Long-term Effect of Low Frequency 60Hz Stimulation on Aspiration, Freezing of Gait and Other Axial and Motor Symptoms in PD Patients With Bilateral STN DBS
Phase: NA
Conditions: Parkinson's Disease
Sponsor: University of Chicago

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A randomized double-blind prospective cross-over study on chronic effect of low frequency 
60Hz stimulation on aspiration, freezing of gait and other axial and motor symptoms in 
Parkinson patients with STN DBS and freezing of gait at 130Hz and on the potential carry-over 
effect of different conditions (60Hz vs 130Hz vs DBS off) 
 
Principal investigator: Tao Xie, MD PhD1, Director of the DBS Program and PD and 
Movement Disorder Clinic, Department of Neurology, University of Chicago Medical Center, 
Chicago, IL 60637 
 
Tel: 773-702-3038; Fax: 773-702-9060 
Email: txie@neurology.bsd.uchicago.edu 
 
Other investigators or consultants: Julie Vigil, MA2; Ellen MacCracken MS2; Wenjun Kang, 
MS3; Jacqueline Bernard, MD1; Peter Warnke, MD4; Un J Kang, MD5. 
 
1Department of Neurology, University of Chicago Medicine, IL; 2Speech and Swallowing 
Section, Department of Surgery, University of Chicago Medicine, IL; 3Center for Research 
Informatics, University of Chicago Medicine, IL; 4Department of Neurosurgery, University of 
Chicago Medicine, IL; 5Department of Neurology, Columbia University Medical Center, NY. 
 
NCT Number: NCT02549859 
 
Date: 01JUL2015 
 
Funded by: Michael J Fox Foundation to Tao Xie. The current study is basically an extension 
study of our previous one (IRB 13-0566; Effects of the stimulation frequency of STN DBS on 
swallowing function in patients with Parkinson's disease) but with a longer follow-up period (at 
least 6 months) in more patients and a full evaluation in each visit of maximum 2 visits in some 
patients. 
 
Study Period: August 15, 2015-March 15, 2017 
 
 
Background & Rationale: 
 
Subthalamic nucleus (STN) deep brain stimulation (DBS) improves the levodopa 
responsive cardinal symptoms (bradykinesia, rigidity and resting tremor), and reduces motor 
fluctuation and dyskinesia in patients with Parkinson’s disease (PD) 1-5. However, DBS was 
less effective at improving the axial symptoms (postural instability, gait disorders such as 
freezing of gait (FOG), speech and swallowing dysfunction), or even could make them worse 
over the course of 2-5 years after STN DBS 6-15. Worth noting that the DBS stimulation 
frequency used in these studies was the traditionally high frequency of 130-185Hz. 
 
Seeking an effective treatment on the axial symptoms is critical, as the axial symptoms are 
common in advanced PD patients, with subsequent falls and aspiration pneumonia being the 

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major causes of mobility and morbidity in PD. Pharmacological treatment is hardly effective in 
treating axial symptoms.  
 
Over the past several years, there were studies suggesting that, compared to the traditionally high 
frequency stimulation of 130Hz, low frequency stimulation of 60Hz improves the FOG 16-19 and 
dysarthria 15, 19. The beneficial effect was not necessarily only seen in chronically stimulated 
patients with disease progression, as it was also seen in patients with newly activated bilateral 
STN DBS 19. 
 
More recently, we for the first time further studied the effect of the 60Hz stimulation on another 
axial symptom, dysphagia, in patients on bilateral STN DBS who had medication refractory 
FOG at 130Hz 20 (supported by MJFF under Rapid Response Innovation Award program to 
TX). We found that 60Hz stimulation, compared to the traditional 130Hz, decreased not only the 
aspiration frequency by modified barium swallowing (MBS) test and swallowing difficulty by 
swallowing questionnaire, but also the medication refractory FOG (by SWS stand-walk-sit test 
and FOG questionnaire), and axial symptom subscore and general parkinsonism motor symptom 
UPDRS-III score 20. The beneficial effect of the 60Hz stimulation persisted during the 6-week 
study period, except that one of the patients had to switch back to 130Hz stimulation in 3 weeks 
due to worsening of the hand tremor. 
 
The effect of the 60Hz stimulation on STN DBS patients without FOG at 130Hz stimulation was 
also studied, with significant improvement on axial and motor symptoms in 14 patients in an 
acute phase study 21, and mild improvement on gait without improvement on other motor 
symptoms in another study 22, suggesting the overall benefit of the 60Hz stimulation, though 
may not as great as seen in these with FOG at 130Hz stimulation. 
 
However, it remains unknown whether the beneficial effect of the 60Hz stimulation would 
persist on extended chronic stimulation beyond the 6-week period, and whether there is 
carry-over effect during the study across different test conditions of 30-minute apart in our 
previous study 20. Clarifying these two questions is crucial for the clinical application of the 
60Hz stimulation chronically and confidently to treat the medication refractory axial 
symptoms. 
 
So far, there was only one study showing persistent benefit of the 60Hz stimulation on FOG in 
85% of the 13 patients with bilateral STN DBS at medication off state following up in 8 
months16. There were two other studies challenging the chronic benefit of the low frequency 
stimulation 23-24. One of them reported an improvement in the gait immediately after switching 
the 130Hz stimulation to 80Hz at medication on state in 11 STN DBS patents, but the benefit 
only lasted for less than 1 month 23. The other one reported no benefit at 80Hz stimulation 
compared to 130Hz in axial symptoms following for almost 4 months (111.5 days on average) in 
45 patients 24. Worth noting that none of these two studies was really studying FOG, as one of 
them had no FOG on exam and the other one was not assessing FOG. Besides, these two studies 
used 80Hz, instead 60Hz, stimulation. None of them studied swallowing function either. 
 
According to our continuous observation since we published our study 20, all of our 5 out of 7 
patients who was on 60Hz simulation for 6-week study period remains on 60Hz since then for 

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its benefit on axial symptoms including FOG, over the period of up to 14 months follow up so 
far, which indicates a sustained chronic benefits. The 2 of the 7 patients were not on 60Hz 
stimulation after the previous study because of slightly worsening of tremor in 1 of them, and 
skin infection after the battery replacement (unrelated to the study) in another one. A formal 
randomized double blind prospective cross-over study on the chronic benefit of the 60Hz 
stimulation over an extended period of at least 6 months, corrected for the potential carry-over 
effects on this crossover study (DBS off, 60Hz or 130Hz while all at medication on state) at the 
acute (visit 1) and chronic phase (visit 2), is needed to enhance the quality of the study, the 
evidence level and the level of the recommendation in clinical applications to treat the axial 
symptoms which are refractory to usual DBS setting and medications with high morbidity and 
mortality of the PD. 
 
 
All Parkinson’s disease patients who have had aspiration pneumonia within the past one month 
before the test will be excluded. 
 
This study is basically an extension study of our previous one (IRB 13-0566; Effects of the 
stimulation frequency of STN DBS on swallowing function in patients with Parkinson's 
disease, with publication in reference 20) but with a longer follow-up period (at least 6 months) 
in more patients and a full evaluation in each visit of maximum 2 visits in some patients. 
 
Hypothesis: 
 
The 60Hz stimulation would have persistent benefit in reducing the aspiration, FOG, other 
axial and motor symptoms in PD patients with bilateral STN DBS and medication refractory 
FOG at 130Hz stimulation over an extended period of at least months, even corrected for the 
potential carry-over effects between different test conditions. 
 
Innovation: 
 
This would be the first study on the chronic effect of the 60Hz stimulation on the dysphagia, 
FOG and other axial and motor symptoms in PD with bilateral STN DBS with medication 
refractory FOG at 130Hz stimulation. 
 
Significance: 
 
This study will provide a high evidence level and clinical recommendation on the chronic effect 
of the 60Hz stimulation on the treatment of the axial symptoms, particularly dysphagia and 
FOG, which are refractory to usual DBS setting and medications and associated with high 
morbidity and mortality in PD. 
 
Aims: 
 
Aim 1a: A study on the chronic effect (at least 6 months) of 60Hz stimulation on axial 
symptoms, including swallowing function and FOG, and parkinsonism to see whether the 
beneficial effect of 60Hz stimulation compared to 130Hz as revealed in our previous study 20, 
could be sustained in PD patients with bilateral STN DBS with medication refractory FOG at 
130Hz. 
 
Aim 1b: This study would also clarify the potential carry-over effect on stimulation (DBS 
60Hz, DBS 130Hz, and DBS off, 30 min apart) on acute and chronic phase of the study to 

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enhance the quality of the study, and the level of evidence and recommendation in clinical 
applications. 
 
Approach: 
 
Towards that aim, we will add 12 patients with medication refractory FOG at 130Hz of bilateral 
STN stimulation at medication on state for two visits of at least 6-months apart. We will plan to 
have 14 patients enrolled for visit 1, as 2 of them might drop off (or being unable to be on 60Hz 
due to worsening tremor) before visit 2 (estimated based on our previous study that 1 out of 7 
patients could not be on 60Hz due to worsening tremor 20). The previous 6 study patients 
remaining on 60Hz stimulation after the completion of our previous study will be assessed again 
at visit 2 at least 12 months after the initial visit 1 once we get the IRB approval here. 
 
We will then combine the data from these 14 newly added patients with the previous 7 patients 
at visit 1 to make 21 patients to complete the visit 1, and 18-20 (12 to 14 newly added patients 
plus previous 6) patients to complete a longer interval visit 2 of at least 6 months apart. 
 
As our previous study20, it will still be a randomized double-blind prospective cross-over study 
with medication on state but with 6-8 patients on each group of starting condition (60Hz vs 130Hz 
vs DBS off, 30 min apart) to allow us analyze the chronic effect and potential carry-over effect 
of stimulation between different conditions to increase the level of evidence, with 80% power to 
detect at least 25% difference at two-tail α level of 0.05, as estimated before 20. Aspiration 
frequency on MBS, difficulty in swallowing on questionnaire, FOG in SWS test and 
questionnaire, and axial subscore and UPDRS-III score will all be assessed accordingly under 
each DBS conditions as we did in our previous study 20, at both visit 1 and visit 2 of at least 6 
months apart. The study will be finished in 2 years. 
 
Specifically, all the study patients will sign a written consent after the IEB approval. The study 
will be conducted at the Parkinson’s Disease and Movement Disorder Center of 
 
Department of Neurology, Department of Radiology, Speech and Swallowing Section of 
Department of Surgery, and Center for Research Informatics at the University of Chicago from 
August 15, 2015 to March 15, 2017. Advanced PD patients with bilateral STN DBS placement 
and medication-refractory FOG at routinely used 130-Hz stimulation will be enrolled. The 
demographics of patients, such as gender, age at the study, disease duration, duration on bilateral 
STN DBS, and their Parkinson medications, electrode position and active contact positions and 
settings will all be recorded. 
 
During visit, each patient will receive 3 routine modified barium swallow (MBS) studies in a 
single day under 3 different DBS frequency conditions (bilateral DBS 130 Hz, DBS 60 Hz, or 
DBS off) with their usual DBS voltage, pulse width, contact setting, and parkinsonian 
medication-on state regardless of the study stimulation frequency used. The study will be 
performed in a randomized and double-blind manner. The order of the DBS conditions will be 
assigned by the neurologist who will randomly pick up one of the 3 folded sheets with different 
conditions written on them and program the DBS accordingly, but will not be allowed to 
participate in any rating or evaluation. Neither the patients, nor the clinical rater, the 
pathologists for speech and swallowing, or the radiologist is aware of the DBS stimulation 
frequency condition. A single certified rater will rate all of the clinical scales and 
questionnaires, and a single swallowing team will conduct all MBS studies and the Penetration-

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Aspiration Scale ratings 25 to ensure consistency and quality of the evaluation. The MBS 
protocol consists of a standardized videofluorographic recording of oropharyngeal swallow in 
lateral and anterior-posterior views, and the anterior-posterior views. The subjects will be given 
radiopaque liquid, pureed contrast material, and solids coated in barium paste. The examinations 
will be recorded on the TIMS-DICOM digital medical recording system at high resolution of 30 
frames per second. Frame-by-frame analysis will be used to evaluate oral, pharyngeal, 
laryngeal, and cricopharyngeal function. For the purposes of this study, special attention will be 
given to aspiration. Laryngeal penetration and aspiration events will be assessed using the 
Penetration-Aspiration Scale. The frequency of aspiration events will be calculated by adding 
the number of swallows within each DBS condition that generates a Penetration-Aspiration 
Scale. The swallowing questionnaire will be completed by each patient after the MBS study 
under each DBS condition26. The parkinsonian motor, axial, and tremor symptoms as reflected 
by the Unified Parkinson’s Disease Rating Scale, Part III (UPDRS-III) score, axial subscore 
(including gait, stance, posture, postural stability, and speech), and tremor subscore, 
respectively, and the FOG as reflected by a FOG questionnaire score,27 and stand-walk-sit 
(SWS) test on FOG spell times and the time needed to finish the test (seconds) will also be 
assessed before the MBS study under each DBS condition. The patients will be on each DBS 
condition for at least 30 minutes before the study. The subjects will be video recorded while 
walking. The DBS condition producing the best gait function (least FOG, which was 60 Hz for 
all of our previous patients) will be continued for at least 6 months for the newly enrolled 
patients. 
 
