Benefits of subthalamic nucleus deep brain stimulation on visually-guided saccades depend on stimulation side and classic paradigm in Parkinson's disease.

OBJECTIVE: We aimed to gain further insight into previously reported beneficial effects of subthalamic nucleus deep brain stimulation (STN-DBS) on visually-guided saccades by examining the effects of unilateral compared to bilateral stimulation, paradigm, and target eccentricity on saccades in individuals with Parkinson's disease (PD). METHODS: Eleven participants with PD and STN-DBS completed the visually-guided saccade paradigms with OFF, RIGHT, LEFT, and BOTH stimulation. Rightward saccade performance was evaluated for three paradigms and two target eccentricities. RESULTS: First, we found that BOTH and LEFT increased gain, peak velocity, and duration compared to OFF stimulation. Second, we found that BOTH and LEFT stimulation decreased latency during the gap and step paradigms but had no effect on latency during the overlap paradigm. Third, we found that RIGHT was not different compared to OFF at benefiting rightward saccade performance. CONCLUSIONS: Left unilateral and bilateral stimulation both improve the motor outcomes of rightward visually-guided saccades. Additionally, both improve latency, a cognitive-motor outcome, but only in paradigms when attention does not require disengagement from a present stimulus. SIGNIFICANCE: STN-DBS primarily benefits motor and cognitive-motor aspects of visually-guided saccades related to reflexive attentional shifting, with the latter only evident when the fixation-related attentional system is not engaged.

Medication only improves limb movements while deep brain stimulation improves eye and limb movements during visually-guided reaching in Parkinson's disease.

Background: Antiparkinson medication and subthalamic nucleus deep brain stimulation (STN-DBS), two common treatments of Parkinson's disease (PD), effectively improve skeletomotor movements. However, evidence suggests that these treatments may have differential effects on eye and limb movements, although both movement types are controlled through the parallel basal ganglia loops. Objective: Using a task that requires both eye and upper limb movements, we aimed to determine the effects of medication and STN-DBS on eye and upper limb movement performance. Methods: Participants performed a visually-guided reaching task. We collected eye and upper limb movement data from participants with PD who were tested both OFF and ON medication (n = 34) or both OFF and ON bilateral STN-DBS while OFF medication (n = 11). We also collected data from older adult healthy controls (n = 14). Results: We found that medication increased saccade latency, while having no effect on reach reaction time (RT). Medication significantly decreased saccade peak velocity, while increasing reach peak velocity. We also found that bilateral STN-DBS significantly decreased saccade latency while having no effect on reach RT, and increased saccade and reach peak velocity. Finally, we found that there was a positive relationship between saccade latency and reach RT, which was unaffected by either treatment. Conclusion: These findings show that medication worsens saccade performance and benefits reaching performance, while STN-DBS benefits both saccade and reaching performance. We explore what the differential beneficial and detrimental effects on eye and limb movements suggest about the potential physiological changes occurring due to treatment.

The Effects of Subthalamic Nucleus Deep Brain Stimulation and Retention Delay on Memory-Guided Reaching Performance in People with Parkinson's Disease.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) improves intensive aspects of movement (velocity) in people with Parkinson's disease (PD) but impairs the more cognitively demanding coordinative aspects of movement (error). We extended these findings by evaluating STN-DBS induced changes in intensive and coordinative aspects of movement during a memory-guided reaching task with varying retention delays. OBJECTIVE: We evaluated the effect of STN-DBS on motor control during a memory-guided reaching task with short and long retention delays in participants with PD and compared performance to healthy controls (HC). METHODS: Eleven participants with PD completed the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and performed a memory-guided reaching task under four different STN-DBS conditions (DBS-OFF, DBS-RIGHT, DBS-LEFT, and DBS-BOTH) and two retention delays (0.5 s and 5 s). An additional 13 HC completed the memory-guided reaching task. RESULTS: Unilateral and bilateral STN-DBS improved the MDS-UPDRS III scores. In the memory-guided reaching task, both unilateral and bilateral STN-DBS increased the intensive aspects of movement (amplitude and velocity) in the direction toward HC but impaired coordinative aspects of movement (error) away from the HC. Furthermore, movement time was decreased but reaction time was unaffected by STN-DBS. Shorter retention delays increased amplitude and velocity, decreased movement times, and decreased error, but increased reaction times in the participants with PD. There were no interactions between STN-DBS condition and retention delay. CONCLUSION: STN-DBS may affect cognitive-motor functioning by altering activity throughout cortico-basal ganglia networks and the oscillatory activity subserving them.

