Keeping time and rhythm by internal simulation of sensory stimuli and behavioral actions.

Effective behavior often requires synchronizing our actions with changes in the environment. Rhythmic changes in the environment are easy to predict, and we can readily time our actions to them. Yet, how the brain encodes and maintains rhythms is not known. Here, we trained primates to internally maintain rhythms of different tempos and performed large-scale recordings of neuronal activity across the sensory-motor hierarchy. Results show that maintaining rhythms engages multiple brain areas, including visual, parietal, premotor, prefrontal, and hippocampal regions. Each recorded area displayed oscillations in firing rates and oscillations in broadband local field potential power that reflected the temporal and spatial characteristics of an internal metronome, which flexibly encoded fast, medium, and slow tempos. The presence of widespread metronome-related activity, in the absence of stimuli and motor activity, suggests that internal simulation of stimuli and actions underlies timekeeping and rhythm maintenance.

Pre-supplementary Motor Cortex Mediates Learning Transfer from Perceptual to Motor Timing.

When we intensively train a timing skill, such as learning to play the piano, we not only produce brain changes associated with task-specific learning but also improve our performance in other temporal behaviors that depend on these tuned neural resources. Since the neural basis of time learning and generalization is still unknown, we measured the changes in neural activity associated with the transfer of learning from perceptual to motor timing in a large sample of subjects (n = 65; 39 women). We found that intense training in an interval discrimination task increased the acuity of time perception in a group of subjects that also exhibited learning transfer, expressed as a reduction in inter-tap interval variability during an internally driven periodic motor task. In addition, we found subjects with no learning and/or generalization effects. Notably, functional imaging showed an increase in pre-supplementary motor area and caudate-putamen activity between the post- and pre-training sessions of the tapping task. This increase was specific to the subjects that generalized their timing acuity from the perceptual to the motor context. These results emphasize the central role of the cortico-basal ganglia circuit in the generalization of timing abilities between tasks.

Amodal population clock in the primate medial premotor system for rhythmic tapping.

The neural substrate for beat extraction and response entrainment to rhythms is not fully understood. Here we analyze the activity of medial premotor neurons in monkeys performing isochronous tapping guided by brief flashing stimuli or auditory tones. The population dynamics shared the following properties across modalities: the circular dynamics of the neural trajectories form a regenerating loop for every produced interval; the trajectories converge in similar state space at tapping times resetting the clock; and the tempo of the synchronized tapping is encoded in the trajectories by a combination of amplitude modulation and temporal scaling. Notably, the modality induces displacement in the neural trajectories in the auditory and visual subspaces without greatly altering the time-keeping mechanism. These results suggest that the interaction between the medial premotor cortex's amodal internal representation of pulse and a modality-specific external input generates a neural rhythmic clock whose dynamics govern rhythmic tapping execution across senses.

Rhythmic tapping to a moving beat motion kinematics overrules natural gravity.

Beat induction is the cognitive ability that allows humans to listen to a regular pulse in music and move in synchrony with it. Although auditory rhythmic cues induce more consistent synchronization than flashing visual metronomes, this auditory-visual asymmetry can be canceled by visual moving stimuli. Here, we investigated whether the naturalness of visual motion or its kinematics could provide a synchronization advantage over flashing metronomes. Subjects were asked to tap in sync with visual metronomes defined by vertically accelerating/decelerating motion, either congruent or not with natural gravity; horizontally accelerating/decelerating motion; or flashing stimuli. We found that motion kinematics was the predominant factor determining rhythm synchronization, as accelerating moving metronomes in any cardinal direction produced more precise and predictive tapping than decelerating or flashing conditions. Our results support the notion that accelerating visual metronomes convey a strong sense of beat, as seen in the cueing movements of an orchestra director.

A framework and resource for global collaboration in non-human primate neuroscience.

