Cortical Patterns Shift from Sequence Feature Separation during Planning to Integration during Motor Execution.

Performing sequences of movements from memory and adapting them to changing task demands is a hallmark of skilled human behavior, from handwriting to playing a musical instrument. Prior studies showed a fine-grained tuning of cortical primary motor, premotor, and parietal regions to motor sequences: from the low-level specification of individual movements to high-level sequence features, such as sequence order and timing. However, it is not known how tuning in these regions unfolds dynamically across planning and execution. To address this, we trained 24 healthy right-handed human participants (14 females, 10 males) to produce four five-element finger press sequences with a particular finger order and timing structure in a delayed sequence production paradigm entirely from memory. Local cortical fMRI patterns during preparation and production phases were extracted from separate No-Go and Go trials, respectively, to tease out activity related to these perimovement phases. During sequence planning, premotor and parietal areas increased tuning to movement order or timing, regardless of their combinations. In contrast, patterns reflecting the unique integration of sequence features emerged in these regions during execution only, alongside timing-specific tuning in the ventral premotor, supplementary motor, and superior parietal areas. This was in line with the participants' behavioral transfer of trained timing, but not of order to new sequence feature combinations. Our findings suggest a general informational state shift from high-level feature separation to low-level feature integration within cortical regions for movement execution. Recompiling sequence features trial-by-trial during planning may enable flexible last-minute adjustment before movement initiation.SIGNIFICANCE STATEMENT Musicians and athletes can modify the timing and order of movements in a sequence trial-by-trial, allowing for a vast repertoire of flexible behaviors. How does the brain put together these high-level sequence features into an integrated whole? We found that, trial-by-trial, the control of sequence features undergoes a state shift from separation during planning to integration during execution across a network of motor-related cortical areas. These findings have implications for understanding the hierarchical control of skilled movement sequences, as well as how information in brain areas unfolds across planning and execution.

A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

BACKGROUND: Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered. OBJECTIVE: To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex. METHODS: Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model. RESULTS: Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies. CONCLUSIONS: The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Surmising synchrony of sound and sight: Factors explaining variance of audiovisual integration in hurdling, tap dancing and drumming.

Auditory and visual percepts are integrated even when they are not perfectly temporally aligned with each other, especially when the visual signal precedes the auditory signal. This window of temporal integration for asynchronous audiovisual stimuli is relatively well examined in the case of speech, while other natural action-induced sounds have been widely neglected. Here, we studied the detection of audiovisual asynchrony in three different whole-body actions with natural action-induced sounds-hurdling, tap dancing and drumming. In Study 1, we examined whether audiovisual asynchrony detection, assessed by a simultaneity judgment task, differs as a function of sound production intentionality. Based on previous findings, we expected that auditory and visual signals should be integrated over a wider temporal window for actions creating sounds intentionally (tap dancing), compared to actions creating sounds incidentally (hurdling). While percentages of perceived synchrony differed in the expected way, we identified two further factors, namely high event density and low rhythmicity, to induce higher synchrony ratings as well. Therefore, we systematically varied event density and rhythmicity in Study 2, this time using drumming stimuli to exert full control over these variables, and the same simultaneity judgment tasks. Results suggest that high event density leads to a bias to integrate rather than segregate auditory and visual signals, even at relatively large asynchronies. Rhythmicity had a similar, albeit weaker effect, when event density was low. Our findings demonstrate that shorter asynchronies and visual-first asynchronies lead to higher synchrony ratings of whole-body action, pointing to clear parallels with audiovisual integration in speech perception. Overconfidence in the naturally expected, that is, synchrony of sound and sight, was stronger for intentional (vs. incidental) sound production and for movements with high (vs. low) rhythmicity, presumably because both encourage predictive processes. In contrast, high event density appears to increase synchronicity judgments simply because it makes the detection of audiovisual asynchrony more difficult. More studies using real-life audiovisual stimuli with varying event densities and rhythmicities are needed to fully uncover the general mechanisms of audiovisual integration.

Competitive state of movements during planning predicts sequence performance.

