Area-specific thalamocortical synchronization underlies the transition from motor planning to execution.

We studied correlated firing between motor thalamic and cortical cells in monkeys performing a delayed-response reaching task. Simultaneous recording of thalamocortical activity revealed that around movement onset, thalamic cells were positively correlated with cell activity in the primary motor cortex but negatively correlated with the activity of the premotor cortex. The differences in the correlation contrasted with the average neural responses, which were similar in all three areas. Neuronal correlations reveal functional cooperation and opposition between the motor thalamus and distinct motor cortical areas with specific roles in planning vs. performing movements. Thus, by enhancing and suppressing motor and premotor firing, the motor thalamus can facilitate the transition from a motor plan to execution.

Area-specific processing of cerebellar-thalamo-cortical information in primates.

The cerebellar-thalamo-cortical (CTC) system plays a major role in controlling timing and coordination of voluntary movements. However, the functional impact of this system on motor cortical sites has not been documented in a systematic manner. We addressed this question by implanting a chronic stimulating electrode in the superior cerebellar peduncle (SCP) and recording evoked multiunit activity (MUA) and the local field potential (LFP) in the primary motor cortex ([Formula: see text]), the premotor cortex ([Formula: see text]) and the somatosensory cortex ([Formula: see text]). The area-dependent response properties were estimated using the MUA response shape (quantified by decomposing into principal components) and the time-dependent frequency content of the evoked LFP. Each of these signals alone enabled good classification between the somatosensory and motor sites. Good classification between the primary motor and premotor areas could only be achieved when combining features from both signal types. Topographical single-site representation of the predicted class showed good recovery of functional organization. Finally, the probability for misclassification had a broad topographical organization. Despite the area-specific response features to SCP stimulation, there was considerable site-to-site variation in responses, specifically within the motor cortical areas. This indicates a substantial SCP impact on both the primary motor and premotor cortex. Given the documented involvement of these cortical areas in preparation and execution of movement, this result may suggest a CTC contribution to both motor execution and motor preparation. The stimulation responses in the somatosensory cortex were sparser and weaker. However, a functional role of the CTC system in somatosensory computation must be taken into consideration.

Parallel processing of internal and external feedback in the spinocerebellar system of primates.

Cerebellar control of voluntary movements is achieved by the integration of external and internal feedback information to adjust and correct properly ongoing actions. In the forelimb of primates, rostral-spinocerebellar tract (RSCT) neurons are thought to integrate segmental, descending, and afferent sources and relay upstream a compound signal that contains both an efference copy of the spinal-level motor command and the state of the periphery. We tested this hypothesis by implanting stimulating electrodes in the superior cerebellar peduncle and recording the activity of cervical spinal neurons in primates. To dissociate motor commands and proprioceptive signals, we used a voluntary wrist task and applied external perturbations to the movement. We identified a large group of antidromically activated RSCT neurons located in deep dorsal sites and a smaller fraction of postsynaptically activated (PSA) cells located in intermediate and ventral laminae. RSCT cells received sensory input from broad, proximally biased receptive fields (RFs) and were not affected by applied wrist perturbations. PSA cells received sensory information from distal RFs and were more strongly related to active and passive movements. The anatomical and functional properties of RSCT and PSA cells suggest that descending signals converging on PSA cells contribute to both motor preparation and motor control. In parallel, RSCT neurons relay upstream an integrated signal that encodes the state of working muscles and can contribute to distal-to-proximal coordination of action. Thus the rostral spinocerebellar system sends upstream an efference copy of the motor command but does not signal abrupt errors in the performed movement.NEW & NOTEWORTHY Cerebellar coordination of voluntary movements relies on integrating feedback information to update motor output. With the use of a novel protocol, we identified spinal neurons constituting the ascending and descending components of the forelimb spinocerebellar system in behaving primates. The data suggest that descending information contributes to both motor preparation and execution, whereas ascending information conveys the spinal level motor command, such that internal and external feedback is relayed through parallel pathways.

Encoding by synchronization in the primate striatum.