As science and technology evolve, there is an increasing need for promotion of international scientific exchange. Collaborations, while offering substantial opportunities for scientists and benefit to society, also present challenges for those working with animal models, such as non-human primates (NHPs). Diversity in regulation of animal research is sometimes mistaken for the absence of common international welfare standards. Here, the ethical and regulatory protocols for 13 countries that have guidelines in place for biomedical research involving NHPs were assessed with a focus on neuroscience. Review of the variability and similarity in trans-national NHP welfare regulations extended to countries in Asia, Europe and North America. A tabulated resource was established to advance solution-oriented discussions and scientific collaborations across borders. Our aim is to better inform the public and other stakeholders. Through cooperative efforts to identify and analyze information with reference to evidence-based discussion, the proposed key ingredients may help to shape and support a more informed, open framework. This framework and resource can be expanded further for biomedical research in other countries.

Macaque monkeys and humans sample temporal regularities in the acoustic environment.

Many animal species show comparable abilities to detect basic rhythms and produce rhythmic behavior. Yet, the capacities to process complex rhythms and synchronize rhythmic behavior appear to be species-specific: vocal learning animals can, but some primates might not. This discrepancy is of high interest as there is a putative link between rhythm processing and the development of sophisticated sensorimotor behavior in humans. Do our closest ancestors show comparable endogenous dispositions to sample the acoustic environment in the absence of task instructions and training? We recorded EEG from macaque monkeys and humans while they passively listened to isochronous equitone sequences. Individual- and trial-level analyses showed that macaque monkeys' and humans' delta-band neural oscillations encoded and tracked the timing of auditory events. Further, mu- (8-15 Hz) and beta-band (12-20 Hz) oscillations revealed the superimposition of varied accentuation patterns on a subset of trials. These observations suggest convergence in the encoding and dynamic attending of temporal regularities in the acoustic environment, bridging a gap in the phylogenesis of rhythm cognition.

Distinct beta frequencies reflect categorical decisions.

Based on prior findings of content-specific beta synchronization in working memory and decision making, we hypothesized that beta oscillations support the (re-)activation of cortical representations by mediating neural ensemble formation. We found that beta activity in monkey dorsolateral prefrontal cortex (dlPFC) and pre-supplementary motor area (preSMA) reflects the content of a stimulus in relation to the task context, regardless of its objective properties. In duration- and distance-categorization tasks, we changed the boundary between categories from one block of trials to the next. We found that two distinct beta-band frequencies were consistently associated with the two relative categories, with activity in these bands predicting the animals' responses. We characterized beta at these frequencies as transient bursts, and showed that dlPFC and preSMA are connected via these distinct frequency channels. These results support the role of beta in forming neural ensembles, and further show that such ensembles synchronize at different beta frequencies.

Mapping between sound, brain and behaviour: four-level framework for understanding rhythm processing in humans and non-human primates.

Humans perceive and spontaneously move to one or several levels of periodic pulses (a meter, for short) when listening to musical rhythm, even when the sensory input does not provide prominent periodic cues to their temporal location. Here, we review a multi-levelled framework to understanding how external rhythmic inputs are mapped onto internally represented metric pulses. This mapping is studied using an approach to quantify and directly compare representations of metric pulses in signals corresponding to sensory inputs, neural activity and behaviour (typically body movement). Based on this approach, recent empirical evidence can be drawn together into a conceptual framework that unpacks the phenomenon of meter into four levels. Each level highlights specific functional processes that critically enable and shape the mapping from sensory input to internal meter. We discuss the nature, constraints and neural substrates of these processes, starting with fundamental mechanisms investigated in macaque monkeys that enable basic forms of mapping between simple rhythmic stimuli and internally represented metric pulse. We propose that human evolution has gradually built a robust and flexible system upon these fundamental processes, allowing more complex levels of mapping to emerge in musical behaviours. This approach opens promising avenues to understand the many facets of rhythmic behaviours across individuals and species. This article is part of the theme issue 'Synchrony and rhythm interaction: from the brain to behavioural ecology'.

