sequence learning, reaction time gain due to training on the SRTT should vary depending on the amount of beta power suppression prior to stimulus onset. We hypothesized to find less pre-stimulus beta power suppression in PD patients as compared to HC associated with reduced motor sequence learning in patients. Behavioral analyses revealed that PD patients exhibited smaller reaction time gain in sequence relative to random control trials than HC indicating reduced learning in PD. This finding was indeed paralleled by reduced pre-stimulus beta power suppression in PD patients. Further strengthening its functional relevance, the amount of pre-stimulus beta power suppression during sequence training significantly predicted subsequent reaction time advantage in sequence relative to random trials in patients. In conclusion, the present data provide first evidence for the contribution of pre-stimulus motor-cortical beta power suppression to motor sequence learning and support the hypothesis that beta oscillations may subserve an anticipatory, predictive function, possibly compromised in PD.

Motor sequence learning is associated with the activation of bilateral primary motor cortices (M1). While previous data support the hypothesis that the contralateral M1 is causally involved in the acquisition as well as early consolidation of a motor sequence, the functional significance of the ipsilateral M1 has yet to be solved. Transcranial direct current stimulation (tDCS) allows the non-invasive modulation of cortical excitability. Anodal tDCS applied to the left M1 has been shown to facilitate implicit motor sequence learning of the right hand most likely due to increased excitability. The present study aims at characterizing the functional contribution of the ipsilateral (right) M1 on implicit motor sequence learning of the right hand. To this end, 24 healthy, right-handed subjects received anodal and sham tDCS to the right M1 in a counterbalanced order. Stimulation started 8 min prior to training on a variant of the serial reaction time task (SRTT) with the right hand and persists over the entire training period. The SRTT comprised a fixed eight-digit sequence. A random pattern served as control condition. Reaction times were assessed before and at the end of the acquisition (EoA) immediately after training on the SRTT. The analysis revealed significantly faster reaction times of both hands independent of tDCS condition in sequential trials. However, the gain of reaction times was significantly smaller following anodal as compared to sham tDCS. The data suggest that anodal tDCS applied to the right M1 impairs implicit motor sequence learning of both hands. The underlying mechanism likely involves alterations of the interaction between bilateral M1.

Motor sequence learning plays a pivotal role in various everyday activities. Motor-cortical beta oscillations have been suggested to be involved in this type of learning. In Parkinson's disease (PD), oscillatory activity within cortico-basal-ganglia circuits is altered. Pathologically increased beta oscillations have received particular attention as they may be associated with motor symptoms such as akinesia. In the present magnetoencephalography (MEG) study, we investigated PD patients and healthy controls (HC) during implicit motor sequence learning with the aim to shed light on the relation between changes of cortical brain oscillations and motor learning in PD with a particular focus on beta power. To this end, 20 PD patients (ON medication) and 20 age- and sex-matched HC were trained on a serial reaction time task while neuromagnetic activity was recorded using a 306-channel whole-head MEG system. PD patients showed reduced motor sequence acquisition and were more susceptible to interference by random trials after training on the task as compared to HC. Behavioral differences were paralleled by changes at the neurophysiological level. Diminished sequence acquisition was paralleled by less training-related beta power suppression in motor-cortical areas in PD patients as compared to HC. In addition, PD patients exhibited reduced training-related theta activity in motor-cortical areas paralleling susceptibility to interference. The results support the hypothesis that the acquisition of a new motor sequence relies on suppression of motor-cortical beta oscillations, while motor-cortical theta activity might be related to stabilization of the learned sequence as indicated by reduced susceptibility to interference. Both processes appear to be impaired in PD.

