Cerebellar Neurodynamics Predict Decision Timing and Outcome on the Single-Trial Level.

Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (>10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.

Evolution, biomechanics, and neurobiology converge to explain selective finger motor control.

Humans use their fingers to perform a variety of tasks, from simple grasping to manipulating objects, to typing and playing musical instruments, a variety wider than any other species. The more sophisticated the task, the more it involves individuated finger movements, those in which one or more selected fingers perform an intended action while the motion of other digits is constrained. Here we review the neurobiology of such individuated finger movements. We consider their evolutionary origins, the extent to which finger movements are in fact individuated, and the evolved features of neuromuscular control that both enable and limit individuation. We go on to discuss other features of motor control that combine with individuation to create dexterity, the impairment of individuation by disease, and the broad extent of capabilities that individuation confers on humans. We comment on the challenges facing the development of a truly dexterous bionic hand. We conclude by identifying topics for future investigation that will advance our understanding of how neural networks interact across multiple regions of the central nervous system to create individuated movements for the skills humans use to express their cognitive activity.

Complementary Contributions of Striatal Projection Pathways to Action Initiation and Execution.

The performance of an action relies on the initiation and execution of appropriate movement sequences. Two basal ganglia pathways have been classically hypothesized to regulate this process via opposing roles in movement facilitation and suppression. By using a series of state-dependent optogenetic manipulations, we dissected the contributions of each pathway and found that both the direct striatonigral pathway and the indirect striatopallidal pathway are necessary for smooth initiation and the execution of learned action sequences. Optogenetic inhibition or stimulation of each pathway before sequence initiation increased the latency for initiation: manipulations of the striatonigral pathway activity slowed action initiation, and those of the striatopallidal pathway aborted action initiation. The inhibition of each pathway after initiation also impaired ongoing execution. Furthermore, the subtle activation of striatonigral neurons sustained the performance of learned sequences, while striatopallidal manipulations aborted ongoing performance. These results suggest a supportive versus permissive model, where patterns of coordinated activity, rather than the relative amount of activity in these pathways, regulate movement initiation and execution.

Kinetic features dictate sensorimotor alignment in the superior colliculus.

The execution of goal-oriented behaviours requires a spatially coherent alignment between sensory and motor maps. The current model for sensorimotor transformation in the superior colliculus relies on the topographic mapping of static spatial receptive fields onto movement endpoints1-6. Here, to experimentally assess the validity of this canonical static model of alignment, we dissected the visuo-motor network in the superior colliculus and performed in vivo intracellular and extracellular recordings across layers, in restrained and unrestrained conditions, to assess both the motor and the visual tuning of individual motor and premotor neurons. We found that collicular motor units have poorly defined visual static spatial receptive fields and respond instead to kinetic visual features, revealing the existence of a direct alignment in vectorial space between sensory and movement vectors, rather than between spatial receptive fields and movement endpoints as canonically hypothesized. We show that a neural network built according to these kinetic alignment principles is ideally placed to sustain ethological behaviours such as the rapid interception of moving and static targets. These findings reveal a novel dimension of the sensorimotor alignment process. By extending the alignment from the static to the kinetic domain this work provides a novel conceptual framework for understanding the nature of sensorimotor convergence and its relevance in guiding goal-directed behaviours.

Volatile working memory representations crystallize with practice.

Working memory, the process through which information is transiently maintained and manipulated over a brief period, is essential for most cognitive functions1-4. However, the mechanisms underlying the generation and evolution of working-memory neuronal representations at the population level over long timescales remain unclear. Here, to identify these mechanisms, we trained head-fixed mice to perform an olfactory delayed-association task in which the mice made decisions depending on the sequential identity of two odours separated by a 5 s delay. Optogenetic inhibition of secondary motor neurons during the late-delay and choice epochs strongly impaired the task performance of the mice. Mesoscopic calcium imaging of large neuronal populations of the secondary motor cortex (M2), retrosplenial cortex (RSA) and primary motor cortex (M1) showed that many late-delay-epoch-selective neurons emerged in M2 as the mice learned the task. Working-memory late-delay decoding accuracy substantially improved in the M2, but not in the M1 or RSA, as the mice became experts. During the early expert phase, working-memory representations during the late-delay epoch drifted across days, while the stimulus and choice representations stabilized. In contrast to single-plane layer 2/3 (L2/3) imaging, simultaneous volumetric calcium imaging of up to 73,307 M2 neurons, which included superficial L5 neurons, also revealed stabilization of late-delay working-memory representations with continued practice. Thus, delay- and choice-related activities that are essential for working-memory performance drift during learning and stabilize only after several days of expert performance.