Strengths and challenges of longitudinal non-human primate neuroimaging.

Longitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power.

A collaborative resource platform for non-human primate neuroimaging.

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field .

Beyond MRI: on the scientific value of combining non-human primate neuroimaging with metadata.

Sharing and pooling large amounts of non-human primate neuroimaging data offer new exciting opportunities to understand the primate brain. The potential of big data in non-human primate neuroimaging could however be tremendously enhanced by combining such neuroimaging data with other types of information. Here we describe metadata that have been identified as particularly valuable by the non-human primate neuroimaging community, including behavioural, genetic, physiological and phylogenetic data.

PREEMACS: Pipeline for preprocessing and extraction of the macaque brain surface.

Accurate extraction of the cortical brain surface is critical for cortical thickness estimation and a key element to perform multimodal imaging analysis, where different metrics are integrated and compared in a common space. While brain surface extraction has become widespread practice in human studies, several challenges unique to neuroimaging of non-human primates (NHP) have hindered its adoption for the study of macaques. Although, some of these difficulties can be addressed at the acquisition stage, several common artifacts can be minimized through image preprocessing. Likewise, there are several image analysis pipelines for human MRIs, but very few automated methods for extraction of cortical surfaces have been reported for NHPs and none have been tested on data from diverse sources. We present PREEMACS, a pipeline that standardizes the preprocessing of structural MRI images (T1- and T2-weighted) and carries out an automatic surface extraction of the macaque brain. Building upon and extending pre-existing tools, the first module performs volume orientation, image cropping, intensity non-uniformity correction, and volume averaging, before skull-stripping through a convolutional neural network. The second module performs quality control using an adaptation of MRIqc method to extract objective quality metrics that are then used to determine the likelihood of accurate brain surface estimation. The third and final module estimates the white matter (wm) and pial surfaces from the T1-weighted volume (T1w) using an NHP customized version of FreeSurfer aided by the T2-weighted volumes (T2w). To evaluate the generalizability of PREEMACS, we tested the pipeline using 57 T1w/T2w NHP volumes acquired at 11 different sites from the PRIME-DE public dataset. Results showed an accurate and robust automatic brain surface extraction from images that passed the quality control segment of our pipeline. This work offers a robust, efficient and generalizable pipeline for the automatic standardization of MRI surface analysis on NHP.

Neural Encoding and Representation of Time for Sensorimotor Control and Learning.

The ability to perceive and produce movements in the real world with precise timing is critical for survival in animals, including humans. However, research on sensorimotor timing has rarely considered the tight interrelation between perception, action, and cognition. In this review, we present new evidence from behavioral, computational, and neural studies in humans and nonhuman primates, suggesting a pivotal link between sensorimotor control and temporal processing, as well as describing new theoretical frameworks regarding timing in perception and action. We first discuss the link between movement coordination and interval-based timing by addressing how motor training develops accurate spatiotemporal patterns in behavior and influences the perception of temporal intervals. We then discuss how motor expertise results from establishing task-relevant neural manifolds in sensorimotor cortical areas and how the geometry and dynamics of these manifolds help reduce timing variability. We also highlight how neural dynamics in sensorimotor areas are involved in beat-based timing. These lines of research aim to extend our understanding of how timing arises from and contributes to perceptual-motor behaviors in complex environments to seamlessly interact with other cognitive processes.

The amplitude in periodic neural state trajectories underlies the tempo of rhythmic tapping.

