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

“Forward internal models provide a solution to the problem of long feedback delays by predicting the sensory consequences of a motor command (Robinson, 1975; Miall et al., 1993; Wolpert et al., 1995; Wolpert and Ghahramani, 2000; Tseng et al., 2007; Shadmehr et al., 2010).”

“Error processing is a central component of many hypotheses of cerebellar function, including motor learning (Marr, 1969; Gilbert and Thach, 1977; Ito, 2002) and providing internal models (Wolpert et al.”

“Detecting and correcting performance errors is essential to finetune motor behavior, including on-line control and motor adaptation (Todorov and Jordan, 2002; Berniker and Kording, 2008; Shadmehr et al., 2010).”

“However, closed loop control using delayed feedback can be inadequate and even unstable (Wolpert and Miall, 1996; Bhushan and Shadmehr, 1999; Kawato, 1999; Wolpert and Ghahramani, 2000).”

“…involvement in implementing a forward internal model, integrating predictions about the consequences of a motor action with the sensory feedback to fine-tune motor behavior and guide motor adaptation (Wolpert and Miall, 1996; Wolpert et al., 1998; Ebner and Pasalar, 2008; Shadmehr et al., 2010).”

“Early concepts focused on closed loop control in which the ongoing motor commands are updated by sensory feedback (Wolpert and Miall, 1996).”

“11) was used to assess directional tuning with PDE (Georgopoulos et al., 1982; Amirikian and Georgopoulos, 2000).”

“The feedback component of the error signals could function to modify a forward model during motor learning (Wolpert and Ghahramani, 2000; Shadmehr et al., 2010).”

“The feedback component of the error signals could function to modify a forward model during motor learning (Wolpert and Ghahramani, 2000; Shadmehr et al., 2010).”

“Error processing is a central component of many hypotheses of cerebellar function, including motor learning (Marr, 1969; Gilbert and Thach, 1977; Ito, 2002) and providing internal models (Wolpert et al., 1998; Kawato, 1999; Shadmehr and Krakauer, 2008; Shadmehr et al., 2010).”

“Forward internal models provide a solution to the problem of long feedback delays by predicting the sensory consequences of a motor command (Robinson, 1975; Miall et al., 1993; Wolpert et al., 1995; Wolpert and Ghahramani, 2000; Tseng et al., 2007; Shadmehr et al., 2010).”

“Generated using the sum of random sine waves (Imamizu et al., 2000; Paninski et al., 2004), the trajectories were lowpass filtered and selected to avoid sharp turns and large changes in speed.”

“Both eye and limb movement studies suggest sensory prediction errors are the critical signals that drive motor adaptation, not the actual motor corrections (Wallman and Fuchs, 1998; Noto and Robinson, 2001; Mazzoni and Krakauer, 2006; Tseng et al., 2007).”

“Both eye and limb movement studies suggest sensory prediction errors are the critical signals that drive motor adaptation, not the actual motor corrections (Wallman and Fuchs, 1998; Noto and Robinson, 2001; Mazzoni and Krakauer, 2006; Tseng et al., 2007).”

“Target speed was controlled by the two-thirds power law, speed cK , where K is the path curvature and c is a constant chosen so that the average speed was 4 cm/s (Viviani and Terzuolo, 1982; Lacquaniti et al., 1983).”

“During arm movements, complex spikes modulate with perturbations (Gilbert and Thach, 1977; Wang et al., 1987), adaptation to visuomotor transformations (Ojakangas and Ebner, 1994), and end point errors (Kitazawa et al.”

“Cerebellar damage results in deficits in adapting limb and eye movements, and impairs a patient’s ability to learn from movement errors (Martin et al., 1996; Maschke et al., 2004; Smith and Shadmehr, 2005; Morton and Bastian, 2006; Xu-Wilson et al., 2009; Criscimagna-Hemminger et al., 2010).”

“Error-related activation occurs in the cerebellum during the learning of visuomotor transformations or force fields (Imamizu et al., 2000; Diedrichsen et al., 2005; Ide and Li, 2011).”

“Cerebellar damage results in deficits in adapting limb and eye movements, and impairs a patient’s ability to learn from movement errors (Martin et al., 1996; Maschke et al., 2004; Smith and Shadmehr, 2005; Morton and Bastian, 2006; Xu-Wilson et al., 2009; Criscimagna-Hemminger et al., 2010).”

