To be and not to be: wide-field Ca2+ imaging reveals neocortical functional segmentation combines stability and flexibility.

The stability and flexibility of the functional parcellation of the cerebral cortex is fundamental to how familiar and novel information is both represented and stored. We leveraged new advances in Ca2+ sensors and microscopy to understand the dynamics of functional segmentation in the dorsal cerebral cortex. We performed wide-field Ca2+ imaging in head-fixed mice and used spatial independent component analysis (ICA) to identify independent spatial sources of Ca2+ fluorescence. The imaging data were evaluated over multiple timescales and discrete behaviors including resting, walking, and grooming. When evaluated over the entire dataset, a set of template independent components (ICs) were identified that were common across behaviors. Template ICs were present across a range of timescales, from days to 30 seconds, although with lower occurrence probability at shorter timescales, highlighting the stability of the functional segmentation. Importantly, unique ICs emerged at the shorter duration timescales that could act to transiently refine the cortical network. When data were evaluated by behavior, both common and behavior-specific ICs emerged. Each behavior is composed of unique combinations of common and behavior-specific ICs. These observations suggest that cerebral cortical functional segmentation exhibits considerable spatial stability over time and behaviors while retaining the flexibility for task-dependent reorganization.

Wide-field calcium imaging reveals widespread changes in cortical functional connectivity following mild traumatic brain injury in the mouse.

>2.5 million individuals in the United States suffer mild traumatic brain injuries (mTBI) annually. Mild TBI is characterized by a brief period of altered consciousness, without objective findings of anatomic injury on clinical imaging or physical deficit on examination. Nevertheless, a subset of mTBI patients experience persistent subjective symptoms and repeated mTBI can lead to quantifiable neurological deficits, suggesting that each mTBI alters neurophysiology in a deleterious manner not detected using current clinical methods. To better understand these effects, we performed mesoscopic Ca2+ imaging in mice to evaluate how mTBI alters patterns of neuronal interactions across the dorsal cerebral cortex. Spatial Independent Component Analysis (sICA) and Localized semi-Nonnegative Matrix Factorization (LocaNMF) were used to quantify changes in cerebral functional connectivity (FC). Repetitive, mild, controlled cortical impacts induce temporary neuroinflammatory responses, characterized by increased density of microglia exhibiting de-ramified morphology. These temporary neuro-inflammatory changes were not associated with compromised cognitive performance in the Barnes maze or motor function as assessed by rotarod. However, long-term alterations in functional connectivity (FC) were observed. Widespread, bilateral changes in FC occurred immediately following impact and persisted for up to 7 weeks, the duration of the experiment. Network alterations include decreases in global efficiency, clustering coefficient, and nodal strength, thereby disrupting functional interactions and information flow throughout the dorsal cerebral cortex. A subnetwork analysis shows the largest disruptions in FC were concentrated near the impact site. Therefore, mTBI induces a transient neuroinflammation, without alterations in cognitive or motor behavior, and a reorganized cortical network evidenced by the widespread, chronic alterations in cortical FC.

Wide-Field Calcium Imaging of Dynamic Cortical Networks during Locomotion.

Motor behavior results in complex exchanges of motor and sensory information across cortical regions. Therefore, fully understanding the cerebral cortex's role in motor behavior requires a mesoscopic-level description of the cortical regions engaged, their functional interactions, and how these functional interactions change with behavioral state. Mesoscopic Ca2+ imaging through transparent polymer skulls in mice reveals elevated activation of the dorsal cerebral cortex during locomotion. Using the correlations between the time series of Ca2+ fluorescence from 28 regions (nodes) obtained using spatial independent component analysis (sICA), we examined the changes in functional connectivity of the cortex from rest to locomotion with a goal of understanding the changes to the cortical functional state that facilitate locomotion. Both the transitions from rest to locomotion and from locomotion to rest show marked increases in correlation among most nodes. However, once a steady state of continued locomotion is reached, many nodes, including primary motor and somatosensory nodes, show decreases in correlations, while retrosplenial and the most anterior nodes of the secondary motor cortex show increases. These results highlight the changes in functional connectivity in the cerebral cortex, representing a series of changes in the cortical state from rest to locomotion and on return to rest.

