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.

Sensorimotor neural dynamics during isochronous tapping in the medial premotor cortex of the macaque.

We determined the response properties of neurons in the primate medial premotor cortex that were classified as sensory or motor during isochronous tapping to a visual or auditory metronome, using different target intervals and three sequential elements in the task. The cell classification was based on a warping transformation, which determined whether the cell activity was statistically aligned to sensory or motor events, finding a large proportion of cells classified as sensory or motor. Two distinctive clusters of sensory cells were observed, i.e. one cell population with short response-onset latencies to the previous stimulus, and another that was probably predicting the occurrence of the next stimuli. These cells were called sensory-driven and stimulus-predicting neurons, respectively. Sensory-driven neurons showed a clear bias towards the visual modality and were more responsive to the first stimulus, with a decrease in activity for the following sequential elements of the metronome. In contrast, stimulus-predicting neurons were bimodal and showed similar response profiles across serial-order elements. Motor cells showed a consecutive activity onset across discrete neural ensembles, generating a rapid succession of activation patterns between the two taps defining a produced interval. The cyclical configuration in activation profiles engaged more motor cells as the serial-order elements progressed across the task, and the rate of cell recruitment over time decreased as a function of the target interval. Our findings support the idea that motor cells were responsible for the rhythmic progression of taps in the task, gaining more importance as the trial advanced, while, simultaneously, the sensory-driven cells lost their functional impact.

Neurophysiology of timing in the hundreds of milliseconds: multiple layers of neuronal clocks in the medial premotor areas.

The precise quantification of time in the subsecond scale is critical for many complex behaviors including music and dance appreciation/execution, speech comprehension/articulation, and the performance of many sports. Nevertheless, its neural underpinnings are largely unknown. Recent neurophysiological experiments from our laboratory have shown that the cell activity in the medial premotor areas (MPC) of macaques can represent different aspects of temporal processing during a synchronization-continuation tapping task (SCT). In this task the rhythmic behavior of monkeys was synchronized to a metronome of isochronous stimuli in the hundreds of milliseconds range (synchronization phase), followed by a period where animals internally temporalized their movements (continuation phase). Overall, we found that the time-keeping mechanism in MPC is governed by different layers of neural clocks. Close to the temporal control of movements are two separate populations of ramping cells that code for elapsed or remaining time for a tapping movement during the SCT. Thus, the sensorimotor loops engaged during the task may depend on the cyclic interplay between two neuronal chronometers that quantify in their instantaneous discharge rate the time passed and the remaining time for an action. In addition, we found MPC neurons that are tuned to the duration of produced intervals during the rhythmic task, showing an orderly variation in the average discharge rate as a function of duration. All the tested durations in the subsecond scale were represented in the preferred intervals of the cell population. Most of the interval-tuned cells were also tuned to the ordinal structure of the six intervals produced sequentially in the SCT. Hence, this next level of temporal processing may work as the notes of a musical score, providing information to the timing network about what duration and ordinal element of the sequence are being executed. Finally, we describe how the timing circuit can use a dynamic neural representation of the passage of time and the context in which the intervals are executed by integrating the time-varying activity of populations of cells. These neural population clocks can be defined as distinct trajectories in the multidimensional cell response-space. We provide a hypothesis of how these different levels of neural clocks can interact to constitute a coherent timing machine that controls the rhythmic behavior during the SCT.

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.