“…signals in the simple spike firing (see Introduction), and functional imaging studies document cerebellum activation with movement errors (Blakemore et al., 2001; Diedrichsen et al., 2005; Miall and Jenkinson, 2005), this is the first demonstration that the simple spike discharge encodes…”

“Cerebellar damage results in deficits in adapting limb and eye movements, and impairs a patient’s ability to learn from movement errors (Martin et al., 1996; Maschke et al., 2004; Smith and Shadmehr, 2005; Morton and Bastian, 2006; Xu-Wilson et al., 2009; Criscimagna-Hemminger et al., 2010).”

“Target speed was controlled by the two-thirds power law, speed cK 1/3, where K is the path curvature and c is a constant chosen so that the average speed was 4 cm/s (Viviani and Terzuolo, 1982; Lacquaniti et al., 1983).”

“Purkinje cells were identified by the presence of complex spikes (Thach, 1968; Ojakangas and Ebner, 1992; Fu et al., 1997; Roitman et al., 2005; Hewitt et al., 2011).”

“Cerebellar damage results in deficits in adapting limb and eye movements, and impairs a patient’s ability to learn from movement errors (Martin et al., 1996; Maschke et al., 2004; Smith and Shadmehr, 2005; Morton and Bastian, 2006; Xu-Wilson et al., 2009; Criscimagna-Hemminger et al., 2010).”

“These measures are similar to error signals involved in human motor adaptation (Berniker and Kording, 2008; Izawa and Shadmehr, 2011).”

“Complex spike discharge is associated with errors during eye movements (Barmack and Simpson, 1980; Graf et al., 1988; Kobayashi et al., 1998; Soetedjo and Fuchs, 2006; Medina and Lisberger, 2008).”

“, 1987), adaptation to visuomotor transformations (Ojakangas and Ebner, 1994), and end point errors (Kitazawa et al., 1998).”

“As in other studies (Ashe and Georgopoulos, 1994; Gomi et al., 1998; Medina and Lisberger, 2009; Hewitt et al., 2011), does not add an additional degree of freedom.”

“The predictive component of the error signals could function as internal feedback used to control movements, thus avoiding the problems of delayed feedback and accounting for cerebellar involvement in compensating for motor command variability (Bhushan and Shadmehr, 1999; Wolpert and Ghahramani, 2000; Xu-Wilson et al.…”

“Several other studies have documented similar encoding of kinematics during arm movements (Marple-Horvat and Stein, 1987; Fortier et al., 1989; Coltz et al., 1999; Roitman et al., 2005).”

“These measures are similar to error signals involved in human motor adaptation (Berniker and Kording, 2008; Izawa and Shadmehr, 2011).”

“Error processing is a central component of many hypotheses of cerebellar function, including motor learning (Marr, 1969; Gilbert and Thach, 1977; Ito, 2002) and providing internal models (Wolpert et al.”

“It has been shown that cerebellum-like structures have the capability to minimize sensory reafference and highlight other signals (Bell et al., 2008).”

“Cerebellar damage results in deficits in adapting limb and eye movements, and impairs a patient’s ability to learn from movement errors (Martin et al., 1996; Maschke et al., 2004; Smith and Shadmehr, 2005; Morton and Bastian, 2006; Xu-Wilson et al., 2009; Criscimagna-Hemminger et al., 2010).”

“Cerebellar damage results in deficits in adapting limb and eye movements, and impairs a patient’s ability to learn from movement errors (Martin et al., 1996; Maschke et al., 2004; Smith and Shadmehr, 2005; Morton and Bastian, 2006; Xu-Wilson et al., 2009; Criscimagna-Hemminger et al., 2010).”

“…error signals might coexist in both the complex and simple spike firing, it is not clear how the low-frequency complex spike discharge could encode, at least at the single cell level, the type of continuous error signals evaluated in this study (Ebner and Bloedel, 1987; Simpson et al., 1996).”

“Learning-related plasticity in the vestibular/cerebellar nuclei also suggests that simple spike firing encodes errors (Lisberger et al., 1994; De Zeeuw and Yeo, 2005; Ohyama et al., 2006).”

“As in other studies (Ashe and Georgopoulos, 1994; Gomi et al., 1998; Medina and Lisberger, 2009; Hewitt et al., 2011), does not add an additional degree of freedom.”

“Both eye and limb movement studies suggest sensory prediction errors are the critical signals that drive motor adaptation, not the actual motor corrections (Wallman and Fuchs, 1998; Noto and Robinson, 2001; Mazzoni and Krakauer, 2006; Tseng et al., 2007).”

