Cerebellar complex spikes multiplex complementary behavioral information.

Purkinje cell (PC) discharge, the only output of cerebellar cortex, involves 2 types of action potentials, high-frequency simple spikes (SSs) and low-frequency complex spikes (CSs). While there is consensus that SSs convey information needed to optimize movement kinematics, the function of CSs, determined by the PC's climbing fiber input, remains controversial. While initially thought to be specialized in reporting information on motor error for the subsequent amendment of behavior, CSs seem to contribute to other aspects of motor behavior as well. When faced with the bewildering diversity of findings and views unraveled by highly specific tasks, one may wonder if there is just one true function with all the other attributions wrong? Or is the diversity of findings a reflection of distinct pools of PCs, each processing specific streams of information conveyed by climbing fibers? With these questions in mind, we recorded CSs from the monkey oculomotor vermis deploying a repetitive saccade task that entailed sizable motor errors as well as small amplitude saccades, correcting them. We demonstrate that, in addition to carrying error-related information, CSs carry information on the metrics of both primary and small corrective saccades in a time-specific manner, with changes in CS firing probability coupled with changes in CS duration. Furthermore, we also found CS activity that seemed to predict the upcoming events. Hence PCs receive a multiplexed climbing fiber input that merges complementary streams of information on the behavior, separable by the recipient PC because they are staggered in time.

Nonhuman primates exploit the prior assumption that the visual world is vertical.

When human subjects tilt their heads in dark surroundings, the noisiness of vestibular information impedes precise reports on objects' orientation with respect to Earth's vertical axis. This difficulty is mitigated if a vertical visual background is available. Tilted visual backgrounds induce feelings of head tilt in subjects who are in fact upright. This is often explained as a result of the brain resorting to the prior assumption that natural visual backgrounds are vertical. Here, we tested whether monkeys show comparable perceptual mechanisms. To this end we trained two monkeys to align a visual arrow to a vertical reference line that had variable luminance across trials, while including a large, clearly visible background square whose orientation changed from trial to trial. On ∼20% of all trials, the vertical reference line was left out to measure the subjective visual vertical (SVV). When the frame was upright, the monkeys' SVV was aligned with the gravitational vertical. In accordance with the perceptual reports of humans, however, when the frame was tilted it induced an illusion of head tilt as indicated by a bias in SVV toward the frame orientation. Thus all primates exploit the prior assumption that the visual world is vertical.NEW & NOTEWORTHY Here we show that the principles that characterize the human perception of the vertical are shared by another old world primate species, the rhesus monkey, suggesting phylogenetic continuity. In both species the integration of visual and vestibular information on the orientation of the head relative to the world is similarly constrained by the prior assumption that the visual world is vertical in the sense of having an orientation that is congruent with the gravity vector.

Resilience of FEF neuronal saccade code to V4 perturbations.

The frontal eye field (FEF) plays a key role in initiating rapid eye movements known as saccades. Accumulation models have been proposed to explain the dynamic of these neurons and how they may enable the initiation of saccades. To update the scope of the viability of this model, we studied single neurons recorded from the FEF of two rhesus monkeys while they performed a memory-guided saccade task. We evaluated the degree to which each type of FEF neuron complied with these models by quantifying how precisely their discharge predicted an imminent saccade based on their immediate presaccadic activity. We found that decoders trained on single neurons with a stronger motor component performed better than decoders trained on neurons with a stronger visual component in predicting the saccade. Importantly, despite a dramatic effect on the reaction times, the perturbations delivered to the FEF neurons via area V4 did not impact their saccade predictability. Our results demonstrate a high degree of resilience of the FEF neuronal presaccadic discharge patterns, fulfilling the predictions of accumulation models.NEW & NOTEWORTHY We studied neurons in the brain's frontal eye field (FEF) to understand how these neurons predict swift eye shifts called saccades. We found that neurons with more movement-related activity were better at predicting saccades than those with sensory-related activity. Interestingly, electrical disruptions of this region strongly impacted saccade onset times but did not affect the individual neuron's saccade predictability, consistent with models suggesting that a specific threshold in neural activity triggers the saccade.

Decoding of the other's focus of attention by a temporal cortex module.