Cerebellar Representations of Errors and Internal Models.

After decades of study, a comprehensive understanding of cerebellar function remains elusive. Several hypotheses have been put forward over the years, including that the cerebellum functions as a forward internal model. Integrated into the forward model framework is the long-standing view that Purkinje cell complex spike discharge encodes error information. In this brief review, we address both of these concepts based on our recordings of cerebellar Purkinje cells over the last decade as well as newer findings from the literature. During a high-dimensionality tracking task requiring continuous error processing, we find that complex spike discharge provides a rich source of non-error signals to Purkinje cells, indicating that the classical error encoding role ascribed to climbing fiber input needs revision. Instead, the simple spike discharge of Purkinje cells carries robust predictive and feedback signals of performance errors, as well as kinematics. These simple spike signals are consistent with a forward internal model. We also show that the information encoded in the simple spike is dynamically adjusted by the complex spike firing. Synthesis of these observations leads to the hypothesis that complex spikes convey behavioral state changes, possibly acting to select and maintain forward models.

Climbing Fibers Control Purkinje Cell Representations of Behavior.

A crucial issue in understanding cerebellar function is the interaction between simple spike (SS) and complex spike (CS) discharge, the two fundamentally different activity modalities of Purkinje cells. Although several hypotheses have provided insights into the interaction, none fully explains or is completely consistent with the spectrum of experimental observations. Here, we show that during a pseudo-random manual tracking task in the monkey (Macaca mulatta), climbing fiber discharge dynamically controls the information present in the SS firing, triggering robust and rapid changes in the SS encoding of motor signals in 67% of Purkinje cells. The changes in encoding, tightly coupled to CS occurrences, consist of either increases or decreases in the SS sensitivity to kinematics or position errors and are not due to differences in SS firing rates or variability. Nor are the changes in sensitivity due to CS rhythmicity. In addition, the CS-coupled changes in encoding are not evoked by changes in kinematics or position errors. Instead, CS discharge most often leads alterations in behavior. Increases in SS encoding of a kinematic parameter are associated with larger changes in that parameter than are decreases in SS encoding. Increases in SS encoding of position error are followed by and scale with decreases in error. The results suggest a novel function of CSs, in which climbing fiber input dynamically controls the state of Purkinje cell SS encoding in advance of changes in behavior.SIGNIFICANCE STATEMENT Purkinje cells, the sole output of the cerebellar cortex, manifest two fundamentally different activity modalities, complex spike (CS) discharge and simple spike (SS) firing. Elucidating cerebellar function will require an understanding of the interactions, both short- and long-term, between CS and SS firing. This study shows that CSs dynamically control the information encoded in a Purkinje cell's SS activity by rapidly increasing or decreasing the SS sensitivity to kinematics and/or performance errors independent of firing rate. In many cases, the CS-coupled shift in SS encoding leads a change in behavior. These novel findings on the interaction between CS and SS firing provide for a new hypothesis in which climbing fiber input adjusts the encoding of SS information in advance of a change in behavior.

Complex Spike Wars: a New Hope.

The climbing fiber-Purkinje cell circuit is one of the most powerful and highly conserved in the central nervous system. Climbing fibers exert a powerful excitatory action that results in a complex spike in Purkinje cells and normal functioning of the cerebellum depends on the integrity of climbing fiber-Purkinje cell synapse. Over the last 50 years, multiple hypotheses have been put forward on the role of the climbing fibers and complex spikes in cerebellar information processing and motor control. Central to these theories is the nature of the interaction between the low-frequency complex spike discharge and the high-frequency simple spike firing of Purkinje cells. This review examines the major hypotheses surrounding the action of the climbing fiber-Purkinje cell projection, discussing both supporting and conflicting findings. The review describes newer findings establishing that climbing fibers and complex spikes provide predictive signals about movement parameters and that climbing fiber input controls the encoding of behavioral information in the simple spike firing of Purkinje cells. Finally, we propose the dynamic encoding hypothesis for complex spike function that strives to integrate established and newer findings.