“Purkinje cells were identified by the presence of complex spikes (Thach, 1968; Ojakangas and Ebner, 1992; Fu et al., 1997; Roitman et al., 2005; Hewitt et al., 2011).”

“The predictive component of the error signals could function as internal feedback used to control movements, thus avoiding the problems of delayed feedback and accounting for cerebellar involvement in compensating for motor command variability (Bhushan and Shadmehr, 1999; Wolpert and Ghahramani, 2000; Xu-Wilson et al.…”

“Error-related activation occurs in the cerebellum during the learning of visuomotor transformations or force fields (Imamizu et al., 2000; Diedrichsen et al., 2005; Ide and Li, 2011).”

“All other kinematic and error variables were derived from the position data (Roitman et al., 2005; Pasalar et al., 2006).”

“Learning-related plasticity in the vestibular/cerebellar nuclei also suggests that simple spike firing encodes errors (Lisberger et al., 1994; De Zeeuw and Yeo, 2005; Ohyama et al., 2006).”

“Decoding of PDE followed a similar approach, but used a population vector analysis (Georgopoulos et al., 1982; Schwartz, 1993).”

“, fractional) intervals that occur at the start and end of each bin (Schwartz, 1992; Taira et al., 1996; Reina et al., 2001).”

“Learning-related plasticity in the vestibular/cerebellar nuclei also suggests that simple spike firing encodes errors (Lisberger et al., 1994; De Zeeuw and Yeo, 2005; Ohyama et al., 2006).”

“, fractional) intervals that occur at the start and end of each bin (Schwartz, 1992; Taira et al., 1996; Reina et al., 2001).”

“As required, the resulting sensory prediction error would be in the same kinematic space as a forward model (Ariff et al., 2002; Flanagan et al., 2003).”

“Several other studies have documented similar encoding of kinematics during arm movements (Marple-Horvat and Stein, 1987; Fortier et al., 1989; Coltz et al., 1999; Roitman et al., 2005).”

“A recent study suggests a novel role for complex spikes during learning with climbing fiber input signaling sensitivity to errors, instead of encoding errors (Marko et al., 2012).”

“Purkinje cells were identified by the presence of complex spikes (Thach, 1968; Ojakangas and Ebner, 1992; Fu et al., 1997; Roitman et al., 2005; Hewitt et al., 2011).”

“During arm movements, complex spikes modulate with perturbations (Gilbert and Thach, 1977; Wang et al., 1987), adaptation to visuomotor transformations (Ojakangas and Ebner, 1994), and end point errors (Kitazawa et al., 1998).”

“During arm movements, complex spikes modulate with perturbations (Gilbert and Thach, 1977; Wang et al., 1987), adaptation to visuomotor transformations (Ojakangas and Ebner, 1994), and end point errors (Kitazawa et al., 1998).”

“Both eye and limb movement studies suggest sensory prediction errors are the critical signals that drive motor adaptation, not the actual motor corrections (Wallman and Fuchs, 1998; Noto and Robinson, 2001; Mazzoni and Krakauer, 2006; Tseng et al., 2007).”

“Several studies failed to find the expected responses to errors or perturbations (Horn et al., 1996; Ebner et al., 2002; Catz et al., 2005; Dash et al., 2010).”

“This hypothesis is based on the observations that motor learning decreases with error size as does the probability of complex spike occurrence with visual errors during saccades (Soetedjo et al., 2008; Marko et al., 2012).”

“DOI:10.1523/JNEUROSCI.2151-12.2012 Copyright © 2012 the authors 0270-6474/12/3215345-14$15.00/0 cerebellar-dependent learning in the vestibulo-ocular reflex (Ke et al., 2009).”

“, fractional) intervals that occur at the start and end of each bin (Schwartz, 1992; Taira et al., 1996; Reina et al., 2001).”

“Several other studies have documented similar encoding of kinematics during arm movements (Marple-Horvat and Stein, 1987; Fortier et al., 1989; Coltz et al., 1999; Roitman et al., 2005).”

“Note this is the same binning used in our previous study that evaluated the simple spike firing with the PVS model (Hewitt et al., 2011).”

“Importantly, it is the difference between the expected and actual sensory consequences that influences adaptation (Wong and Shelhamer, 2011).”

“Complex spike discharge is associated with errors during eye movements (Barmack and Simpson, 1980; Graf et al., 1988; Kobayashi et al., 1998; Soetedjo and Fuchs, 2006; Medina and Lisberger, 2008).”

“As in other studies (Ashe and Georgopoulos, 1994; Gomi et al., 1998; Medina and Lisberger, 2009; Hewitt et al., 2011), does not add an additional degree of freedom.”

