Highlights d High-frequency stimulation blocked cerebellar outflow and impaired motor behavior d Response patterns and coordinated firing of CTC neurons were disrupted d The spatial tuning and early preparatory activity of neurons were unaffected d Cerebellar control of local and global cortical synchrony supports motor timing

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.

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.

22 23 24 Nashef et al. 2018 SUMMARY 25Coordinated movements are achieved by selecting muscles and activating them at 26 specific times. This process relies on intact cerebellar circuitry, as demonstrated by 27 motor impairments triggered by cerebellar lesions. Based on anatomical connectivity 28 and symptoms observed in cerebellar patients, we hypothesized that cerebellar 29 dysfunction should disrupt the temporal patterns of motor cortical activity but not the 30 selected motor plan. To test this hypothesis, we reversibly blocked cerebellar outflow 31 in primates while monitoring motor behavior and neural activity. This manipulation 32 replicated the impaired motor timing and coordination characteristic of cerebellar 33 ataxia. We found extensive changes in motor cortical activity, including a loss of 34 response transients at movement onset and a decoupling of task-related activity. 35Nonetheless, the spatial tuning of cells was unaffected and their early preparatory 36 activity was mostly intact. These results indicate that the timing of actions, but not the 37 selection of muscles, is regulated through cerebellar control of motor cortical activity. 38 39 HIGHLIGHTS 40  High frequency stimulation blocked cerebellar outflow and impaired motor 41 behavior 42  Response patterns and coordinated firing of CTC neurons were disrupted 43  The spatial tuning and early preparatory activity of neurons were unaffected 44  Cerebellar control of local and global cortical synchrony supports motor timing 45 46 IN BRIEF 47 Nashef et al. used high frequency stimulation to block cerebellar outflow. This 48 manipulation impaired motor timing and coordination similarly to symptoms found in 49 cerebellar patients. In parallel, the response patterns of cortical neurons and cell-to-50 cell synchronization were altered, yet spatial tuning was maintained. Motor timing 51 and coordination are regulated by a dedicated cerebellar signal that organizes 52 execution-related activity of a motor cortical subnetwork.53 54 83 cortical activity (Hore and Flament, 1988; Meyer-Lohmann et al., 1975), most of 84 which involved decreased activity at movement onset. These results indicate that the 85 CTC system has online access to evolving motor commands and thereby affects 86 motor actions. However, it remains unclear what features and parameters of the87 4motor command are specifically dictated by the CTC system, and in what way the 88 loss of the CTC drive, which apparently constitutes only a small fraction of the input 89 to motor cortical neurons (Bopp et al., 2017), affects the firing of single cells thus 90 leading to impaired timing and coordination across multiple effectors. 91To address these questions, we trained two monkeys to perform a center-out 92 reaching task which relied on predictive timing (Bares et al., 2007; Bo et al., 2008). 93Stimulating electrodes were chronically implanted in the superior cerebellar peduncle 94 (SCP) and recordings were made simultaneously from multiple cortical sites. Single-95 pulse stimulation was use...

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.