Comparison of adaptation characteristics between visually and memory-guided saccades.

Saccade adaptation plays a crucial role in maintaining saccade accuracy. The behavioral characteristics and neural mechanisms of saccade adaptation for an externally cued movement, such as visually guided saccades (VGS), are well studied in nonhuman primates. In contrast, little is known about the saccade adaptation of an internally driven movement, such as memory-guided saccades (MGS), which are guided by visuospatial working memory. As the oculomotor plant changes because of growth, aging, or skeletomuscular problems, both types of saccades need to be adapted. Do both saccade types engage a common adaptation mechanism? In this study, we compared the characteristics of amplitude decrease adaptation in MGS with VGS in nonhuman primates. We found that the adaptation speed was faster for MGS than for VGS. Saccade duration changed during MGS adaptation, whereas saccade peak velocity changed during VGS adaptation. We also compared the adaptation field, that is, the gain change for saccade amplitudes other than the adapted. The gain change for MGS declines on both smaller and larger sides of adapted amplitude, more rapidly for larger than smaller amplitudes, whereas the decline in VGS was reversed. Thus, the differences between VGS and MGS adaptation characteristics support the previously suggested hypothesis that the adaptation mechanisms of VGS and MGS are distinct. Furthermore, the result suggests that the MGS adaptation site is a brain structure that influences saccade duration, whereas the VGS adaptation site influences saccade peak velocity. These results should be beneficial for future neurophysiological experiments.NEW & NOTEWORTHY Plasticity helps to overcome persistent motor errors. Such motor plasticity or adaptation can be investigated with saccades. Thus far our knowledge is primarily about visually guided saccades, an externally cued movement, which we can make only when the object is visible at the time of saccade. However, as the world is complex, we can make saccades even when the object is not visible. Here, we investigate the adaptation of an internally driven movement: the memory-guided saccade.

P-sort: an open-source software for cerebellar neurophysiology.

Analysis of electrophysiological data from Purkinje cells (P-cells) of the cerebellum presents unique challenges to spike sorting. Complex spikes have waveforms that vary significantly from one event to the next, raising the problem of misidentification. Even when complex spikes are detected correctly, the simple spikes may belong to a different P-cell, raising the danger of misattribution. To address these identification and attribution problems, we wrote an open-source, semiautomated software called P-sort, and then tested it by analyzing data from P-cells recorded in three species: marmosets, macaques, and mice. Like other sorting software, P-sort relies on nonlinear dimensionality reduction to cluster spikes. However, it also uses the statistical relationship between simple and complex spikes to merge disparate clusters and split a single cluster. In comparison with expert manual curation, occasionally P-sort identified significantly more complex spikes, as well as prevented misattribution of clusters. Three existing automatic sorters performed less well, particularly for identification of complex spikes. To improve the development of analysis tools for the cerebellum, we provide labeled data for 313 recording sessions, as well as statistical characteristics of waveforms and firing patterns of P-cells in three species.NEW & NOTEWORTHY Algorithms that perform spike sorting depend on waveforms to cluster spikes. However, a cerebellar Purkinje-cell produces two types of spikes; simple and complex spikes. A complex spike coincides with the suppression of generating simple spikes. Here, we recorded neurophysiological data from three species and developed a spike analysis software named P-sort that relies on this statistical property to improve both the detection and the attribution of simple and complex spikes in the cerebellum.

Encoding of action by the Purkinje cells of the cerebellum.

Execution of accurate eye movements depends critically on the cerebellum, suggesting that the major output neurons of the cerebellum, Purkinje cells, may predict motion of the eye. However, this encoding of action for rapid eye movements (saccades) has remained unclear: Purkinje cells show little consistent modulation with respect to saccade amplitude or direction, and critically, their discharge lasts longer than the duration of a saccade. Here we analysed Purkinje-cell discharge in the oculomotor vermis of behaving rhesus monkeys (Macaca mulatta) and found neurons that increased or decreased their activity during saccades. We estimated the combined effect of these two populations via their projections to the caudal fastigial nucleus, and uncovered a simple-spike population response that precisely predicted the real-time motion of the eye. When we organized the Purkinje cells according to each cell's complex-spike directional tuning, the simple-spike population response predicted both the real-time speed and direction of saccade multiplicatively via a gain field. This suggests that the cerebellum predicts the real-time motion of the eye during saccades via the combined inputs of Purkinje cells onto individual nucleus neurons. A gain-field encoding of simple spikes emerges if the Purkinje cells that project onto a nucleus neuron are not selected at random but share a common complex-spike property.

