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.

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.

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.

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.

Gaze and Arrows: does the Gaze Following Patch in the posterior temporal cortex differentiate social and symbolic spatial cues?

The Gaze Following Patch (GFP) is located in the posterior temporal cortex and has been described as a cortical module dedicated to processing other people's gaze direction in a domain-specific manner. Thus, it appears to be the neural correlate of Baron-Cohen's Eye-Direction Detector (EDD) which is one of the core modules in his Mindreading System - a neurocognitive model for the Theory of Mind concept. Inspired by Jerry Fodor's ideas on the modularity of the mind, Baron-Cohen proposed that, among other things, the individual modules are domain-specific. In the case of the EDD this means that it exclusively processes eye-like stimuli to extract gaze direction and that other stimuli, that may carry directional information as well, are processed elsewhere. If the GFP is indeed EDD's neural correlate it must meet this expectation. To test this, we compared the GFP's BOLD activity during gaze-direction following with the activity during arrow-direction following in the present human fMRI study. Contrary to the expectation based on the assumption of domain specificity we did not find a differentiation between gaze and arrow-direction following. In fact, we were not able to reproduce the GFP as presented in previous studies. A possible explanation is that in the present study - unlike previous work -, the gaze stimuli did not contain an obvious change of direction that represented a visual motion. Hence, the critical stimulus component responsible for the identification of the GFP in previous experiments might have been visual motion.Significance Statement This study presents evidence against the notion of domain-specificity of an area in the posterior temporal cortex (the gaze-following-patch; GFP) previously described to specifically serve eye gaze following. This conclusion is suggested by the finding that using arrows to identify a target object among distractors is accompanied by a comparable or even larger BOLD response than when the participants are asked to use the gaze direction of a demonstrator face for target selection. The fact that even the best candidate to date, the posterior temporal GFP, does not stand up to critical scrutiny casts doubt on the assumption that the brain uses a specific module to enable gaze following, as proposed by Simon Baron-Cohen.

Pontine reference frames for the sensory guidance of movement.

The pontine nuclei (PN) are the major intermediary elements in the corticopontocerebellar pathway. Here we asked if the PN may help to adapt the spatial reference frames used by cerebrocortical neurons involved in the sensory guidance of movement to a format potentially more appropriate for the cerebellum. To this end, we studied movement-related neurons in the dorsal PN (DPN) of monkeys, most probably projecting to the cerebellum, executing fixed vector saccades or, alternatively, fixed vector hand reaches from different starting positions. The 83 task-related neurons considered fired movement-related bursts before saccades (saccade-related) or before hand movements (hand movement-related). About 40% of the SR neurons were "oculocentric," whereas the others were modulated by eye starting position. A third of the HMR neurons encoded hand reaches in hand-centered coordinates, whereas the remainder exhibited different types of dependencies on starting positions, reminiscent in general of cortical responses. All in all, pontine reference frames for the sensory guidance of movement seem to be very similar to those in cortex. Specifically, the frequency of orbital position gain fields of SR neurons is identical in the DPN and in one of their major cortical inputs, lateral intraparietal area (LIP).

Encoding of smooth-pursuit eye movement initiation by a population of vermal Purkinje cells.

Lesion studies suggest that the oculomotor vermis (OMV) is critical for the initiation of smooth-pursuit eye movements (SPEMs); yet, its specific role has remained elusive. In this study, we tested the hypothesis that vermal Purkinje cells (PCs) may be needed to fine-tune the kinematic description of SPEM initiation. Recording from identified PCs from the monkey OMV, we observed that SPEM-related PCs were characterized by a formidable diversity of response profiles with typically only modest reflection of eye movement kinematics. In contrast, the PC population discharge could be perfectly predicted based on a linear combination of eye acceleration, velocity, and position. This finding is in full accord with a role of the OMV in shaping eye movement kinematics. It, moreover, supports the notion that this shaping action is based on a population code, whose anatomic basis is the convergence of PCs on target neurons in the cerebellar nuclei.

A prosocial function of head-gaze aversion and head-cocking in common marmosets.