Climbing fibers predict movement kinematics and performance errors.

Requisite for understanding cerebellar function is a complete characterization of the signals provided by complex spike (CS) discharge of Purkinje cells, the output neurons of the cerebellar cortex. Numerous studies have provided insights into CS function, with the most predominant view being that they are evoked by error events. However, several reports suggest that CSs encode other aspects of movements and do not always respond to errors or unexpected perturbations. Here, we evaluated CS firing during a pseudo-random manual tracking task in the monkey (Macaca mulatta). This task provides extensive coverage of the work space and relative independence of movement parameters, delivering a robust data set to assess the signals that activate climbing fibers. Using reverse correlation, we determined feedforward and feedback CSs firing probability maps with position, velocity, and acceleration, as well as position error, a measure of tracking performance. The direction and magnitude of the CS modulation were quantified using linear regression analysis. The major findings are that CSs significantly encode all three kinematic parameters and position error, with acceleration modulation particularly common. The modulation is not related to "events," either for position error or kinematics. Instead, CSs are spatially tuned and provide a linear representation of each parameter evaluated. The CS modulation is largely predictive. Similar analyses show that the simple spike firing is modulated by the same parameters as the CSs. Therefore, CSs carry a broader array of signals than previously described and argue for climbing fiber input having a prominent role in online motor control.NEW & NOTEWORTHY This article demonstrates that complex spike (CS) discharge of cerebellar Purkinje cells encodes multiple parameters of movement, including motor errors and kinematics. The CS firing is not driven by error or kinematic events; instead it provides a linear representation of each parameter. In contrast with the view that CSs carry feedback signals, the CSs are predominantly predictive of upcoming position errors and kinematics. Therefore, climbing fibers carry multiple and predictive signals for online motor control.

The Roles of the Olivocerebellar Pathway in Motor Learning and Motor Control. A Consensus Paper.

For many decades, the predominant view in the cerebellar field has been that the olivocerebellar system's primary function is to induce plasticity in the cerebellar cortex, specifically, at the parallel fiber-Purkinje cell synapse. However, it has also long been proposed that the olivocerebellar system participates directly in motor control by helping to shape ongoing motor commands being issued by the cerebellum. Evidence consistent with both hypotheses exists; however, they are often investigated as mutually exclusive alternatives. In contrast, here, we take the perspective that the olivocerebellar system can contribute to both the motor learning and motor control functions of the cerebellum and might also play a role in development. We then consider the potential problems and benefits of it having multiple functions. Moreover, we discuss how its distinctive characteristics (e.g., low firing rates, synchronization, and variable complex spike waveforms) make it more or less suitable for one or the other of these functions, and why having multiple functions makes sense from an evolutionary perspective. We did not attempt to reach a consensus on the specific role(s) the olivocerebellar system plays in different types of movements, as that will ultimately be determined experimentally; however, collectively, the various contributions highlight the flexibility of the olivocerebellar system, and thereby suggest that it has the potential to act in both the motor learning and motor control functions of the cerebellum.

Changes in Purkinje cell simple spike encoding of reach kinematics during adaption to a mechanical perturbation.

