The Role of the Subthalamic Nucleus in Inhibitory Control of Oculomotor Behavior in Parkinson's Disease

Abstract

Inhibiting inappropriate actions in a context is an important part of the human cognitive repertoire, and deficiencies in this ability are common in neurological and psychiatric disorders. An anti-saccade is a simple oculomotor task that tests this ability by requiring inhibition of saccades to peripheral targets (pro-saccade) and producing voluntary eye movements toward the mirror position (anti-saccades). Previous studies provide evidence for a possible contribution from the basal ganglia in anti-saccade behavior, but the precise role of different components is still unclear. Parkinson's disease patients with implanted deep brain stimulators (DBS) in subthalamic nucleus (STN) provide a unique opportunity to investigate the role of the STN in anti-saccade behavior. Previous attempts to show the effect of STN DBS on anti-saccades have produced conflicting observations. For example, the effect of STN DBS on anti-saccade error rate is not yet clear. Part of this inconsistency may be related to differences in dopaminergic states in different studies. Here, we tested Parkinson's disease patients on anti- and pro-saccade tasks ON and OFF STN DBS, in ON and OFF dopaminergic medication states. First, STN DBS increases anti-saccade error rate while patients are OFF dopamine replacement therapy. Second, dopamine replacement therapy and STN DBS interact: L-dopa reduces the effect of STN DBS on anti-saccade error rate. Third, STN DBS induces different effects on pro- and anti-saccades in different patients. These observations provide evidence for an important role for the STN in the circuitry underlying context-dependent modulation of visuomotor action selection.

Figure 1

Experiment paradigm and the eye movement task. Top: Each box shows one of the test conditions. Bottom: The schematic figure shows the pro-saccade (top row) and the anti-saccade (bottom row) tasks.

Figure 2

Anti-saccade error rate for different stimulation and L-dopa states. The small diamonds show the measured values for individual patients, and small horizontal lines show the median values. DBS increased the error rate during the Off L-dopa condition ($p<0.001$). Based on our analysis of variance (two-way ANOVA), DBS also increases the error rate while on L-dopa, but not significantly ($p=0.15$). L-dopa does not have any significant effect on the error rate On or Off DBS (off DBS $p=0.32$, on DBS $p=0.24$). All statistics are driven from a fitted mixed-effect generalized linear model (GLME), where the L-dopa and DBS conditions were used as the fixed-effects and the patient’s identity as the random-effect.

Figure 3

Anti-saccade and pro-saccade latencies for different stimulation and L-dopa states. The small diamonds show the measured values for individual patients, and small horizontal lines show the median values. (a) The effect of DBS and L-dopa on the pro-saccade latency. Based on our analysis of variance (two-way ANOVA), DBS decreases the pro-saccade latency in both L-dopa conditions ($p<0.001$). L-dopa increases pro-saccade latency, but it is marginally significance ($p=0.062$). (b) The effect of DBS and L-dopa on the correct anti-saccade latency. DBS decreases the correct anti-saccade latency in both L-dopa conditions ($p=0.011$). The effect of L-dopa on the correct anti-saccade latency is not statistically significant, but follows the same pattern as in the pro-saccade latency. (c) The effect of DBS and L-dopa on the erroneous pro-saccade latency in the anti-saccade task. All statistics are driven from a fitted mixed-effect generalized linear model (GLME), where the L-dopa and DBS conditions were used as the fixed-effects and the patients’ identity as the random-effect.

Figure 4

DBS (right) and L-dopa (left) effects on pro-saccade and anti-saccade latencies. Small diamonds show the estimated effects for individual patients ($fixedeffect+randomeffect$ from the GLME models), and the small horizontal lines show the average effect across subjects ($fixedeffect$ from the GLME model). Positive and negative values show decrease and increase in the saccade latencies, respectively. The estimated effect sizes show that DBS decreases both pro-saccade and anti-saccade latencies. The effect is larger on pro-saccades than anti-saccades. L-dopa causes an increase in pro-saccade latency, but has a close to zero effect on the anti-saccade latency.

Figure 5

The effect of DBS on pro- vs. anti-saccade latencies. Blue circles show the change in latencies for pro- and anti-saccade in each individual participant. The dark line is the fitter linear model to the data. (Top-left) There is a strong positive correlation between the change in the pro-saccade latencies in the both pro-saccade and the anti-saccade tasks ($r=0.6$, $p<0.001$). (Top-right) The changes in the pro-saccade latency and the anti-saccade latency caused by DBS are not correlated ($r=0.07$, $p=0.12$). (Bottom) A schematic of the oculomotor network that involves the basal ganglia and relevant projections. Excitatory (green) and inhibitory (red) projections are shown. SNr and GPi, the two output nuclei of the basal ganglia, project to SC and thalamus (Th). STN DBS can influence saccades through either the GPi-Th-Frontal Cortex pathway, or the SNr-SC pathway. Lower brainstem, cerebellar and extra-frontal cortical oculomotor pathways are not illustrated.