Cerebellar output encodes a corrective saccadic command (Commentary on Sun et al.)

The integrity of the cerebellum is critical for accurate eye movements. Disruption of neurons in either the cerebellar oculomotor vermis or its projections to the most medial output nucleus of the cerebellum, the caudal fastigial nucleus (cFN), results in significant saccadic dysmetria (Ritchie, 1976; Ohtsuka et al., 1994; Goffart et al., 2004; Buzunov et al., 2013). The relationship between cFN neuron firing rates and saccade kinematic parameters is quite variable across neurons (Hepp et al., 1982; Fuchs et al., 1993), suggesting that a direct encoding of saccade parameters may not occur in the responses of individual neurons of cFN. However, previous studies have generally agreed that saccaderelated cFN neurons tend to fire earlier for horizontal saccades made in the contraversive vs. ipsiversive directions (Ohtsuka & Noda, 1991; Fuchs et al., 1993; Helmchen & B€uttner, 1995; Kleine et al., 2003). Taken together, these results have led to the hypothesis that saccade properties are related to the timing of responses in cFN rather than response magnitude. Under this hypothesis, neurons should fire early for contraversive saccades, helping to accelerate the eye, whereas the delayed firing of ipsiversive neurons serves to decelerate and stop the eye at saccade termination. However, new data reported by Sun et al. (2016) call this view into question. Sun and colleagues recorded single-unit cFN neuron activity while primates made saccades of various magnitudes. These saccades included very small saccades, made during periods of fixation (microsaccades), as well as larger magnitude goal-directed saccades to peripheral targets. Their results suggest that cFN neuron responses exist on a continuum between these two types of saccades. That is, microand macrosaccades likely share common neural mechanisms of generation. Therefore, the responses of cFN neurons can be interpreted similarly across a large range of saccadic amplitudes (e.g. 0.5–15°). The duration of a typical saccade is on the order of 60 ms. Taking advantage of the temporally short nature of saccades, Sun et al. combined the responses of individual cFN neurons recorded across different sessions to yield an estimate of the firing of a population of simultaneously recorded neurons. This population response represents an estimate of the combined response of all saccade-related cFN neurons during a saccade. Strikingly, the timing of the population response did not occur earlier for contraversive compared to ipsiversive saccades, as would be anticipated by previous single-unit studies. Rather, both directions of saccades resulted in a population response that preceded the start of the saccade, and began at approximately the same time. How can these two deep nuclei be involved in saccade acceleration and deceleration when the timing of the responses to contraversive and ipsiversive saccades are not different? We recently suggested that populations of Purkinje cells (P-cells) in the oculomotor vermis (OMV) of the cerebellum encode the velocity and direction of an impending eye movement as a gain-field (Herzfeld et al., 2015). In this encoding, the population response of P-cells in OMV increases linearly with increasing eye velocity, whereas the direction is encoded as a cosine in which the population response is smallest for the direction of error that produces the highest probability of complex spikes (called CS-on), and highest for the direction of error that produces the lowest probability of complex spikes (CS-off). Given that inferior olive neurons project to the contralateral P-cells, P-cell simple spike encoding has the highest gain for contraversive saccades, and lowest gain for ipsiversive saccades. These P-cells inhibit neurons in cFN. Data from Sun et al. are consistent with this P-cell encoding, demonstrating that the cFN population response is larger for ipsiversive saccades than contraversive, a property which is not reliably found in the responses of individual cells. Combining this new experimental evidence with previous studies, it seems likely that the encoding of saccade kinematic parameters in cFN is not temporal in nature but rather results from differences in the magnitude of the overall cFN response. How can we interpret the results of previous studies in this framework? Goffart et al. (2004) have previously suggested that cFN inactivation and lesion studies could be understood by interpreting experimental results in the context of the bilaterality of cFN. Under this encoding scheme, cFN activity does not strictly encode acceleration and deceleration, but rather the two nuclei act as antagonists, in which one cFN can be thought of as ‘pushing’ the eye while the other cFN ‘pulls. ’ In this framework, equal activity in the two nuclei does not result in horizontal movement of the eye – cerebellar-dependent movement results only when the magnitude of the responses in the two nuclei are different. In this way, the output of the cerebellum is defined by the difference in the activities of the two cFNs, providing a ‘correction’ on top of the current movement (Fuchs et al., 1993). The population-level analysis presented by Sun et al. further clarifies this hypothesis. During a saccade, both sides of OMV are simultaneously active with a higher gain on the contralateral side (Herzfeld et al., 2015). This, in turn, results in the opposite scenario for the fastigial nuclei: higher firing rates for the ipsilateral vs. contralateral sides, without any differences in the timing of the response. Projections from cFN synapse throughout the brainstem saccadic circuitry, particularly on inhibitory and excitatory burst neurons, eventually acting on the motor