Knowledge generalization and the costs of multitasking.

Humans are able to rapidly perform novel tasks, but show pervasive performance costs when attempting to do two things at once. Traditionally, empirical and theoretical investigations into the sources of such multitasking interference have largely focused on multitasking in isolation to other cognitive functions, characterizing the conditions that give rise to performance decrements. Here we instead ask whether multitasking costs are linked to the system's capacity for knowledge generalization, as is required to perform novel tasks. We show how interrogation of the neurophysiological circuitry underlying these two facets of cognition yields further insights for both. Specifically, we demonstrate how a system that rapidly generalizes knowledge may induce multitasking costs owing to sharing of task contingencies between contexts in neural representations encoded in frontoparietal and striatal brain regions. We discuss neurophysiological insights suggesting that prolonged learning segregates such representations by refining the brain's model of task-relevant contingencies, thereby reducing information sharing between contexts and improving multitasking performance while reducing flexibility and generalization. These proposed neural mechanisms explain why the brain shows rapid task understanding, multitasking limitations and practice effects. In short, multitasking limits are the price we pay for behavioural flexibility.

Modulation of inhibitory communication coordinates looking and reaching.

Looking and reaching are controlled by different brain regions and are coordinated during natural behaviour1. Understanding how flexible, natural behaviours such as coordinated looking and reaching are controlled depends on understanding how neurons in different regions of the brain communicate2. Neural coherence in a gamma-frequency (40-90 Hz) band has been implicated in excitatory multiregional communication3. Inhibitory control mechanisms are also required to flexibly control behaviour4, but little is known about how neurons in one region transiently suppress individual neurons in another to support behaviour. How neuronal firing in a sender region transiently suppresses firing in a receiver region remains poorly understood. Here we study inhibitory communication during a flexible, natural behaviour, termed gaze anchoring, in which saccades are transiently inhibited by coordinated reaches. During gaze anchoring, we found that neurons in the reach region of the posterior parietal cortex can inhibit neuronal firing in the parietal saccade region to suppress eye movements and improve reach accuracy. Suppression is transient, only present around the coordinated reach, and greatest when reach neurons fire spikes with respect to beta-frequency (15-25 Hz) activity, not gamma-frequency activity. Our work provides evidence in the activity of single neurons for a novel mechanism of inhibitory communication in which beta-frequency neural coherence transiently inhibits multiregional communication to flexibly coordinate natural behaviour.

Limb-related sensory prediction errors and task-related performance errors facilitate human sensorimotor learning through separate mechanisms.

The unpredictable nature of our world can introduce a variety of errors in our actions, including sensory prediction errors (SPEs) and task performance errors (TPEs). SPEs arise when our existing internal models of limb-environment properties and interactions become miscalibrated due to changes in the environment, while TPEs occur when environmental perturbations hinder achievement of task goals. The precise mechanisms employed by the sensorimotor system to learn from such limb- and task-related errors and improve future performance are not comprehensively understood. To gain insight into these mechanisms, we performed a series of learning experiments wherein the location and size of a reach target were varied, the visual feedback of the motion was perturbed in different ways, and instructions were carefully manipulated. Our findings indicate that the mechanisms employed to compensate SPEs and TPEs are dissociable. Specifically, our results fail to support theories that suggest that TPEs trigger implicit refinement of reach plans or that their occurrence automatically modulates SPE-mediated learning. Rather, TPEs drive improved action selection, that is, the selection of verbally sensitive, volitional strategies that reduce future errors. Moreover, we find that exposure to SPEs is necessary and sufficient to trigger implicit recalibration. When SPE-mediated implicit learning and TPE-driven improved action selection combine, performance gains are larger. However, when actions are always successful and strategies are not employed, refinement in behavior is smaller. Flexibly weighting strategic action selection and implicit recalibration could thus be a way of controlling how much, and how quickly, we learn from errors.

Low and high beta rhythms have different motor cortical sources and distinct roles in movement control and spatiotemporal attention.

