Modulation of saccades in humans by electrical stimulation of the posterior subthalamic area

Abstract

OBJECTIVEPosterior subthalamic area (PSA) deep brain stimulation (DBS) targeting the zona incerta (ZI) is an emerging treatment for tremor syndromes, including Parkinson’s disease (PD) and essential tremor (ET). Evidence from animal studies has indicated that the ZI may play a role in saccadic eye movements via pathways between the ZI and superior colliculus (incerto-collicular pathways). PSA DBS permitted testing this hypothesis in humans.METHODSSixteen patients (12 with PD and 4 with ET) underwent DBS using the MRI-directed implantable guide tube technique. Active electrode positions were confirmed at the caudal ZI. Eye movements were tested using direct current electrooculography (EOG) in the medicated state pre- and postoperatively on a horizontal predictive task subtending 30°. Postoperative assessments consisted of stimulation-off, constituting a microlesion (ML) condition, and high-frequency stimulation (HFS; frequency = 130 Hz) up to 3 V.RESULTSWith PSA HFS, the first saccade amplitude was significantly reduced by 10.4% (95% CI 8.68%–12.2%) and 12.6% (95% CI 10.0%–15.9%) in the PD and ET groups, respectively. With HFS, peak velocity was reduced by 14.7% (95% CI 11.7%–17.6%) in the PD group and 27.7% (95% CI 23.7%–31.7%) in the ET group. HFS led to PD patients performing 21% (95% CI 16%–26%) and ET patients 31% (95% CI 19%–38%) more saccadic steps to reach the target.CONCLUSIONSPSA DBS in patients with PD and ET leads to hypometric, slowed saccades with an increase in the number of steps taken to reach the target. These effects contrast with the saccadometric findings observed with subthalamic nucleus DBS. Given the location of the active contacts, incerto-collicular pathways are likely responsible. Whether the acute finding of saccadic impairment persists with chronic PSA stimulation is unknown.

Deep brain stimulation and eye movements

“…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).…”

“…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).…”

“…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.…”

“…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.…”

“…latency) are improved only for visually guided saccades, and other parameters (gain of first saccade) only for voluntary saccades (Antoniades, Carpenter, et al, 2012; Fawcett et al, 2010; Fischer et al, 2016; Pinkhardt et al, 2012; Rivaud‐Pechoux et al, 2000; Temel, Visser‐Vandewalle, et al, 2009; Tokushige et al, 2018). There are also studies where DBS fails to produce any effect at all (Schmalbach et al, 2014; Tokushige et al, 2018), and it was even reported to worsen saccadic performance in a study with 12 PD patients and four ET patients (Bangash et al, 2019). Because L‐DOPA seems to have an opposite effect on saccadic eye movements as DBS STN (it improves voluntary saccades, but prolongs latency of visually guided saccades—for more details see the section below, and Table 1) (Dec‐Cwiek et al, 2017), the variability of reported outcomes may relate to differing methodologies (ON or OFF medications) employed.…”