Adaptive deep brain stimulation as advanced Parkinson’s disease treatment (ADAPT study): protocol for a pseudo-randomised clinical study

Introduction Adaptive deep brain stimulation (aDBS), based on the detection of increased beta oscillations in the subthalamic nucleus (STN), has been assessed in patients with Parkinson’s disease (PD) during the immediate postoperative setting. In these studies, aDBS was shown to be at least as effective as conventional DBS (cDBS), while stimulation time and side effects were reduced. However, the effect of aDBS on motor symptoms and stimulation-induced side effects during the chronically implanted phase (after the stun effect of DBS placement has disappeared) has not yet been determined. Methods and analysis This protocol describes a single-centre clinical study in which aDBS will be tested in 12 patients with PD undergoing battery replacement, with electrodes implanted in the STN, and as a proof of concept in the internal globus pallidus. Patients included will be allocated in a pseudo-randomised fashion to a three-condition (no stimulation/cDBS/ aDBS), cross-over design. A battery of tests will be conducted and recorded during each condition, which aim to measure the severity of motor symptoms and side effects. These tests include a tablet-based tapping test, a subscale of the Movement Disorder Society-unified Parkinson’s disease rating scale (subMDS-UPDRS), the Speech Intelligibility Test (SIT) and a tablet-based version of the Stroop test. SubMDS-UPDRS and SIT recordings will be blindly assessed by independent raters. Data will be analysed using a linear mixed-effects model. Ethics and dissemination This protocol was approved by the Ethical Committee of the University Medical Centre Groningen, where the study will be carried out. Data management and compliance to research policies and standards of our centre, including data privacy, storage and veracity, will be controlled by an independent monitor. All the scientific findings derived from this protocol are aimed to be made public through publication of articles in international journals. Trial registration number NTR 5456; Pre-results.


REVIEWER
Atsushi Umemura National Hospital Organization Utano Hospital, Department of Neurology REVIEW RETURNED 14-Feb-2019 GENERAL COMMENTS 1) In the Introduction section, the authors report that DBS can induce side effects, such as dysarthria and impulse control disorder, and aDBS could potentially help to tackle those nonmotor side effects. It could be useful to add to the psychological assessment focusing on impulse control disorder not only the SIT and Stroop test.
2) The words "cognitive side-effect profile (page 4, line 43)" is unclear. Do the authors want to evaluate executive functions using the Stroop Test?
3) As the authors are described, crossover design is need to minimize the impact of incomplete washout-effect. The authors should specify the washout time between the three conditions. 4) According to the inclusion and exclusion criteria, this study protocol allows the candidate in a wide age range. The vulnerability to neuropsychiatric disorders in PD patients varies by age; younger patients are susceptible to be impulse control disorder, and older patients are to be cognitive dysfunctions.
Those variances among the participants may obscure the statistical results. This is an interesting protocol regarding the study of adaptive DBS as compared to conventional DBS. The introduction is balanced and the aims are clearly stated. However, this reviewer feels that some issues require additional attention. In particular:

VERSION 1 -AUTHOR RESPONSE
1) Testing adaptive DBS in patients that have already received 3-5 years of previous stimulation has to be discussed as a possible bias rather than a strength of the study. We do not know to what extent 3-5 years of previous non-adaptive stimulation might have influenced brain plasticity and, therefore, to what extent the study findings will be generalizable to a population of DBS-naive PD patients.
Adaptive DBS has virtually only been tested on patients in the immediate postoperative setting, i.e. on DBS-naïve patients (Little et al. 2013(Little et al. , 2016Arlotti et al. 2018), in which it was shown to be at least as effective as conventional DBS, with potential benefits of facilitate (initial) programming, battery-saving properties, and better side-effect profile (Tripoliti et al. 2016). Therefore, our research protocol focuses on patients who already have electrodes implanted for a long time, in order to see whether beta power is still a reliable biomarker for the clinical status of the patient, and to see how the aforementioned plasticity might have an effect on the response to adaptive DBS. By doing the measurement in the battery replacement phase, we are aiming to complement the knowledge available by addressing this issue, and for that reason we consider that a strength of our protocol. 2) I am not convinced by the sample size calculation. First of all, the sample size calculation has to be based on the primary outcome measure. The authors should either replace the order of the aims or re-calculate the sample size based on motor improvement and provide a rationale to justify that the sample size calculated covers also the other aims. Also, additional details should be provided on previous literature used to calculate the sample size. Finally, the number of 14 patients seems very low. I strongly recommend a statistical revision of the sample size calculation.
We have recalculated the sample size based on our primary outcome (clinical response in aDBS compared to cDBS), together with references to the literature used for the calculation. As this is a cross-over design, in which we are aiming to demonstrate the non-inferiority of aDBS,compared to cDBS, the number of patients needed is lower than, for example, parallel designs.
3) The inclusion of both STN-DBS and GPi-DBS requires additional analysis to estimate the efficacy of adaptive DBS in the two targets, which significantly differ for anatomical and functional connections. Either the authors decide to focus on one target (reasonably STN) or (even better) they increase the sample of patients included in order to guarantee that the study is appropriately powered to demonstrate the effect (and possibly differences) of adaptive DBS in the two separate population of patients. Also, the authors need to consider that the efficacy of DBS in GPI usually requires weeks to fully manifest, differently from STN-DBS. This point has to be carefully addressed.
We have focused our design primarily in DBS-STN patients, as the majority of the patients coming to this center have been implanted in the STN. We have left an optional space of two patients above the target of our sample size calculation, in order to explore the effects of aDBS on the GPi of PD patients.
Reviewer: 2 Reviewer Name: Atsushi Umemura Institution and Country: National Hospital Organization Utano Hospital, Department of Neurology Please state any competing interests or state 'None declared': None declared.
Please leave your comments for the authors below 1) In the Introduction section, the authors report that DBS can induce side effects, such as dysarthria and impulse control disorder, and aDBS could potentially help to tackle those non-motor side effects. It could be useful to add to the psychological assessment focusing on impulse control disorder not only the SIT and Stroop test.
Due to the intraoperative nature of the experiment, and the time constrains that this involves, it is not feasible for us to perform a thorough psychological assessment in order to explore a possible impulse control disorder. Therefore, we have only approached impulsivity as a symptom throughout this protocol. The Stroop test has been used to evaluate the effect of medication (Djamshidian et al. 2011) and DBS (Jahanshahi et at. 2000) on inhibition, in which a reduction on reaction time were demonstrated on both (faster responses compared to no stimulation/no medication).While this effect could in theory be beneficial, the synergy of both treatments could cause the development of impulsivity in predisposed patients.
2) The words "cognitive side-effect profile (page 4, line 43)" is unclear. Do the authors want to evaluate executive functions using the Stroop Test?
We have changed the word to disinhibition side-effect profile, as that is the main function we want to assess with the Stroop test.
3) As the authors are described, crossover design is need to minimize the impact of incomplete washout-effect. The authors should specify the washout time between the three conditions.
This has been added to the protocol. The minimum washout period will be 1 min between conditions, and more time could be allocated to the washout period, depending on the remaining time available between conditions, for each patient. However, as we have stated, we also tried to control for this factor with the randomisation block.
4) According to the inclusion and exclusion criteria, this study protocol allows the candidate in a wide age range. The vulnerability to neuropsychiatric disorders in PD patients varies by age; younger patients are susceptible to be impulse control disorder, and older patients are to be cognitive dysfunctions. Those variances among the participants may obscure the statistical results.
While no age range was established for this experiment (besides patients being older than 18 years old), the population group will very likely be composed mainly by somewhat older patients. This is because we aim to include patients who already have DBS implanted for at least 3-5 year. Next to this, DBS is usually indicated several years after the beginning of the disease (when fluctuations in medication are becoming troublesome). The age range of the population sample will be further narrowed by our exclusion criteria, which exclude patients who present cognitive decline.

REVIEWER
Aristide Merola University of Cincinnati, USA REVIEW RETURNED 09-Mar-2019

GENERAL COMMENTS
The authors nicely addressed all of my comments. I only have a minor request. Please make sure that the abstract accurately reflects modifications applied to the main text, including the selection of STN as a primary target and GPi as an exploratory outcome.