Low and high beta frequency rhythms were observed in the motor cortex, but their respective sources and behavioral correlates remain unknown. We studied local field potentials (LFPs) during pre-cued reaching behavior in macaques. They contained a low beta band (<20 Hz) dominant in primary motor cortex and a high beta band (>20 Hz) dominant in dorsal premotor cortex (PMd). Low beta correlated positively with reaction time (RT) from visual cue onset and negatively with uninstructed hand postural micro-movements throughout the trial. High beta reflected temporal task prediction, with selective modulations before and during cues, which were enhanced in moments of increased focal attention when the gaze was on the work area. This double-dissociation in sources and behavioral correlates of motor cortical low and high beta, with respect to both task-instructed and spontaneous behavior, reconciles the largely disparate roles proposed for the beta rhythm, by suggesting band-specific roles in both movement control and spatiotemporal attention.

Contextual inference underlies the learning of sensorimotor repertoires.

ASBTRACT: Humans spend a lifetime learning, storing and refining a repertoire of motor memories. For example, through experience, we become proficient at manipulating a large range of objects with distinct dynamical properties. However, it is unknown what principle underlies how our continuous stream of sensorimotor experience is segmented into separate memories and how we adapt and use this growing repertoire. Here we develop a theory of motor learning based on the key principle that memory creation, updating and expression are all controlled by a single computation-contextual inference. Our theory reveals that adaptation can arise both by creating and updating memories (proper learning) and by changing how existing memories are differentially expressed (apparent learning). This insight enables us to account for key features of motor learning that had no unified explanation: spontaneous recovery1, savings2, anterograde interference3, how environmental consistency affects learning rate4,5 and the distinction between explicit and implicit learning6. Critically, our theory also predicts new phenomena-evoked recovery and context-dependent single-trial learning-which we confirm experimentally. These results suggest that contextual inference, rather than classical single-context mechanisms1,4,7-9, is the key principle underlying how a diverse set of experiences is reflected in our motor behaviour.

Neural dynamics underlying birdsong practice and performance.

Musical and athletic skills are learned and maintained through intensive practice to enable precise and reliable performance for an audience. Consequently, understanding such complex behaviours requires insight into how the brain functions during both practice and performance. Male zebra finches learn to produce courtship songs that are more varied when alone and more stereotyped in the presence of females1. These differences are thought to reflect song practice and performance, respectively2,3, providing a useful system in which to explore how neurons encode and regulate motor variability in these two states. Here we show that calcium signals in ensembles of spiny neurons (SNs) in the basal ganglia are highly variable relative to their cortical afferents during song practice. By contrast, SN calcium signals are strongly suppressed during female-directed performance, and optogenetically suppressing SNs during practice strongly reduces vocal variability. Unsupervised learning methods4,5 show that specific SN activity patterns map onto distinct song practice variants. Finally, we establish that noradrenergic signalling reduces vocal variability by directly suppressing SN activity. Thus, SN ensembles encode and drive vocal exploration during practice, and the noradrenergic suppression of SN activity promotes stereotyped and precise song performance for an audience.

Cortex-dependent corrections as the tongue reaches for and misses targets.

Precise tongue control is necessary for drinking, eating and vocalizing1-3. However, because tongue movements are fast and difficult to resolve, neural control of lingual kinematics remains poorly understood. Here we combine kilohertz-frame-rate imaging and a deep-learning-based neural network to resolve 3D tongue kinematics in mice drinking from a water spout. Successful licks required corrective submovements that-similar to online corrections during primate reaches4-11-occurred after the tongue missed unseen, distant or displaced targets. Photoinhibition of anterolateral motor cortex impaired corrections, which resulted in hypometric licks that missed the spout. Neural activity in anterolateral motor cortex reflected upcoming, ongoing and past corrective submovements, as well as errors in predicted spout contact. Although less than a tenth of a second in duration, a single mouse lick exhibits the hallmarks of online motor control associated with a primate reach, including cortex-dependent corrections after misses.

Actions chains and intention understanding in 3- to 6-year-old children.