Faces attract the observer's attention toward objects and locations of interest for the other, thereby allowing the two agents to establish joint attention. Previous work has delineated a network of cortical "patches" in the macaque cortex, processing faces, eventually also extracting information on the other's gaze direction. Yet, the neural mechanism that links information on gaze direction, guiding the observer's attention to the relevant object, has remained elusive. Here we present electrophysiological evidence for the existence of a distinct "gaze-following patch" (GFP) with neurons that establish this linkage in a highly flexible manner. The other's gaze and the object, singled out by the gaze, are linked only if this linkage is pertinent within the prevailing social context. The properties of these neurons establish the GFP as a key switch in controlling social interactions based on the other's gaze.

V1 neurons encode the perceptual compensation of false torsion arising from Listing's law.

We try to deploy the retinal fovea to optimally scrutinize an object of interest by directing our eyes to it. The horizontal and vertical components of eye positions acquired by goal-directed saccades are determined by the object's location. However, the eccentric eye positions also involve a torsional component, which according to Donder's law is fully determined by the two-dimensional (2D) eye position acquired. According to von Helmholtz, knowledge of the amount of torsion provided by Listing's law, an extension of Donder's law, alleviates the perceptual interpretation of the image tilt that changes with 2D eye position, a view supported by psychophysical experiments he pioneered. We address the question of where and how Listing's law is implemented in the visual system and we show that neurons in monkey area V1 use knowledge of eye torsion to compensate the image tilt associated with specific eye positions as set by Listing's law.

Sensitivity of express saccades to the expected value of the target.

Express saccades, a distinct fast mode of visually guided saccades, are probably underpinned by a specific pathway that is at least partially different from the one underlying regular saccades. Whether and how this pathway deals with information on the subjective value of a saccade target is unknown. We studied the influence of varying reward expectancies and compared it with the impact of a temporal gap between the disappearance of the fixation dot and the appearance of the target on the visually guided saccades of two rhesus macaques (Macaca mulatta). We found that increasing reward expectancy increased the probability and decreased the reaction time of express saccades. The latter influence was stronger in the later parts of the reaction time distribution of express saccades, satisfactorily captured by a linear shift model of change in the saccadic reaction time distribution. Although different in strength, increasing reward expectancy and inserting a temporal gap resulted in similar effects on saccadic reaction times, suggesting that these two factors summon the same mechanism to facilitate saccadic reaction times.NEW & NOTEWORTHY Express saccades are the fastest visually driven way of shifting gaze to targets of interest. We examined whether the pathway underlying these saccades has access to information on the value of saccade targets. We found that not only regular saccades but also express saccades occur earlier in case of higher expectations of reward. Yet, the sensitivity of express saccades to reward decreases linearly when approaching the earliest possible reaction time.

Variability of neuronal responses in the posterior superior temporal sulcus predicts choice behavior during social interactions.

Recent studies have shown that neural activity in a well-defined patch in the posterior superior temporal sulcus (the "gaze-following patch," GFP) of the primate brain is strongly modulated when the other's gaze attracts the observer's attention to locations/objects, the other is looking at. Changes of the mean discharge rate of neurons in the monkey GFP indicate that they are involved in two distinct computations: the allocation of spatial attention guided by the other's gaze vector and the suppression of gaze following if inappropriate in a given situation. Here, we asked if and how the discharge variability of neurons in the GFP is related to the task and if it carries information on behavioral performance. To this end, we calculated the Fano factor as a measure of across-trial discharge variability as a function of time. Our results show that all neurons exhibiting a task-related discharge-rate modulation also exhibit a stimulus onset-dependent drop in the Fano factor. Furthermore, the amplitude of the Fano factor reduction is modulated by task condition and the neuron's selectivity in this regard. We found that these effects are directly related to the monkeys' behavioral performance in that the Fano factor is predictive about upcoming correct or wrong decisions. Our results indicate that neuronal discharge variability as gauged by the Fano factor, hitherto primarily studied in the context of visual perception or motor control, is an informative measure also in studies of the neural underpinnings of complex social behavior.NEW & NOTEWORTHY Quenching of neural variability following stimulus onset is a widely accepted phenomenon. However, the relevance of quenching for the shaping of complex social behaviors remains to be explored. Here, we show that task selective neurons in the GFP exhibit a higher degree of variability quenching than their neighboring unselective neurons. Furthermore, we demonstrate that behavioral errors are not only associated with lower firing rates but also less variability quenching, suggesting that both facilitate optimal performance.

Learning from the past: A reverberation of past errors in the cerebellar climbing fiber signal.