Information is encoded in the nervous system through the discharge and synchronization of single neurons. The striatum, the input stage of the basal ganglia, is divided into three territories: the putamen, the caudate, and the ventral striatum, all of which converge onto the same motor pathway. This parallel organization suggests that there are multiple and competing systems in the basal ganglia network controlling behavior. To explore which mechanism(s) enables the different striatal domains to encode behavioral events and to control behavior, we compared the neural activity of phasically active neurons [medium spiny neurons (MSNs), presumed projection neurons] and tonically active neurons (presumed cholinergic interneurons) across striatal territories from monkeys during the performance of a well practiced task. Although neurons in all striatal territories displayed similar spontaneous discharge properties and similar temporal modulations of their discharge rates to the behavioral events, their correlation structure was profoundly different. The distributions of signal and noise correlation of pairs of putamen MSNs were strongly shifted toward positive correlations and these two measures were correlated. In contrast, MSN pairs in the caudate and ventral striatum displayed symmetrical, near-zero signal and noise correlation distributions. Furthermore, only putamen MSN pairs displayed different noise correlation dynamics to rewarding versus neutral/aversive cues. Similarly, the noise correlation between tonically active neuron pairs was stronger in the putamen than in the caudate. We suggest that the level of synchronization of the neuronal activity and its temporal dynamics differentiate the striatal territories and may thus account for the different roles that striatal domains play in behavioral control.

Functional organization of information flow in the corticospinal pathway.

Transmission of information in the corticospinal (CS) route constitutes the fundamental infrastructure for voluntary actions. The anatomy of this pathway has been studied extensively, but there is little direct evidence regarding its functional organization. Here we explored the areal specificity of CS connections by studying two related questions: the functional significance of the parallel, motor, and premotor CS pathways; and the way in which finger-related motor commands are handled by this pathway. We addressed these questions by recording from primary motor (M1) and premotor cortical sites in primates (Maccaca fascicularis) performing a motor task, while measuring the evoked intraspinal unit response to single pulse cortical stimulation. Stimulation in M1 evoked spinal neuronal responses more frequently than stimulation in premotor cortex. The number of muscles excited by M1 stimulation was higher than the number excited by premotor stimulation. Within subregions of M1 finger-related sites were sparsely connected with intermediate zone interneurons and tended to affect the ventrally located motoneurons directly. These results suggest that, despite the parallel anatomical organization, the flow of motor commands is predominantly relayed via M1 to downstream elements. The functional impact of premotor cortex is weak, possibly due to inhibitory systems that can shape the flow of information in the CS pathway. Finally, the difference in spinal processing of finger versus wrist-related motor commands points to a different motor control strategy of finger versus wrist movements.

Disentangling acute motor deficits and adaptive responses evoked by the loss of cerebellar output.

Cerebellar patients exhibit a broad range of impairments when performing voluntary movements. However, the sequence of events leading to these deficits and the distinction between primary and compensatory processes remain unclear. We addressed this question by reversibly blocking cerebellar outflow in monkeys performing a planar reaching task. We found that the reduced hand velocity observed under cerebellar block is driven by a combination of a general decrease in muscle torque and a spatially tuned reduction in velocity, particularly pronounced in movements involving inter-joint interactions. The time course of these two processes was examined using repeated movements to the same target under cerebellar block. We found that the reduced velocity was driven by an acute onset of weakness superimposed on a gradually emergent strategy aimed to minimize passive inter-joint interactions. Finally, although the reduced velocity affected movements to all targets, it could not explain the enhanced motor noise observed under cerebellar block, which manifested as decomposed and variable trajectories. Our results suggest that cerebellar deficits lead to motor impairments through a loss of muscle strength and altered motor control strategy to compensate for the impaired control of limb dynamics. However, the loss of feedforward control also leads to increased motor noise, which cannot be strategically eliminated. Significance Statement: Our study examined the impact of cerebellar dysfunction on motor control by reversibly blocking the cerebellar output in monkeys. Under cerebellar block, movements initially slowed due to acute-onset muscle weakness. Beyond this primary deficit, there was a secondary, seemingly strategic, slowing of movements aimed at mitigating inter-joint interactions associated with rapid, ballistic movements. Finally, during the cerebellar block we observed movement variability increased independently of the reduced velocity, likely reflecting errors in movement planning. Taken together, these findings highlight the role of cerebellar information in motor control and delineate the sequence of processes following cerebellar dysfunction that culminate in a broad range of motor impairments.