Humans can learn and produce skilled movement sequences from memory, yet the nature of sequence planning is not well understood. Previous computational and neurophysiological work suggests that movements in a sequence are planned as parallel graded activations and selected for output through competition. However, the relevance of this planning pattern to sequence production fluency and accuracy, as opposed to the temporal structure of sequences, is unclear. To resolve this question, we assessed the relative availability of constituent movements behaviorally during the preparation of motor sequences from memory. In three separate multisession experiments, healthy participants were trained to retrieve and produce four-element finger press sequences with particular timing according to an abstract sequence cue. We evaluated reaction time (RT) and error rate as markers of movement availability to constituent movement probes. Our results demonstrate that longer preparation time produces more pronounced differences in availability between adjacent sequence elements, whereas no effect was found for sequence speed or temporal grouping. Further, participants with larger position-dependent differences in movement availability tended to initiate correct sequences faster and with a higher temporal accuracy. Our results suggest that competitive preactivation is established gradually during sequence planning and predicts sequence skill, rather than the temporal structure of the motor sequence.NEW & NOTEWORTHY Sequence planning is an integral part of motor sequence control. Here, we demonstrate that the competitive state of sequential movements during sequence planning can be read out behaviorally through movement probes. We show that position-dependent differences in movement availability during planning reflect sequence preparedness and skill but not the timing of the planned sequence. Behavioral access to the preparatory state of movements may serve as a marker of sequence planning capacity.

Neural Competitive Queuing of Ordinal Structure Underlies Skilled Sequential Action.

Fluent retrieval and execution of movement sequences is essential for daily activities, but the neural mechanisms underlying sequence planning remain elusive. Here participants learned finger press sequences with different orders and timings and reproduced them in a magneto-encephalography (MEG) scanner. We classified the MEG patterns for each press in the sequence and examined pattern dynamics during preparation and production. Our results demonstrate the "competitive queuing" (CQ) of upcoming action representations, extending previous computational and non-human primate recording studies to non-invasive measures in humans. In addition, we show that CQ reflects an ordinal template that generalizes across specific motor actions at each position. Finally, we demonstrate that CQ predicts participants' production accuracy and originates from parahippocampal and cerebellar sources. These results suggest that the brain learns and controls multiple sequences by flexibly combining representations of specific actions and interval timing with high-level, parallel representations of sequence position.

A unifying motor control framework for task-specific dystonia.

Task-specific dystonia is a movement disorder characterized by a painless loss of dexterity specific to a particular motor skill. This disorder is prevalent among writers, musicians, dancers and athletes. No current treatment is predictably effective, and the disorder generally ends the careers of affected individuals. Traditional disease models of dystonia have a number of limitations with regard to task-specific dystonia. We therefore discuss emerging evidence that the disorder has its origins within normal compensatory mechanisms of a healthy motor system in which the representation and reproduction of motor skill are disrupted. We describe how risk factors for task-specific dystonia can be stratified and translated into mechanisms of dysfunctional motor control. The proposed model aims to define new directions for experimental research and stimulate therapeutic advances for this highly disabling disorder.

Encoding Temporal Features of Skilled Movements-What, Whether and How?

In order to reliably produce intelligible speech or fluently play a melody on a piano, learning the precise timing of muscle activations is essential. Surprisingly, the fundamental question of how memories of complex temporal dynamics of movement are stored across the brain is still unresolved. This review outlines the constraints that determine whether and how the timing of skilled movements is represented in the central nervous system and introduces different computational and neural mechanisms that can be harnessed for temporal encoding. It concludes by proposing a schematic model of how these different mechanisms may complement and interact with each other in fast feedback loops to achieve skilled motor timing.

Unsupervised vector-based classification of single-molecule charge transport data.