The cerebellum is essential in motor learning. At the cellular level, changes occur in both the simple spike and complex spike firing of Purkinje cells. Because simple spike discharge reflects the main output of the cerebellar cortex, changes in simple spike firing likely reflect the contribution of the cerebellum to the adapted behavior. Therefore, we investigated in Rhesus monkeys how the representation of arm kinematics in Purkinje cell simple spike discharge changed during adaptation to mechanical perturbations of reach movements. Monkeys rapidly adapted to a novel assistive or resistive perturbation along the direction of the reach. Adaptation consisted of matching the amplitude and timing of the perturbation to minimize its effect on the reach. In a majority of Purkinje cells, simple spike firing recorded before and during adaptation demonstrated significant changes in position, velocity, and acceleration sensitivity. The timing of the simple spike representations change within individual cells, including shifts in predictive versus feedback signals. At the population level, feedback-based encoding of position increases early in learning and velocity decreases. Both timing changes reverse later in learning. The complex spike discharge was only weakly modulated by the perturbations, demonstrating that the changes in simple spike firing can be independent of climbing fiber input. In summary, we observed extensive alterations in individual Purkinje cell encoding of reach kinematics, although the movements were nearly identical in the baseline and adapted states. Therefore, adaption to mechanical perturbation of a reaching movement is accompanied by widespread modifications in the simple spike encoding.

Abnormal excitability and episodic low-frequency oscillations in the cerebral cortex of the tottering mouse.

The Ca(2+) channelopathies caused by mutations of the CACNA1A gene that encodes the pore-forming subunit of the human Cav2.1 (P/Q-type) voltage-gated Ca(2+) channel include episodic ataxia type 2 (EA2). Although, in EA2 the emphasis has been on cerebellar dysfunction, patients also exhibit episodic, nonmotoric abnormalities involving the cerebral cortex. This study demonstrates episodic, low-frequency oscillations (LFOs) throughout the cerebral cortex of tottering (tg/tg) mice, a widely used model of EA2. Ranging between 0.035 and 0.11 Hz, the LFOs in tg/tg mice can spontaneously develop very high power, referred to as a high-power state. The LFOs in tg/tg mice are mediated in part by neuronal activity as tetrodotoxin decreases the oscillations and cortical neuron discharge contain the same low frequencies. The high-power state involves compensatory mechanisms because acutely decreasing P/Q-type Ca(2+) channel function in either wild-type (WT) or tg/tg mice does not induce the high-power state. In contrast, blocking l-type Ca(2+) channels, known to be upregulated in tg/tg mice, reduces the high-power state. Intriguingly, basal excitatory glutamatergic neurotransmission constrains the high-power state because blocking ionotropic or metabotropic glutamate receptors results in high-power LFOs in tg/tg but not WT mice. The high-power LFOs are decreased markedly by acetazolamide and 4-aminopyridine, the primary treatments for EA2, suggesting disease relevance. Together, these results demonstrate that the high-power LFOs in the tg/tg cerebral cortex represent a highly abnormal excitability state that may underlie noncerebellar symptoms that characterize CACNA1A mutations.

The Errors of Our Ways: Understanding Error Representations in Cerebellar-Dependent Motor Learning.

The cerebellum is essential for error-driven motor learning and is strongly implicated in detecting and correcting for motor errors. Therefore, elucidating how motor errors are represented in the cerebellum is essential in understanding cerebellar function, in general, and its role in motor learning, in particular. This review examines how motor errors are encoded in the cerebellar cortex in the context of a forward internal model that generates predictions about the upcoming movement and drives learning and adaptation. In this framework, sensory prediction errors, defined as the discrepancy between the predicted consequences of motor commands and the sensory feedback, are crucial for both on-line movement control and motor learning. While many studies support the dominant view that motor errors are encoded in the complex spike discharge of Purkinje cells, others have failed to relate complex spike activity with errors. Given these limitations, we review recent findings in the monkey showing that complex spike modulation is not necessarily required for motor learning or for simple spike adaptation. Also, new results demonstrate that the simple spike discharge provides continuous error signals that both lead and lag the actual movements in time, suggesting errors are encoded as both an internal prediction of motor commands and the actual sensory feedback. These dual error representations have opposing effects on simple spike discharge, consistent with the signals needed to generate sensory prediction errors used to update a forward internal model.

Cerebral cortical functional hyperconnectivity in a mouse model of spinocerebellar ataxia type 8 (SCA8).