Temporal convergence of dynamic cell assemblies in the striato-pallidal network.

The basal ganglia (BG) have been hypothesized to implement a reinforcement learning algorithm. However, it is not clear how information is processed along this network, thus enabling it to perform its functional role. Here we present three different encoding schemes of visual cues associated with rewarding, neutral, and aversive outcomes by BG neuronal populations. We studied the response profile and dynamical behavior of two populations of projection neurons [striatal medium spiny neurons (MSNs), and neurons in the external segment of the globus pallidus (GPe)], and one neuromodulator group [striatal tonically active neurons (TANs)] from behaving monkeys. MSNs and GPe neurons displayed sustained average activity to cue presentation. The population average response of MSNs was composed of three distinct response groups that were temporally differentiated and fired in serial episodes along the trial. In the GPe, the average sustained response was composed of two response groups that were primarily differentiated by their immediate change in firing rate direction. However, unlike MSNs, neurons in both GPe response groups displayed prolonged and temporally overlapping persistent activity. The putamen TANs stereotyped response was characterized by a single transient response group. Finally, the MSN and GPe response groups reorganized at the outcome epoch, as different task events were reflected in different response groups. Our results strengthen the functional separation between BG neuromodulators and main axis neurons. Furthermore, they reveal dynamically changing cell assemblies in the striatal network of behaving primates. Finally, they support the functional convergence of the MSN response groups onto GPe cells.

Descending systems translate transient cortical commands into a sustained muscle activation signal.

Controlling motor actions requires online adjustments of time-varying parameters. Although numerous studies have attempted to identify the parameters coded in different motor sites, the relationships between the temporal profile of neuronal responses and the dynamics of motor behavior remain poorly understood in particular because motor parameters such as force and movement direction often change over time. We studied time-dependent coding of cortical and spinal neurons in primates performing an isometric wrist task with an active hold period, which made it possible to segregate motor behavior into its phasic and sustained components. Here, we show that cortical neurons transiently code motor-related parameters when actively acquiring a goal, whereas spinal interneurons provide persistent information regarding maintained torque level and posture. Moreover, motor cortical neurons differed substantially from spinal neurons with regard to the evolvement of parameter-specific coding over the course of a trial. These results suggest that the motor cortex and spinal cord use different control policies: Cortical neurons produce transient motor commands governing ensuing actions, whereas spinal neurons exhibit sustained coding of ongoing motor states. Hence, motor structures downstream to M1 need to integrate cortical commands to produce state-dependent spinal firing.

A cerebellar origin of feedforward inhibition to the motor cortex in non-human primates.

Voluntary movements are driven by coordinated activity across a large population of motor cortical neurons. Formation of this activity is controlled by local interactions and long-range inputs. How remote areas of the brain communicate with motor cortical neurons to effectively drive movement remains unclear. We address this question by studying the cerebellar-thalamocortical system. We find that thalamic input to the motor cortex triggers feedforward inhibition by contacting inhibitory cells via highly effective GluR2-lacking AMPA receptors and that, during task performance, the activity of parvalbumin (PV) and pyramidal cells exhibits relations comparable with movement parameters. We also find that the movement-related activity of PV interneurons precedes firing of pyramidal cells. This counterintuitive sequence of events, where inhibitory cells are recruited more strongly and before excitatory cells, may amplify the cortical effect of cerebellar signals in a way that exceeds their sheer synaptic efficacy by suppressing other inputs.

Population-based corticospinal interactions in macaques are correlated with visuomotor processing.