In intentional behavior, the final goal of an action is crucial in determining the entire sequence of motor acts. Neurons have been described in the inferior parietal lobule of monkeys, which besides encoding a specific motor act (e.g., grasping), have their discharge modulated by the final goal of the intended action (e.g., grasping-to-eat). Many of these "action-constrained" neurons have mirror properties responding to the observation of the motor act they encode, provided that this is embedded in a specific action. Thanks to this mechanism, the observers have an internal copy of the whole action before its execution and may, in this way, understand the agent's intention. The chained organization of motor acts has been demonstrated in schoolchildren. Here, we examined whether this organization is already present in very young children. To this purpose, we recorded EMG from the mylohyoid (MH) muscle in the children aged 3 to 6 y. The results showed that preschoolers, like older children, possess the chained organization of motor acts in execution. Interestingly, in comparison to older children, they have a delayed ability to use this mechanism to infer others' intentions by observation. Finally, we found a significant negative association between the children's age and the activation of the MH muscle during the grasp-to-eat phase in the observation condition. We, tentatively, interpreted it as a sign of an immature control of motor acts.

Pink noise promotes sooner state transitions during bimanual coordination.

The seemingly straightforward task of tying one's shoes requires a sophisticated interplay of joints, muscles, and neural pathways, posing a formidable challenge for researchers studying the intricacies of coordination. A widely accepted framework for measuring coordinated behavior is the Haken-Kelso-Bunz (HKB) model. However, a significant limitation of this model is its lack of accounting for the diverse variability structures inherent in the coordinated systems it frequently models. Variability is a pervasive phenomenon across various biological and physical systems, and it changes in healthy adults, older adults, and pathological populations. Here, we show, both empirically and with simulations, that manipulating the variability in coordinated movements significantly impacts the ability to change coordination patterns-a fundamental feature of the HKB model. Our results demonstrate that synchronized bimanual coordination, mirroring a state of healthy variability, instigates earlier transitions of coordinated movements compared to other variability conditions. This suggests a heightened adaptability when movements possess a healthy variability. We anticipate our study to show the necessity of adapting the HKB model to encompass variability, particularly in predictive applications such as neuroimaging, cognition, skill development, biomechanics, and beyond.

Visual guidance fine-tunes probing movements of an insect appendage.

Visually guided reaching, a regular feature of human life, comprises an intricate neural control task. It includes identifying the target's position in 3D space, passing the representation to the motor system that controls the respective appendages, and adjusting ongoing movements using visual and proprioceptive feedback. Given the complexity of the neural control task, invertebrates, with their numerically constrained central nervous systems, are often considered incapable of this level of visuomotor guidance. Here, we provide mechanistic insights into visual appendage guidance in insects by studying the probing movements of the hummingbird hawkmoth's proboscis as they search for a flower's nectary. We show that visually guided proboscis movements fine-tune the coarse control provided by body movements in flight. By impairing the animals' view of their proboscis, we demonstrate that continuous visual feedback is required and actively sought out to guide this appendage. In doing so, we establish an insect model for the study of neural strategies underlying eye-appendage control in a simple nervous system.

Spike-timing-dependent plasticity induction reveals dissociable supplementary- and premotor-motor pathways to automatic imitation.

Humans tend to spontaneously imitate others' behavior, even when detrimental to the task at hand. The action observation network (AON) is consistently recruited during imitative tasks. However, whether automatic imitation is mediated by cortico-cortical projections from AON regions to the primary motor cortex (M1) remains speculative. Similarly, the potentially dissociable role of AON-to-M1 pathways involving the ventral premotor cortex (PMv) or supplementary motor area (SMA) in automatic imitation is unclear. Here, we used cortico-cortical paired associative stimulation (ccPAS) to enhance or hinder effective connectivity in PMv-to-M1 and SMA-to-M1 pathways via Hebbian spike-timing-dependent plasticity (STDP) to test their functional relevance to automatic and voluntary motor imitation. ccPAS affected behavior under competition between task rules and prepotent visuomotor associations underpinning automatic imitation. Critically, we found dissociable effects of manipulating the strength of the two pathways. While strengthening PMv-to-M1 projections enhanced automatic imitation, weakening them hindered it. On the other hand, strengthening SMA-to-M1 projections reduced automatic imitation but also reduced interference from task-irrelevant cues during voluntary imitation. Our study demonstrates that driving Hebbian STDP in AON-to-M1 projections induces opposite effects on automatic imitation that depend on the targeted pathway. Our results provide direct causal evidence of the functional role of PMv-to-M1 projections for automatic imitation, seemingly involved in spontaneously mirroring observed actions and facilitating the tendency to imitate them. Moreover, our findings support the notion that SMA exerts an opposite gating function, controlling M1 to prevent overt motor behavior when inadequate to the context.