The cerebellum allows us to rapidly adjust motor behavior to the needs of the situation. It is commonly assumed that cerebellum-based motor learning is guided by the difference between the desired and the actual behavior, i.e., by error information. Not only immediate but also future behavior will benefit from an error because it induces lasting changes of parallel fiber synapses on Purkinje cells (PCs), whose output mediates the behavioral adjustments. Olivary climbing fibers, likewise connecting with PCs, are thought to transport information on instant errors needed for the synaptic modification yet not to contribute to error memory. Here, we report work on monkeys tested in a saccadic learning paradigm that challenges this concept. We demonstrate not only a clear complex spikes (CS) signature of the error at the time of its occurrence but also a reverberation of this signature much later, before a new manifestation of the behavior, suitable to improve it.

Representation of the observer's predicted outcome value in mirror and nonmirror neurons of macaque F5 ventral premotor cortex.

In the search for the function of mirror neurons, a previous study reported that F5 mirror neuron responses are modulated by the value that the observing monkey associates with the grasped object. Yet we do not know whether mirror neurons are modulated by the expected reward value for the observer or also by other variables, which are causally dependent on value (e.g., motivation, attention directed at the observed action, arousal). To clarify this, we trained two rhesus macaques to observe a grasping action on an object kept constant, followed by four fully predictable outcomes of different values (2 outcomes with positive and 2 with negative emotional valence). We found a consistent order in population activity of both mirror and nonmirror neurons that matches the order of the value of this predicted outcome but that does not match the order of the above-mentioned value-dependent variables. These variables were inferred from the probability not to abort a trial, saccade latency, modulation of eye position during action observation, heart rate, and pupil size. Moreover, we found subpopulations of neurons tuned to each of the four predicted outcome values. Multidimensional scaling revealed equal normalized distances of 0.25 between the two positive and between the two negative outcomes suggesting the representation of a relative value, scaled to the task setting. We conclude that F5 mirror neurons and nonmirror neurons represent the observer's predicted outcome value, which in the case of mirror neurons may be transferred to the observed object or action.NEW & NOTEWORTHY Both the populations of F5 mirror neurons and nonmirror neurons represent the predicted value of an outcome resulting from the observation of a grasping action. Value-dependent motivation, arousal, and attention directed at the observed action do not provide a better explanation for this representation. The population activity's metric suggests an optimal scaling of value representation to task setting.

Using deep neural networks to detect complex spikes of cerebellar Purkinje cells.

One of the most powerful excitatory synapses in the brain is formed by cerebellar climbing fibers, originating from neurons in the inferior olive, that wrap around the proximal dendrites of cerebellar Purkinje cells. The activation of a single olivary neuron is capable of generating a large electrical event, called "complex spike," at the level of the postsynaptic Purkinje cell, comprising of an initial large-amplitude spike followed by a long polyphasic tail of small-amplitude spikelets. Several ideas discussing the role of the cerebellum in motor control are centered on these complex spike events. However, these events, only occurring one to two times per second, are extremely rare relative to Purkinje cell "simple spikes" (standard sodium-potassium action potentials). As a result, drawing conclusions about their functional role has been very challenging. In fact, because standard spike sorting approaches cannot fully handle the polyphasic shape of complex spike waveforms, the only safe way to avoid omissions and false detections has been to rely on visual inspection by experts, which is both tedious and, because of attentional fluctuations, error prone. Here we present a deep learning algorithm for rapidly and reliably detecting complex spikes. Our algorithm, utilizing both action potential and local field potential signals, not only detects complex spikes much faster than human experts, but it also reliably provides complex spike duration measures similar to those of the experts. A quantitative comparison of our algorithm's performance to both classic and novel published approaches addressing the same problem reveals that it clearly outperforms these approaches.NEW & NOTEWORTHY Purkinje cell "complex spikes", fired at perplexingly low rates, play a crucial role in cerebellum-based motor learning. Careful interpretations of these spikes require manually detecting them, since conventional online or offline spike sorting algorithms are optimized for classifying much simpler waveform morphologies. We present a novel deep learning approach for identifying complex spikes, which also measures additional relevant neurophysiological features, with an accuracy level matching that of human experts yet with very little time expenditure.

Bilateral recruitment of prefrontal cortex in working memory is associated with task demand but not with age.