Visuomotor transformation is a fundamental process in executing voluntary actions. The final steps of this transformation are presumed to take place in the corticospinal (CS) system, yet the way in which the motor cortex (MC) interacts with spinal circuitry during this process is unclear. We studied neural correlates of visuomotor transformation in the MC and cervical spinal cord while monkeys performed an isometric wrist task. We recorded 2 measures of population activity: local field potential (LFP), reflecting local synaptic inputs and multi-unit activity (MUA), reflecting spiking activity emitted by nearby neurons. We found robust cortical and spinal responses locked to visual and motor events. In motor cortex, LFP responses were predominantly visually related; MUA responses were mostly motor related. Spinal LFP responses were generally weak, yet spinal MUAs showed visual and motor responses with distinctive patterns. For both structures, amplitudes of visual responses were positively correlated with amplitudes of motor responses and negatively correlated with reaction times. The temporal relations of cortical and spinal responses shifted from weak coactivation before movement to increased coupling following torque onset, with cortical leading spinal activity. Thus, ongoing CS interactions may exist at early stages of movement preparation. These interactions are dynamic and may shape the executed motor action.

Neurons in both pallidal segments change their firing properties similarly prior to closure of the eyes.

Current anatomical models of the cortico-basal ganglia (BG) network predict reciprocal discharge patterns between the external and internal segments of the globus pallidus (GPe and GPi, respectively), as well as cortical driving of BG activity. However, physiological studies revealing similarity in the transient responses of GPe and GPi neurons cast doubts on these predictions. Here, we studied the discharge properties of GPe, GPi, and primary motor cortex neurons of two monkeys in two distinct states: when eyes are open versus when they are closed. Both pallidal populations exhibited decreased discharge rates in the "eye closed" state accompanied by elevated values of the coefficient of variation (CV) of their interspike interval (ISI) distributions. The pallidal modulations in discharge patterns were partially attributable to larger fractions of longer ISIs in the "eye closed" state. In addition, the pallidal discharge modulations were gradual, starting prior to closing of the eyes. Cortical neurons, as opposed to pallidal neurons, increased their discharge rates steeply on closure of the eyes. Surprisingly, the cortical rate modulations occurred after pallidal modulations. However, as in the pallidum, the CV values of cortical ISI distributions increased in the "eye closed" state, indicating a more bursty discharge pattern in that state. Thus changes in GPe and GPi discharge properties were positively correlated, suggesting that the subthalamic nucleus and/or the striatum constitute the main common driving force for both pallidal segments. Furthermore, the early, unexpected changes in the pallidum are better explained by a subcortical rather than a cortical loop through the BG.

Coordinate transformation is first completed downstream of primary motor cortex.

It was suggested previously that the transformation of action to muscle-based coding is completed in the primary motor cortex (M1). This is consistent with a predominant direct pathway leading from M1 to motoneurons. Accordingly, spinal segmental interneurons that are located downstream to M1 are expected to show muscle-like coding properties. We addressed this hypothesis using simultaneous recording of cortical and spinal activity in primates performing an isometric wrist task with multiple targets and two hand postures. Here we show that while the motor cortex follows an intermediate coordinate frame, spinal interneurons already follow a muscle-like coordinate frame. We thus suggest that the final steps in coordinate transformation of motor commands take place downstream of M1 via corticospinal interactions.

Low-pass filter properties of basal ganglia cortical muscle loops in the normal and MPTP primate model of parkinsonism.

Oscillatory bursting activity is commonly found in the basal ganglia (BG) and the thalamus of the parkinsonian brain. The frequency of these oscillations is often similar to or higher than that of the parkinsonian tremor, but their relationship to the tremor and other parkinsonian symptoms is still under debate. We studied the frequency dependency of information transmission in the cortex-BG and cortex-periphery loops by recording simultaneously from multiple electrodes located in the arm-related primary motor cortex (MI) and in the globus pallidus (GP) of two vervet monkeys before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and induction of parkinsonian symptoms. We mimicked the parkinsonian bursting oscillations by stimulating with 35 ms bursts given at different frequencies through microelectrodes located in MI or GP while recording the evoked neuronal and motor responses. In the normal state, microstimulation of MI or GP does not modulate the discharge rate in the other structure. However, the functional-connectivity between MI and GP is greatly enhanced after MPTP treatment. In the frequency domain, GP neurons usually responded equally to 1-15 Hz stimulation bursts in both states. In contrast, MI neurons demonstrated low-pass filter properties, with a cutoff frequency above 5 Hz for the MI stimulations, and below 5 Hz for the GP stimulations. Finally, muscle activation evoked by MI microstimulation was markedly attenuated at frequencies higher than 5 Hz. The low-pass properties of the pathways connecting GP to MI to muscles suggest that parkinsonian tremor is not directly driven by the BG 5-10 Hz burst oscillations despite their similar frequencies.