Our motor commands can be exquisitely timed according to the demands of the environment, and the ability to generate rhythms of different tempos is a hallmark of musical cognition. Yet, the neuronal underpinnings behind rhythmic tapping remain elusive. Here, we found that the activity of hundreds of primate medial premotor cortices (MPCs; pre-supplementary motor area [preSMA] and supplementary motor area [SMA]) neurons show a strong periodic pattern that becomes evident when their responses are projected into a state space using dimensionality reduction analysis. We show that different tapping tempos are encoded by circular trajectories that travelled at a constant speed but with different radii, and that this neuronal code is highly resilient to the number of participating neurons. Crucially, the changes in the amplitude of the oscillatory dynamics in neuronal state space are a signature of duration encoding during rhythmic timing, regardless of whether it is guided by an external metronome or is internally controlled and is not the result of repetitive motor commands. This dynamic state signal predicted the duration of the rhythmically produced intervals on a trial-by-trial basis. Furthermore, the increase in variability of the neural trajectories accounted for the scalar property, a hallmark feature of temporal processing across tasks and species. Finally, we found that the interval-dependent increments in the radius of periodic neural trajectories are the result of a larger number of neurons engaged in the production of longer intervals. Our results support the notion that rhythmic timing during tapping behaviors is encoded in the radial curvature of periodic MPC neural population trajectories.

The scalar property during isochronous tapping is disrupted by a D2-like agonist in the nonhuman primate.

Dopamine, and specifically the D2 system, has been implicated in timing tasks where the absolute duration of individual time intervals is encoded discretely, yet the role of D2 during beat perception and entrainment remains largely unknown. In this type of timing, a beat is perceived as the pulse that marks equally spaced points in time and, once extracted, produces the tendency in humans to entrain or synchronize their movements to it. Hence, beat-based timing is crucial for musical execution. In this study we investigated the effects of systemic injections of quinpirole (0.005-0.05 mg/kg), a D2-like agonist, on the isochronous rhythmic tapping of rhesus monkeys, a classical task for the study of beat entrainment. We compared the rhythmic timing accuracy, precision, and the asynchronies of the monkeys with or without the effects of quinpirole, as well as their reaction times in a control serial reaction time task (SRTT). The results showed a dose-dependent disruption in the scalar property of rhythmic timing due to quinpirole administration. Specifically, we found similar temporal variabilities as a function of the metronome tempo at the largest dose, instead of the increase in variability across durations that is characteristic of the timing Weber law. Notably, these effects were not due to alterations in the basic sensorimotor mechanism for tapping to a sequence of flashing stimuli, because quinpirole did not change the reaction time of the monkeys during SRTT. These findings support the notion of a key role of the D2 system in the rhythmic timing mechanism, especially in the control of temporal precision. NEW & NOTEWORTHY Perceiving and moving to the beat of music is a fundamental trait of musical cognition. We measured the effect of quinpirole, a D2-like agonist, on the precision and accuracy of rhythmic tapping to a metronome in two rhesus monkeys. Quinpirole produced a flattening of the temporal variability as a function of tempo duration, instead of the increase in variability across durations that is characteristic of the scalar property, a hallmark property of timing.

Entrainment and maintenance of an internal metronome in supplementary motor area.

To prepare timely motor actions, we constantly predict future events. Regularly repeating events are often perceived as a rhythm to which we can readily synchronize our movements, just as in dancing to music. However, the neuronal mechanisms underlying the capacity to encode and maintain rhythms are not understood. We trained nonhuman primates to maintain the rhythm of a visual metronome of diverse tempos and recorded neural activity in the supplementary motor area (SMA). SMA exhibited rhythmic bursts of gamma band (30-40 Hz) reflecting an internal tempo that matched the extinguished visual metronome. Moreover, gamma amplitude increased throughout the trial, providing an estimate of total elapsed time. Notably, the timing of gamma bursts and firing rate modulations allowed predicting whether monkeys were ahead or behind the correct tempo. Our results indicate that SMA uses dynamic motor plans to encode a metronome for rhythms and a stopwatch for total elapsed time.

Rhesus Monkeys (Macaca mulatta) Sense Isochrony in Rhythm, but Not the Beat: Additional Support for the Gradual Audiomotor Evolution Hypothesis.