“…spike firing (see Introduction), and functional imaging studies document cerebellum activation with movement errors (Blakemore et al., 2001; Diedrichsen et al., 2005; Miall and Jenkinson, 2005), this is the first demonstration that the simple spike discharge encodes specific performance errors.”

“Several studies failed to find the expected responses to errors or perturbations (Horn et al., 1996; Ebner et al., 2002; Catz et al., 2005; Dash et al., 2010).”

“During arm movements, simple spike activity modulates with trial success or failure (Greger and Norris, 2005) and correlates with several error measures (Roitman et al., 2009).”

“These observations may explain why motor adaptation in the presence of continuous sensory input differs from adaptation based only on endpoint or reward feedback (Magescas et al., 2009; Izawa and Shadmehr, 2011).”

“Many groups have attempted to identify the neural bases of foresight, and despite considerable ongoing debate, a consensus exists on the importance of the cerebellum in prediction [177].”

“Such error signals have been observed in the simple spiking of Purkinje cells in a manner that is independent of Cspks (Popa et al., 2012; Popa et al., 2017; Streng et al., 2018).”

“simple spike signals thought to be involved in the computation of sensory prediction errors [113, 115] suggest that the teaching signals driving adaptation are conveyed by the simple”

“Recent single-cell recording studies within the cerebellar cortex in monkeys are also in line with this assumption: both simple and complex spike firing rates at the same Purkinje cell encode movement kinematics and sensory feedback, but also motor predictions (Popa et al., 2012; Streng et al., 2017a; Streng et al., 2…”

“Various studies on the internal forward model have demonstrated that the cerebellum generates motorto-somatosensory predictions (Izawa et al., 2012; Popa et al., 2012; Knolle et al., 2013).”

“Our recent work demonstrates that SS firing encodes performance errors during a manual task in which monkeys are required to track an unpredictable target [10, 55].”

“…under circumstances of robust activation of the cerebellar system (Schweighofer et al., 2004a,b); however, this issue must be addressed further as other views are also clearly present (Gilbert and Thach, 1977; Horn et al., 2004; Catz et al., 2005; Kojima et al., 2010; Popa et al., 2012, 2013).”

“…forward prediction and feedback error-related signals, consistent with an involvement of the cerebellum in the prediction of expected sensorimotor states and the detection and correction of motor errors (Pasalar et al., 2006; for a recent review, see Ebner et al., 2011; Popa et al., 2012, 2013).”

“, 2015), including the predictive processing of perceptual events (Shadmehr et al., 2010; Popa et al., 2012; Roth et al., 2013).”

“The frequency of significant error-related modulation was extremely high, with over 90% of Purkinje cells modulated with respect to XE, YE, and RE and over 80% with PDE.”

“This involved fitting the SS firing to each kinematic and error parameters using the temporal linear regressions on firing residuals, as described previously (Popa et al., 2012; Hewitt et al., 2015).”

“YE, RE, and PDE) from the simple spike discharge [11].”

“Unexpected events which could lead to motor errors would then be corrected and participate in the adjustments of the cerebellar internal models through learning (Diedrichsen et al., 2005; Popa et al., 2012).”

“Crucially, Purkinje cell SSpk output often correlates with these corrective movements 34,37,38 , raising the possibility that they could provide their own instructive signals for plasticity—either in addition to, or independently of, CSpk acti vity 30,36,39–44 .”

“This approach was validated previously with control regressions to confirm that the FRs contained no information about the other parameters (Popa et al., 2012).”

“The random tracking paradigm also indicated a modulation of simple spike activity during error processing, especially during performance error, defined as the difference between the intended action and its consequences [46,49].”

“The cerebellar cortex is a prototypical microcircuit known to be important for generating temporally precise motor 22 and cognitive behaviors 23 – 26 on the sub-second timescale.”

“Kinematic parameters of arm movements have been found to be related to single neuron activity in the cerebellum (Hewitt et al., 2011; Popa et al., 2012) and in the motor cortex (Ashe and Georgopoulos, 1994; Yu et al., 2007) of non-human primates.”

“As shown previously, the animals use these measures to perform the task as they strive to minimize these errors (Popa et al., 2012).”

“…their ability to predict movement outcomes, forward models are believed to serve an important role in the supervised learning mechanisms associated with the cerebellum (54–56) by permitting comparison between what the body expects to sense as a consequence of movement, to what it actually senses.”