Phasic dopamine (DA) signals conveyed from the substantia nigra to the striatum and the prefrontal cortex crucially affect learning from feedback, with DA bursts facilitating learning from positive feedback and DA dips facilitating learning from negative feedback. Consequently, diminished nigro-striatal dopamine levels as in unmedicated patients suffering from Parkinson's Disease (PD) have been shown to lead to a negative learning bias. Recent studies suggested a diminished striatal contribution to feedback processing when the outcome of an action is temporally delayed. This study investigated whether the bias towards negative feedback learning induced by a lack of DA in PD patients OFF medication is modulated by feedback delay. To this end, PD patients OFF medication and healthy controls completed a probabilistic selection task, in which feedback was given immediately (after 800 ms) or delayed (after 6800 ms). PD patients were impaired in immediate but not delayed feedback learning. However, differences in the preference for positive/negative learning between patients and controls were seen for both learning from immediate and delayed feedback, with evidence of stronger negative learning in patients than controls. A Bayesian analysis of the data supports the conclusion that feedback timing did not affect the learning bias in the patients. These results hint at reduced, but still relevant nigro-striatal contribution to feedback learning, when feedback is delayed.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that allows the modulation of cortical excitability as well as neuroplastic reorganization using a weak constant current applied through the skull on the cerebral cortex. TDCS has been found to improve motor performance in general and motor learning in particular. However, these effects have been reported almost exclusively for unimanual motor tasks such as serial reaction time tasks, adaptation tasks, or visuo-motor tracking. Despite the importance of bimanual actions in most activities of daily living, only few studies have investigated the effects of tDCS on bimanual motor skills. The objectives of this review article are: (i) to provide a concise overview of the few existing studies in this area; and (ii) to discuss the effects of tDCS on bimanual motor skills in healthy volunteers and patients suffering from neurological diseases. Despite considerable variations in stimulation protocols, the bimanual tasks employed, and study designs, the data suggest that tDCS has the potential to enhance bimanual motor skills. The findings imply that the effects of tDCS vary with task demands, such as complexity and the level of expertise of the participating volunteers. Nevertheless, optimized stimulation protocols tailored to bimanual tasks and individual performance considering the underlying neural substrates of task execution are required in order to probe the effectiveness of tDCS in greater detail, thus creating an opportunity to support motor recovery in neuro-rehabilitation.

Pitch memory is a resource which is shared by music and language. Neuroimaging studies have shown that the right dorsolateral prefrontal cortex (DLPFC) is activated during pitch memory processes. The present study investigated the causal significance of this brain area for pitch memory in non-musicians by applying cathodal and sham transcranial direct current stimulation (tDCS) over the right DLPFC and examining the impact on offline pitch and visual memory span performances. On the overall sample (N = 22) no significant modulation effect of cathodal stimulation on the pitch span task was found. However, when dividing the sample by means of a median split of pre-test pitch memory abilities into a high and low performing group, a selective effect of significantly impaired pitch memory after cathodal tDCS in good performers was revealed. The visual control task was not affected by the stimulation in either group. The results support previous neuroimaging studies that the right DLPFC is involved in pitch memory processes in non-musicians and highlights the importance of baseline pitch memory abilities for the modulatory effect of tDCS.

Movement timing in the sub-second range engages a brain network comprising cortical and sub-cortical areas. The present study aims at investigating the functional significance of the left dorsolateral premotor cortex (dPMC) for precise movement timing as determined by sensorimotor synchronization and rhythm reproduction. To this end, 18 healthy volunteers performed an auditorily paced synchronization-continuation task with the right hand. A simple reaction time task served as control condition. Transcranial direct current stimulation (tDCS) was applied over the left dPMC in order to modulate cortical excitability either with anodal or cathodal polarity or as sham stimulation. TDCS was applied for 10 minutes, respectively on separate days. For the continuation task the analysis revealed significantly smaller inter-tap intervals (ITIs) following cathodal tDCS suggesting movement hastening as well as a trend towards larger ITIs following anodal stimulation suggesting movement slowing. No significant effect was found following sham stimulation. Neither for synchronization nor for reaction time tasks significant polarity-specific effects emerged. The data suggest the causal involvement of the dPMC in temporally precisereproduction of isochronous rhythms rather than sensorimotor synchronization. The present findings support the hypothesis that different cortical brain areas within the motor-control-network distinctively contribute to movement timing in the sub-second range.

Functional brain imaging studies and non-invasive brain stimulation methods have shown the importance of the left supramarginal gyrus (SMG) for pitch memory. The extent to which this brain region plays a crucial role in memory for other auditory material remains unclear. Here, we sought to investigate the role of the left and right SMG in pitch and rhythm memory in non-musicians. Anodal or sham transcranial direct current stimulation (tDCS) was applied over the left SMG (Experiment 1) and right SMG (Experiment 2) in two different sessions. In each session participants completed a pitch and rhythm recognition memory task immediately after tDCS. A significant facilitation of pitch memory was revealed when anodal stimulation was applied over the left SMG. No significant effects on pitch memory were found for anodal tDCS over the right SMG or sham condition. For rhythm memory the opposite pattern was found; anodal tDCS over the right SMG led to an improvement in performance, but anodal tDCS over the left SMG had no significant effect. These results highlight a different hemispheric involvement of the SMG in auditory memory processing depending on auditory material that is encoded.