Gaze aversion is a behavior adopted by several mammalian and non-mammalian species in response to eye contact, and is usually interpreted as a reaction to a perceived threat. Unlike many other primate species, common marmosets (Callithrix jacchus) are thought to have a high tolerance for direct gaze, barely exhibiting gaze avoidance towards conspecifics and humans. Here we show that this does not hold for marmosets interacting with a familiar experimenter who suddenly establishes eye contact in a playful interaction (peekaboo). Video footage synchronously recorded from the perspective of the marmoset and the experimenter showed that the monkeys consistently alternated between eye contact and head-gaze aversion, and that these responses were often preceded by head-cocking. We hypothesize that this behavioral strategy helps marmosets to temporarily disengage from emotionally overwhelming social stimulation due to sight of another individual's face, in order to prepare for a new round of affiliative face-to-face interactions.

The absence of eye muscle fatigue indicates that the nervous system compensates for non-motor disturbances of oculomotor function.

The physical properties of our bodies are subject to change (due to fatigue, heavy equipment, injury or aging) as we move around in the surrounding environment. The traditional definition of motor adaptation dictates that a mechanism in our brain needs to compensate for such alterations by appropriately modifying neural motor commands, if the vitally important accuracy of executed movements is to be preserved. In this article we describe how a repetitive eye movement task brings about changes in eye saccade kinematics that compromise accurate motor performance in the absence of a proper compensatory response. Surgical lesions in animals and human patient studies have previously demonstrated that an intact cerebellum is necessary for the compensation to arise and prevent the occurrence of hypometric movements. Here we identified the dynamic properties of the eye plant by recording from abducens motoneurons responsible for the required movement and measured the muscle response to microstimulation of the abducens nucleus in rhesus monkeys. The ensuing results demonstrate that the muscular periphery remains intact during the fatiguing eye movement task, while internal sources of noise (drowsiness, attentional modulation, neuronal fatigue etc.) must be responsible for a diminished oculomotor performance. This finding leads to the important realization that while supervising the accuracy of our movements, the nervous system takes additionally into account and adapts to any disruptive processes within the brain itself, clearly unrelated to the dynamical behavior of muscles or the environment. The existence of this supplementary mechanism forces a reassessment of traditional views of cerebellum-dependent motor adaptation.

Cortical processing of head- and eye-gaze cues guiding joint social attention.

Previous fMRI experiments showed an involvement of the STS in the processing of eye-gaze direction in joint attention. Since head-gaze direction can also be used for the assessment of another person's attentional focus, we compared the mechanisms underlying the processing of head- and eye-gaze direction using a combined psychophysical and fMRI approach. Subjects actively followed the head- or eye-gaze direction of a person in a photograph towards one of seven possible targets by moving their eyes. We showed that the right posterior superior temporal sulcus (STS) as well as the right fusiform gyrus (FSG) were involved in both processing of head- as well as eye-gaze direction. Another finding was a bilateral deactivation of a distinct area in the middle STS (mSTS) as well as the left anterior STS (aSTS), that was stronger when subjects followed eye-gaze direction than when they followed head-gaze direction. We assume that this deactivation is based on an active suppression of information arising from the distracting other directional cue, i.e. head-gaze direction in the eye-gaze direction task and eye-gaze direction in the head-gaze direction task. These results further support the hypothesis that the human equivalent of the gaze sensitive area in monkeys lies in more anterior parts of the STS than previously thought.

Cerebellar-dependent motor learning is based on pruning a Purkinje cell population response.

The improvement of motor behavior, based on experience, is a form of learning that is critically dependent on the cerebellum. A well studied example of cerebellar motor learning is short-term saccadic adaptation (STSA). In STSA, information on saccadic errors is used to improve future saccades. The information optimizing saccade metrics is conveyed by Purkinje cells simple spikes (PC-SS) because they are the critical input to the premotor circuits for saccades. We recorded PC-SS of monkeys undergoing STSA to reveal the code used for improving behavior. We found that the discharge of individual PC-SS was unable to account for the behavioral changes. The PC-SS population burst (PB), however, exhibited changes that closely paralleled the qualitatively different changes of saccade kinematics associated with gain-increase and gain-decrease STSA, respectively. Gain-increase STSA, characterized by an increase in saccade duration, replicates the relationship between saccade duration and the end of the PB valid for unadapted saccades. In contrast, gain-decrease STSA, which sports normal saccade duration but reduced saccadic velocity, is characterized by a PB that ends well before the adapted saccade. This suggests that the duration of normal as well as gain-increased saccades is determined by appropriately setting the end of PB end. However, the duration of gain-decreased saccades is apparently not modified by the cerebellum because the PB signals ends too early to determine saccade end. In summary, STSA, and most probably cerebellar-dependent learning in general, is based on optimizing the shape of a PC-SS population response.