“Ebner and colleagues (Hewitt et al., 2015, 2011; Popa et al., 2012; Streng et al., 2018) recorded from hundreds of P-cells in the intermediate and lateral regions of lobule IV-VI and used linear regression to first account for the variance in the simple spike rate with respect to motion of the arm,…”

“For example, using th int rnal forwa d model, the cer b llum erves as a predictive co troller [27,28].”

“1A) (Hewitt et al. 2011; Popa et al. 2012).”

“In the motor domain, the cerebellum is supposed to predict the sensory consequences of motor actions and to learn from expectation violations, that is, the occurrence of a mismatch between prediction and sensory feedback [8, 9] (for reviews, see [10–12]).”

“Despite the prevailing view that CS discharge responds to passive motion caused by error events (Ito, 1972), some investigators thought that SS discharges encode errors (Popa et al., 2012, 2013).”

“The cortico-cerebello-cortical loop is believed to be organized in parallel segregated modules (Ramnani, 2006).”

“The spike trains were converted into instantaneous firing rate with 200 ms binning using fractional intervals, a method used to determine the instantaneous firing rate in equal bins based on the inverse of the interspike intervals (Chen et al., 2009; Popa et al., 2012).”

“Importantly, SS modulation both leads and lags behavior, which means that individual PCs may carry predictive and feedback signals about motor commands and corresponding behaviors (Hewitt et al., 2015; Popa et al., 2015; Chen et al., 2016; Streng et al., 2018).”

“Sensorimotor control in the brain is often attributed to the cerebellum (Kawato and Gomi, 1992; Schweighofer et al., 1998; Thach, 1998; Ito, 2002; Nowak et al., 2007; Haith and Vijayakumar, 2009; Popa et al., 2012), which has been known to play roles in the error correction based control (Tseng et al.”

“…studies have assumed that the cerebellum functions as an internal forward model controller to coordinate various movements, i.e., a controller that predicts the future state of a motion consequence by solving dynamics with a given e ff erence copy of motor commands and the current states [16,35,36].”

“The observation that PCs can signal in a fashion compatible with an internal model representation (Pasalar et al., 2006; Popa et al., 2012, 2013) could be due to the information conveyed by the spinocerebellar systems.”

“It also found that the same Purkinje cells simultaneously encoded kinematics independent of these error signals (Popa et al. 2012).”

“For a fixed desired trajectory, changes in sensory inputs can produce increases in sensory errors, enabling complex spikes.”

“Recent data suggest that Purkinje single cell spiking in the cerebellar cortex, which inhibit the deep cerebellar nuclei, is associated with failure or success of a trial (Greger and Norris, 2005; Roitman et al., 2009) and can predict performance errors (Kitazawa et al., 1998; Popa et al., 2012).”

“This type of state estimation has been observed in other tasks (Dimitriou et al. 2013; Golub et al. 2015; Mehta and Schaal 2002; Popa et al. 2012; Saunders and Knill 2003) but the fact that it can be elicited in a variable manner (by changing ) in nonhuman primates suggests that the CST could be…”

“This is crucial for clarifying how the cerebellum processes and integrates different types of information during motor tasks, suggesting a sophisticated mechanism by which the cerebellum contributes to motor control and learning [165 ].”

“A consensus exists that such an internal forward model embedded within the cerebellum acts as a neural substrate for predictive motor control [74,75].”

“[27] Laurentiu S Popa, Angela L Hewitt, and Timothy J Ebner.”

“This pathway primarily features a feedforward architecture, though Purkinje cell simple spike discharges may provide feedback [260,261].”

“This finding supports the hypothesis that the SS activity of Purkinje cells carry sensory prediction error signals, a critical component of a dynamical control framework supporting optimal sensorimotor functions (Shadmehr et al. 2010; Popa et al. 2012; 2013; 2016; 2017; Streng et al. 2018).”

“Both passive movements (Carel et al., 2000) and active motor learning (Della-Maggiore & McIntosh, 2005; Herzfeld et al., 2015; Popa et al., 2012; Izawa et al., 2012; Tseng et al., 2007; Gibo et al., 2013; Maschke et al., 2004) are known to involve both the primary motor cortex (M1) and the…”

“Poppa et al. 22 demonstrated this was both predictive and feedback-based, suggesting the presence of the internal forward model in the cerebellum.”

“, 2016), that of the cerebellum in learning how to adapt these movements is 31 less clear (Popa et al., 2012; Chen et al., 2016, 2017).”

“The results of more recent physiological investigations have suggested that the core function of the cerebellum lies in predictive control [37].”