Charles Darwin suggested the perception of rhythm to be common to all animals. While only recently experimental research is finding some support for this claim, there are also aspects of rhythm cognition that appear to be species-specific, such as the capability to perceive a regular pulse (or beat) in a varying rhythm. In the current study, using EEG, we adapted an auditory oddball paradigm that allows for disentangling the contributions of beat perception and isochrony to the temporal predictability of the stimulus. We presented two rhesus monkeys (Macaca mulatta) with a rhythmic sequence in two versions: an isochronous version, that was acoustically accented such that it could induce a duple meter (like a march), and a jittered version using the same acoustically accented sequence but that was presented in a randomly timed fashion, as such disabling beat induction. The results reveal that monkeys are sensitive to the isochrony of the stimulus, but not its metrical structure. The MMN was influenced by the isochrony of the stimulus, resulting in a larger MMN in the isochronous as opposed to the jittered condition. However, the MMN for both monkeys showed no interaction between metrical position and isochrony. So, while the monkey brain appears to be sensitive to the isochrony of the stimulus, we find no evidence in support of beat perception. We discuss these results in the context of the gradual audiomotor evolution (GAE) hypothesis (Merchant and Honing, 2014) that suggests beat-based timing to be omnipresent in humans but only weakly so or absent in non-human primates.

Predictive rhythmic tapping to isochronous and tempo changing metronomes in the nonhuman primate.

Beat entrainment is the ability to entrain one's movements to a perceived periodic stimulus, such as a metronome or a pulse in music. Humans have a capacity to predictively respond to a periodic pulse and to dynamically adjust their movement timing to match the varying music tempos. Previous studies have shown that monkeys share some of the human capabilities for rhythmic entrainment, such as tapping regularly at the period of isochronous stimuli. However, it is still unknown whether monkeys can predictively entrain to dynamic tempo changes like humans. To address this question, we trained monkeys in three tapping tasks and compared their rhythmic entrainment abilities with those of humans. We found that, when immediate feedback about the timing of each movement is provided, monkeys can predictively entrain to an isochronous beat, generating tapping movements in anticipation of the metronome pulse. This ability also generalized to a novel untrained tempo. Notably, macaques can modify their tapping tempo by predicting the beat changes of accelerating and decelerating visual metronomes in a manner similar to humans. Our findings support the notion that nonhuman primates share with humans the ability of temporal anticipation during tapping to isochronous and smoothly changing sequences of stimuli.

The Synaptic Properties of Cells Define the Hallmarks of Interval Timing in a Recurrent Neural Network.

Extensive research has described two key features of interval timing. The bias property is associated with accuracy and implies that time is overestimated for short intervals and underestimated for long intervals. The scalar property is linked to precision and states that the variability of interval estimates increases as a function of interval duration. The neural mechanisms behind these properties are not well understood. Here we implemented a recurrent neural network that mimics a cortical ensemble and includes cells that show paired-pulse facilitation and slow inhibitory synaptic currents. The network produces interval selective responses and reproduces both bias and scalar properties when a Bayesian decoder reads its activity. Notably, the interval-selectivity, timing accuracy, and precision of the network showed complex changes as a function of the decay time constants of the modeled synaptic properties and the level of background activity of the cells. These findings suggest that physiological values of the time constants for paired-pulse facilitation and GABAb, as well as the internal state of the network, determine the bias and scalar properties of interval timing.SIGNIFICANCE STATEMENT Timing is a fundamental element of complex behavior, including music and language. Temporal processing in a wide variety of contexts shows two primary features: time estimates exhibit a shift toward the mean (the bias property) and are more variable for longer intervals (the scalar property). We implemented a recurrent neural network that includes long-lasting synaptic currents, which cannot only produce interval-selective responses but also follow the bias and scalar properties. Interestingly, only physiological values of the time constants for paired-pulse facilitation and GABAb, as well as intermediate background activity within the network can reproduce the two key features of interval timing.