Encoding type, medication, and deep brain stimulation differentially affect memory-guided sequential reaching movements in Parkinson's disease.

Memory-guided movements, vital to daily activities, are especially impaired in Parkinson's disease (PD). However, studies examining the effects of how information is encoded in memory and the effects of common treatments of PD, such as medication and subthalamic nucleus deep brain stimulation (STN-DBS), on memory-guided movements are uncommon and their findings are equivocal. We designed two memory-guided sequential reaching tasks, peripheral-vision or proprioception encoded, to investigate the effects of encoding type (peripheral-vision vs. proprioception), medication (on- vs. off-), STN-DBS (on- vs. off-, while off-medication), and compared STN-DBS vs. medication on reaching amplitude, error, and velocity. We collected data from 16 (analyzed n = 7) participants with PD, pre- and post-STN-DBS surgery, and 17 (analyzed n = 14) healthy controls. We had four important findings. First, encoding type differentially affected reaching performance: peripheral-vision reaches were faster and more accurate. Also, encoding type differentially affected reaching deficits in PD compared to healthy controls: peripheral-vision reaches manifested larger deficits in amplitude. Second, the effect of medication depended on encoding type: medication had no effect on amplitude, but reduced error for both encoding types, and increased velocity only during peripheral-vision encoding. Third, the effect of STN-DBS depended on encoding type: STN-DBS increased amplitude for both encoding types, increased error during proprioception encoding, and increased velocity for both encoding types. Fourth, STN-DBS was superior to medication with respect to increasing amplitude and velocity, whereas medication was superior to STN-DBS with respect to reducing error. We discuss our findings in the context of the previous literature and consider mechanisms for the differential effects of medication and STN-DBS.

Medication adversely impacts visually-guided eye movements in Parkinson's disease.

OBJECTIVE: We examined whether previous inconsistent findings about the effect of anti-Parkinsonian medication on visually-guided saccades (VGS) were due to the use of different paradigms, which change the timing of fixation offset and target onset, or different target eccentricities. METHODS: Thirty-three participants with Parkinson's disease (PD) completed the VGS tasks OFF and ON medication, along with 13 healthy controls. Performance on 3 paradigms (gap, step, and overlap) and 2 target eccentricities was recorded. We used mixed models to determine the effect of medication, paradigm, and target eccentricity on saccade latency, gain, and peak velocity. RESULTS: First, we confirmed known paradigm effects on latency, and target eccentricity effects on gain and peak velocity in participants with PD. Second, latency was positively associated with OFF medication Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score in PD. Third, medication prolonged latency for the larger target eccentricity across the 3 paradigms, while decreasing gain and peak velocity in the step paradigm across target eccentricities. CONCLUSIONS: Medication adversely affected and was not therapeutically beneficial for VGS. Previous inconsistencies may have resulted from chosen target eccentricity. SIGNIFICANCE: The negative medication effect on VGS may be clinically significant, as many activities in daily life require oculomotor control, inhibitory control, and visually-guided shifts of attention.

A Genetic Toggle for Chemical Control of Individual Plk1 Substrates.

Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphoproteomic analysis of mitotic cell extracts showed that Plk1S (L197F) and Plk1T (L197S/L211A) selectively phosphorylate Ser and Thr, respectively. Plk1S but not Plk1T sustains mitotic progression to anaphase, affording the opportunity to toggle substrate residues between Ser and Thr to place them under chemical control. Using this system, we evaluated Kif2b, a known substrate of Plk1 that regulates chromosome alignment. Toggling Ser to Thr on Kif2b places these phosphorylation sites under reversible chemical control, as indicated by a sharp increase in the frequency of misaligned chromosomes and prometaphase arrest. Thus, we demonstrate the ability to chemically control a single substrate by a genetic Ser/Thr toggle.