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.

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.

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.

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.

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.

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.

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.

An assumption-free quantification of neural responses to electrical stimulations.

BACKGROUND: Connectivity between brain regions provides the fundamental infrastructure for information processing. The standard way to characterize these interactions is to stimulate one site while recording the evoked response from a second site. The average stimulus-triggered response is usually compared to the pre-stimulus activity. This requires a set of prior assumptions regarding the amplitude and duration of the evoked response. NEW METHOD: We introduce an assumption-free method for detecting and clustering evoked responses. We used Independent Component Analysis to reduce the dimensions of the response vectors, and then clustered them according to a Gaussian mixture model. This enables both the detection and categorization of responsive sites into different subtypes. RESULTS: Our method is demonstrated on recordings obtained from the sensory-motor cortex of behaving primates in response to stimulation of the cerebello-thalamo-cortical tract. We detected and classified the evoked responses of local field potential (LFP) and local spiking activity (multiunit activity-MUA). We found a strong association between specific input (LFP) and output (MUA) patterns across cortical sites, further supporting the physiological relevance of the proposed method. COMPARISON WITH EXISTING METHODS: Our method detected the vast majority of sites found in the conventional, significant threshold-crossing method. However, we found a subgroup of sites with a robust response that were missed when using the conventional method. CONCLUSION: Our method provides a useful, assumption-free tool for detecting and classifying neural evoked responses in a physiologically-relevant manner.

Do sensorimotor ß-oscillations maintain muscle synergy representations in primary motor cortex?

Coherent ß-oscillations are a dominant feature of the sensorimotor system yet their function remains enigmatic. We propose that, in addition to cell intrinsic and/or local network interactions, they are supported by activity propagating recurrently around closed neural 'loops' between primary motor cortex (M1), muscles, and back to M1 via somatosensory pathways. Individual loops reciprocally connect individual muscle synergies ('motor primitives') with their representations in M1, and the conduction time around each loop resonates with the periodic spiking of its constituent neurons/muscles. During ß-oscillations, this resonance strengthens within-loop connectivity (via long-term potentiation, LTP), whereas non-resonance between different loops weakens connectivity (via long-term depression, LTD) between M1 representations of different muscle synergies. In this way, ß-oscillations help maintain accurate and discrete representations of muscle synergies in M1.

Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons.

The striatum is populated by a single projection neuron group, the medium spiny neurons (MSNs), and several groups of interneurons. Two of the electrophysiologically well-characterized striatal interneuron groups are the tonically active neurons (TANs), which are presumably cholinergic interneurons, and the fast spiking interneurons (FSIs), presumably parvalbumin (PV) expressing GABAergic interneurons. To better understand striatal processing it is thus crucial to define the functional relationship between MSNs and these interneurons in the awake and behaving animal. We used multiple electrodes and standard physiological methods to simultaneously record MSN spiking activity and the activity of TANs or FSIs from monkeys engaged in a classical conditioning paradigm. All three cell populations were highly responsive to the behavioral task. However, they displayed different average response profiles and a different degree of response synchronization (signal correlation). TANs displayed the most transient and synchronized response, MSNs the most diverse and sustained response and FSIs were in between on both parameters. We did not find evidence for direct monosynaptic connectivity between the MSNs and either the TANs or the FSIs. However, while the cross correlation histograms of TAN to MSN pairs were flat, those of FSI to MSN displayed positive asymmetrical broad peaks. The FSI-MSN correlogram profile implies that the spikes of MSNs follow those of FSIs and both are driven by a common, most likely cortical, input. Thus, the two populations of striatal interneurons are probably driven by different afferents and play complementary functional roles in the physiology of the striatal microcircuit.

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.

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.

Spatiotemporal organization of neuronal activity in the cervical cord of behaving primates.

Spinal neurons operate as a processing link that integrates descending and peripheral information and in turn, generates a specific yet complex muscle command. The functional organization of spinal circuitry during normal motor behavior dictates the way in which this translation process is achieved. Nonetheless, little is known about this organization during normal motor behavior. We examined the spatial organization of neural activity in the cervical spinal cord of behaving primates performing an isometric wrist task by estimating the averaged intraspinal activity of neuronal populations. We measured population response profiles and frequency content around torque onset and tested the tendency of these profiles to exhibit a specific organization within the spinal volume. We found that the spatial distribution of characteristic response profiles was non-uniform; namely, sites with a specific response profile tended to have a preferred spatial localization. Physiologically, this finding suggests that specific spinal circuitry that controls a unique feature of motor actions (with a particular task-related response pattern) may have a segregated spinal organization. Second, attempts to restore motor function via intraspinal stimulation may be more successful when the spatial distribution of these task-related profiles is taken into account.

Getting ready to move: transmitted information in the corticospinal pathway during preparation for movement.

Corticospinal interactions are considered to play a key role in executing voluntary movements. Nonetheless several different studies have shown directly and indirectly that these interactions take place long before movement starts, when preparation for forthcoming movements dominates. When motor-related parameters are continuously processed in several premotor cortical sites, segmental circuitry is directly exposed to this processing via descending pathways which originate from these sites in parallel to descending fibers that derive from primary motor cortex. Recent studies have highlighted the functional role of these interactions in priming downstream elements for the ensuing motor actions. Time-resolved analysis has further emphasized the dynamic properties of pre-movement preparatory activity.

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.

Synchronization of midbrain dopaminergic neurons is enhanced by rewarding events.

The basal ganglia network is divided into two functionally related subsystems: the neuromodulators and the main axis. It is assumed that neuromodulators adjust cortico-striatal coupling. This adjustment might depend on the response properties and temporal interactions between neuromodulators. We studied functional interactions between simultaneously recorded pairs of neurons in the basal ganglia while monkeys performed a classical conditioning task that included rewarding, neutral, and aversive events. Neurons that belong to a single neuromodulator group exhibited similar average responses, whereas main axis neurons responded in a highly diverse manner. Dopaminergic neuromodulators transiently increased trial-to-trial (noise) correlation following rewarding but not aversive events, whereas cholinergic neurons of the striatum decreased their trial-to-trial correlation. These changes in functional connectivity occurred at different epochs of the trial. Thus, the coding scheme of neuromodulators (but not main axis neurons) can be viewed as a single-dimensional code that is further enriched by dynamic neuronal interactions.