Elderly adults may master challenging cognitive demands by additionally recruiting the cross-hemispheric counterparts of otherwise unilaterally engaged brain regions, a strategy that seems to be at odds with the notion of lateralized functions in cerebral cortex. We wondered whether bilateral activation might be a general coping strategy that is independent of age, task content and brain region. While using functional magnetic resonance imaging (fMRI), we pushed young and old subjects to their working memory (WM) capacity limits in verbal, spatial, and object domains. Then, we compared the fMRI signal reflecting WM maintenance between hemispheric counterparts of various task-relevant cerebral regions that are known to exhibit lateralization. Whereas language-related areas kept their lateralized activation pattern independent of age in difficult tasks, we observed bilaterality in dorsolateral and anterior prefrontal cortex across WM domains and age groups. In summary, the additional recruitment of cross-hemispheric counterparts seems to be an age-independent domain-general strategy to master cognitive challenges. This phenomenon is largely confined to prefrontal cortex, which is arguably less specialized and more flexible than other parts of the brain.

A loss of a velocity-duration trade-off impairs movement precision in patients with cerebellar degeneration.

Current theories discussing the role of the cerebellum have been consistently pointing towards the concept of motor learning. The unavailability of a structure for motor learning able to use information on past errors to change future movements should cause consistent metrical deviations and an inability to correct them; however, it should not boost "motor noise." However, dysmetria, a loss of endpoint precision and an increase in endpoint variability ("motor noise") of goal-directed movements is the central aspect of cerebellar ataxia. Does the prevention of dysmetria or "motor noise" by the healthy cerebellum tell us anything about its normal function? We hypothesize that the healthy cerebellum is able to prevent dysmetria by adjusting movement duration such as to compensate changes in movement velocity. To address this question, we studied fast goal-directed index finger movements in patients with global cerebellar degeneration and in healthy subjects. We demonstrate that healthy subjects are able to maintain endpoint precision despite continuous fluctuations in movement velocity because they are able to adjust the overall movement duration in a fully compensatory manner ("velocity-duration trade-off"). We furthermore provide evidence that this velocity-duration trade-off accommodated by the healthy cerebellum is based on a priori information on the future movement velocity. This ability is lost in cerebellar disease. We suggest that the dysmetria observed in cerebellar patients is a direct consequence of the loss of a cerebellum-based velocity-duration trade-off mechanism that continuously fine-tunes movement durations using information on the expected velocity of the upcoming movement.

Short-term adaptation of saccades does not affect smooth pursuit eye movement initiation.

Scrutiny of the visual environment requires saccades that shift gaze to objects of interest. In case the object should be moving, smooth pursuit eye movements (SPEM) try to keep the image of the object within the confines of the fovea in order to ensure sufficient time for its analysis. Both saccades and SPEM can be adaptively changed by the experience of insufficiencies, compromising the precision of saccades or the minimization of object image slip in the case of SPEM. As both forms of adaptation rely on the cerebellar oculomotor vermis (OMV), most probably deploying a shared neuronal machinery, one might expect that the adaptation of one type of eye movement should affect the kinematics of the other. In order to test this expectation, we subjected two monkeys to a standard saccadic adaption paradigm with SPEM test trials at the end and, alternatively, the same two monkeys plus a third one to a random saccadic adaptation paradigm with interleaved trials of SPEM. In contrast to our expectation, we observed at best marginal transfer which, moreover, had little consistency across experiments and subjects. The lack of consistent transfer of saccadic adaptation decisively constrains models of the implementation of oculomotor learning in the OMV, suggesting an extensive separation of saccade- and SPEM-related synapses on P-cell dendritic trees.

Microsaccade control signals in the cerebellum.

Microsaccades, the small saccades made when we try to keep the eyes still, were once believed to be inconsequential for vision, but recent studies suggest that they can precisely relocate gaze to tiny visual targets. Because the cerebellum is necessary for motor precision, we investigated whether microsaccades may exploit this neural machinery in monkeys. Almost all vermal Purkinje cells, which provide the eye-related output of the cerebellar cortex, were found to increase or decrease their simple spike firing rate during microsaccades. At both the single-cell and population level, microsaccade-related activity was highly similar to macrosaccade-related activity and we observed a continuous representation of saccade amplitude that spanned both the macrosaccade and microsaccade domains. Our results suggest that the cerebellum's role in fine-tuning eye movements extends even to the oculomotor system's smallest saccades and add to a growing list of observations that call into question the classical categorical distinction between microsaccades and macrosaccades.

Individual neurons in the caudal fastigial oculomotor region convey information on both macro- and microsaccades.