Spinocerebellar Ataxia Type 8 (SCA8) is an inherited neurodegenerative disease caused by a bidirectionally expressed CTG●CAG expansion mutation in the ATXN-8 and ATXN8-OS genes. While primarily a motor disorder, psychiatric and cognitive symptoms have been reported. It is difficult to elucidate how the disease alters brain function in areas with little or no degeneration producing both motor and cognitive symptoms. Using transparent polymer skulls and CNS-wide GCaMP6f expression, we studied neocortical networks throughout SCA8 progression using wide-field Ca2+ imaging in a transgenic mouse model of SCA8. We observed that neocortical networks in SCA8+ mice were hyperconnected globally which led to network configurations with increased global efficiency and centrality. At the regional level, significant network changes occurred in nearly all cortical regions, however mainly involved sensory and association cortices. Changes in functional connectivity in anterior motor regions worsened later in the disease. Near perfect decoding of animal genotype was obtained using a generalized linear model based on canonical correlation strengths between activity in cortical regions. The major contributors to decoding were concentrated in the somatosensory, higher visual and retrosplenial cortices and occasionally extended into the motor regions, demonstrating that the areas with the largest network changes are predictive of disease state.

Predictive and feedback performance errors are signaled in the simple spike discharge of individual Purkinje cells.

The cerebellum has been implicated in processing motor errors required for on-line control of movement and motor learning. The dominant view is that Purkinje cell complex spike discharge signals motor errors. This study investigated whether errors are encoded in the simple spike discharge of Purkinje cells in monkeys trained to manually track a pseudorandomly moving target. Four task error signals were evaluated based on cursor movement relative to target movement. Linear regression analyses based on firing residuals ensured that the modulation with a specific error parameter was independent of the other error parameters and kinematics. The results demonstrate that simple spike firing in lobules IV-VI is significantly correlated with position, distance, and directional errors. Independent of the error signals, the same Purkinje cells encode kinematics. The strongest error modulation occurs at feedback timing. However, in 72% of cells at least one of the R(2) temporal profiles resulting from regressing firing with individual errors exhibit two peak R(2) values. For these bimodal profiles, the first peak is at a negative τ (lead) and a second peak at a positive τ (lag), implying that Purkinje cells encode both prediction and feedback about an error. For the majority of the bimodal profiles, the signs of the regression coefficients or preferred directions reverse at the times of the peaks. The sign reversal results in opposing simple spike modulation for the predictive and feedback components. Dual error representations may provide the signals needed to generate sensory prediction errors used to update a forward internal model.

Purkinje cell simple spike discharge encodes error signals consistent with a forward internal model.

Processing motor errors is essential for online control of goal-directed movements and motor learning. Evidence from psychophysical and imaging studies supports the long-standing view that error processing is central to cerebellar function. The dominant view is that error-related signals are encoded in the complex spike discharge of Purkinje cells. However, the findings are inconsistent on whether complex spike activity correlates with motor errors. Recently, we examined if simple spike firing carries error signals in monkeys trained to manually track a randomly moving target. The task requires continuous processing of motor errors characterized by the relative movements between the hand-driven cursor and the target center. Linear regression models show that error parameters are robustly represented in the simple spike activity of most Purkinje cells. At the single cell level, the error signals are encoded independently and integrated with kinematic signals. In a large majority of Purkinje cells, correlation strengths between the simple spike discharge and an error parameter have bimodal profiles with respect to time, exhibiting a local maxima corresponding to firing leading the behavior and another one corresponding to firing lagging behavior. The bimodal temporal profiles suggest that individual error parameters are dually encoded as both an internal prediction used for feedback-independent, compensatory movements and the actual sensory feedback used to monitor performance. Approximately 75 % of the dual representations have opposing modulations of the simple spike activity, one increasing firing and the other depressing firing, as reflected by the reversed signs of the regression coefficients corresponding to the local maxima of the R (2) profile. These dual representations of individual parameters with opposing modulation of the simple spike firing are consistent with the signals needed to generate sensory prediction errors used to update an internal model.

