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

Abstract

, christopher c. pack & Abbas f. Sadikot * 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 antisaccade 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. Neuromodulation or Deep Brain Stimulation (DBS) of several subcortical areas significantly improves motor function in Parkinson's disease (PD) 1,2. Stimulation of the subthalamic nucleus (STN) improves tremor, drug-induced dyskinesias and motor fluctuations, and may also modulate aspects of executive cognition or emotion 3-6. However, unlike its motor outcome, the effect of subthalamic DBS on higher order executive functions remains uncertain. An important component of executive function is inhibitory control: the ability to suppress an impulsive response to external events due to an inappropriate context 7. Dysfunction of inhibitory control is involved in several psychiatric conditions, such as mood disorders, disorders of thought, and addiction 8,9. In PD, a deficiency of inhibitory control has been reported in different experimental tasks, such as the stop signal task 10 , and the Stroop task 11 , and impulse control may be worsened by therapies in some patients 12,13. Eye movements can be measured precisely and objectively (with 1 ms temporal resolution and approximately 0.5 degree spatial resolution) by using state-of-the-art eye-tracking technologies. This advance has made eye movements a popular readout behavior for probing different aspects of cognition with potential applications in clinical assessments 14. One well-...

Reverse Visually Guided Reaching in Patients with Parkinson’s Disease

“…In patients with PD, increased impulsivity is related to impaired motor and behavioral inhibitory control [ 28 ] and may worsen following STN-DBS in spite of motor benefit [ 54 , 77 , 78 ]. The detrimental effects of STN-DBS on executive cognitive function in patients with PD have been shown using a variety of tasks such as the go/no go paradigm [ 79 – 81 ], Stroop task [ 45 , 54 , 82 ], and antisaccade task [ 48 – 50 , 83 ]. It has been hypothesized that these effects are related to DBS of the ventral STN leading to impairments in automating responses in tasks with increased cognitive loads [ 45 , 80 , 81 ].…”

“…It has been hypothesized that these effects are related to DBS of the ventral STN leading to impairments in automating responses in tasks with increased cognitive loads [ 45 , 80 , 81 ]. Assessment of the effects of STN-DBS on oculomotor control in PD using the antisaccade task has also shown improved motor performance coupled with impaired cognitive control with stimulation [ 48 – 50 , 83 ]. Specifically, bilateral stimulation of the STN produced lower saccade latencies (RTs), increased fixation during the preparatory period, increased amplitudes, and increased error rates in the antisaccade task [ 48 – 50 , 83 ].…”

“…Assessment of the effects of STN-DBS on oculomotor control in PD using the antisaccade task has also shown improved motor performance coupled with impaired cognitive control with stimulation [ 48 – 50 , 83 ]. Specifically, bilateral stimulation of the STN produced lower saccade latencies (RTs), increased fixation during the preparatory period, increased amplitudes, and increased error rates in the antisaccade task [ 48 – 50 , 83 ]. Goelz et al also reported an association between the number of saccades that were made during the fixation/preparatory period and the onset of errors [ 83 ].…”

“…STN-DBS causes delays in the preparation phase of the compensatory steps in a posture perturbation task [ 47 ]. Interestingly, bilateral STN-DBS may increase the antisaccade error rate [ 48 ] in an amplitude-dependent manner [ 49 ], indicating that complex aspects of oculomotor control can be adversely affected [ 50 ]. However, a large study did not report an adverse effect of STN-DBS with an antisaccade task [ 51 ].…”

“…Common habitual responses are saccades and reaching movements. In the former, errors in the inhibition of habitual pro-saccades during antisaccade trials in patients with PD have been shown to be a useful marker of generalized measures of cognitive control of complex motor behaviors involving both inhibitory and task-switching abilities (when interlaced with pro-saccades) [ 55 , 56 ] and may be adversely affected by DBS [ 48 , 49 , 57 ] or dopamine overdosing in patients with earlier disease onset and milder motor symptoms [ 58 ]. In patients with PD, the assessment of limb movement is clinically more relevant than eye movements.…”