The stochastic nature of single-molecule charge transport measurements requires collection of large data sets to capture the full complexity of a molecular system. Data analysis is then guided by certain expectations, for example, a plateau feature in the tunnelling current distance trace, and the molecular conductance extracted from suitable histogram analysis. However, differences in molecular conformation or electrode contact geometry, the number of molecules in the junction or dynamic effects may lead to very different molecular signatures. Since their manifestation is a priori unknown, an unsupervised classification algorithm, making no prior assumptions regarding the data is clearly desirable. Here we present such an approach based on multivariate pattern analysis and apply it to simulated and experimental single-molecule charge transport data. We demonstrate how different event shapes are clearly separated using this algorithm and how statistics about different event classes can be extracted, when conventional methods of analysis fail.

Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice.

Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval.

Motor skill learning between selection and execution.

Learning motor skills evolves from the effortful selection of single movement elements to their combined fast and accurate production. We review recent trends in the study of skill learning which suggest a hierarchical organization of the representations that underlie such expert performance, with premotor areas encoding short sequential movement elements (chunks) or particular component features (timing/spatial organization). This hierarchical representation allows the system to utilize elements of well-learned skills in a flexible manner. One neural correlate of skill development is the emergence of specialized neural circuits that can produce the required elements in a stable and invariant fashion. We discuss the challenges in detecting these changes with fMRI.

Human premotor areas parse sequences into their spatial and temporal features.

Skilled performance is characterized by precise and flexible control of movement sequences in space and time. Recent theories suggest that integrated spatio-temporal trajectories are generated by intrinsic dynamics of motor and premotor networks. This contrasts with behavioural advantages that emerge when a trained spatial or temporal feature of sequences is transferred to a new spatio-temporal combination arguing for independent neural representations of these sequence features. We used a new fMRI pattern classification approach to identify brain regions with independent vs integrated representations. A distinct regional dissociation within motor areas was revealed: whereas only the contralateral primary motor cortex exhibited unique patterns for each spatio-temporal sequence combination, bilateral premotor areas represented spatial and temporal features independently of each other. These findings advocate a unique function of higher motor areas for flexible recombination and efficient encoding of complex motor behaviours.

Sensory-guided motor tasks benefit from mental training based on serial prediction.

Mental strategies have been suggested to constitute a promising approach to improve motor abilities in both healthy subjects and patients. This behavioural effect has been shown to be associated with changes of neural activity in premotor areas, not only during movement execution, but also while performing motor imagery or action observation. However, how well such mental tasks are performed is often difficult to assess, especially in patients. We here used a novel mental training paradigm based on the serial prediction task (SPT) in order to activate premotor circuits in the absence of a motor task. We then tested whether this intervention improves motor-related performance such as sensorimotor transformation. Two groups of healthy young participants underwent a single-blinded five-day cognitive training schedule and were tested in four different motor tests on the day before and after training. One group (N=22) received the SPT-training and the other one (N=21) received a control training based on a serial match-to-sample task. The results revealed significant improvements of the SPT-group in a sensorimotor timing task, i.e. synchronization of finger tapping to a visually presented rhythm, as well as improved visuomotor coordination in a sensory-guided pointing task compared to the group that received the control training. However, mental training did not show transfer effects on motor abilities in healthy subjects beyond the trained modalities as evident by non-significant changes in the Jebsen-Taylor handfunctiontest. In summary, the data suggest that mental training based on the serial prediction task effectively engages sensorimotor circuits and thereby improves motor behaviour.

Interaction of temporal and ordinal representations in movement sequences.

The production of movement sequences requires an accurate control of muscle activation in time. How does the nervous system encode the precise timing of these movements? One possibility is that the timing of movements (temporal sequence) is an emergent property of the dynamic state of the nervous system and therefore intimately linked to a representation of the sequence of muscle commands (ordinal sequence). Alternatively, timing may be represented independently of the motor effectors and would be transferable to a new ordinal sequence. Some studies have found that a learned temporal sequence cannot be transferred to a new ordinal sequence, thus arguing for an integrated representation. Others have observed temporal transfer across movement sequences and have advocated an independent representation of temporal information. Using a modified serial reaction time task, we tested alternative models of the representation of temporal structure and the interaction between the output of separate ordinal and temporal sequence representations. Temporal transfer depended on whether a novel ordinal sequence was fixed within each test block. Our results confirm the presence of an independent representation of temporal structure and advocate a nonlinear multiplicative neural interaction of temporal and ordinal signals in the production of movements.

