SummaryUpper-limb movements are often composed of regular submovements, and neural correlates of submovement frequencies between 1 and 4 Hz have been found in the motor cortex. The temporal profile of movements is usually assumed to be determined by extrinsic factors such as limb biomechanics and feedback delays, but another possibility is that an intrinsic rhythmicity contributes to low frequencies in behavior. We used multielectrode recordings in monkeys performing an isometric movement task to reveal cyclic activity in primary motor cortex locked to submovements, and a distinct oscillation in premotor cortex. During ketamine sedation and natural sleep, cortical activity traversed similar cycles and became synchronized across areas. Because the same cortical dynamics are coupled to submovements and also observed in the absence of behavior, we conclude that the motor networks controlling the upper limb exhibit an intrinsic periodicity at submovement frequencies that is reflected in the speed profile of movements.

Graphical abstract

Sequential firing of neurons during sleep is thought to play a role in the consolidation of learning. However, direct evidence for such sequence replay is limited to only a few brain areas and sleep states mainly in rodents. Using a custom-designed wearable neural data logger and chronically implanted electrodes, we made long-term recordings of neural activity in the primary motor cortex of two female nonhuman primates during free behavior and natural sleep. We used the local field potential (LFP) spectrogram to characterize sleep cycles, and examined firing rates, correlations, and sequential firing of neurons at different frequency bands through the cycle. Slow-wave sleep (SWS) was characterized by low neural firing rates and high synchrony, reflecting slow oscillations between cortical down and up states. However, the order in which neurons entered up states was similar to the sequence of neural activity observed at low frequencies during waking behavior. In addition, we found evidence of brief bursts of theta oscillation, associated with non-SWS states, during which neurons fired in strikingly regular sequential order phase-locked to the LFP. Theta sequences were preserved between waking and sleep, but appeared not to resemble the order of neural activity observed at lower frequencies. The sequential firing of neurons during slow oscillations and theta bursts may contribute to the consolidation of procedural memories during sleep. SIGNIFICANCE STATEMENT Replay of sequential neural activity during sleep is believed to support consolidation of daytime learning. Despite a wealth of studies investigating sequential replay in association with episodic and spatial memory, it is unknown whether similar sequences occur in motor areas during sleep. Within long-term neural recordings from monkey motor cortex, we found two distinct patterns of sequential activity during different phases of the natural sleep cycle. Slow-wave sleep was associated with delta-band sequences that resembled low-frequency activity during movement, while occasional brief bursts of theta oscillation were associated with a different order of sequential firing. Our results are the first report of sequential sleep replay in the motor cortex, which may play an important role in consolidation of procedural learning.

The long-latency stretch reflex (LLSR) in human elbow muscles probably depends on multiple pathways; one possible contributor is the reticulospinal tract. Here we attempted to induce plastic changes in the LLSR by pairing noninvasive stimuli that are known to activate reticulospinal pathways, at timings predicted to cause spike timing-dependent plasticity in the brainstem. In healthy human subjects, reflex responses in flexor muscles were recorded following extension perturbations at the elbow. Subjects were then fitted with a portable device that delivered auditory click stimuli through an earpiece, and electrical stimuli around motor threshold to the biceps muscle via surface electrodes. We tested the following four paradigms: biceps stimulus 10 ms before click (Bi-10ms-C); click 25 ms before biceps (C-25ms-Bi); click alone (C only); and biceps alone (Bi only). The average stimulus rate was 0.67 Hz. Subjects left the laboratory wearing the device and performed normal daily activities. Approximately 7 h later, they returned, and stretch reflexes were remeasured. The LLSR was significantly enhanced in the biceps muscle (on average by 49%) after the Bi-10ms-C paradigm, but was suppressed for C-25ms-Bi (by 31%); it was unchanged for Bi only and C only. No paradigm induced LLSR changes in the unstimulated brachioradialis muscle. Although we cannot exclude contributions from spinal or cortical pathways, our results are consistent with spike timing-dependent plasticity in reticulospinal circuits, specific to the stimulated muscle. This is the first demonstration that the LLSR can be modified via paired-pulse methods, and may open up new possibilities in motor systems neuroscience and rehabilitation.

The presented platform allows neural activity to be unobtrusively monitored and processed in real-time in freely behaving untethered animals-revealing insights that are not attainable through scheduled recording sessions. This system achieves the lowest power per channel to date and provides a robust, low-latency, low-bandwidth and verifiable output suitable for BMIs, closed loop neuromodulation, wireless transmission and long term data logging.