Shape-invariant encoding of dynamic primate facial expressions in human perception.

Dynamic facial expressions are crucial for communication in primates. Due to the difficulty to control shape and dynamics of facial expressions across species, it is unknown how species-specific facial expressions are perceptually encoded and interact with the representation of facial shape. While popular neural network models predict a joint encoding of facial shape and dynamics, the neuromuscular control of faces evolved more slowly than facial shape, suggesting a separate encoding. To investigate these alternative hypotheses, we developed photo-realistic human and monkey heads that were animated with motion capture data from monkeys and humans. Exact control of expression dynamics was accomplished by a Bayesian machine-learning technique. Consistent with our hypothesis, we found that human observers learned cross-species expressions very quickly, where face dynamics was represented largely independently of facial shape. This result supports the co-evolution of the visual processing and motor control of facial expressions, while it challenges appearance-based neural network theories of dynamic expression recognition.

The role of the monkey dorsal pontine nuclei in goal-directed eye and hand movements.

Prevailing concepts on the control of goal-directed hand movements (HM) have focused on a network of cortical areas whose early parieto-occipital stages are thought to extract and integrate information on target and hand location, involving subsequent stages in frontal cortex forming and executing movement plans. The substantial experimental results supporting this "cortical network" concept for hand movements notwithstanding, the concept clearly needs refinement to account for the surprisingly mild HM disturbances resulting from disconnecting the parieto-occipital from the frontal stages of the network. Clinical observations have suggested the cerebropontocerebellar projection as an alternative pathway for the sensory guidance of HM. As a first step in assessing its role, we explored the pontine nuclei (PN) of rhesus monkeys, trained to make goal-directed hand and eye movements guided by spatial memory. We were indeed able to delineate a distinct cluster of neurons in the rostrodorsal PN, activated by the preparation and the execution of hand reaches, close to but distinct from the region in which saccade-related neurons may be observed. The movement-related activity of HM-related neurons starts earlier than that of saccade-related neurons and both neuron types are usually effector specific, i.e., they respond only to the movement of the preferred effector. This is also the case when motor synergies involving both effectors are executed. Our findings support the notion of a distinct precerebellar, pontine visuomotor channel for hand reaches that is anatomically and functionally largely separated from the one serving eye movements.

Characteristics of responses of Golgi cells and mossy fibers to eye saccades and saccadic adaptation recorded from the posterior vermis of the cerebellum.

The anatomical organization of the granular layer of the cerebellum suggests an important function for Golgi cells (GC) in the pathway conveying mossy fiber (MF) afferents to Purkinje cells. Based on such anatomic observations, early proposals have attributed a role in "gain control" for GCs, a function disputed by recent investigations, which assert that GCs instead contribute to oscillatory mechanisms. However, conclusive physiological evidence based on studies of cerebellum-dependent behavior supporting/dismissing the gain control proposition has been lacking as of yet. We addressed the possible function of this interneuron by recording the activity of a large number of both MFs and GCs during saccadic eye movements from the same cortical area of the monkey cerebellum, namely the oculomotor vermis (OMV). Our cellular identification conformed to previously established criteria, mainly to juxtacellular labeling studies correlating physiological parameters with cell morphology. Response patterns of both MFs and GCs were highly heterogeneous. MF discharges correlated linearly with eye saccade metrics and timing, showing directional preference and precise direction tuning. In contrast, GC discharges did not correlate strongly with the metrics or direction of movement. Their discharge properties were also unaffected by motor learning during saccadic adaptation. The OMV therefore receives a barrage of information about eye movements from different oculomotor areas over the MF pathway, which is not reflected in GCs. The unspecificity of GCs has important implications for the intricacies of neuronal processing in the granular layer, clearly discrediting their involvement in gain control and instead suggesting a more secluded role for these interneurons.

Specific vermal complex spike responses build up during the course of smooth-pursuit adaptation, paralleling the decrease of performance error.