Recent studies have suggested that microsaccades, the small amplitude saccades made during fixation, are precisely controlled. Two lines of evidence suggest that the cerebellum plays a key role not only in improving the accuracy of macrosaccades but also of microsaccades. First, lesions of the fastigial oculomotor regions (FOR) cause horizontal dysmetria of both micro- and macrosaccades. Secondly, our previous work on Purkinje cell simple spikes in the oculomotor vermis (OV) has established qualitatively similar response preferences for these two groups of saccades. In this work, we investigated the control signals for micro- and macrosaccades in the FOR, the target of OV Purkinje cell axons. We found that the same FOR neurons discharged for micro- and macrosaccades. For both groups of saccades, FOR neurons exhibited very similar dependencies of their discharge strength on direction and amplitude and very similar burst onset time differences for ipsi- and contraversive saccades and, in both, response duration reflected saccade duration, at least at the population level. An intriguing characteristic of microsaccade-related responses is that immediate pre-saccadic firing rates decreased with distance to the target center, a pattern that strikingly parallels the eye position dependency of both microsaccade metrics and frequency, which may suggest a potential neural mechanism underlying the role of FOR in fixation. Irrespective of this specific consideration, our study supports the view that microsaccades and macrosaccades share the same cerebellar circuitry and, in general, further strengthens the notion of a microsaccade-macrosaccade continuum.

Encoding of point of view during action observation in the local field potentials of macaque area F5.

The discovery of mirror neurons compellingly shows that the monkey premotor area F5 is active not only during the execution but also during the observation of goal-directed motor acts. Previous studies have addressed the functioning of the mirror-neuron system at the single-unit level. Here, we tackled this research question at the network level by analysing local field potentials in area F5 while the monkey was presented with goal-directed actions executed by a human or monkey actor and observed either from a first-person or third-person perspective. Our analysis showed that rhythmic responses are not only present in area F5 during action observation, but are also modulated by the point of view. Observing an action from a subjective point of view produced significantly higher power in the low-frequency band (2-10 Hz) than observing the same action from a frontal view. Interestingly, an increase in power in the 2-10 Hz band was also produced by the execution of goal-directed motor acts. Independently of the point of view, action observation also produced a significant decrease in power in the 15-40 Hz band and an increase in the 60-100 Hz band. These results suggest that, depending on the point of view, action observation might activate different processes in area F5. Furthermore, they may provide information about the functional architecture of action perception in primates.

Monkeys head-gaze following is fast, precise and not fully suppressible.

Human eye-gaze is a powerful stimulus, drawing the observer's attention to places and objects of interest to someone else ('eye-gaze following'). The largely homogeneous eyes of monkeys, compromising the assessment of eye-gaze by conspecifics from larger distances, explain the absence of comparable eye-gaze following in these animals. Yet, monkeys are able to use peer head orientation to shift attention ('head-gaze following'). How similar are monkeys' head-gaze and human eye-gaze following? To address this question, we trained rhesus monkeys to make saccades to targets, either identified by the head-gaze of demonstrator monkeys or, alternatively, identified by learned associations between the demonstrators' facial identities and the targets (gaze versus identity following). In a variant of this task that occurred at random, the instruction to follow head-gaze or identity was replaced in the course of a trial by the new rule to detect a change of luminance of one of the saccade targets. Although this change-of-rule rendered the demonstrator portraits irrelevant, they nevertheless influenced performance, reflecting a precise redistribution of spatial attention. The specific features depended on whether the initial rule was head-gaze or identity following: head-gaze caused an insuppressible shift of attention to the target gazed at by the demonstrator, whereas identity matching prompted much later shifts of attention, however, only if the initial rule had been identity following. Furthermore, shifts of attention prompted by head-gaze were spatially precise. Automaticity and swiftness, spatial precision and limited executive control characterizing monkeys' head-gaze following are key features of human eye-gaze following. This similarity supports the notion that both may rely on the same conserved neural circuitry.

Mirror neurons encode the subjective value of an observed action.

Objects grasped by an agent have a value not only for the acting agent, but also for an individual observing the grasping act. The value that the observer attributes to the object that is grasped can be pivotal for selecting a possible behavioral response. Mirror neurons in area F5 of the monkey premotor cortex have been suggested to play a crucial role in the understanding of action goals. However, it has not been addressed if these neurons are also involved in representing the value of the grasped object. Here we report that observation-related neuronal responses of F5 mirror neurons are indeed modulated by the value that the monkey associates with the grasped object. These findings suggest that during action observation F5 mirror neurons have access to key information needed to shape the behavioral responses of the observer.