Elimination of the error signal in the superior colliculus impairs saccade motor learning.

When movements become dysmetric, the resultant motor error induces a plastic change in the cerebellum to correct the movement, i.e., motor adaptation. Current evidence suggests that the error signal to the cerebellum is delivered by complex spikes originating in the inferior olive (IO). To prove a causal link between the IO error signal and motor adaptation, several studies blocked the IO, which, unfortunately, affected not only the adaptation but also the movement itself. We avoided this confound by inactivating the source of an error signal to the IO. Several studies implicate the superior colliculus (SC) as the source of the error signal to the IO for saccade adaptation. When we inactivated the SC, the metrics of the saccade to be adapted were unchanged, but saccade adaptation was impaired. Thus, an intact rostral SC is necessary for saccade adaptation. Our data provide experimental evidence for the cerebellar learning theory that requires an error signal to drive motor adaptation.

How cerebellar motor learning keeps saccades accurate.

The neuronal substrate underlying the learning of a sophisticated task has been difficult to study. However, the advent of a behavioral paradigm that deceives the saccadic system into thinking it is making an error has allowed the mechanisms of the adaptation that corrects this error to be revealed in a primate. The neural elements that fashion the command signal for the generation of accurate saccades involve subcortical structures in the brain stem and cerebellum. In this review we show that sites in both those structures also are involved with the gradual adaptation of saccade size, a form of motor learning. Pharmacological manipulation of the oculomotor vermis (lobules VIc and VII) impairs mechanisms that either increase or decrease saccade size during adaptation. The net saccade-related simple spike (SS) activity of its Purkinje cells is correlated with the changes in saccade characteristics that occur during adaptation. These changes in SS activity are driven by an error signal delivered over climbing fibers, which create complex spikes whose probability of occurrence reflects the motor error between the actual and desired saccade size. These climbing fibers originate in the part of the inferior olive that receives projections from the superior colliculus (SC). Disabling the SC prevents adaptation and stimulation of the SC just after a normal saccade produces a surrogate error signal that drives adaptation without an actual visual error. Therefore, the SC provides not only the initial command that generates a saccade, as shown by others, but also the error signal that ensures that saccades remain accurate.

Adaptation and adaptation transfer characteristics of five different saccade types in the monkey.

Shifts in the direction of gaze are accomplished by different kinds of saccades, which are elicited under different circumstances. Saccade types include targeting saccades to simple jumping targets, delayed saccades to visible targets after a waiting period, memory-guided (MG) saccades to remembered target locations, scanning saccades to stationary target arrays, and express saccades after very short latencies. Studies of human cases and neurophysiological experiments in monkeys suggest that separate pathways, which converge on a common locus that provides the motor command, generate these different types of saccade. When behavioral manipulations in humans cause targeting saccades to have persistent dysmetrias as might occur naturally from growth, aging, and injury, they gradually adapt to reduce the dysmetria. Although results differ slightly between laboratories, this adaptation generalizes or transfers to all the other saccade types mentioned above. Also, when one of the other types of saccade undergoes adaptation, it often transfers to another saccade type. Similar adaptation and transfer experiments, which allow inferences to be drawn about the site(s) of adaptation for different saccade types, have yet to be done in monkeys. Here we show that simian targeting and MG saccades adapt more than express, scanning, and delayed saccades. Adaptation of targeting saccades transfers to all the other saccade types. However, the adaptation of MG saccades transfers only to delayed saccades. These data suggest that adaptation of simian targeting saccades occurs on the pathway common to all saccade types. In contrast, only the delayed saccade command passes through the adaptation site of the MG saccade.

Cerebellar fastigial nucleus influence on ipsilateral abducens activity during saccades.

To characterize the cerebellar influence on neurons in the abducens (ABD) nucleus, we recorded ABD neurons before and after we inactivated the caudal part of the ipsilateral cerebellar fastigial nucleus (cFN) with muscimol injection. cFN activity influences the horizontal component of saccades. cFN inactivation increased the activity of most ipsilateral ABD neurons (19/22 in 2 monkeys) during ipsiversive (hypermetric) saccades, primarily by increasing burst duration. During contraversive (hypometric) saccades, the off-direction pause of most (10/15) ABD neurons was shorter than normal because of the early resumption of ABD activity. Early ABD firing caused the early contraction of antagonist muscles that reduced eye rotation and made contraversive saccades hypometric. Thus the cerebellum controls ipsilateral ABD activity by truncating on-direction bursts during ipsiversive saccades and extending off-direction pauses during contraversive saccades. We conclude that cFN output keeps saccades accurate by controlling when ABD on-direction bursts and off-direction pauses end.