Wide-Field Calcium Imaging of Neuronal Network Dynamics In Vivo.

A central tenet of neuroscience is that sensory, motor, and cognitive behaviors are generated by the communications and interactions among neurons, distributed within and across anatomically and functionally distinct brain regions. Therefore, to decipher how the brain plans, learns, and executes behaviors requires characterizing neuronal activity at multiple spatial and temporal scales. This includes simultaneously recording neuronal dynamics at the mesoscale level to understand the interactions among brain regions during different behavioral and brain states. Wide-field Ca2+ imaging, which uses single photon excitation and improved genetically encoded Ca2+ indicators, allows for simultaneous recordings of large brain areas and is proving to be a powerful tool to study neuronal activity at the mesoscopic scale in behaving animals. This review details the techniques used for wide-field Ca2+ imaging and the various approaches employed for the analyses of the rich neuronal-behavioral data sets obtained. Also discussed is how wide-field Ca2+ imaging is providing novel insights into both normal and altered neural processing in disease. Finally, we examine the limitations of the approach and new developments in wide-field Ca2+ imaging that are bringing new capabilities to this important technique for investigating large-scale neuronal dynamics.

Representation of limb kinematics in Purkinje cell simple spike discharge is conserved across multiple tasks.

Encoding of movement kinematics in Purkinje cell simple spike discharge has important implications for hypotheses of cerebellar cortical function. Several outstanding questions remain regarding representation of these kinematic signals. It is uncertain whether kinematic encoding occurs in unpredictable, feedback-dependent tasks or kinematic signals are conserved across tasks. Additionally, there is a need to understand the signals encoded in the instantaneous discharge of single cells without averaging across trials or time. To address these questions, this study recorded Purkinje cell firing in monkeys trained to perform a manual random tracking task in addition to circular tracking and center-out reach. Random tracking provides for extensive coverage of kinematic workspaces. Direction and speed errors are significantly greater during random than circular tracking. Cross-correlation analyses comparing hand and target velocity profiles show that hand velocity lags target velocity during random tracking. Correlations between simple spike firing from 120 Purkinje cells and hand position, velocity, and speed were evaluated with linear regression models including a time constant, τ, as a measure of the firing lead/lag relative to the kinematic parameters. Across the population, velocity accounts for the majority of simple spike firing variability (63 ± 30% of R(adj)(2)), followed by position (28 ± 24% of R(adj)(2)) and speed (11 ± 19% of R(adj)(2)). Simple spike firing often leads hand kinematics. Comparison of regression models based on averaged vs. nonaveraged firing and kinematics reveals lower R(adj)(2) values for nonaveraged data; however, regression coefficients and τ values are highly similar. Finally, for most cells, model coefficients generated from random tracking accurately estimate simple spike firing in either circular tracking or center-out reach. These findings imply that the cerebellum controls movement kinematics, consistent with a forward internal model that predicts upcoming limb kinematics.

What features of limb movements are encoded in the discharge of cerebellar neurons?

This review examines the signals encoded in the discharge of cerebellar neurons during voluntary arm and hand movements, assessing the state of our knowledge and the implications for hypotheses of cerebellar function. The evidence for the representation of forces, joint torques, or muscle activity in the discharge of cerebellar neurons is limited, questioning the validity of theories that the cerebellum directly encodes the motor command. In contrast, kinematic parameters such as position, direction, and velocity are widely and robustly encoded in the activity of cerebellar neurons. These findings favor hypotheses that the cerebellum plans or controls movements in a kinematic framework, such as the proposal that the cerebellum provides a forward internal model. Error signals are needed for on-line correction and motor learning, and several hypotheses postulate the need for their representations in the cerebellum. Error signals have been described mostly in the complex spike discharge of Purkinje cells, but no consensus has emerged on the exact information signaled by complex spikes during limb movements. Newer studies suggest that simple spike firing may also encode error signals. Finally, Purkinje cells located more posterior and laterally in the cerebellar cortex and dentate neurons encode nonmotor, task-related signals such as visual cues. These results suggest that cerebellar neurons provide a complement of information about motor behaviors. We assert that additional single unit studies are needed using rich movement paradigms, given the power of this approach to directly test specific hypotheses about cerebellar function.

