Limitations
PD, bradykinesia
DISEASE, PATHOPHYSIOLOGY
The experiments were all performed off medication and thus we cannot assert whether or not medication improved the sequence effect of this particular task, calculated by this metric. The study was focused on a novel metric of the sequence effect, its validation as a measure of bradykinesia and overall PD disease severity, and the effect of DBS. The correlations with bradykinesia and MDS-UPDRS III were performed before activation of DBS. To answer whether the sequence effect became worse over time and to examine the effect of DBS on the sequence effect, testing began after withdrawal of DBS for at least 60 min. After turning off STN DBS we have demonstrated that the resting state local field potential spectrum, and specifically beta band power, was stable and unchanged among recordings performed immediately (14 s) and every 15 min up to 60 min later, suggesting that this is enough time to wash out the effect of DBS on underlying pathophysiology [An additional limitation is the presence of study dropout for the longitudinal OFF therapy protocol. Dropout was due to a combination of IPG replacement to a non-research device following battery depletion, moving out of state, or progression of disease that made OFF therapy testing intolerable. Due to their ability to account for missing data due to the participant dropout, linear mixed effect models were used in the analysis. Additionally, study exits prior to 3 years do not bias the results because participants are typically exiting the study once their bradykinesia has worsened so much that they are unable to perform the WFE task. These participants remaining in the study would have pushed the results even further in favor of the observed conclusion that sequence effect, which is related to bradykinesia, worsens over time.One potential limitation for the titration experiment is there may be a ‘cumulative” effect of increasing doses of DBS on behavior as seen for attenuation of the beta band [Finally, as the neural closed loop sequence effect data is preliminary data taken from a single subject, it is difficult to conclude whether the noted behavioral improvement will be seen in a larger group of people with PD. For transparency, we included all data regardless of whether parameters such as stimulation delay are critical to the clinical significance.