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

Abstract

The ability to inhibit an inappropriate action 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 experimental task within the oculomotor repertoire that can be used to test this ability. The task involves an inhibition of a saccade to the peripheral target (pro-saccade) and generation of a voluntary eye movement toward the mirror position (anti-saccade). Previous studies provide evidence for a possible contribution from the basal ganglia in anti-saccade behavior. However, the precise role of different components in generation of anti-saccade behavior is still uncertain. Parkinson's disease patients with implanted deep brain stimulation (DBS) in subthalamic nucleus (STN) provide us with a unique opportunity to investigate the role of 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 and ON and OFF dopaminergic medication. We made three main observations. First, STN DBS increases the anti-saccade error rate while patients are OFF dopamine replacement therapy. Second, there is an interaction between dopamine replacement therapy and STN DBS. More specifically, L-dopa reduces the effect of STN DBS on anti-saccade error rate. Third, STN DBS can induce 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.

Deep brain stimulation and eye movements

“…Subthalamic nucleus deep brain stimulation (STN DBS) is the most common location for treating symptoms in PD patients. It decreases tremor, helps with drug‐induced dyskinesias and motor fluctuations, and might modulate aspects of executive cognition or emotion (Bakhtiari, Altinkaya, Pack, & Sadikot, 2020; Hartmann, Fliegen, Fliegen, Groiss, Wojtecki, & Schnitzler, 2019). STN sends stimulatory glutamatergic projection to SNr, which when active, inhibits SC (Figure 2).…”

“…Such interactions between L‐DOPA and DBS may be a consequence of L‐DOPA altering the balance between the direct and indirect pathways of the BG circuit (Lu et al, 2019); as memory‐guided saccades depend predominantly on the direct pathway, its facilitation might contribute to an L‐DOPA positive effect on voluntary saccades. On the other hand, STN DBS is believed to directly modulate the excessive SC inhibition, due to SNr (Bakhtiari et al, 2020; Dec‐Cwiek et al, 2017) influencing the common saccadic pathway and improving also reflexive saccade latency.…”

“…It has in fact been suggested that considerable part of oculomotor PD deficits are caused by non‐dopaminergic dysfunction, especially impaired top‐down frontostriatal saccadic control due to frontal lobe pathology in PD (Pinkhardt et al, 2012), explaining also why saccadic latency correlates with cognitive status in PD. Regardless, studies have shown that L‐DOPA might increase latency for reflexive prosaccades and at the same time reduce error rate for voluntary antisaccades (Bakhtiari et al, 2020; Hood et al, 2007; Lu, Buchanan, Buchanan, Kennard, FitzGerald, & Antoniades, 2019). In the case of L‐DOPA ON state, dopaminergic therapy seems to interfere with the effects of DBS, modestly prolonging saccadic latency, or at least diminishing any DBS‐related reduction in latency of reflexive saccades.…”

“…In the case of L‐DOPA ON state, dopaminergic therapy seems to interfere with the effects of DBS, modestly prolonging saccadic latency, or at least diminishing any DBS‐related reduction in latency of reflexive saccades. Similarly, L‐DOPA ON state has been shown to decrease the antisaccadic error rate, that can be increased by STN DBS (Bakhtiari et al, 2020).…”

Boost converter design for ferrite core compatible with strong magnetic fields

“…Neurostimulators are active implantable medical devices that deliver electrical pulses to different nerves to modulate corresponding neurological functions [1][2][3]. They include deep brain stimulators that treat Parkinson's disease by stimulating the subthalamic nucleus of patients [4,5]. In addition, vagus nerve stimulators have had positive therapeutic effects on intractable epilepsy [6,7].…”