Purkinje Cell Representations of Behavior: Diary of a Busy Neuron.

Fundamental for understanding cerebellar function is determining the representations in Purkinje cell activity, the sole output of the cerebellar cortex. Up to the present, the most accurate descriptions of the information encoded by Purkinje cells were obtained in the context of motor behavior and reveal a high degree of heterogeneity of kinematic and performance error signals encoded. The most productive framework for organizing Purkinje cell firing representations is provided by the forward internal model hypothesis. Direct tests of this hypothesis show that individual Purkinje cells encode two different forward models simultaneously, one for effector kinematics and one for task performance. Newer results demonstrate that the timing of simple spike encoding of motor parameters spans an extend interval of up to ±2 seconds. Furthermore, complex spike discharge is not limited to signaling errors, can be predictive, and dynamically controls the information in the simple spike firing to meet the demands of upcoming behavior. These rich, diverse, and changing representations highlight the integrative aspects of cerebellar function and offer the opportunity to generalize the cerebellar computational framework over both motor and non-motor domains.

Cerebellum, Predictions and Errors.

Making predictions and validating the predictions against actual sensory information is thought to be one of the most fundamental functions of the nervous system. A growing body of evidence shows that the neural mechanisms controlling behavior, both in motor and non-motor domains, rely on prediction errors, the discrepancy between predicted and actual information. The cerebellum has been viewed as a key component of the motor system providing predictions about upcoming movements and receiving feedback about motor errors. Consequentially, studies of cerebellar function have focused on the motor domain with less consideration for the wider context in which movements are generated. However, motor learning experiments show that cognition makes important contributions to motor adaptation that involves the cerebellum. One of the more successful theoretical frameworks for understanding motor control and cerebellar function is the forward internal model which states that the cerebellum predicts the sensory consequences of the motor commands and is involved in computing sensory prediction errors by comparing the predictions to the sensory feedback. The forward internal model was applied and tested mainly for effector movements, raising the question whether cerebellar encoding of behavior reflects task performance measures associated with cognitive involvement. Electrophysiological studies based on pseudo-random tracking in monkeys show that the discharge of Purkinje cell, the sole output neurons of the cerebellar cortex, encodes predictive and feedback signals not only of the effector kinematics but also of task performance. The implications are that the cerebellum implements both effector and task performance forward models and the latter are consistent with the cognitive contributions observed during motor learning. The implications of these findings include insights into recent psychophysical observations on moving with reduced feedback and motor learning. The findings also support the cerebellum's place in hierarchical generative models that work in concert to refine predictions about behavior and the world. Therefore, cerebellar representations bridge motor and non-motor domains and provide a better understanding of cerebellar function within the functional architecture of the brain.

Modulation of sensory prediction error in Purkinje cells during visual feedback manipulations.

It is hypothesized that the cerebellum implements a forward internal model that transforms motor commands into predictions about upcoming movements. The predictions are compared with sensory feedback to generate sensory prediction errors critical to controlling movements. The simple spike firing of cerebellar Purkinje cells both lead and lag movement consistent with representations of motor predictions and sensory feedback. This study tests whether this leading and lagging modulation provides the prediction and sensory feedback necessary to compute sensory prediction errors. Two manipulations of the visual feedback are used in rhesus monkeys performing pseudo-random tracking. Consistent with a forward model, delaying the visual feedback demonstrates that the leading simple spike modulation with position error is time-locked to the hand movement. Reducing the feedback shows that the lagged modulation is directly driven by visual inputs. Therefore, Purkinje cell discharge carries both the motor predictions and sensory feedback required of a forward internal model.