The superior colliculus projection upon the macaque inferior olive.

Saccade accommodation is a productive model for exploring the role of the cerebellum in behavioral plasticity. In this model, the target is moved during the saccade, gradually inducing a change in the saccade vector as the animal adapts. The climbing fiber pathway from the inferior olive provides a visual error signal generated by the superior colliculus that is believed to be crucial for cerebellar adaptation. However, the primate tecto-olivary pathway has only been explored using large injections of the central portion of the superior colliculus. To provide a more detailed picture, we have made injections of anterograde tracers into various regions of the macaque superior colliculus. As shown previously, large central injections primarily label a dense terminal field within the C subdivision at caudal end of the contralateral medial inferior olive. Several, previously unobserved, sites of sparse terminal labeling were noted: bilaterally in the dorsal cap of Kooy and ipsilaterally in the C subdivision of the medial inferior olive. Small, physiologically directed, injections into the rostral, small saccade portion of the superior colliculus produced terminal fields in the same regions of the medial inferior olive, but with decreased density. Small injections of the caudal superior colliculus, where large amplitude gaze changes are encoded, again labeled a terminal field located in the same areas. The lack of a topographic pattern within the main tecto-olivary projection suggests that either the precise vector of the visual error is not transmitted to the vermis, or that encoding of this error is via non-topographic means.

Cognition and saccadic eye movement performance are impaired in chronic rhinosinusitis.

BACKGROUND: Patients with chronic rhinosinusitis (CRS) can experience cognitive dysfunction. The literature on this topic mostly reflects patient-reported measurements. Our goal was to assess cognitive function in patients with CRS using objective measures, including saccadic eye movements-a behavioral response reflecting cognitive and sensory information integration that is often compromised in conditions with impaired cognition. METHODS: Participants (N = 24 with CRS, N = 23 non-CRS healthy controls) enrolled from rhinology clinic underwent sinonasal evaluation, quality of life assessment (Sino-nasal Outcome Test 22 [SNOT-22]), and cognitive assessment with the Neuro-QOL Cognitive Function-Short Form, the Montreal Cognitive Assessment (MoCA), and recording of eye movements using video-oculography. RESULTS: Participants with CRS were more likely to report cognitive dysfunction (Neuro-QOL; 45.8% vs. 8.7%; p = 0.005) and demonstrate mild or greater cognitive impairment (MoCA; 41.7% vs. 8.7%; p = 0.005) than controls. Additionally, participants with CRS performed worse on the MoCA overall and within the executive functioning and memory domains (all p < 0.05) and on the anti-saccade (p = 0.014) and delay saccade (p = 0.044) eye movement tasks. Poorer performance on the MoCA (r = -0.422; p = 0.003) and the anti-saccade (r = -0.347; p = 0.017) and delay saccade (r = -0.419; p = 0.004) eye movement tasks correlated with worse CRS severity according to SNOT-22 scores. CONCLUSION: This study is the first to utilize objective eye movement assessments in addition to researcher-administered cognitive testing in patients with CRS. These patients demonstrated a high prevalence of cognitive dysfunction, most notably within executive functioning and memory domains, with the degree of dysfunction correlating with the severity of CRS.

Activity of the Substantia Nigra Pars Reticulata during Saccade Adaptation.

When movements become inaccurate, the resultant error induces motor adaptation to improve accuracy. This error-based motor learning is regarded as a cerebellar function. However, the influence of the other brain areas on adaptation is poorly understood. During saccade adaptation, a type of error-based motor learning, the superior colliculus (SC) sends a postsaccadic error signal to the cerebellum to drive adaptation. Since the SC is directly inhibited by the substantia nigra pars reticulata (SNr), we hypothesized that the SNr might influence saccade adaptation by affecting the SC error signal. In fact, previous studies indicated that the SNr encodes motivation and motivation influences saccade adaptation. In this study, we first established that the SNr projects to the rostral SC, where small error signals are generated, in nonhuman primates. Then, we examined SNr activity while the animal underwent adaptation. SNr neurons paused their activity in association with the error. This pause was shallower and delayed compared with those of no-error trial saccades. The pause at the end of the adaptation was shallower and delayed compared with that at the beginning of the adaptation. The change in the intertrial interval, an indicator of motivation, and adaptation speed had a positive correlation with the changes in the error-related pause. These results suggest that (1) the SNr exhibits a unique activity pattern during the error interval; (2) SNr activity increases during adaptation, consistent with the decrease in SC activity; and (3) motivational decay during the adaptation session might increase SNr activity and influence the adaptation speed.