Implications of Lateral Cerebellum in Proactive Control of Saccades

Abstract

Although several lines of evidence establish the involvement of the medial and vestibular parts of the cerebellum in the adaptive control of eye movements, the role of the lateral hemisphere of the cerebellum in eye movements remains unclear. Ascending projections from the lateral cerebellum to the frontal and parietal association cortices via the thalamus are consistent with a role of these pathways in higher-order oculomotor control. In support of this, previous functional imaging studies and recent analyses in subjects with cerebellar lesions have indicated a role for the lateral cerebellum in volitional eye movements such as anti-saccades. To elucidate the underlying mechanisms, we recorded from single neurons in the dentate nucleus of the cerebellum in monkeys performing anti-saccade/pro-saccade tasks. We found that neurons in the posterior part of the dentate nucleus showed higher firing rates during the preparation of anti-saccades compared with pro-saccades. When the animals made erroneous saccades to the visual stimuli in the anti-saccade trials, the firing rate during the preparatory period decreased. Furthermore, local inactivation of the recording sites with muscimol moderately increased the proportion of error trials, while successful anti-saccades were more variable and often had shorter latency during inactivation. Thus, our results show that neuronal activity in the cerebellar dentate nucleus causally regulates anti-saccade performance. Neuronal signals from the lateral cerebellum to the frontal cortex might modulate the proactive control signals in the corticobasal ganglia circuitry that inhibit early reactive responses and possibly optimize the speed and accuracy of anti-saccades.

Significance statement: Although the lateral cerebellum is interconnected with the cortical eye fields via the thalamus and the pons, its role in eye movements remains unclear. We found that neurons in the caudal part of the lateral (dentate) nucleus of the cerebellum showed the increased firing rate during the preparation of anti-saccades. Inactivation of the recording sites modestly elevated the rate of erroneous saccades to the visual stimuli in the anti-saccade trials, while successful anti-saccades during inactivation tended to have a shorter latency. Our data indicate that neuronal signals in the lateral cerebellum may proactively regulate anti-saccade generation through the pathways to the frontal cortex, and may inhibit early reactive responses and regulate the accuracy of anti-saccades.

Keywords: anti-saccade; cerebellum; dentate nucleus; inactivation; primate; single neurons.

Figure 1.

Behavioral tasks and locations of task-related neurons. A, Trial type was indicated by the color of the FP. A white target spot appeared 16° eccentrically at the time of the FP offset. Animals were required to make a saccade toward (pro-saccade) or away from (anti-saccade) the target within 350 or 400 ms. B, Recording sites reconstructed from histological sections in monkey G. Drawings of horizontal sections are arranged from the most dorsal to ventral portions of the dentate nucleus. The electrode penetrations were perpendicular to the drawings. Size of symbols indicates the number of task-related neurons recorded from each site. Blue diamonds indicate inactivation sites.

Figure 2.

Neuronal activity in the dentate nucleus during anti-saccade (Anti)/pro-saccade (Pro)tasks. A, A representative neuron showing different firing rate during the tasks. Color of the FP differed between the tasks during the 800 ms period delimited by two vertical lines. The yellow symbol on each raster line indicates the time of saccade. B, Each data point compares the firing rate of individual neurons during anti-saccades with that during pro-saccades. Neuronal activity was measured for a 400 ms interval starting from 300 ms before the FP offset (black bars in A and C). To examine the activity during the instruction period, data for saccades in both directions were combined. Filled symbols indicate the data showing a significant difference (Wilcoxon rank sum test, p < 0.05). C, Time courses of the population activity during the instruction period. The shaded areas indicate ±SEM. D, Activities around the time of saccades were compared between anti-saccade trials and pro-saccade trials. The firing rate was measured for a 100 ms interval before saccades (black bar in E). Circles and triangles indicate ipsiversive (Ipsi) and contraversive (Contra) saccades, respectively. E, Time courses of the population activity aligned with saccade initiation. Solid and dashed traces indicate the data for ipsiversive and contraversive saccades, respectively. The shaded areas indicate ±SEM of the data for ipsiversive saccades. div, Division.

Figure 3.

Analysis of neuronal activity in error trials. A, Activity of a single dentate neuron during correct and erroneous anti-saccade trials. Black traces and rasters indicate correct trials, while red traces and rasters indicate error trials. Blue broken trace on the bottom panel indicates the data for correct pro-saccades (Pro). B, Each data point compares the firing rate of individual neurons during correct anti-saccades (Anti) trials with that during erroneous anti-saccade trials. Neuronal activity was measured for a 400 ms interval starting from 300 ms before the FP offset (black bars in A and C). Data for both saccade directions were combined. C, Time courses of the population activity for correct anti-saccade, erroneous anti-saccade, and correct pro-saccade trials. The shaded areas indicate ±SEM. D, Activities around the time of saccades were compared between correct and erroneous anti-saccade trials. The firing rate was measured for a 100 ms interval before saccades (black bar in E). E, Time courses of the population activity aligned on saccade initiation. The shaded areas indicate ±SEM. div, Division.

Figure 4.

Inactivation effects on the rate of error trials. A, Traces of eye position before and during inactivation of the left dentate nucleus. Data are aligned with the target onset. Red traces indicate error trials. The open triangles indicate the time of target relocation in the anti-saccade (Anti) task. Note that the animal redirected her eyes to the goal immediately following erroneous pro-saccades (Pro). B, Changes in error rate for all injection experiments. Filled symbols indicate the data showing a significant difference (χ² test, p < 0.01). Dashed lines indicate the means of the data of the previous inactivation experiments performed in the oculomotor thalamus (Kunimatsu and Tanaka, 2010). Ipsi, Ipsilateral; Contra, contralateral.

Figure 5.

Inactivation effects on saccade parameters. A, Comparison of reaction time (top) and accuracy (bottom) before and during inactivation. Left and right columns indicate contraversive (Contra) and ipsiversive (Ipsi) saccades, respectively. On each panel, red circles and blue crosses denote the data for anti-saccades (Anti) and pro-saccades (Pro), respectively. B, Correlation between the changes in reaction time and accuracy. Numbers on each panel indicate Pearson's correlation coefficient, and the asterisk denotes the statistically significant correlation (Contra, Anti). Critical p values for correlation coefficient were 0.03 (Contra, Anti), 0.69 (Contra, Pro), 0.31 (Ipsi, Anti), and 0.57 (Ipsi, Pro). Regression line is shown only for a significant correlation.

Figure 6.

A, Comparison of the time courses of the population activity for neurons in the dentate nucleus, oculomotor thalamus, and the globus pallidus externus (GPe). Data for anti-saccades/pro-saccades are shown separately in different columns. On each column, the top traces plot the population activity shown in Figure 2E. For neurons previously recorded from the ventrolateral, ventroanterior, and intralaminar nuclei of the thalamus (Kunimatsu and Tanaka, 2010), the data are separately plotted for neurons with or without the instruction period activity. For neurons in the GPe (Yoshida and Tanaka, 2016), the data are shown for those exhibiting the increased or decreased activity during saccades. For the cerebellum, solid and dashed traces indicate the data for ipsiversive and contraversive saccades, respectively. For the other brain regions, the data for contraversive saccades only are shown. B, A hypothetical diagram of neural mechanism for the generation of anti-saccades. BG, Basal ganglia; Cb, cerebellum; SC, superior colliculus.