Reversible Block of Cerebellar Outflow Reveals Cortical Circuitry for Motor Coordination.

Coordinated movements are achieved by well-timed activation of selected muscles. This process relies on intact cerebellar circuitry, as demonstrated by motor impairments following cerebellar lesions. Based on anatomical connectivity and symptoms observed in cerebellar patients, we hypothesized that cerebellar dysfunction should disrupt the temporal patterns of motor cortical activity, but not the selected motor plan. To test this hypothesis, we reversibly blocked cerebellar outflow in primates while monitoring motor behavior and neural activity. This manipulation replicated the impaired motor timing and coordination characteristic of cerebellar ataxia. We found extensive changes in motor cortical activity, including loss of response transients at movement onset and decoupling of task-related activity. Nonetheless, the spatial tuning of cells was unaffected, and their early preparatory activity was mostly intact. These results indicate that the timing of actions, but not the selection of muscles, is regulated through cerebellar control of motor cortical activity.

Connected corticospinal sites show enhanced tuning similarity at the onset of voluntary action.

Corticospinal (CS) pathways provide the structural foundation for executing voluntary movements. Although the anatomy of these pathways is well explored, little is known about spinal decoding of parametric information transmitted via this route during voluntary movements. We addressed this question by simultaneously recording cortical and spinal activity in primates performing an isometric wrist task with multiple targets while measuring CS interactions. Single-pulse cortical stimulation effectively produced a short-latency (presumably monosynaptic) spinal response and thus revealed functionally connected CS sites. Spinal and cortical neurons recorded from connected CS sites showed alignment of directional-torque tuning that peaked at torque onset, consistent with the enhanced cortical drive active during this period. This increased tuning similarity was accompanied by an increased trial-to-trial covariability of firing. Whereas functional CS interactions were dynamic, the efficacy of cortical stimulation was unaffected by the motor state. These results suggest that around the onset of motor action there is a period of facilitated information transfer during which cortical command has greater efficacy in recruiting spinal neurons with matching tuning properties. Dynamic alignment of response properties may form the basis for a spinal readout mechanism of descending motor commands in which directional-torque is a parameter that is preserved across interacting CS sites.

Computation in spinal circuitry: lessons from behaving primates.

Performing voluntary motor actions requires the translation of motor commands into a specific set of muscle activation. While it is assumed that this process is carried out via cooperative interactions between supraspinal and spinal neurons, the unique contribution of each of these areas to the process is still unknown. Many studies have focused on the neuronal representation of the motor command, mostly in the motor cortex. Nonetheless, to execute these commands there must be a mechanism that can translate this representation into a sustained drive to the spinal motoneurons (MNs). Here we review different candidate mechanisms for activating MNs and their possible role in voluntary movements. We discuss recent studies which directly estimate the contribution of segmental INs to the transmission of cortical command to MNs, both in terms of functional connectivity and as a computational link. Finally, we suggest a conceptual framework in which the cortical motor command is processed simultaneously via MNs and INs. In this model, the motor cortex provides a transient signal which is important for initiating new patterns of recruited muscles, whereas the INs translate this command into a sustained, amplified and muscle-based signal which is necessary to maintain ongoing muscle activity.

Cerebellar Shaping of Motor Cortical Firing Is Correlated with Timing of Motor Actions.

In higher mammals, motor timing is considered to be dictated by cerebellar control of motor cortical activity, relayed through the cerebellar-thalamo-cortical (CTC) system. Nonetheless, the way cerebellar information is integrated with motor cortical commands and affects their temporal properties remains unclear. To address this issue, we activated the CTC system in primates and found that it efficiently recruits motor cortical cells; however, the cortical response was dominated by prolonged inhibition that imposed a directional activation across the motor cortex. During task performance, cortical cells that integrated CTC information fired synchronous bursts at movement onset. These cells expressed a stronger correlation with reaction time than non-CTC cells. Thus, the excitation-inhibition interplay triggered by the CTC system facilitates transient recruitment of a cortical subnetwork at movement onset. The CTC system may shape neural firing to produce the required profile to initiate movements and thus plays a pivotal role in timing motor actions.