Impairment of auditory-motor timing and compensatory reorganization after ventral premotor cortex stimulation.

Integrating auditory and motor information often requires precise timing as in speech and music. In humans, the position of the ventral premotor cortex (PMv) in the dorsal auditory stream renders this area a node for auditory-motor integration. Yet, it remains unknown whether the PMv is critical for auditory-motor timing and which activity increases help to preserve task performance following its disruption. 16 healthy volunteers participated in two sessions with fMRI measured at baseline and following rTMS (rTMS) of either the left PMv or a control region. Subjects synchronized left or right finger tapping to sub-second beat rates of auditory rhythms in the experimental task, and produced self-paced tapping during spectrally matched auditory stimuli in the control task. Left PMv rTMS impaired auditory-motor synchronization accuracy in the first sub-block following stimulation (p<0.01, Bonferroni corrected), but spared motor timing and attention to task. Task-related activity increased in the homologue right PMv, but did not predict the behavioral effect of rTMS. In contrast, anterior midline cerebellum revealed most pronounced activity increase in less impaired subjects. The present findings suggest a critical role of the left PMv in feed-forward computations enabling accurate auditory-motor timing, which can be compensated by activity modulations in the cerebellum, but not in the homologue region contralateral to stimulation.

Inhibitory stimulation of the ventral premotor cortex temporarily interferes with musical beat rate preference.

Behavioral studies suggest that preference for a beat rate (tempo) in auditory sequences is tightly linked to the motor system. However, from a neuroscientific perspective the contribution of motor-related brain regions to tempo preference in the auditory domain remains unclear. A recent fMRI study (Kornysheva et al. [2010]: Hum Brain Mapp 31:48-64) revealed that the activity increase in the left ventral premotor cortex (PMv) is associated with the preference for a tempo of a musical rhythm. The activity increase correlated with how strongly the subjects preferred a tempo. Despite this evidence, it remains uncertain whether an interference with activity in the left PMv affects tempo preference strength. Consequently, we conducted an offline repetitive transcranial magnetic stimulation (rTMS) study, in which the cortical excitability in the left PMv was temporarily reduced. As hypothesized, 0.9 Hz rTMS over the left PMv temporarily affected individual tempo preference strength depending on the individual strength of tempo preference in the control session. Moreover, PMv stimulation temporarily interfered with the stability of individual tempo preference strength within and across sessions. These effects were specific to the preference for tempo in contrast to the preference for timbre, bound to the first half of the experiment following PMv stimulation and could not be explained by an impairment of tempo recognition. Our results corroborate preceding fMRI findings and suggest that activity in the left PMv is part of a network that affects the strength of beat rate preference.

Tuning-in to the beat: Aesthetic appreciation of musical rhythms correlates with a premotor activity boost.

Listening to music can induce us to tune in to its beat. Previous neuroimaging studies have shown that the motor system becomes involved in perceptual rhythm and timing tasks in general, as well as during preference-related responses to music. However, the role of preferred rhythm and, in particular, of preferred beat frequency (tempo) in driving activity in the motor system remains unknown. The goals of the present functional magnetic resonance imaging (fMRI) study were to determine whether the musical rhythms that are subjectively judged as beautiful boost activity in motor-related areas and if so, whether this effect is driven by preferred tempo, the underlying pulse people tune in to. On the basis of the subjects' judgments, individual preferences were determined for the different systematically varied constituents of the musical rhythms. Results demonstrate the involvement of premotor and cerebellar areas during preferred compared to not preferred musical rhythms and indicate that activity in the ventral premotor cortex (PMv) is enhanced by preferred tempo. Our findings support the assumption that the premotor activity increase during preferred tempo is the result of enhanced sensorimotor simulation of the beat frequency. This may serve as a mechanism that facilitates the tuning-in to the beat of appealing music.