Contemporary theories of the cerebellum hold that the complex spike (CS) fired by cerebellar Purkinje cells (PCs) reports the error signal essential for motor adaptation, i.e., the CS serves as a teacher reducing the performance error. This hypothesis suggests a monotonic relationship between CS modulation and performance error: the modulation of CS responses should be maximal at adaptation onset and turn back to its pre-adaptation state when the error is nulled. An alternative viewpoint based on studies of saccades suggests that the modulation of the CS discharge builds up as performance error decreases, and maximum and stable CS modulation is found after adaptation has been completed (Catz et al. 2005). We wanted to know whether this pattern can be generalized to other forms of motor adaptation. We resorted to smooth-pursuit adaptation (SPA) as an example of cerebellar-dependent adaptation. SPA is induced by increasing or decreasing target velocity during pursuit initiation that leads to a gradual increase or decrease in eye velocity. We trained 2 rhesus monkeys and recorded CS from PC in vermal lobuli VI and VII during SPA. We find that SPA is accompanied by a pattern of CS firing, which at the onset of adaptation, i.e., when the error is large, is not modulated significantly. On the other hand, when initial eye velocity is stably increased or decreased by adaptation, the probability of CS occurrence during pursuit initiation decreases or increases, respectively. Overall, our results deviate from the predictions made by the classical error-coding concept.

A Naturalistic Dynamic Monkey Head Avatar Elicits Species-Typical Reactions and Overcomes the Uncanny Valley.

Research on social perception in monkeys may benefit from standardized, controllable, and ethologically valid renditions of conspecifics offered by monkey avatars. However, previous work has cautioned that monkeys, like humans, show an adverse reaction toward realistic synthetic stimuli, known as the "uncanny valley" effect. We developed an improved naturalistic rhesus monkey face avatar capable of producing facial expressions (fear grin, lip smack and threat), animated by motion capture data of real monkeys. For validation, we additionally created decreasingly naturalistic avatar variants. Eight rhesus macaques were tested on the various videos and avoided looking at less naturalistic avatar variants, but not at the most naturalistic or the most unnaturalistic avatar, indicating an uncanny valley effect for the less naturalistic avatar versions. The avoidance was deepened by motion and accompanied by physiological arousal. Only the most naturalistic avatar evoked facial expressions comparable to those toward the real monkey videos. Hence, our findings demonstrate that the uncanny valley reaction in monkeys can be overcome by a highly naturalistic avatar.

Neuronal substrates of gaze following in monkeys.

Human and non-human primates follow the gaze of their respective conspecific to identify objects of common interest. Whereas humans rely on eye-gaze for such purposes, monkeys preferentially use head-gaze information. Functional magnetic resonance imaging (fMRI) studies have delineated an area in the human superior temporal sulcus (STS), which is specifically activated when subjects actively follow the eye-gaze of others. Similarly, using fMRI, we have identified an analogous region in the monkey's middle STS responding to gaze following. Hence, although humans and monkeys might rely on different directional cues guiding their attention, they seem to deploy a similar and possibly homologous cortical area to follow the gaze of a conspecific. Our results support the idea that the eyes developed a new social function in human evolution, most likely to support cooperative mutual social interactions building on a phylogenetically old STS module for the processing of head cues.

Demonstration of an eye-movement-induced visual motion illusion (Filehne illusion) in Rhesus monkeys.

During pursuit eye movements, the world around us remains perceptually stable despite the retinal-image slip induced by the eye movement. It is commonly held that this perceptual invariance is achieved by subtracting an internal reference signal, reflecting the eye movement, from the retinal motion signal. However, if the reference signal is too small or too large, a false eye-movement-induced motion of the external world, the Filehne illusion (FI), will be perceived. A reference signal of inadequate size can be simulated experimentally by asking human subjects to pursue a target across backgrounds with externally added motion that are perceived as moving. In the present study we asked if non-human primates respond to such manipulation in a way comparable to humans. Using psychophysical methods, we demonstrate that Rhesus monkeys do indeed experience a percept of pursuit-induced background motion. In this study we show that an FI can be predictably induced in Rhesus monkeys. The monkey FI shows dependencies on the size and direction of background movement, which is very similar to the ones characterizing the human FI. This congruence suggests that the perception of self-induced visual motion is based on similar inferential mechanisms in non-human and human primates.