Analysis: Changes in measurements between the 60Hz and 130Hz will be analyzed using paired 
t-test, with swallowing function (objective MBS study and subjective swallowing questionnaire) 
and FOG (objective SWS study and subjective questionnaire) as primary outcomes, and the rest 
(UPDRS-III score, axial subscore and tremor subscore) as the secondary outcomes in both acute 
visit1 and chronic visit 2 phase. Changes between other clinically relevant DBS conditions, 
including 60Hz vs DBS off, 130Hz vs DBS off, and 60Hz vs 60Hz follow-up (for >8 months on 
average) will also be explored and similarly analyzed with Bonferroni correction. A two-tailed 
alpha level of 0.05 will be taken as statistically significant for the comparisons. 
 
Foreseeable difficulty or complications: 
 
We don’t anticipate any difficulty in conducting this study, as we had a successful 
similar study before 20, with IRB approval (University of Chicago). Medication 
refractory tremor could offset the 60Hz use as the tremor could be worse compared to 
130Hz. However, most of the patient with axial symptoms has less tremor, and 
medication refractory tremor is even less. In the past, we had only 1 out of 7 patients 
who could not be on 60Hz stimulation due to the worsening of the tremor 20. No 
complication of aspiration pneumonia was found or reported before. The DBS 
condition used in the study will be the routine range of condition used in daily living 
without side effects. There is no alternative ways to conduct current study in order to 
get the important questions answered. 
 
Pregnant woman, children or mentally retarded patients: None of them will be involved, as 
these advanced patients are all at the post-menopausal age. No children will be involved in 

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these advanced PD patient population. No mental retarded patient will be involved. All the 
patients will have the capacity to consent. 
 
All study subjects will be paid $200 for their participation in each visit study. 
 
Research Environments: 
 
We have a good team to accomplish this study, consisted of PD and DBS specialists (TX, UJK, 
JB, PW), speech and swallowing specialist (JV and EM), functional neurosurgeon (PW), and 
biostatistician (WK). Dr. Xie is the PI of the previous acute phase of 6-week period study funded 
by MJFF resulting in an important publication in Neurology 20. He has published 5 peer-
reviewed papers on DBS as the first and corresponding author, with many other publications on 
PD and movement disorders. He is the Director of the DBS Program and the PD & Movement 
Disorder Clinic at the University of Chicago. Dr. UJ Kang is the internationally recognized PD 
and movement disorder specialist and the Chief of the Movement Disorder Section at Columbia 
University Medical Center. He will serve as the consultant in our study. Dr. Bernard is a 
movement disorder neurologist who will help the double blind operation of the study. Ms. Vigil 
and Ms. MacCracken are the speech and swallowing experts with Ms. MacCracken being the 
Chief of the Speech and Swallowing Section in Department of Surgery at University of Chicago. 
Dr. Warnke is the Director of the Stereotactic Functional Neurosurgery at the University of 
Chicago. Mr. W Kang is the experienced statistician who also did data analysis for our previous 
study 20. 
 
Time Frame and Budget: 
 
The study will be finished in 2 years. The total budget (direct cost) will be $ 145,000/year x 2 years 
= $290,000. Year 1: a) month 1–2: IRB and paper work; b) month 3- 6: finish visit 2 on the 
remaining 5 patients from previous study 20, who have been on 60Hz stimulation for up to 15 
months by then; c) month 7-12: enroll the first 7 newly added patients and finish the visit 1 study on 
them. Year 2: a) month 1-6: enroll the remaining 7 newly added patients and finish the visit 1 study 
on them; b) month 7-12: finish the visit 2 on all the newly added 12 patients (2 of the 14 newly 
enrolled patients on visit 1 might have dropped at visit 2). 
 
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