Impact of Auditory Context on Executed Motor Actions.

The auditory and motor systems are strongly coupled, as is evident in the specifically tight motor synchronization that occurs in response to regularly occurring auditory cues compared with cues of other modalities. Timing of rhythmic action is known to rely on multiple neural centers including the cerebellum and the basal-ganglia which have access to both motor cortical and spinal circuitries. To date, however, there is little information on the motor mechanisms that operate during preparation and execution of rhythmic vs. non-rhythmic movements. We measured acceleration profile and muscle activity while subjects performed tapping movements in response to auditory cues. We found that when tapping at random intervals there was a higher variability of both acceleration profile and muscle activity during motor preparation compared to rhythmic tapping. However, the specific rhythmic context (cued, self-paced, or syncopation) did not affect the motor parameters of the executed taps. Finally, during entrainment we found a gradual as opposed to episodic change in low-level motor parameters (i.e., preparatory muscle activity) that was strongly correlated with changes in high-level parameters (i.e., shift in the reaction time to negative asynchrony). These findings suggest that motor entrainment involves not only adjusting the timing of movement but also modifying parameters that are related to its production. These changes in motor output were insensitive to the specifics of the rhythmic cue: although it took subjects different times to become entrained to different types of rhythmic cues, the motor actions produced once entrainment was obtained were indistinguishable. These findings suggest that motor entrainment involves not only adjusting the timing of movement but also modifying parameters related to its production. The reduced variability of muscle activity during the preparatory period could be one mechanism used by the motor system to enhance the accuracy of motor timing.

Firing properties of spinal interneurons during voluntary movement. I. State-dependent regularity of firing.

The firing properties of single spinal interneurons (INs) were studied in five awake, behaving monkeys performing isometric or auxotonic flexion-extension torques at the wrist. INs tended to fire tonically at rest (mean rate, 14 spikes (sp)/sec) and during generation of static torque (mean rate, 19 sp/sec in flexion, 24 sp/sec in extension). INs exhibited regular firing, with autocorrelation functions showing clear periodic features and a mean coefficient of variation of interspike intervals (CV) of 0.55 during production of static torque. For the population, there was an inverse correlation between CV and mean rate. However, 46% of the INs had task-dependent changes in regularity that were not predicted by changes in firing rate, suggesting that their firing pattern is determined not only by the intrinsic properties of the neurons but also by the properties of its synaptic inputs. INs showed two main response types to passive wrist displacement: biphasic and coactivation. Cells with these sensory responses had different, stereotypical temporal activity profiles and firing regularity during active movement. However, INs having correlational linkages with forearm muscles, identified as features in spike-triggered averages of electromyographic activity, did not exhibit unique responses or firing properties, although they tended to fire more regularly than other INs. This suggests the lack of a precise mapping of inputs to outputs for the spinal premotor network.

Firing properties of spinal interneurons during voluntary movement. II. Interactions between spinal neurons.

The relationship between the activity of pairs of simultaneously recorded spinal interneurons (INs) in the cervical enlargement was studied in five monkeys performing voluntary wrist movements. The tendency for INs to exhibit similar response properties and synchronized firing was tested as a function of physical distance between the cells and their correlational linkages with forearm muscles. Nearby INs tended to have more similar torque and direction turning (signal correlation) and more similar response profiles (e.g., tonic vs phasic firing) than INs that were far apart. This suggests that nearby cells receive common synaptic input. In contrast, the trial-to-trial covariation of rate around the mean rate for all trials (noise correlation) was independent of the distance between the neurons. Furthermore, signal and noise correlation were independent, suggesting different underlying mechanisms. Surprisingly, spike-to-spike correlation between INs was relatively infrequent and weak, as measured by cross-correlation histograms. In contrast, single motor units (SMUs) in forearm muscles fired more synchronously, particularly for SMUs in single extensor muscles. Either common drive to INs is too weak to induce synchronized firing, or there is an active decorrelation mechanism within IN networks.