Towards real-world generalizability of a circuit for action-stopping.

Two decades of cross-species neuroscience research on rapid action-stopping in the laboratory has provided motivation for an underlying prefrontal-basal ganglia circuit. Here we provide an update of key studies from the past few years. We conclude that this basic neural circuit is on increasingly firm ground, and we move on to consider whether the action-stopping function implemented by this circuit applies beyond the simple laboratory stop signal task. We advance through a series of studies of increasing 'real-worldness', starting with laboratory tests of stopping of speech, gait and bodily functions, and then going beyond the laboratory to consider neural recordings and stimulation during moments of control presumably required in everyday activities such as walking and driving. We end by asking whether stopping research has clinical relevance, focusing on movement disorders such as stuttering, tics and freezing of gait. Overall, we conclude there are hints that the prefrontal-basal ganglia action-stopping circuit that is engaged by the basic stop signal task is recruited in myriad scenarios; however, truly proving this for real-world scenarios requires a new generation of studies that will need to overcome substantial technical and inferential challenges.

Nearest neighbours reveal fast and slow components of motor learning.

Changes in behaviour resulting from environmental influences, development and learning1-5 are commonly quantified on the basis of a few hand-picked features2-4,6,7 (for example, the average pitch of acoustic vocalizations3), assuming discrete classes of behaviours (such as distinct vocal syllables)2,3,8-10. However, such methods generalize poorly across different behaviours and model systems and may miss important components of change. Here we present a more-general account of behavioural change that is based on nearest-neighbour statistics11-13, and apply it to song development in a songbird, the zebra finch3. First, we introduce the concept of 'repertoire dating', whereby each rendition of a behaviour (for example, each vocalization) is assigned a repertoire time, reflecting when similar renditions were typical in the behavioural repertoire. Repertoire time isolates the components of vocal variability that are congruent with long-term changes due to vocal learning and development, and stratifies the behavioural repertoire into 'regressions', 'anticipations' and 'typical renditions'. Second, we obtain a holistic, yet low-dimensional, description of vocal change in terms of a stratified 'behavioural trajectory', revealing numerous previously unrecognized components of behavioural change on fast and slow timescales, as well as distinct patterns of overnight consolidation1,2,4,14,15 across the behavioral repertoire. We find that diurnal changes in regressions undergo only weak consolidation, whereas anticipations and typical renditions consolidate fully. Because of its generality, our nonparametric description of how behaviour evolves relative to itself-rather than to a potentially arbitrary, experimenter-defined goal2,3,14,16-appears well suited for comparing learning and change across behaviours and species17,18, as well as biological and artificial systems5.

Adaptive control is reversed between hands after left hemisphere stroke and lost following right hemisphere stroke.

Human motor adaptability is of utmost utility after neurologic injury such as unilateral stroke. For successful adaptive control of movements, the nervous system must learn to correctly identify the source of a movement error and predictively compensate for this error. The current understanding is that in bimanual tasks, this process is flexible such that errors are assigned to, and compensated for, by the limb that is more likely to produce those errors. Here, we tested the flexibility of the error assignment process in right-handed chronic stroke survivors using a bimanual reaching task in which the hands jointly controlled a single cursor. We predicted that the nondominant left hand in neurotypical adults and the paretic hand in chronic stroke survivors will be more responsible for cursor errors and will compensate more within a trial and learn more from trial to trial. We found that in neurotypical adults, the nondominant left hand does compensate more than the right hand within a trial but learns less trial-to-trial. After a left hemisphere stroke, the paretic right hand compensates more than the nonparetic left hand within-trial but learns less trial-to-trial. After a right hemisphere stroke, the paretic left hand neither corrects more within-trial nor learns more trial-to-trial. Thus, adaptive control of visually guided bimanual reaching movements is reversed between hands after the left hemisphere stroke and lost following the right hemisphere stroke. These results indicate that responsibility assignment is not fully flexible but depends on a central mechanism that is lateralized to the right hemisphere.

Erroneous Compensation for Long-Latency Feedback Delays as Origin of Essential Tremor.

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with 24 ET patients (14 female; 10 male) and 28 neurologically intact (NI) human volunteers (17 female; 11 male) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients' early muscular responses (short and long-latency responses, 20-50 and 50-100 ms, respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor.